WO2013122553A1

WO2013122553A1 - A pharmaceutical formulation comprising an atp-ase inhibitor and method for this formulation

Info

Publication number: WO2013122553A1
Application number: PCT/TR2013/000059
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2012-02-14
Filing date: 2013-02-14
Publication date: 2013-08-22

Abstract

The present invention relates to pharmaceutical compositions comprising an ATPase inhibitor to be used in treatment of diseases associated with gastric acid secretion disorder.

Description

A PHARMACEUTICAL FORMULATION COMPRISING AN ATP ASE INHIBITOR AND METHOD FOR THIS FORMULATION

The present invention relates to a production method developed for controlled release drug formulations comprising ATPase inhibitor. The present invention further relates to enterically coated formulation of an ATPase inhibitor.

Hydrogen potassium ATPase (H^{+ +} ATPase) enzymes provide stomach acidity. The activity of H⁺/K⁺ ATPase enzymes should be blocked in order to regularize acidity in the stomach in the diseases such as dyspepsia, peptic ulcer and gastroesophageal reflux (GERD). H²- receptor antagonists or proton pump inhibitors (PPIs) are used for this blockage. H²- receptor antagonists prevent signal pathway activating ATPase and proton pump inhibitors block ATPase. The most frequently used H²- receptor antagonists are cimetidine, ranitidine, famotidine and nizatidine. In addition, the most frequently used PPIs are omeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole and revaprazan.

PPIs are not durable to acidic medium and they decompose easily. However, they are stabile in alkaline mediums. PPIs are indicated for treatment of gastroesophageal reflux (GERD), erosive reflux oesophagitis and Zollinger - Ellison syndrome; for prevention of relapses, for long-term maintenance treatment of healed reflux oesophagitis and for symptomatic treatment of gastroesophageal reflux. In the case that the treatment cannot be implemented by the oral route, parenteral treatment is implemented. Together with a suitable antibiotic combination, they are indicated for treatment of helicobacter pylori eradication and helicobacter pylori induced duodenal ulcers and for prevention of relapses in helicobacter pylori induced peptic ulcers. They are indicated for patients in need for maintenance NSAIDs (non-steroidal anti-inflammatory drugs) treatment; for treatment of gastric ulcers induced by NSAIDs including COX-2 selective NSAIDs and for prevention of gastric and duodenal ulcers induced by NSAIDs including COX-2 selective NSAIDs in patients at risk.

Proton pump inhibitors have short decomposition half-life which varies depending on the temperature. For instance, while decomposition half-life of esomeprazole is 19 hours when its pH is 6.8 and temperature is 25 °C, it is 8 hours at 37°C. Due to this property, PPIs decompose during production and their shelf life shortens.

In the prior art, non-enteric coated tablets and/or pellets were generally preferred. Because enteric coatings are generally acidic and they interact with pyrazoles and decompose. While inert coatings and enteric coatings were used in some cases, non-enteric coating forms were produced in some cases. When intermediate coatings are used in order to reduce negative effects of enteric coating, the granules, which are not sufficiently firm, may decompose during production because of the number of the process steps. Due to this situation, the substances in the newly formed granules disintegrate and they interact with each other and this poses some problems such as the fact that stability and homogenization cannot be provided, the granules cannot be treated as required or active agent amount decreases.

In addition, in order for the drugs comprising proton pump inhibitors to be indicated for the abovementioned diseases, they should not be contact with the acidic gastric juice and they should reach the small intestine without decomposing. Therefore, the active agents belonging to the group of pyrazoles should be protected from both acidic enteric coating and gastric juice.

In the prior art, various methods have been used in order for proton pump inhibitors to remain stable in the formulation. These are generally not to use acidic enteric coatings; to use inert intermediate layers or to mix them with the alkaline compounds. Because, it has been seen that acidic enteric coating interacts with the active agent. In the enterically coated tablets or capsules, interaction between the active agent and acidic enteric coating is prevented by using one or more inert coatings.

In the patent numbered EP 1 185254 B l, a fluid drug solution was prepared by mixing lansoprazole or omeprazole with a non-ionic surface active agent and water. Then, the filling agent comprising sugar, starch or cellulose was coated with the fluid drug solution. The granules comprising drug solution was coated with the base coating and enteric coating. One of the characteristic features is to use pyrazoles instead of salts of pyrazoles. Another characteristic feature is to prepare fluid drug solution by mixing pyrazoles and non-ionic surface active agent.

The inventors have found that a formulation produced by using the method described below can remain stable longer and the firm, homogeneous granules, which do not disintegrate during production, are obtained: a. Sugar spheres are taken as the filling agent.

b. The wet binder solution comprising sucrose is prepared separately.

c. The dry ATPase inhibitor, tampon agent/agents and sucrose are mixed separately.

d. The sugar spheres in step (a) are granulated with the mixture prepared in step (c). Then, the mixture prepared in step (b) is used as the last layer.

e. The granules obtained in step (d) are coated with the base coating.

f. Then the granules obtained in step (e) are coated with the enteric coating.

