FIELD OF THE INVENTION

The present invention relates to the orally disintegrating tablets comprising delayed release Lansoprazole and the process for preparation of the same.

BACKGROUND OF THE INVENTION

Lansoprazole is a substituted benzimidazole 2-[[[3-methyl-4-(2, 2, 2-trifluoroethoxy)- 2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion.

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethyl formamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water. Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH. The degradation half-life of the drug substance in aqueous solution at 25°C is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0.

Lansoprazole is sold under the brand name PREVACID SOLUTAB which is marketed by Takeda Pharmaceuticals. Prevacid SoluTab is available as delayed release orally disintegrating tablets in 15mg and 30 mg strength. Each PREVACID SOLUTAB delayed-release orally disintegrating tablet contains enteric-coated micro granules consisting of 15 mg or 30 mg of Lansoprazole (active ingredient) and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, magnesium carbonate, hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, mannitol, methacrylic acid, polyacrylate, polyethylene glycol, Glyceryl monostearate, polysorbate 80, Triethyl citrate, ferric oxide, citric acid, crospovidone, aspartame, artificial strawberry flavor and magnesium stearate.

US Patent 6,328,994 discloses an orally disintegrating Lansoprazole tablet which comprises fine enteric coated granules having an average particle diameter of 400µm or less.

US patent 7,431,942 discloses an orally disintegrating tablet comprising the fine granules having an average particle diameter of 300 to 400pm which fine granules comprising a core, an enteric coating layer for the core composition comprising a first component that is an enteric coating agent and a second component that is a sustained release agent and a coating layer comprising the mannitol outside the enteric coating layer. As a result the compression of the individual units mixed with tablet excipients into the multiple unit tablet dosage form reportedly does not affect the acid resistance of the individually enteric coating layered units.

The present invention is to produce Lansoprazole orally disintegrating tablets, which easily disintegrate in the mouth with highly compressible characteristics that is resistant to the acidic conditions before absorption in the digestive tract.

SUMMARY OF THE INVENTION

The present invention relates to an orally disintegrable tablet which comprises (i) the granules having an average particle diameter of more than 400pm which granules comprise a composition coated by an enteric coating layer comprising an enteric coating agent and viscosity imparting agent and (ii) an additive.

An orally disintegrable tablet of the present invention comprises the granules having the average particle diameter of more than 400µm.

An orally disintegrable tablet comprises the granules wherein the granules further comprise a basic inorganic salt.

An orally disintegrable tablet comprises the additive wherein the additive is a water soluble sugar alcohol.

An orally disintegrate tablet of the present invention further comprises the microcrystalline cellulose as an additive.

An orally disintegrate tablet of the present invention comprises the acid labile physiologically active substance wherein the acid labile physiologically active substance is a benzimidazole compound or a crystal thereof.

An orally disintegrate tablet of the present invention wherein the benzimidazole compound is Lansoprazole.

An orally disintegrate tablet of the present invention wherein the basic inorganic salt is a salt of magnesium and/or a salt of calcium.

An orally disintegrate tablet of the present invention wherein the composition comprises a core being coated by a benzimidazole compound and a basic inorganic salt, said core comprises a non-pariel bead that is a sugar sphere.

An orally disintegrate tablet of the present invention wherein the composition comprises 1 to 20% weight of an acid-labile physiologically active substance.
An Orally disintegrate tablet of the present invention wherein the enteric coating layer comprises an aqueous enteric polymer agent.

An orally disintegrate tablet of the present invention wherein the enteric coated polymer agent is a methacrylate co-polymer.

An orally disintegrate tablet of the present invention wherein the enteric coated layer further comprises a viscosity imparting agent.

An orally disintegrate tablet of the present invention where in the viscosity imparting agent is polyvinyl alcohol.

