WO2010122583A2

WO2010122583A2 - Oral pharmaceutical compositions of acid labile substances

Info

Publication number: WO2010122583A2
Application number: PCT/IN2010/000261
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi; Atul A. Kelkar
Original assignee: Rubicon Research Private Limited
Priority date: 2009-04-24
Filing date: 2010-04-26
Publication date: 2010-10-28
Also published as: WO2010122583A3

Abstract

The present invention relates to oral pharmaceutical compositions of acid labile substances, particularly proton pump inhibitors. These pharmaceutical compositions comprise one or more active units with each active unit comprising a core of a proton pump inhibitor, an intermediate layer of at least one lipophilic substance and an enteric layer. The invention also relates to a method for preparing one or more active units wherein the intermediate layer of lipophilic substances is applied to the core of a proton pump inhibitor in an aqueous emulsified form.

Description

ORAL PHARMACEUTICAL COMPOSITIONS OF ACID LABILE SUBSTANCES

Field of the Invention

The present invention relates to oral pharmaceutical compositions of acid labile substances, particularly proton pump inhibitors. These pharmaceutical compositions comprise one or more active units with each unit comprising a core of a proton pump inhibitor, an intermediate layer of at least one lipophilic substance and an enteric layer. The present invention also relates to providing oral pharmaceutical compositions of acid labile substances in the form of orally disintegrating tablets, swallow tablets, bite-dispersion tablets, capsules, granules, dispersible tablets, dry suspensions or the like. Furthermore, the present invention also provides a method for preparing one or more active units wherein the intermediate layer of lipophilic substances is applied to the core of a proton pump inhibitor in an aqueous emulsified form by a standard coating process. The invention also relates to a method of treatment or prevention of gastric acid related conditions using the compositions of the present invention.

Background of the Invention

Chemical substances that become unstable and/or are inactivated by an acid (i.e. labile in an acid medium) are referred to herein as "acid-labile substances". Proton pump inhibitors, one of the key therapeutic classes belong to the family of acid labile substances. These proton pump inhibitors are known to block the hydrogen/potassium adenosine triphosphatase enzyme system (the H7K⁺ ATPase, or more commonly gastric proton pump) of the gastric parietal cell. This gastric proton pump H⁺/K⁺- ATPase is present in the cytoplasmic membranes of the resting parietal cell. On activation, the pump is translocated to the canalicular membrane, where it pumps out H⁺ ions into the canalicular space in exchange for K⁺ ions. This gastric acid secretion by the parietal cell is controlled through food-stimulated and neuroendocrine pathways involving the activity of gastrin, histamine, pituitary adenylate cyclase-activating peptide and acetylcholine. The excessive secretion of gastric acid must be controlled as it can lead to gastritis, gastric ulcers or peptic ulcer and many other diseases and disorders. There are several potential ways in which gastric acid secretion can be controlled and one ideal way is the physiological control of gastric acid secretion by targeting the final effector in the secretion pathway - the gastric H+/K+- ATPase, using the proton pump inhibitors. Structurally, a vast majority of proton pump inhibitors are substituted benzimidazoles that contain a sulfinyl group bridging substituted benzimidazole and pyridine rings, for example, omeprazole, lansoprazole, pantoprazole, leminoprazole, pariprazole, rabeprazole, esomeprazole, or other benzimidazole derivatives. Once these compounds reach the parietal cells and diffuse into the secretory canaliculi, they become protonated and thereby trapped. The protonated compounds then rearrange to form a sulfenic acid and then a sulfenamide. The sulfenamide, in turn, is understood to interact covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H⁺, K⁺-ATPase. Inhibition occurs when two molecules of the inhibitor are bound per molecule of the enzyme. The specificity of these proton pump inhibitors arises from the selective distribution of the (H⁺, K⁺)-ATPase, the acid-catalyzed rearrangement of the compounds to generate the active inhibitor, and the trapping of the protonated compound and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. Also included in the class of proton pump inhibitors are the newer imidazopyridine derivatives such as tenatoprazole and others, as well as their salts, enantiomers or polymorphic forms. In addition to these irreversible proton pump inhibitors, this class of proton pump inhibitors, also includes the reversible proton pump inhibitors such as AZ0865, CS526, revaprazan, AG-2000, AU-461, BY112, soraprazan and the like.

