WO2006111853A2 - Stable solid dosage forms of acid labile drug - Google Patents
Stable solid dosage forms of acid labile drug Download PDFInfo
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- WO2006111853A2 WO2006111853A2 PCT/IB2006/001089 IB2006001089W WO2006111853A2 WO 2006111853 A2 WO2006111853 A2 WO 2006111853A2 IB 2006001089 W IB2006001089 W IB 2006001089W WO 2006111853 A2 WO2006111853 A2 WO 2006111853A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Definitions
- the present invention relates to novel composition containing an acid- labile benzimidazole compound. More particularly, the present invention relates to novel composition containing an acid-labile benzimidazole having at least two subcoating layers.
- the present invention also relates to a process for the preparation of novel composition containing an acid-labile benzimidazole compound.
- Acid-labile benzimidazole compounds that intensively suppress secretion of gastric acid have been used for treatment of gastric and duodenal ulcers.
- these benzimidazole compounds decompose in an acidic environment.
- a formulation is conventionally used, such as a capsule or tablet which contains a core (tablet, microgranule, pellet, etc) containing the acid-labile active substance and an outer layer that surrounds this core and which consists of a gastro-resistant composition that is entero-soluble.
- the coating agent is a compound that is particularly insoluble in an acid medium, but which is soluble in a neutral or alkaline medium.
- an inert substance to the composition for substances that are highly labile in an acid medium and more stable in a neutral or alkaline medium, such as omeprazole, pantoprazole, lansoprazole, rabeprazole, which leads to provide an alkaline environment aimed at improving stability of the active substance during manufacture thereof, and during storage of the pharmaceutical form.
- compositions which consists essentially of: a core containing a pharmacologically effective amount of a acid-unstable benzimidazole compound; a slightly water-soluble first coating layer, coated on the core, comprising a slightly water-soluble, film-forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substance selected from the group consisting of magnesium oxide, silicic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate, magnesium stearate and sucrose fatty acid esters suspended in the first layer, and a second coating layer, coated on the first layer, of an enteric polymer film.
- U.S. Pat. No. 5,232,706 discloses novel compositions comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating.
- omeprazole in the form of an alkali metal or alkaline-earth salt, or a mixture of omeprazole with a basic compound or by a combination of these two possibilities; and secondly by incorporating an intermediate layer between the core and the enteric coating for preventing the alkaline core from causing breakdown of the enteric coating.
- U.S. Patent No. 5,997,903 discloses orally administerable medicament in pellet or tablet form which is resistant to gastric juice, and in which each pellet or tablet consists of : a) a core in which active compound or its physiologically-tolerated salt is in admixture with binder, filler and, optionally, a member selected from the group consisting of another tablet auxiliary and a basic physiologically-tolerated inorganic compound, b) an inert water-soluble intermediate layer surrounding the core and c) an outer layer which is resistant to gastric juice, wherein the active compound is pantoprazole, the binder is polyvinylpyrrolidone and/or hydroxypropylmethylcellulose and, optionally, the filler is mannitol.
- U.S. Patent No. 4,853,230 discloses a pharmaceutical preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region,. said subcoating comprising one or more layers comprising materials selected from the group consisting of tablet excipients, film-forming compounds and alkaline compounds; and (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.
- U.S. Pat. No. 6,013,281 discloses in situ formation of separating layer as a water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer.
- U.S. Pat. No. 6,207,198 discloses compositions that are exempt of alkaline-reacting compounds comprising: a core containing an acid-labile benzimidazole, and said active principle not being in the form of an alkaline salt; an intermediate layer; and an enteric layer.
- U.S. Pat. No. 6,346,269 discloses oral formulations for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, and an enteric coating is applied over the. drug substance layer.
- compositions comprising a core containing an active ingredient unstable to acid, an intermediate film enveloping the core, and an enteric film further enveloping the intermediate film, and the intermediate film comprises a matrix sparsely soluble in water and water- soluble fine particles dispersed therein.
- compositions comprising a core containing the active ingredient and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.