The polyvinyl alcohol has the viscosity ranging from 3.4 - 9.2mPas with the degree of hydrolysis from 85-89%.
An orally disintegrable tablet of the present invention wherein the viscosity imparting agent is in an amount of 5 to 15% by weight relative to 100% by weight of the aqueous enteric coating polymer.

An orally disintegrable tablet of the present invention wherein the water soluble alcohol is mannitol.

An orally disintegrable tablet of the present invention further comprises the crospovidone as the disintegrant.

An orally disintegrable tablet of the present invention where in the orally disintegrating time is less than 30 seconds.

In the preferred embodiment the granules have an average diameter of more than 400pm; preferably the average particle diameter of the granules is 425 µm to 600 µm.
The active substance of the present invention preferably is a benzimidazole compound or a salt thereof such as Lansoprazole, Pantoprazole, Rabeprazole, Omeprazole and Esomeprazole. Most preferably the drug is Lansoprazole.

In the composition the basic inorganic salt is preferably incorporated with the acid labile active substance or coated separately onto the drug layer.
The basic inorganic salt includes for example, a basic inorganic salt of sodium, potassium, magnesium and/or calcium. The preferred one is basic inorganic salt of magnesium.

The basic inorganic salt of magnesium includes, for example, heavy magnesium carbonate, light magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, aluminum magnesium hydroxide etc. Among others, preferred is light magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc

The enteric coating layer comprises the aqueous enteric coating agent polymers such as cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxy methyl cellulose acetate succinate, methacrylate co-polymer (e.g. Eudragit L-30 D-55 etc., Kollicoat MAE30DP, polyquid PA-30, carboxymethylcellulose, shellac etc and a viscosity imparting agent preferably polyvinyl alcohol.

The polyvinyl alcohol is selected from the group having the viscosity ranging from 3.4 - 9.2mPas with the degree of hydrolysis from 85-89%.

The aqueous enteric coating agent is preferably a methacrylate polymer.
The viscosity imparting agent is used in an amount of 5 to 15% by weight relative to 100% by weight of the aqueous enteric coating polymer.

The additives of the orally disintegrating tablet which comprises (i) the granules having an average particle diameter of more than 400µm which granules comprise a composition coated by an enteric coating layer comprising an enteric coating agent and viscosity imparting agent and (ii) an additive may be ones commonly employed as pharmaceutical materials. The amount of such additives to be used is selected from amounts commonly employed in the manufacture of preparations in general dosage forms.

The additives include for example a water soluble sugar alcohol, crystalline cellulose as well as binders, acids, foaming agents, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients, disintegrants etc,.

The water soluble alcohol is preferably mannitol, xylitol and erythritol. More preferred is mannitol and erythritol. Especially preferred is mannitol.
The water soluble alchol is preferably employed in an amount of 5 to 97% by weight, preferably about 10 to 90% relative to 100% by weight of the orally disintegrate tablet apart from the granules in order to obtain sufficient strength of the preparation and sufficient disintegration or dissolution in the oral cavity.

For example, mannitol is usually employed in an amount of about 5 to 90 weight %, preferably about 10 to 80 weight %, more preferably about 20 to 80 weight %, especially preferably about 50 to 80 weight % relative to 100 weight % of the orally disintegrable tablet apart from the granules.

The crystalline cellulose includes microcrystalline cellulose which includes CEOLUS KG 801, CEOLUS KG 1000, AVICEL PH 102, AVICEL PH 301 and AVICEL PH 302. Among these preferably employed is CEOLUS KG 801, CEOLUS KG 1000 or the combinations thereof is pieferably employed because of high compressibility.
The binders include, for example, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, starch (pregelatinized starch), polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan etc.

The acids include, for example, citric acid (e.g., citric acid anhydrous), tartaric acid, malic acid, etc.

The foaming agents include, for example, sodium hydrogen carbonate, etc.
The "artificial sweeteners" include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.

The flavorants include synthetic flavorants or natural flavorants, such as lemon, lime, orange, menthol, strawberry, etc.

The lubricants include, for example, magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, etc.

