Classifications

• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • 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
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• Benzimidazolic compounds such as Omeprazole, Lansoprazole, Pantoprazole, Pariprazole, Leminoprazole, and Rabeprazole are potent proton pump inhibitor known for inhibition of gastric acid secretion. They a re used i n the therapeutics of d iseases related to gastric acidity in mammals, especially in humans, including gastric and duodenal ulcers, reflux oesophagitis, gastritis, duodenitis and Zollinger-Ellison syndrome.
• Benzimidazole such as omeprazole, lansoprazole are sensitive to light, heat and moisture. They exhibit fast decomposition below pH 7.8 and has maximum stability at pH 11. Hence the oral dosage form containing benzimidazole needs to be p rotected from the acidic ingredient used to manufacture the dosage form a nd from the acidic gastric fluid so that they reach intactly in the small intestine from where they are absorbed systemically. They also have very low aqueous solubility and the solubility is pH dependent.
• Various related art have addressed and have tried to overcome the issue of
• U.S. Patent No. 4,786,505 describes extrusion spheronization process for omeprazole preparation wherein omeprazole core is prepared by granulating the mixture of mannitol powder with lactose anhydrous, hydroxypropylcellulose and microcrystalline cellulose with water containing alkaline compound and surfactant. Omeprazole is either suspended in granulating liquid or added in above powder mixture. Separating layer that separates the omeprazole core and enteric layer contains alkaline pH buffering compounds and film coating polymer, which is deposited on the pellets, followed by deposition of enteric layer in coating pan or fluidized bed coater.
• Efficient drying is essential to reduce the water content of the final dosage form of not more than 1.5 % w/w, which is an absolute requirement for the stable formulation.
• the process involves use of surfactant, disintegrating agent and filler in the composition, which are in contact with omeprazole thereby helping in the dissolution of omeprazole.
• the process is a batch process using multiple equipments, which makes it laborious and time consuming.
• U.S. Patent No. 5385739 describes microgranules dosage form containing omeprazole.
• Powder mixture of omeprazole, mannitol, disintegrating agent carboxymethylstarch and surfactant sodium lauryl sulfate is layered on neutral core of sugar and starch in circular turbine with inclined flat bottom. Further the core contains protective layer consisting of mannitol, sucrose and binding agent, which isolate the active agent from external enteric coating layer.
• Omeprazole and excipients used require additional micronisation steps to achieve particle size below 100 microns. Efficient drying is essential to reduce the moisture level of active layer to preferably less than 0.5 % to ensure good stability. The process also requires stringent temperature control for the granules to be maintained between 32°C and 38°C.
• U.S. Patent No. 6077541 describes process for manufacture of omeprazole enteric- coated pellets wherein the drug layer comprises of 20-70% w/w omeprazole. Enteric coating layer is directly applied to the drug layer. The process requires additional step of micronization of omeprazole. The process also requires alkaline agents, surface- active agents and binder, which along with micronised omeprazole is suspended in aqueous or non-aqueous solvents. This suspension containing omeprazole is coated on non-pariel sugar sphere in fluid bed coater.
• EP 1108425 describes multiunit pharmaceutical preparation manufactured by coating aqueous suspension of substituted benzimidazole or its acceptable salts in the micronized form onto inert core to obtain drug core.
• the invention requires use of surfactants and disaggregants in the layer-containing drug, which are mixed in a suitable proportion in order to allow disaggregation of the formulations and dissolution of the active ingredients.
• Drug core in turn is coated with an insulating layer free from alkaline agent of minimum thickness of 15-mu m, and finally with gastro resistant layer of minimum thickness of 30-mu m.
• the formulation has stringent requirement to have humidity less than 1.5% for good stability.
• PCT Publication W0 9819668 describes delayed drug delivery system where micronised omeprazole in aqueous suspension containing water soluble binder is deposited on core containing alkaline material.
• the alkaline core structure is obtained by depositing powder blend of alkaline material and spheronizing / disintegrating agent on non-pariel seeds with the help of polymeric binding agent in fluid bed granulator with rotor insert.
• the drug core is further coated with non-enteric moisture barrier followed by delayed release enteric barrier.
• the formulation releases only 60 - 80% of omeprazole after 45 minutes in buffer of pH 6.8.