- WO 03/077829 discloses a process for preparation of a pharmaceutical composition for oral use with desired dissolution profile and stability comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials such as hydroxypropylmethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, dextran and optionally water insoluble particles such as magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate, c) second coat, termed as a seal coat, comprising of a mixture of polymers like hydroxypropylmethyl cellulose, cellulose acetate phthalate, and ethyl cellulose over the subcoat, d
- the main objective of the present invention is to provide a stable pharmaceutical dosage form of acid labile benzimidazole compound with at least two subcoating layers.
- Yet another objective of the present invention is to provide a stable pharmaceutical dosage form of acid labile benzimidazole compounds that has bioavailability comparable to the reference product.
- alkaline reacting compound in the core is favorable since it prevents degradation of the active ingredient unstable to acid.
- alkaline reacting compound includes carbonates, bicarbonates ⁇ oxides, hydroxides of alkali and alkaline earth metal salts such as sodium, potassium, magnesium, calcium and the like.
- the core compositions of the present invention further comprise one or more pharmaceutically acceptable excipients such as binder, diluents, disintegrants, lubricants and the like.
- Suitable disintegrating agent used in accordance with the present invention are selected from crosscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, alginates, polacrilin potassium, and the like or combination thereof.
- Suitable diluents used of the invention include calcium phosphate- dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, mannitol, sorbitol, xylitol, maltitol, sucrose, lactose, starch and combination thereof.
- the core is formed by blending a mixture of acid labile benzimidazole compound, alkaline reacting agent and other excipients, and directly compressing the blend into tablets or forming pellets or granules.
- the rapidly dissolving or disintegrating water soluble subcoating layer comprises hydrophilic excipients selected from the group consisting of copovidone, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like.
- the sub coating layers may optionally contain one or more pharmaceutically acceptable excipients such as sodium lauryl sulfate, talc, polyethylene glycol, propylene glycol polysorbate, calcium carbonate, sodium carbonate, silicon dioxide, magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate, sodium stearylfumarate and the like and coloring agents such as iron oxide yellow or red.
- pharmaceutically acceptable excipients such as sodium lauryl sulfate, talc, polyethylene glycol, propylene glycol polysorbate, calcium carbonate, sodium carbonate, silicon dioxide, magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate, sodium stearylfumarate and the like and coloring agents such as iron oxide yellow or red.
- the subcoating layers are applied onto the core by conventional coating techniques such as coating in a tank or a fluidized bed employing coating solution in water or in organic solvents or using latex suspensions.
- the subcoating layers may be applied in any manner.
- the water-soluble material layer may be applied first and then, water insoluble layer may applied or vice versa.
- the number of subcoating layers does not influence the disintegration time of the dosage form.
- the thickness of the subcoating layers influence the disintegration time. Accordingly, when the amount of the subcoating layers applied onto the surface of the core varies due to changes in operational conditions, such as temperature and moisture, of the intermediate film coating process, the disintegration time of the dosage form varies. Hence, it is important to adjust the thickness of the subcoating layers.
- the number of subcoating layers applied may vary from two to three layers.
- the enteric coating comprises enteric polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic acid polymers such as Eudragit and the like or a combination there of.
- enteric polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic acid polymers such as Eudragit and the like or a combination there of.
- the enteric coating layer may additionally contain plasticizer and/or conventional pharmaceutical excipients used to facilitate coating such as sodium lauryl sulfate, talc, colloidal silica, sodium stearylfumarate and the like.
- plasticizers include triethyl citrate, polysorbate 80, triacetin, and the like.
- the coating aids include, for example, fatty acid glycerol esters, polyethylene glycol and the like.
- the solid dosage form is in the form of tablet or capsule.
- a process for the preparation of stable solid dosage forms of acid labile drugs comprising : (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound;
- the core tablets may be prepared by direct compression, granulation techniques such as wet or dry granulation methods.
- the enteric-coated dosage forms are further coated with film forming agents.
- Example 1 prepared as per the process described above further exemplify the inventions and are not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
- Example 1
- step (i) blended a mixture of pantoprazole , microcrystalline cellulose, calcium carbonate, calcium silicate and calcium stearate, ii) compressed the blend obtained in step (i) into tablets.