These proton pump inhibitors are used for the prevention and treatment of acid-related conditions such as, ulcers, gastroesophageal reflux disease (GERD), gastritis, duodenitis and Zollinger-Ellison syndrome. They are also used in combination with antibiotics for eradicating Helicobacter pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g., Non Ulcer Dyspepsia, symptomatic gastro-esophageal reflux disease, gastrinomas and for patients on NSAID therapy. These proton pump inhibitors may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively, to prevent acid aspiration of gastric acid, and to prevent and treat stress ulceration. They may also be useful for prevention and treatment of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, laryngitis, Barret's syndrome, sleep apnea, sleep disturbance, and psoriasis. Proton pump inhibitors are, however susceptible to degradation/transformation in acidic and neutral media. This degradation is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The stability of these active substances is also affected by moisture, heat, organic solvent content and, to some degree, by light. For example, the half-life of omeprazole in aqueous solutions at pH-values less than four is shorter than ten minutes. Also at neutral pH-values, the degradation reaction proceeds rapidly, e.g., at pH=7 the half-life of omeprazole is about 14 hours, while at higher pH-values the stability in solution is much better. The stability profile is similar in solid phase.

Due to the chemical properties of the proton pump inhibitors, it is obvious that an oral solid dosage form comprising these actives must be protected from contact with the acidic gastric juice and must reach the proximal part of the gastrointestinal canal where pH is near neutral and where rapid absorption can occur without degradation. A pharmaceutical oral dosage form of proton pump inhibitor can be protected from contact with acidic gastric juice by an enteric coating layer.The enteric coating of the oral pharmaceutical formulation, however, presents its own problems as enteric polymers have acidic moiety, which can cause the decomposition of the acid-labile compound like a proton pump inhibitor during preparation and storage of formulation, thus leading to the reduced pharmacologic action. Various attempts have been made by researchers to provide intermediate layers or subcoats between the active core and the enteric coating, in order to physically separate the two incompatible layers and avoid stability issues arising during manufacturing as well as during storage.

U.S. Patent No. 4,786,505 discloses an oral pharmaceutical preparation comprising (a) a core region that has the active together with an alkaline reacting compound and/or as alkaline salts; (b) an inert subcoating which is soluble or rapidly disintegrating in water disposed on core region with subcoating comprising one or more layers of materials selected from among tablet excipients and polymeric film-forming compounds; and (c) an outer enteric coating layer. U.S. Patent Publication 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. U.S. Patent

No. 6,013,281 discloses in situ formation of separating layer as water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer by a reaction between the enteric coating polymer(s) and the alkaline reacting compound(s) in the core material during the enteric coating process.

PCT Publication 03/077829 discloses a process for preparation of a pharmaceutical composition for oral use comprising steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with the alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials and optionally water insoluble particles c) second coat, termed seal coat, comprising of a mixture of water insoluble and water permeable polymers like hydroxypropylmethyl cellulose, cellulose acetate phthalate, and ethylcellulose 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 layer. Coating materials for the subcoat are polymers that are water-soluble or swellable and coating material for the seal coat is selected from water insoluble but water permeable coating agents. Subcoating and seal coating is carried out using organic solvents which are environmentally unfriendly and hazardous. Further, the water-soluble, permeable or swellable nature of the polymers utilized for the subcoat or seal coat can lead to altered stability and bioavailability of the proton pump inhibitor, especially when used together with enteric polymers that are even slightly permeable to gastric fluids.