In one aspect, the present invention relates to a production method containing the abovementioned steps for a controlled release formulation comprising an ATPase inhibitor.

In another aspect, the present invention relates to controlled release drug formulations obtained by using said method and use of these drug formulations in treatment of stomach disorders. The inventors have found that use of the active agent and other excipients after mixing them dryly makes the tablets and pellets more durable. Because, dry-mixing the proton pump inhibitors, which are not durable under heat and in acidic mediums, reduces possible decompositions.

Thanks to use of sugar spheres as the filling agent, durable, homogeneous pellet or tablets, which do not disintegrate during production, have been obtained.

The granules, which can remain stabile longer, have been obtained by using sucrose as one of the diluents and by using it in binder solution during production. In addition, coating the sugar spheres with sucrose during production after they are granulated with the active agent mixture increases efficiency of the drug. It has been observed that the active agent becomes more durable in gastric juice with the sucrose coating used along with the base and enteric coatings. The fact that active agent which is not durable in acidic medium is absorbed through the small intestine without decomposing in the stomach increases efficiency of the drug.

The pharmaceutical compositions of the present invention are selected from solid oral forms comprising tablet; layered tablet (for instance double-layer tablet); capsule; enterically coated or modified release tablets; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; microtablet in capsule.

The formulation can preferably be in the form of tablet, controlled release tablet, pellet, controlled release pellet, capsule. The abovementioned tablets and pellets can be enterically coated in a preferred embodiment of the present invention.

Another characteristic feature of the present invention is that the ratio of sucrose, which is used in solid form together with the active agent, is in the range of 20% to 40% in the upper layer during granulating the active agent. In addition, the amount of sucrose comprised in the wet binder solution is in the range of 5% to 1 %. The ratios were calculated according to total weight of the tablet or pellet.

Salt forms of proton pump inhibitors are more durable. Therefore, salt forms are preferred in the formulations.

As the excipients; filling agent, buffer agent/agents, intermediate coating agents, enteric coating agents, diluent, binder, colouring agent, lubricant and surfactants can be used in the formulation. The filling agent that can be used in the formulations is used in order to carry the active agent and it is selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol. Preferably sugar spheres are used.

As the buffering agent; sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminium hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or combinations thereof can be used in the formulation.

The base coating agents that can be used in the formulation are selected from a group comprising hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol, methyl cellulose, amylopectin or hydroxy methylcellulose (MHC) or a combination thereof. The surfactants, binders and lubricants can be used in the base coating in the formulation in addition to the base coating agent.

Another diluent can be used along with sucrose in the formulation. This diluent can be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives thereof or combinations thereof.

The ratio of sucrose to a second diluent used in the formulation varies in the range of 1 : 1 to 10: 1. The second diluent can be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates thereof and /or pharmaceutically acceptable derivatives thereof or combinations thereof. Sucrose and preferably mannitol can be used in the formulation as the diluent. The ratio of sucrose to mannitol that can be used in the formulation is in the range of 2: 1 to 6: 1. The lubricants that can be used in the formulations can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.

The binders that can be used in the formulations can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.

The pharmaceutically acceptable surfactants can be selected from, but not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, aminoacids such as L- leucine, sugar esters of fatty acids, glycerides of fatty acids or a combination thereof.

The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or a combination thereof. The enteric coating used in the formulation can comprise buffering agent, lubricants, surfactants, binders or colouring agents in addition to the coating agent.

EXAMPLES EXAMPLE 1 Content % of amount in unit dose

Active Aeent

Esomeprazole 25

Excipients

Filling agent 7

Sucrose 27

Diluent-2 8

Buffering agent/agents 4

Other excipients 29

Total 100

a. Sugar spheres are taken as the filling agent.

b. The wet binder solution comprising sucrose is prepared separately.

c. The dry esomeprazole magnesium, buffering agent/agents and sucrose are mixed separately. d. The sugar spheres in step (a) are granulated with the mixture prepared in step (c). Then, sucrose taken from the mixture in step (c) is used as the last layer.

e. The granules obtained in step (d) are coated with the base coating.

f. Then the granules obtained in step (e) are coated with the enteric coating.

EXAMPLE 2: Content % of amount in unit dose

Active Aeent

ATPase inhibitor 30

Excinients

Filling agent 5

Sucrose 30

Diluent-2 10

: Buffering agent/agents 2.5

Other excipients 22.5

Total 100

a. Sugar spheres are taken as the filling agent.

b. The wet binder solution comprising sucrose is prepared separately.

c. The dry ATPase inhibitor, buffering agent/agents and sucrose are mixed; some amount of sucrose is taken aside from the mixture.

d. The sugar spheres in step (a) are granulated with the mixture prepared in step (c). Then, sucrose taken from the mixture in step (c) is used as the last layer.

e. The granules obtained in step (d) are coated with the base coating.

f. Then the granules obtained in step (e) are coated with the enteric coating.