- step (i) prepared subcoating suspension- 1 by dispersing copovidone, in ethanol using suitable stirrer, iv) coated the tablets in coating pan by applying the subcoating suspension-
- PEG 6000 in ethanol vi) coated the tablets in coating pan by applying subcoating suspension-2, vii) prepared subcoating suspension-Ill by dispersing copovidone and iron oxide yellow in ethanol, viii) coated the tablets in coating pan by applying the subcoating suspension- Ill and ix) the tablets are enteric coated using enteric coating suspension to obtain enteric coated tablets.
- the tablets were subjected to an in vitro dissolution method to determine the rate at which the Pantoprazole sodium was released from the tablets.
- the tablets were placed into a dissolution medium for 2 hours in acid followed by pH 6.8 phosphate buffer and stirred with paddles at 75 rpm.
- the dissolution profile is given in Table 1. .
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Abstract
The present invention relates to novel composition containing an acid- labile benzimidazole compound. More particularly, the present invention relates to novel composition containing an acid-labile benzimidazole having at least two subcoating layers.
Description
STABLE DOSAGE FORMS OF ACID LABILE DRUG
Field of the invention
The present invention relates to novel composition containing an acid- labile benzimidazole compound. More particularly, the present invention relates to novel composition containing an acid-labile benzimidazole having at least two subcoating layers.
The present invention also relates to a process for the preparation of novel composition containing an acid-labile benzimidazole compound. Background of the invention
Chemical substances that are easily destroyed in an acid medium (which is expressed herein by the term "acid-labile"), such as benzimidazoles and, in particular, omeprazole, lansoprazole, pantoprazole and rabeprazole create a special problem for formulators when it is required to provide a pharmaceutical form designed for oral administration.
Acid-labile benzimidazole compounds that intensively suppress secretion of gastric acid have been used for treatment of gastric and duodenal ulcers. However, these benzimidazole compounds decompose in an acidic environment. In order to avoid contact between the substances and the gastric juice following oral administration of the substance, a formulation is conventionally used, such as a capsule or tablet which contains a core (tablet, microgranule, pellet, etc) containing the acid-labile active substance and an outer layer that surrounds this core and which consists of a gastro-resistant composition that is entero-soluble. Generally, the coating agent is a compound that is particularly insoluble in an acid medium, but which is soluble in a neutral or alkaline medium.
It is necessary to add an inert substance to the composition for substances that are highly labile in an acid medium and more stable in a neutral or alkaline medium, such as omeprazole, pantoprazole, lansoprazole, rabeprazole, which leads to provide an alkaline environment aimed at
improving stability of the active substance during manufacture thereof, and during storage of the pharmaceutical form.
Several prior art references describe such compositions that are suitable for oral' administration of acid-labile substances. U.S. Pat. No. 5,035,899 discloses compositions which consists essentially of: a core containing a pharmacologically effective amount of a acid-unstable benzimidazole compound; a slightly water-soluble first coating layer, coated on the core, comprising a slightly water-soluble, film-forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substance selected from the group consisting of magnesium oxide, silicic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate, magnesium stearate and sucrose fatty acid esters suspended in the first layer, and a second coating layer, coated on the first layer, of an enteric polymer film.
U.S. Pat. No. 5,232,706 discloses novel compositions comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating. It is stated that the problem of the poor stability of the omeprazole is resolved, firstly, by increasing the way the core behaves as a base either by introducing omeprazole in the form of an alkali metal or alkaline-earth salt, or a mixture of omeprazole with a basic compound or by a combination of these two possibilities; and secondly by incorporating an intermediate layer between the core and the enteric coating for preventing the alkaline core from causing breakdown of the enteric coating.