PCT Publication 06/085335 highlights a pharmaceutical composition for oral use comprising: a) a core comprising an effective amount of acid-labile pharmaceutically active substance and an organic stabilizing agent b) an intermediate layer comprising of a water insoluble polymer and an organic stabilizer c) an outer enteric coating layer. The water insoluble polymer is ethylcellulose, polyvinyl acetate, Eudragit RS, Eudragit RL or mixtures thereof. These water insoluble polymers of the intermediate layer, exhibiting either swelling or permeable properties, can lead to reduction in the stability of the drug and the dosage form.

U.S. Patent No. 5,385,739 discloses stable compositions of microgranules of gastro- protected omeprazole as well as their preparation. Particularly disclosed is a microgranule formulation of omeprazole comprising a neutral core consisting of sugar and starch covered with an active layer constituted by omeprazole diluted in mannitol in substantially equal amounts, and an intermediate layer comprising mannitol; an outer layer formed from an enteric coating being optionally present. Supplementary protection of omeprazole applied to neutral grains is obtained by means of a second protective layer consisting of mannitol and a binder solution (high viscosity hydroxypropyl methylcellulose) in order to definitively isolate the core onto which the omeprazole is applied from the outer coating layer that is designed to ensure gastro-protection of the active cores.

Researchers have thus employed polymeric excipients for preparing the subcoat between the inner core or the active layer and the enteric coat. The use of such polymers for the subcoat layer has drawbacks associated with either their swelling, dissolution or water permeability which in turn can have adverse effects on the performance of the dosage form in vivo and can affect the bioavailability of the active agent. These polymeric subcoats or intermediate layers in many instances cannot even sufficiently stabilize an acid-unstable compound during storage. Also, use of hydrophilic substances like mannitol for the subcoat does not substantially enhance the stability of formulations containing proton pump inhibitors as it does not have film forming property. Further, subcoatings have also been carried out using organic solvents that are environmentally unfriendly and may leave undesirable components and/or impurities in the medicament compositions. Such solvents may also pose health and safety concerns for patients consuming the medication as well as for plant personnel producing such medicaments. Employing, organic solvent based coatings also require special expensive fireproof equipments. Thus there exists a need to provide formulations of acid labile substances, such as proton pump inhibitors, that overcome the drawbacks associated with the use of water-soluble, swellable or permeable polymeric intermediate layers for protection of proton pump inhibitors. Further, there exists a need to provide stable compositions of these actives wherein hazardous organic solvents have not been employed for application of the intermediate layers.

Attempts have been made to utilize non-polymeric hydrophobic substances in the subcoat layer to obtain stable dosage forms of proton pump inhibitors. PCT Publication Number 06/111853 discloses 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. This disclosure is based on utilization of at least two subcoats; with one of the subcoat based on utilization of rapidly dissolving or disintegrating water soluble material, while the other based on use of hydrophobic excipient. Further, the coating using hydrophobic substances like stearic acid is done herein by employing organic solvents that are environmentally unfriendly and hazardous to health. U.S. Publication 2001/0053387 discloses a pharmaceutical composition which is a solid pellet comprising an inert core, a benzimidazole in or on the core, a moisture resistant coating around the core, the moisture resistant coating comprising at least one hydrophobic material, and an enteric coating around the moisture resistant coating. The hydrophobic material for the moisture resistant coating is selected from the group consisting of a polyalkylsiloxane, castor oil, mineral oil, isopropyl myristate, stearic acid and cetyl alcohol, the preferred being polydimethylsiloxane, a silicon-based organic polymer. This though used for forming a moisture resistant coating does not exhibit good, uniform film forming property.

Further, researchers have also attempted to introduce hydrophobic substances along with the proton pump inhibitor to develop oral pharmaceutical formulations.