The pharmaceutical formulations of the present invention comprising the proton pump inhibitor Esomeprazole as the active agent are indicated for treatment of gastroesophageal reflux (GERD), erosive reflux oesophagitis; for prevention of relapses, for long-term maintenance treatment of healed reflux oesophagitis and symptomatic treatment of gastroesophageal reflux. In the case that the treatment cannot be implemented by the oral route, parenteral treatment is implemented. Together with a suitable antibiotic combination, they are indicated for treatment of helicobacter pylori eradication and helicobacter pylori-induced duodenal ulcers and for prevention of relapses in helicobacter pylori-induced peptic ulcers. They are indicated for patients in need of maintenance NSAIDs (non-steroidal anti-inflammatory drugs) treatment; for treatment of gastric ulcers induced by NSAIDs including COX-2 selective NSAIDs and for prevention of gastric and duodenal ulcers induced by NSAIDs including COX-2 selective NSAIDs in patients at risk. Furthermore Esomeprazole is used for treatment of gastro-intestinal ulcer and duodenal ulcer in Chorn disease.

Claims

1. A method to be implemented in production of a controlled release drug comprising an ATPase inhibitor, wherein said method is composed of the following steps: a) Taking sugar spheres as the filling agent

b) Preparing wet binder solution comprising sucrose

c) Preparing a dry mixture comprising a dry ATPase inhibitor, buffering agent/agents, sucrose and optionally other excipients; taking 1-10% of sucrose from the mixture d) Granulating the core with the mixtures in steps (a) and (b); using 1 -10% of sucrose as the last layer

e) Implementing the first coating comprising hydroxypropyl methyl cellulose (HPMC) onto the granules after they are dried

f) Coating the granules with the enteric coating after they are dried.

2. The pharmaceutical method according to claim 1 , wherein omeprazole, esomeprazole, rabeprazole, dexrabeprazole, pantoprazole or pharmaceutically acceptable salts thereof can be used as the active agent.

3. According to claim 2, wherein sodium salt of rabeprazole is used as the active agent.

4. According to claim 2, wherein sodium salt of dexrabeprazole is used as the active agent.

5. According to claim 2, wherein magnesium salt of omeprazole is used as the active agent.

6. According to claim 2, wherein magnesium salt of esomeprazole is used as the active agent.

7. According to claim 2, wherein sodium salt of pantoprazole is used as the active agent.

8. The pharmaceutical method according to claim 1 , wherein the ratio of sucrose used together with the active agent and comprised in the upper layer during granulating the active agent is in the range of 20% to 40% in proportion to total weight of the tablet/pellet.

9. The pharmaceutical method according to claim 1, wherein the ratio of sucrose comprised in the wet binder solution is in the range of 5% to 1% in proportion to total weight of the tablet/pellet.

10. The pharmaceutical method according to claim 1, wherein filling agent,buffering agent/agents, intermediate coating agents, enteric coating agents, diluent, binder, colouring agent, lubricant and surfactants can be used as the excipient.

1 1 . The pharmaceutical method according to claim 1 , wherein the filling agent is selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol.

12. The pharmaceutical method according to claim 1 , wherein sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminium hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or a combination thereof can be used as the buffering agent.

13. The pharmaceutical formulation according to claim 1, wherein sucrose and another diluent can be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.

14. The pharmaceutical formulation according to claim 10, wherein the ratio of sucrose to the second diluent varies in the range of 1 : 1 to 10: 1.

15. The pharmaceutical formulation according to claim 1 1 , wherein mannitol can be used as the second diluent and the ratio of sucrose to mannitol is in the range of 2: 1 to 6: 1.

16. The pharmaceutical formulation according to claim 1, wherein hydroxypropyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol, methyl cellulose, amylopectin or hydroxy methylcellulose (MHC) or combinations thereof can be used as the base coating agent.

17. The pharmaceutical formulation according to claim 1, wherein the base coating agent,

surfactants, binders and lubricants can be used in the base coating.

18. The pharmaceutical formulation according to claim 1 , wherein cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof can be used as the enteric coating agent.

19. The pharmaceutical formulation according to claim 1 , wherein the enteric coating agent, buffering agent, lubricants, surfactants, binders or colouring agents can be comprised in the enteric coating.

20. The pharmaceutical formulation according to claim 1 , wherein the lubricants in the formulation can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or combinations thereof.

21. The pharmaceutical formulation according to claim 1 , wherein the binders comprised in the formulation can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glycose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; alcohols such as polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.

22. The pharmaceutical formulation according to claim 1, wherein the surfactants in the formulation can be selected from polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, aminoacids such as L-leucine, sugar esters of fatty acids, glycerides of fatty acids or a combination thereof.

23. The pharmaceutical formulation according to claim 1, wherein said formulation can be used in treatment of stomach disorders.

24. The pharmaceutical formulation according to claim 1 , wherein said formulation can be in the form of tablet, controlled release tablet, pellet, controlled release tablet, capsule.

25. A galenic substance according to claim 1, wherein said substance comprises

a. sugar spheres as the inert core,

b. the first layer of the core comprising dry ATPase inhibitor, sucrose and other excipients, c. sucrose inert coating,

d. the base coating comprising HPMC,

e. the enteric coating.