U.S. Patent No. 5,997,903 discloses orally administerable medicament in pellet or tablet form which is resistant to gastric juice, and in which each pellet or tablet consists of : a) a core in which active compound or its
physiologically-tolerated salt is in admixture with binder, filler and, optionally, a member selected from the group consisting of another tablet auxiliary and a basic physiologically-tolerated inorganic compound, b) an inert water-soluble intermediate layer surrounding the core and c) an outer layer which is resistant to gastric juice, wherein the active compound is pantoprazole, the binder is polyvinylpyrrolidone and/or hydroxypropylmethylcellulose and, optionally, the filler is mannitol.
U.S. Patent No. 4,853,230 discloses a pharmaceutical preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region,. said subcoating comprising one or more layers comprising materials selected from the group consisting of tablet excipients, film-forming compounds and alkaline compounds; and (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.
U.S. Pat. No. 6,013,281 discloses in situ formation of separating layer as a water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer.
U.S. Pat. No. 6,207,198 discloses compositions that are exempt of alkaline-reacting compounds comprising: a core containing an acid-labile benzimidazole, and said active principle not being in the form of an alkaline salt; an intermediate layer; and an enteric layer. U.S. Pat. No. 6,346,269 discloses oral formulations for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, and an enteric coating is applied over the. drug substance layer.
US 2004/0146558 discloses compositions comprising a core containing an active ingredient unstable to acid, an intermediate film enveloping the core, and an enteric film further enveloping the intermediate film, and the intermediate film comprises a matrix sparsely soluble in water and water- soluble fine particles dispersed therein.
US 2005/042277 discloses compositions comprising a core containing the active ingredient and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.
WO 03/077829 discloses a process for preparation of a pharmaceutical composition for oral use with desired dissolution profile and stability comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials such as hydroxypropylmethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, dextran and optionally water insoluble particles such as magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate, c) second coat, termed as a seal coat, comprising of a mixture of polymers like hydroxypropylmethyl cellulose, cellulose acetate phthalate, and ethyl cellulose over the subcoat, d) an enteric coating layer surrounding said seal coat layer, wherein the seal coat layer isolates the core and the subcoat layer from the enteric coating layer.
Even though many patents discloses stable formulations for acid labile drugs, still there is need to develop dosage forms for acid labile drugs in which drug substances will not be exposed to acid in the stomach, but will be rapidly released when the dosage form enters a more alkaline environment.
The prior art patents disclose stable dosage forms for acid labile drugs containing core with or without alkaline reactive compound, an intermediate
layer and an enteric coating. The inventors of the present invention during their efforts to develop stable dosage forms, found that the presence of at least two subcoating layers produce more stable dosage forms for acid labile drugs by providing the more protective separation between core and enteric coating and to create a pH gradient across the tablet from alkaline (core) to acidic (enteric layer) environment.
Accordingly, the main objective of the present invention is to provide a stable pharmaceutical dosage form of acid labile benzimidazole compound with at least two subcoating layers. Yet another objective of the present invention is to provide a stable pharmaceutical dosage form of acid labile benzimidazole compounds that has bioavailability comparable to the reference product.
Summary of the invention According to the main embodiment of the present invention, there is provided stable solid dosage forms of acid labile drugs comprising :
(a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound;
(b) at least two inert subcoating layers comprising rapidly dissolving or disintegrating water soluble material layer comprising hydrophilic excipients and water insoluble layer comprising hydrophobic excipient selected from the group consisting of ethyl cellulose, stearic acid, hydrogenated vegetable oil and the like and c) an enteric coating layer surrounding said subcoating layer. Detailed description of the invention The presence of one subcoating layer between the alkaline core and acidic enteric coating is not sufficient to ensure effective separation and hence the stability. There is a requirement of primary layer being slightly alkaline and secondary layer of slightly acidic, so as to establish a pH gradient system from highly alkaline environment to acidic environment.
The presence of alkaline reacting compound in the core is favorable since it prevents degradation of the active ingredient unstable to acid. Examples of alkaline reacting compound includes carbonates, bicarbonates^ oxides, hydroxides of alkali and alkaline earth metal salts such as sodium, potassium, magnesium, calcium and the like.
The acid-labile pharmaceutically active substance of the preset invention includes omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole and the like.