U.S. Patent No. 6,391 ,342 discloses an oral formulation of proton pump inhibitor comprising granules having a substantially inert core coated with i) an inner coating layer comprising the benzimidazole, a disintegrant and a surfactant in a matrix of a melt coating substance essentially consisting of one or more esters of glycerol and fatty acids, ii) an outer coating layer being an enteric coating, and iii) an intermediate coating layer separating the enteric coating layer from the inner coating layer comprising hydroxypropyl methylcellulose. U.S. Patent No. 7,147,869 highlights a rapidly disintegrating tablet for oral administration of an acid-labile active ingredient comprising a plurality of individual active ingredient units together with one or more pharmaceutical excipients. The acid-labile active ingredient is present in the individual active ingredient units in a matrix composed of a mixture comprising at least solid paraffin and one or more substances from the group of fatty alcohol, triglyceride and fatty acid ester. The active ingredient units are prepared by spray prilling wherein the hydrophobic excipients are liquefied to give a clear melt in which the proton pump inhibitor is dispersed or dissolved and the resulting solution or dispersion is prilled in a suitable apparatus. That proton pump inhibitors are heat sensitive in nature, melt coating or spray pilling exposes the active to high temperatures which can be deleterious to the stability of the drug.

Though attempts have been made to utilize lipophilic materials either in the intermediate layer or together with the active for preparing formulations of proton pump inhibitors, their incorporation involves either environmentally unfriendly organic solvents for coating purposes or use of higher processing temperatures that may have an impact on stability of the active.

There exists a need, therefore, for development of oral pharmaceutical formulations of acid labile substances, such as proton pump inhibitors, that would overcome not only the drawbacks associated with the use of water soluble, swellable or permeable polymeric intermediate layers or subcoats along with even slightly permeable enteric coatings, but also those associated with the use of lipophilic excipients such as organic coating solvents or higher temperatures impacting the stability of the active. Thus formulations of proton pump inhibitors that are stable during storage and which provide desired in vitro release and bioavailability, without the use of high process temperatures or use of organic solvents for coating of the intermediate layer, are desired.

After rigorous experimentation, it was surprisingly found that coating of proton pump inhibitors using intermediate layer of lipophilic substances that are non polymeric, non swelling and substantially insoluble in gastric fluids not only achieves the desired stability for the active agents, but also provides desired in vitro release profile and bioavailability. The intermediate layer of lipophilic substances can be applied to the core of a proton pump inhibitor in an aqueous emulsified form by standard coating process. Such processes neither expose the active to increased processing temperatures nor require use of expensive, specialized equipments. These active units can further be enteric coated and incorporated into oral pharmaceutical compositions.

Summary of the Invention

The present invention relates to oral pharmaceutical compositions for administration of acid labile substances, particularly proton pump inhibitors. These pharmaceutical compositions comprise one or more active units, with each active unit comprising a core of a proton pump inhibitor, an intermediate layer of at least one lipophilic substance and an enteric layer. The present invention also relates to providing oral pharmaceutical compositions of acid labile substances in the form of orally disintegrating tablets, swallow tablets, bite-dispersion tablets, capsules, granules, dispersible tablets, dry suspensions or the like. Furthermore, the present invention provides a method for the preparation of one or more active units wherein the intermediate layer of lipophilic substances is applied to the core of proton pump inhibitor in an aqueous emulsified form.

Detailed Description of the Invention

Inhibition of the gastric proton pump is gaining acceptance as the treatment of choice for severe gastro esophageal reflux disease, and for treatment of duodenal and gastric ulceration. The stability of proton pump inhibitors in aqueous media is a function of pH with an increased rate of degradation as the pH decreases. A conventional way to solve this problem is to coat a dosage form containing such an active with an enteric coating. These enteric coatings are substances or polymers with a common feature of being practically insoluble in acid media, while they are soluble in neutral to alkaline media. However, these enteric polymers have acidic moieties that can cause decomposition of an acid-labile compound, like a proton pump inhibitor, during manufacturing and storage of the formulation. Further, various strategies, such as use of an alkaline substance, for example, a sodium, potassium, calcium or aluminium salt of an organic acid such as phosphoric acid, carbonic acid or citric acid, or use of an antacid substance, for example, an aluminium, magnesium or calcium oxide or hydroxide, or use of an organic buffer substance, such as a basic amino acid or one of their salts, in particular trihydroxymethylaminomethane, that may be employed to stabilize the active agent in the core and provide an alkaline microenvironment around the active, may, in fact, create a problem. This may be the case as the enteric coating may partially or even completely dissolve from inside because of this alkaline interior, allowing the free carboxyl groups of this enteric coating to promote degradation of the active ingredient and/or failure of enteric function. It is, therefore, further necessary to provide a sealing intermediate layer (subcoating) between the enteric coating and the active core.