• U.S. Patent No. 6207198 describes omeprazole composition where alkaline reacting substance is not present in the composition. It describes a process, which involves granulating omeprazole with inert nuclei or aqueous layering containing suspended omeprazole onto inert nuclei. The granules or the layered nuclei are compressed to form micro tablets, which are coated with intermediate layer followed by enteric layer. The composition makes use of disintegrants and surfactants in the intermediate layer, which is in immediate contact with a core containing omeprazole to improve the dissolution of omeprazole. The process described is operator dependant and makes use of multiple equipments making it time laborious and consuming.
• None of the related art teaches process for manufacture of a stable, oral, multiple unit pharmaceutical composition containing high concentration of benzimidazole upto about 40%w/w without the use of micronized benzimidazole, disintegrating agent, fillers and surfactant in contact with benzimidazole, having minimum acid degradation in 0.1 N HCI after two hours and buffer release of more than 85% w/w in pH 6.8 after 45 minutes in a single equipment fluid bed bottom spray processor and capable of being filled in smallest size (size 5) capsule for ease of administration and patient acceptance.
• the o bject of the invention i s to provide a process for manufacture of a stable, oral, multiple unit pharmaceutical composition containing high concentration of benzimidazole upto about 40%w/w without the use of micronized benzimidazole, disintegrating agent, fillers and surfactants in contact with benzimidazole, having minimum acid degradation in 0.1N HCI after two h ours a nd pH 6.8 buffer release of more than 85% w/w after 45 minutes in a single equipment fluid bed bottom spray processor and capable of being filled in capsule size 5 to size 0 for ease of administration and patient acceptance.
• the object of t he invention i s to p rovide a p rocess f or m anufacture of stable, oral, multiple unit pharmaceutical composition containing high concentration of benzimidazole upto about 40%w/w which may be carried out continuously or in batches and is unaffected by high moisture content, which may be present in the composition.
• the object of the invention is to provide a process for manufacture of a stable, oral, multiple unit pharmaceutical composition containing high concentration of benzimidazole upto about 40%w/w capable of being filled in capsule size 5 for the dose of upto 40mg for omeprazole or upto 30mg for lansoprazole.
• Further objects of the invention is to provide a process for manufacture of alkaline material treated non-pariel seeds suitable for deposition of alkaline benzimidazole dispersion containing dissolved benzimidazole and t o w ithstand r igors a nd attrition of fluid bed processor.
• the object of the invention is to provide a process, which consists of spraying aqueous or hydroalcoholic solution of benzimidazole in alkali metal hydroxide solution on treated non-pariel seeds to obtain drug pellets, which are further coated with sealant polymer followed by enteric polymer in a single equipment to obtain unagglomerated, uniformly shaped and sized pellets.
• This invention relates to process for manufacture of a stable, oral, multiple unit pharmaceutical composition containing high concentration of benzimidazole upto about 40%w/w without the use of micronized benzimidazole, disintegrating agent and fillers.
• Surfactants in these compositions are part of enteric polymer system and are not in contact with benzimidazole.
• Multiple unit pharmaceutical composition is in the form unagglomerated, u niformly s hape a nd sized enteric-coated pellets that are processed continuously or in batches in single equipment fluid bed bottom spray processor.
• the enteric-coated pellets obtained by the process of the invention are capable of being filled in smallest size capsule (size 5) for ease of administration and patient acceptance.
• the process is environmental friendly as it involves aqueous or hydroalcoholic media.
• Benzimidazole derivative is selected form omeprazole, lansoprazole, rabeprazole, pantoprazole, or their optically active isomer.
• omeprazole i s selected as the benzimidazole d erivative.
• the process may be carried out in batches or continuously in single equipment to give enteric-coated pellets.
• the invention involves sequential deposition of: a) alkaline material layer on non-pariel seeds to obtain treated non-pariel seeds b) drug layer to obtain drug pellets c) sealant polymer layer to obtain sealed pellets d) enteric polymer layer to obtain enteric coated pellets
• Enteric coated pellets containing benzimidazole has minimum acid degradation after 2 hours in 0.1 N HCI and buffer release of not less than 85% after 45 minutes when tested in-vitro and is capable of being filled into size 5 to size 0 capsule. This is distinct from the prior art as
• the moisture content in the formulation is less than 5% w/w and preferably less than 3% w/w without having adverse effect on the stability of the formulation.