The amount of acid labile compound in the core is in the range from about 1 to 40 mass %, preferably about 5 to 30 mass %, of the weight of the composition.
The core compositions of the present invention further comprise one or more pharmaceutically acceptable excipients such as binder, diluents, disintegrants, lubricants and the like. Suitable disintegrating agent used in accordance with the present invention are selected from crosscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, alginates, polacrilin potassium, and the like or combination thereof. Suitable diluents used of the invention include calcium phosphate- dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, mannitol, sorbitol, xylitol, maltitol, sucrose, lactose, starch and combination thereof.
Suitable lubricants of the present invention include sodium stearylfumarate, magnesium stearate, hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium lauryl sulfate, talc and the like..
Suitable binders of the present invention include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxymethyl cellulose and the like.
In an embodiment of the present invention, the core may be in the form of pellet, tablet, minitablet, granule and the like.
The core is formed by blending a mixture of acid labile benzimidazole compound, alkaline reacting agent and other excipients, and directly compressing the blend into tablets or forming pellets or granules.
In an embodiment of the present invention, the rapidly dissolving or disintegrating water soluble subcoating layer comprises hydrophilic excipients selected from the group consisting of copovidone, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like. In an embodiment of the present invention, the sub coating layers may optionally contain one or more pharmaceutically acceptable excipients such as sodium lauryl sulfate, talc, polyethylene glycol, propylene glycol polysorbate, calcium carbonate, sodium carbonate, silicon dioxide, magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate, sodium stearylfumarate and the like and coloring agents such as iron oxide yellow or red.
The subcoating layers are applied onto the core by conventional coating techniques such as coating in a tank or a fluidized bed employing coating solution in water or in organic solvents or using latex suspensions.
Use of at least two coating layers consisting of one water soluble material and one water insoluble polymeric layer stabilize the time of releasing of active compound contained in the core.
In yet another embodiment of the present invention, the subcoating layers may be applied in any manner. For example the water-soluble material layer may be applied first and then, water insoluble layer may applied or vice versa.
The number of subcoating layers does not influence the disintegration time of the dosage form. However, the thickness of the subcoating layers
influence the disintegration time. Accordingly, when the amount of the subcoating layers applied onto the surface of the core varies due to changes in operational conditions, such as temperature and moisture, of the intermediate film coating process, the disintegration time of the dosage form varies. Hence, it is important to adjust the thickness of the subcoating layers.
In yet another embodiment of the present invention, the number of subcoating layers applied may vary from two to three layers.
In yet another embodiment of the present invention, the enteric coating comprises enteric polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic acid polymers such as Eudragit and the like or a combination there of.
The enteric coating layer may additionally contain plasticizer and/or conventional pharmaceutical excipients used to facilitate coating such as sodium lauryl sulfate, talc, colloidal silica, sodium stearylfumarate and the like. The plasticizers include triethyl citrate, polysorbate 80, triacetin, and the like.
The coating aids include, for example, fatty acid glycerol esters, polyethylene glycol and the like.
Typical solvents which may be used to apply the subcoating layer and acid resistant enteric coating layer include water, isopropyl alcohol, ethanol, acetone, methylene chloride and the like.
In yet another embodiment of the present invention, the solid dosage form is in the form of tablet or capsule.
In yet another embodiment, there is provided a method of treating gastric and duodenal ulcers by administering the stable solid dosage form of the present invention.
In yet another embodiment of the present invention,. there is provided a process for the preparation of stable solid dosage forms of acid labile drugs comprising :
(a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound;
(b) at least two inert subcoating layers comprising rapidly dissolving or disintegrating water soluble material layer comprising hydrophilic excipients and water insoluble layer comprising hydrophobic excipients selected from the group consisting of ethyl cellulose, stearic acid, hydrogenated vegetable oil and the like and c) an enteric coating layer surrounding said subcoating layer, which comprises the steps of i) blending a mixture of active substance, an alkaline reacting and one or more excipients, ii) lubricating the blend of step (i), iii) compressing the lubricated blend into tablets, iv) coating the tablets by applying subcoating suspension- 1, v) coating the tablets of step (iv) by applying subcoating suspension-2 and vi) applying enteric coating to obtain enteric coated dosage forms of acid labile substance.