The colorants include, for example, various food colorants such as Food Yellow No. 5, Food RED No.2, Food Blue No.2, etc., food lakes, red iron oxide, etc.

The stabilizers include, for example, the above-mentioned basic inorganic salt.
The disintegrants include those conventionally used in the pharmaceutical field, such as crospovidone, croscarmellose sodium and sodium carboxy methyl cellulose. Preferably the disintegrant used is crospovidone.

The average diameter of the core is more than 250µm, more preferably about 250µm to 300µm.
Examples of the core include the spherical granulated product comprising the microcrystalline cellulose (Celephere-203) or the sugar spheres (Non pariel beads).
The core may contain the active substance such as the above described pharmaceutical ingredient. Also the core may not contain the acid labile active substance because the release of the acid labile active substance is controlled by a coating layer containing the acid labile active substance.

The core is preferably as uniform a sphere as possible, for reducing the irregularity of coating in addition to being a powdery core.

The coating layer may be constructed by plural layers. At least one layer of the plural layers must contain the active substance. The combination of various layers such as the coating layer not containing the active ingredient, a base coating layer, and an enteric coating layer which constitute the coating layer can be suitably selected.
The enteric coating layer is optionally constructed by plural (e.g., 2 or 3) layers. For example the used is the method which comprises coating a composition with an enteric coating layer having polyethylene glycol and then with an enteric coating layer having Triethyl citrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is more specifically explained by the means of the following examples. It is to be understood that the present invention is not limited to these examples.

Example-1

1. Seal coating of the core
A fluid bed coater is charged with 150 g of sugar spheres USP-NF (Pharma- A spheres) with particle diameter of 250 µm to 300µm. With the inlet air temperature of 40-50°C a bulk liquid of the following composition prepared in advance is sprayed at a spray rate of 15-90 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 40±5°C for a period of 30 minutes to provide 160g of the granules having the seal coating.


2. Drug layering of the seal coated granules
A fluid bed coater is charged with 1 10g of the above granules having the seal coating. With the inlet air temperature of 50-60°C a drug layering liquid of the following composition prepared in advance is sprayed at a spray rate of 15- 120 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 55±5°C for a period of 30 minutes. The resulting granules are sieved through a #40 mesh and a #50 mesh to provide 210g of the drug loaded granules.

3. Sub-coating of the drug layered granules
A fluid bed coater is charged with 168g of the above drug loaded granules. With the inlet air temperature of 40-50°C a Sub coating liquid of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 40±5°C for a period of 30 minutes to provide 214g of the sub coated granules.

4. Enteric coating of the sub-coated granules Enteric coating is doing is done in two layers a) Enteric coating-I
A fluidized bed coater is charged with 143g of sub-coated granules. With the inlet temperature of 40°C-50°C enteric coating liquid-I of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 35±5°C for a period of 30 minutes to provide 178g of the enteric coated-I granules.

b) Enteric coating-II

A fluidized bed coater is charged with 134 g of enteric coated-I granules. With the inlet temperature of 40°C-50°C enteric coating liquid-II of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 35±5°C for a period of 30 minutes. The resulting granules are sieved through a #30 mesh and a #40 mesh to provide 166 g of the enteric coated-II granules.

5. Production of mixed powders
To 1 l0g of the above enteric coated granules, 98.3g of mannitol, 63g of microcrystalline cellulose (CEOLUS KG802), 7g of microcrystalline cellulose (CEOLUS KG1000), 2g of anhydrous citric acid,10g of colloidal silicon dioxide, 4.5g of aspartame, 1.5g of strawberry flavor and 2.7g of magnesium stearate is added and admixed in a bag to obtain 300g of the mixed powder.

6. Production of orally disintegrating tablets
About 250g of the above mixed powder is tableted using the tabletting machine with round punches of 12mm diameter to provide each tablet weighing 600mg.
The hardness and oral disintegration time of each tablet thus obtained are 4-5.5 kg/cm2 and less than 30 seconds respectively. The acid resistance of the Lansoprazole orally disintegrating tablet is less than 10%.