• Stage I Treated Non-pariel Seeds
• the first stage in the manufacture of pharmaceutical composition as enteric-coated pellets containing omeprazole is the deposition of alkaline material layer on the non- pariel seeds.
• aqueous alkaline dispersion containing dissolved omeprazole was sprayed on non-pariel seeds there was problem of breakages of non-pariel seeds in fluid bed bottom spray processor. It was surprisingly found that when non - pariel seeds were treated with alkaline material the problem of breakage was solved.
• This treatment to non-pariel seeds involves spraying alkaline material along with binder on non-pariel seeds to produce treated non-pariel seeds.
• treated non-pariel seeds may also be obtained by blending alkaline material with starch during the production of non-pariel seeds.
• This alkaline material treated non-pariel seeds produced are possessing high integrity and strength and can withstand the further process of manufacturing enteric-coated pellets containing benzimidazole leading to uniform loading of benzimidazole thus resulting into high processing and batch yields.
• Treatment of non-pariel seeds is carried out in fluid bed bottom processor wherein the non-pariel seeds a re coated with mixture of water-soluble polymer, which is selected from the group of hydroxypropylmethylcellulose and alkaline material for e.g. light magnesium carbonate.
• the ratio of the polymer to alkaline material is about 1 : 0.1 to 0.1 : 1 and is preferably about 1 : 0.5 to 0.5: 1.
• the total coating of this mixture is 1 - 4 % w/w of non-pariel seeds and the solid content of the spraying suspension is about 5 - 15 % w/w.
• the process is carried out in fluid bed processor with inlet air temperature between 60 - 90°C, outlet air temperature 40 - 55°C, atomization air pressure 1.0 - 3.5 bars, fluidization flap open between 15 - 90% and continuous spray rate between 1 - 300 ml / min. These treated non-pariel seeds are used for the production of drug pellet and subsequent stage.
• the next stage is the deposition of drug layer on treated non-pariel seeds to obtain drug pellets or d rug core. It i nvolves deposition of suspension of dissolved omeprazole on treated non-pariel seeds.
• the solution of omeprazole is prepared by dissolving omeprazole in aqueous solution of alkali metal hydroxide.
• the next step is the preparation of binder solution wherein the binder is dispersed and dissolved in water.
• the drug solution is mixed with aqueous binder solution.
• Antitack agent is added to above solution.
• the suspension is filtered through appropriate mesh and is sprayed on treated non pariel seeds in fluid bed processor with inlet air temperature between 60 - 90°C, outlet air temperature 40 - 55°C, atomization air pressure 1.0 - 3.5 bars, fluidization flap open between 15 - 90% and continuous spray rate between 1 - 300 ml / min.
• Drug pellets are obtained after complete spraying of aqueous suspension containing omeprazole in dissolved form.
• the drug pellets are dried in Fluid bed bottom spray processor to arrive moisture content of less than 5%w/w and preferably less than
• the content of omeprazole in the drug pellets is 5-60% w/w.
• the moisture content of the drug pellets is less than 5% w/w preferably less than 3% w/w.
• the particle size of the drug pellets ranges from about 600 - 2057 microns and preferably about 710 -
• the particle size of treated non-pariel seeds size may be from 420-1405 microns and preferably from about 710-1204 microns.
• the alkali metal hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and their mixtures thereof and preferably is sodium hydroxide.
• the concentration of sodium hydroxide in the drug pellets is about between 12 - 30 %w/w of omeprazole and is preferably about 12 - 25% w/w.
• the binder is selected from the group of water soluble binder which can withstand high pH, consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrollidone, sodiumcarboxymethylcellulose, methylcellulose and their mixtures and is preferably hydroxypropylmethylcellulose alone or in combination with polyvinylpyrollidone.
• Hydroxypropylmethylcellulose used as a binder has a nominal viscosity of 5 - 100cps and preferably about 5 - 15 cps measured on 2% w/w solution at 20°C.
• the concentration of the binder in drug pellets is about 10 - 40 % w/w of omeprazole and is preferably about 15 - 35 % w/w of omeprazole.
• Antitack agents is selected form the group consisting of talc, colloidal silicon dioxide, glyceryl monostearate, glyceryl behenate and their mixtures, the preferable choice being talc with or without colloidal silicon dioxide and are used in the concentration level of about 7.5 - 25 % w/w of omeprazole.