The core tablets may be prepared by direct compression, granulation techniques such as wet or dry granulation methods. In another embodiment of the present invention, the enteric-coated dosage forms are further coated with film forming agents.
The following examples prepared as per the process described above further exemplify the inventions and are not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example 1
The processing steps involved are given below : i) blended a mixture of pantoprazole , microcrystalline cellulose, calcium carbonate, calcium silicate and calcium stearate, ii) compressed the blend obtained in step (i) into tablets. iii) prepared subcoating suspension- 1 by dispersing copovidone, in ethanol using suitable stirrer, iv) coated the tablets in coating pan by applying the subcoating suspension-
1, v) prepared subcoating suspension-2 by dispersing stearic acid, talc and
PEG 6000 in ethanol,
vi) coated the tablets in coating pan by applying subcoating suspension-2, vii) prepared subcoating suspension-Ill by dispersing copovidone and iron oxide yellow in ethanol, viii) coated the tablets in coating pan by applying the subcoating suspension- Ill and ix) the tablets are enteric coated using enteric coating suspension to obtain enteric coated tablets.
Formulations described in examples 2 to 7 were prepared using the procedure similar to the one described in example 1.
Example 2
Example 4
Example 5
Example 7
The tablets were subjected to an in vitro dissolution method to determine the rate at which the Pantoprazole sodium was released from the tablets. The tablets were placed into a dissolution medium for 2 hours in acid followed by pH 6.8 phosphate buffer and stirred with paddles at 75 rpm. The dissolution profile is given in Table 1. .
Dissolution data
Claims
1. A stable solid dosage form of acid labile drugs comprising :
(a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound;
(b) at least two inert subcoating layers comprising rapidly dissolving or disintegrating water soluble material layer comprising hydrophilic excipients and water insoluble layer comprising hydrophobic excipient selected from the group consisting of ethyl cellulose, stearic acid, hydrogenated vegetable oil and c) an enteric coating layer surrounding said subcoating layer.
2. The solid dosage form as claimed in claim 1, wherein the acid-labile pharmaceutically active substance is omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole.
3. The solid dosage form as claimed in claim 1, wherein alkaline reacting compound is selected from carbonates, bicarbonates, oxides, hydroxides of alkali and alkaline earth metal salts such as sodium, potassium, magnesium, calcium.
4. The solid dosage form as claimed in claim 1, wherein the core further comprise one or more pharmaceutically" acceptable excipients such as binder, diluents, disintegrants, lubricants.
5. The solid dosage form as claimed in claim 4, wherein the disintegrating' agent is selected from the group consisting of crosscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, alginates, polacrilin potassium.
6. The solid dosage form as claimed in claim 4, wherein the diluent is selected from calcium phosphate-dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, mannitol, sorbitol, xylitol, maltitol, sucrose, lactose, starch or combination thereof.
7. The solid dosage form as claimed in claim 4, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxymethyl cellulose.
8. The solid dosage form as claimed in claim 1, wherein hydrophilic excipient is selected from the group consisting of copovidone, polyethylene oxide, hydroxypropyl methylcellulose or hydroxypropyl cellulose.
9. The solid dosage form as claimed in claim 1, wherein the sub coating layers further contain one or more pharmaceutically acceptable excipients such as sodium lauryl sulfate, talc, polyethylene glycol, propylene glycol polysorbate, calcium carbonate, sodium carbonate, silicon dioxide, magnesium oxide, silica anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate and sodium stearylfumarate.
10. The solid dosage form as claimed in claim 1, wherein enteric coating comprises enteric polymers selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic acid polymers.
11. The solid dosage form as claimed in claim 1, wherein the amount of acid labile compound in the core is present in the range from about 1 to 40 % by weight of the composition.