Example-2

1. Seal coating of the core
A fluid bed coater is charged with 9.775 kg of sugar spheres USP-NF (Pharma-A spheres) with particle diameter of 250 µm to 300µm. With the inlet air temperature of 40-50°C a bulk liquid of the following composition prepared in advance is sprayed at a spray rate of 15-90 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 40±5°C for a period of 30 minutes to provide 9.35 kg of the granules having the seal coating.

2. Drug layering of the seal coated granules
A fluid bed coater is charged with 9.35kg of the above granules having the seal coating. With the inlet air temperature of 50-60°C a drug layering liquid of the following composition prepared in advance is sprayed at a spray rate of 15-120 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 55±5°C for a period of 30 minutes. The resulting granules are sieved through a #40 mesh and a #50 mesh to provide 18.4 kg of the drug loaded granules.

3. Sub-coating of the drug layered granules

A fluid bed coater is charged with 18.4 kg of the above drug loaded granules. With the inlet air temperature of 40-50°C a Sub coating liquid of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 40±5°C for a period of 30 minutes to provide 19.2kg of the sub coated granules.
4. Enteric coating of the sub-coated granules Enteric coating is doing is done in two layers

a) Enteric coating-I

A fluidized bed coater is charged with 9.6 kg of sub-coated granules. With the inlet temperature of 40°C-50°C enteric coating liquid-I of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 35±5°C for a period of 30 minutes to provide 10.2 kg of the enteric coated-I granules.

b) Enteric coating-II

A fluidized bed coater is charged with 10.2 kg of enteric coated-I granules. With the inlet temperature of 40°C-50°C enteric coating liquid-II of the following composition prepared in advance is sprayed at a spray rate of 15-70 g/min and then drying is carried out in the Fluidized bed coater with an inlet temperature maintained at 35±5°C for a period of 30 minutes. The resulting granules are sieved through a #30 mesh and a #40 mesh to provide 15.2kg of the enteric coated-II granules.

5. Production of mixed powders

To 1.98 kg of the above enteric coated granules, 1350g of mannitol, 1287g of microcrystalline cellulose (CEOLUS KG802), 225g of microcrystalline cellulose (CEOLUS KG 1000), 36g of anhydrous citric acid, 56g colloidal silicon dioxide, 27g of strawberry flavor, 81g of Aspartame and 48g of
magnesium stearate are added and admixed in octagonal blender to obtain 5kg of the mixed powder.

6. Production of orally disintegrating tablets

About 4.8kg of the above mixed powder is tableted using the tabletting machine with round punches of 12mm diameter to provide each tablet weighing 600mg.

The hardness and oral disintegration time of each tablet thus obtained are 4-5.5 kg/cm2 and less than 30 seconds respectively. The acid resistance of the Lansoprazole orally disintegrating tablet is less than 10%.

We claim

1. An orally disintegrable tablet comprising (i) the granules having an average particle diameter of more than 400µm which granules comprise a composition coated by an enteric coating layer comprising an aqueous enteric polymer agent and viscosity imparting agent and (ii) an additive

2. An orally disintegrating tablet of claim 1 wherein the aqueous enteric polymer agent is methacrylate copolymer.

3. An orally disintegrable tablet of claim 1 wherein the viscosity imparting agent is polyvinyl alcohol.

4. An orally disintegrable tablet of claim 3 wherein the polyvinyl alcohol has a degree of hydrolysis ranging from 85-89%.

5. An orally disintegrating tablet of claim 3 wherein the polyvinyl alcohol has a viscosity of 3.4-4.6mPas.

6. An orally disintegrating tablet of claim 1 wherein the additive comprises a sugar alcohol.

7. An orally disintegrating tablet of claim 1 wherein the disintegration time is less than 30 seconds.