The nature of the intermediate layer, as discussed in the background section, affects the stability and shelf-life of the active, especially when used with enteric layers that are slightly permeable to gastric fluids; with the water-swellable, water-soluble or water-permeable polymeric intermediate layers or coats, not providing adequate protection as well as desired drug release profile with acid labile substances such as proton pump inhibitors. Further, even when lipophilic agents are employed in intermediate layers, environmentally unfriendly organic coating procedures are employed, which may pose health and safety hazards. In other cases when lipophilic agents are employed for preparing proton pump inhibitor formulations, the preparation methods involve exposure of the active to high temperatures, thereby in fact destabilizing the active than preparing stabilized formulations of the same.

The present invention provides pharmaceutical formulations comprising one or more active units of acid labile compounds, particularly proton pump inhibitors wherein the active agent is stable both during manufacturing and storage. The active units are manufactured using ecofriendly and cost effective processes without compromising on in vitro release profile or bioavailability of the active agent. The present inventors have surprisingly found that using lipophilic substances in the intermediate layer or subcoat between the active core and the enteric layer in the active units, overcomes drawbacks of the prior art. Further, the application of an intermediate layer of lipophilic substances to the core containing a proton pump inhibitor in an aqueous emulsified form by standard coating process avoids the use of organic solvents, thereby preventing the harmful environmental and health effects associated with their use. Application of the intermediate layer of lipophilic substances in such a manner also prevents exposure of the active core to high processing temperatures otherwise associated with the use of lipophilic coating agents. The present invention provides oral pharmaceutical compositions for administration of acid labile compounds comprising one or more active units, wherein each active unit comprises a core of at least one acid labile compound, an intermediate layer of at least one lipophilic substance and an enteric layer. In one embodiment of the present invention, the acid-labile compound is a proton pump inhibitor. The various components of the active units have been discussed in further detail below.

Pharmaceutically active agent

Formulations of the present invention comprise at least one pharmaceutically acceptable acid labile compound. In one embodiment the formulations of the present invention comprise at least one acid labile proton pump inhibitor. The term "proton pump inhibitor", as employed herein refers to any compound that reversibly or irreversibly blocks gastric acid secretion by inhibiting the H ⁺ K ⁺ - ATPase enzyme system or the proton pump at the secretory surface of the gastric parietal cell and may be in the form of free base, salt, ester, hydrate, polymorph, amorphous modification, co-crystal, amide, enantiomer, isomer, tautomer, racemic mixture, prodrug, or any other pharmacologically suitable derivative or metabolite that is therapeutically active or undergoes conversion within or outside of the body to a therapeutically active form.

Irreversible proton pump inhibitors for use in the present invention non-exclusively include substituted benzimidazoles and imidazopyridine derivatives including, but not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, dontoprazole, habeprazole, ransoprazole, pariprazole, disulprazole, esomeprazole or combinations thereof or their pharmaceutically acceptable salts, esters, hydrates, isomers, enantiomers, tautomers, racemic mixtures, prodrugs, polymorphs, amorphous modifications, co-crystals, metabolites or derivatives thereof.