• the total solid content of the spraying suspension containing dissolved omeprazole is not more than 30 % w/w and is preferably about 15 - 20 % w/w.
• the final pH of the spraying suspension is in the range of about 11-14.
• the drug pellets after drying shows about 100% of drug release within about 10 minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution apparatus.
• sealant polymer layer on drug pellets to obtain sealed layer.
• Seal coating suspension is prepared by dispersing and / or dissolving sealant polymer in water.
• Antitack agent is added to the above solution.
• Suspension is filtered through appropriate mesh and is sprayed on drug pellets in fluid bed processor to form a seal coat, which prevents the contact of acidic enteric coating material with drug layer.
• the coating parameters are same as per the drug pellets stage.
• the sealed pellets are dried for about 20 - 40 minutes to achieve the moisture level less than 5% and preferably less than 3%w/w.
• the sealant polymer is selected from group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose and their mixtures and is preferable hydroxypropylmethylcellulose.
• the concentration of hydroxypropylmethylcellulose is about 10 to 150 % w/w of omeprazole.
• Hydroxypropylmethylcellulose used as a sealant polymer has a nominal viscosity of about 3 - 100 cps and preferably about 5 - 15 cps measured on 2% w/w solution at
• the solid content of the above seal coating suspension is between about 8 - 12% w/w.
• the antitack agent is selected from the group consisting of talc, colloidal silicon dioxide, glyceryl monostearate, glyceryl behenate and their mixtures used in the concentration level of about 10 - 30 % w/w of the sealant polymer and preferably talc.
• alkaline agent such as light magnesium carbonate may also be added to these seal coating suspension to improve the barrier property of the membrane.
• the sealed pellets after drying shows about 100% of drug release within about 10 minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution apparatus.
• enteric coating suspension is prepared by dissolving neutralizing agent in water, which is slowly added u nder stirring to aqueous dispersion of methacrylic acid copolymer.
• This aqueous dispersion of methacrylic acid is ready to use dispersion and may contain upto about 3% w/w of surfactants of the total solid content present in the dispersion. Hence the surfactants are present in enteric polymer layer only and in no way comes in contact with omeprazole.
• the plasticizers are selected from the group consisting of polyethylene glycol, triethyl citrate, triacetin, tributyl citrate, castor oil, dibutyl sebacate, tween 80 and is used in the concentration of about 10 - 25 % w/w of the enteric coat polymer and preferably is polyethylene glycol.
• the neutralizing agent is selected from the group consisting of sodium, potassium, calcium, magnesium, ammonium hydroxide and their mixtures and preferably is sodium hydroxide and is used in the concentration of about 1 - 2 % w/w of enteric coat polymer. Any other agent that is capable of neutralizing the acidic group of methacrylic acid copolymer may also be used.
• the antitack agent is selected from the group consisting of talc, colloidal silicon dioxide, glyceryl monostearate, glyceryl behenate and their mixtures used in the concentration level of about 10 - 30 % w/w of the polymer for enteric coating.
• the preferable choice is talc with or without colloidal silicon dioxide.
• the solid content of the final enteric coating suspension is in the range of about 15 - 25% w/w.
• the amount of enteric polymer guarantees gastric resistance and allows the dissolution of omeprazole in proximal part of the small intestine.
• the final enteric-coated product is sieved through appropriate mesh and is capable of being encapsulated in hard gelatin capsules from size 5 to size 0.
• the entire manufacturing process is aqueous and it results in spherical, glossy pellets containing negligible amount of twins or triplet.
• the benzimidazole content in the final enteric-coated pellets is about upto 40% w/w.
• the yield of the final product is about in the range of 95 - 100% and usually above 98% w/w.
• the process involving all the stages that is treated non-pariel seed stage, drug pellet stage, sealed pellets stage and enteric- coated pellets stage are carried out continuously in a single equipment fluid bed processor.
• the process is a batch process, but all the stages that is treated non-pariel seed stage, drug pellet stage, sealed pellets stage and enteric-coated pellets stage are carried out in a single equipment fluid bed processor, where the representative sample a re sampled at the end of each stages that is drug pellet stage, sealed pellets stage and enteric-coated pellets stage for analysis.
• Other equipments such as coating pan, tangential spray coater may also be used for manufacturing enteric-coated pellets containing benzimidazole using the above process.