12. A method of treating gastric and duodenal ulcers by administering the stable solid dosage form claimed in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN444CH2005 | 2005-04-18 | ||
| IN444/CHE/2005 | 2005-04-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006111853A2 true WO2006111853A2 (en) | 2006-10-26 |
| WO2006111853A3 WO2006111853A3 (en) | 2007-03-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2006/001089 WO2006111853A2 (en) | 2005-04-18 | 2006-04-18 | Stable solid dosage forms of acid labile drug |
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| Country | Link |
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| WO (1) | WO2006111853A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080311195A1 (en) * | 2007-04-12 | 2008-12-18 | Nipro Corporation | Basis particles, method for manufacturing the same, and orally-disintegrating tablet |
| WO2010122583A2 (en) | 2009-04-24 | 2010-10-28 | Rubicon Research Private Limited | Oral pharmaceutical compositions of acid labile substances |
| US8865212B2 (en) * | 2006-01-16 | 2014-10-21 | Jubilant Generics Limited | Stable pharmaceutical formulation of an acid labile compound and process for preparing the same |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244380A2 (en) * | 1986-04-30 | 1987-11-04 | Aktiebolaget Hässle | Pharmaceutical formulations of acid labile substances for oral use |
| EP0496437A2 (en) * | 1986-04-30 | 1992-07-29 | Aktiebolaget Hässle | Use of specific core material and layers to obtain pharmaceutical formulations stable to discolouration of omeprazole |
| WO1999032093A1 (en) * | 1997-12-22 | 1999-07-01 | Astrazeneca Ab | Oral pharmaceutical pulsed release dosage form |
| EP1086694A2 (en) * | 1999-09-13 | 2001-03-28 | Laboratorios Del Dr. Esteve, S.A. | Solid oral pharmaceutical formulation of modified release that contains an acid labile benzimidazole compound |
| WO2003077829A2 (en) * | 2002-03-08 | 2003-09-25 | Modi, Rajiv, Indravadan | Process for preparation of a pharmaceutical composition containing acid labile compounds |
| EP1454634A1 (en) * | 2001-11-21 | 2004-09-08 | Eisai Co., Ltd. | Preparation compositions containing acid-unstable physiologically acitve compounds and process for producing the same |
-
2006
- 2006-04-18 WO PCT/IB2006/001089 patent/WO2006111853A2/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244380A2 (en) * | 1986-04-30 | 1987-11-04 | Aktiebolaget Hässle | Pharmaceutical formulations of acid labile substances for oral use |
| EP0496437A2 (en) * | 1986-04-30 | 1992-07-29 | Aktiebolaget Hässle | Use of specific core material and layers to obtain pharmaceutical formulations stable to discolouration of omeprazole |
| WO1999032093A1 (en) * | 1997-12-22 | 1999-07-01 | Astrazeneca Ab | Oral pharmaceutical pulsed release dosage form |
| EP1086694A2 (en) * | 1999-09-13 | 2001-03-28 | Laboratorios Del Dr. Esteve, S.A. | Solid oral pharmaceutical formulation of modified release that contains an acid labile benzimidazole compound |
| EP1454634A1 (en) * | 2001-11-21 | 2004-09-08 | Eisai Co., Ltd. | Preparation compositions containing acid-unstable physiologically acitve compounds and process for producing the same |
| WO2003077829A2 (en) * | 2002-03-08 | 2003-09-25 | Modi, Rajiv, Indravadan | Process for preparation of a pharmaceutical composition containing acid labile compounds |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8865212B2 (en) * | 2006-01-16 | 2014-10-21 | Jubilant Generics Limited | Stable pharmaceutical formulation of an acid labile compound and process for preparing the same |
| US20080311195A1 (en) * | 2007-04-12 | 2008-12-18 | Nipro Corporation | Basis particles, method for manufacturing the same, and orally-disintegrating tablet |
| WO2010122583A2 (en) | 2009-04-24 | 2010-10-28 | Rubicon Research Private Limited | Oral pharmaceutical compositions of acid labile substances |
| WO2010122583A3 (en) * | 2009-04-24 | 2011-04-28 | Rubicon Research Private Limited | Oral pharmaceutical compositions of acid labile substances |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006111853A3 (en) | 2007-03-08 |
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