• Enteric-coated pellets containing omeprazole involves following manufacturing stages, which are as follows. Stage I: Preparation of treated non-pariel seeds
• HPMC Hydroxypropylmethylcellulose
• Magnesium carbonate is added to this solution to obtain a fine suspension, which is filtered through a ppropriate m esh. This suspension is sprayed on non-pariel seeds in fluid bed bottom spray processor to obtain treated non - pariel seeds, which are used for further process.
• Hydroxypropylmethylcellulose and magnesium carbonate are used in the ratio of 1 :0.5 to 0.5:1 and are used in the concentration level of 1 - 4% w/w of the non-pariel seeds.
• Sodium hydroxide is dissolved in water followed by cooling to room temperature.
• Omeprazole is added to this solution. Separately disperse and / or dissolve hydroxypropylmethylcellulose E15 in water.
• Omeprazole solution is mixed with hydroxypropylmethylcellulose solution.
• Talc is added to above solution and the resulting suspension is filtered through appropriate mesh.
• the above suspension is sprayed on treated non-pariel seeds in fluid bed bottom spray processor to obtain drug pellets, which are dried in the same equipment to moisture content of less than 5% w/w and preferably less than 3% w/w.
• the drug pellets after drying shows about 100% of drug release within about 10 minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution apparatus.
• Seal coating suspension is prepared by dispersing and / or dissolving hydroxypropylmethylcellulose E5 in water. Talc is added to above solution. The resulting suspension is filtered through appropriate mesh and is sprayed on drug pellets in fluid bed processor to form sealed pellets. These sealed pellets are dried to moisture content of less than 5% w/w and preferably less than 3% w/w. The sealed pellets after drying shows about 100% of drug release within about 10 minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution apparatus. Stage IV: Enteric Coated Pellets
• Enteric coating suspension is prepared by dissolving sodium hydroxide in water, which is slowly added under stirring to aqueous dispersion of methacrylic acid copolymer type
• the process of the invention results in the production of enteric-coated pellets containing omeprazole that does not require micronisation of omeprazole or any additional excipients like disintegrating agents, fillers or surfactant in contact with omeprazole for improving the dissolution of omeprazole.
• enteric-coated pellets containing omeprazole thus obtained is tested in-vitro for acid resistance in 0.1 N HCI after 2 hours and buffer dissolution in pH 6.8 after 45 which is described below.
• the acceptance criteria for these pellets are laid down in the specification below.
• the pellets may receive an additional coat of an enteric layer if it does not comply with the specification for acid degradation as specified below.
• enteric-coated pellets containing omeprazole are filled in capsule of varying sizes that is from size 5 to size 0 depending on the final concentration of omeprazole in enteric-coated pellets.
• the p rocess for t he m anufacture of enteric-coated p ellets containing Lansoprazole is same as described a bove except that Lansoprazole is dissolved in sodium hydroxide solution in water containing small quantity of isopropyl alcohol. In-vitro dissolution studies of these pellets are carried out as described below. The acceptance criteria for these pellets are laid down in the specification below. The pellets may receive an additional coat of an enteric layer if it does not comply with the specification for acid degradation as specified below.
• pellets which meets the requirements of the above mentioned specification are filled in capsule of different sizes containing unit dose of benzimidazole.
• the pellets containing upto about 40% w/w of omeprazole are capable of being filled in size 5 capsule for the dose of upto about 40mg of omeprazole.
• the enteric-coated pellets containing about 30% w/w of lansoprazole are capable of being filled in size 5 capsule for the dose of upto about 30 mg of lansoprazole.
• the enteric-coated pellets containing about 20 mg omeprazole prepared as described in example above were encapsulated in size 5 hard gelatin capsules and subjected to accelerated stability condition at 40° C/75% RH and 25°C/60 % RH.
• the stability results are as follows.
• enteric-coated pellets containing omeprazole of the present invention are stable atleast for a period 2 years.

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• 2003
  • 2003-08-04 WO PCT/IB2003/003514 patent/WO2004016242A2/en not_active Ceased
  • 2003-08-04 AU AU2003250468A patent/AU2003250468A1/en not_active Abandoned
  • 2003-08-04 EP EP03787961A patent/EP1530460A2/de not_active Withdrawn
  • 2003-08-04 CA CA002496044A patent/CA2496044A1/en not_active Abandoned

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