Reversible proton pump inhibitors as per the present invention include, but are not limited to, pumaprazole, AZ0865, CS526, revaprazan, AG-2000, AU-461, BY112, soraprazan (BY359), BY841 , BY067, BY574, BY841 , CP-113411 , DBM-819, KR-60436, SKF-96067, SKF- 96356, SKF-97574, T-330, T-776, WY-27198, YH-1885, YH-1238, fpl-65372-XX, YJA-20379-8, YM- 19020, SCH-28080, SCH-32651, AZD-0865, AR-H047108, H-335/25, HN-11203, SK&F- 95601, NC-1300 and NC-1300-B, N-2220, Hoe-731 (Saviprazole), IY-81149 (llaprazole); H- 405/02 and R-105266, TY-11345 or nepaprazole sodium, TU-199, and 2, 3-dimethyl-8-(2- ethyl-6-methylbenzylamino)-imidazo (1 ,2-a) pyridine-6-carboxamide or combinations thereof or their pharmaceutically acceptable salts, esters, hydrates, isomers, enantiomers, tautomers, racemic mixtures, prodrugs, polymorphs, amorphous modifications, co-crystals, metabolites or derivatives thereof.

"Pharmaceutically acceptable salts" or "salts" of proton pump inhibitors include, but are not limited to, a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or esomeprazole magnesium trihydrate, omeprazole magnesium (U.S. Patent No. 5,900,424), a calcium salt form, or a potassium salt form such as the potassium salt of esomeprazole (U.S. Patent No. 6,511,996), salt hydrate forms including, but not limited to, sodium hydrate salt forms, for example, tenatoprazole sodium hydrate or omeprazole sodium hydrate. Other salts of esomeprazole are described in U.S. Patent Nos. 4,738,974, and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Patent Nos. 4,758,579 and 4,628,098, respectively. The foregoing list of suitable salts of proton pump inhibitors is meant to be illustrative and not exhaustive as a person of ordinary skill in the art would recognize that other pharmaceutically acceptable salts of a proton pump inhibitor could be created and employed for the purpose of the present invention.

A pharmaceutically effective amount of a proton pump inhibitor is employed in the formulations of the present invention. The term "effective amount" refers to an amount effective to achieve the desired therapeutic, preventive and/or beneficial effect. Therapeutic, preventive or beneficial effect may be desired in various conditions such as gastric ulcers, gastroesophageal reflux disease (GERD), gastritis, duodenitis, Zollinger-Ellison syndrome, non ulcer dyspepsia. Gastrinomas, acute upper gastrointestinal bleeding, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, laryngitis, Barret's syndrome, sleep apnea, sleep disturbance, psoriasis or Helicobacter pylori infection. The proton pump inhibitors are present in the compositions of the present invention in an amount from about 0.1% w/w to about 75 % w/w. In another embodiment, the proton pump inhibitors are present in the compositions of the present invention in an amount from about 0.1% w/w to about 50% w/w. The dose used may vary depending on the proton pump inhibitor employed and the therapeutic or beneficial effect desired. The proton pump inhibitors of the present invention include, but are not limited to, esomeprazole, esomeprazole magnesium trihydrate, lansoprazole, rabeprazole, pantoprazole or pantoprazole sodium sesquihydrate, or any combinations thereof.

The pharmaceutical composition of the present invention comprising one or more active units, with each unit comprising a core of a proton pump inhibitor, an intermediate layer of at least one lipophilic substance and an enteric layer is in the form of a multiparticulate or monolithic dosage form. In one embodiment the pharmaceutical composition of the present invention is in the form of a multiparticulate delivery system comprising a multitude of active units having an active core, intermediate layer of lipophilic substances and an enteric layer. In another embodiment the pharmaceutical composition of the present invention is in the form of a monolithic dosage form comprising one active unit having an active core, intermediate layer of lipophilic substances and an enteric layer. In one embodiment the pharmaceutical composition of the present invention comprises an active core, intermediate layer of lipophilic substances and an enteric layer.

Active core The active core of one or more active units comprising proton pump inhibitor may be prepared according to various embodiments of the present invention. In one embodiment, the active core comprises a pharmaceutically active agent loaded on an inert core. In another embodiment, the inert core is made of inert non-pareil sugar spheres, microcrystalline cellulose (MCC) spheres, glass beads or coarse grade silicon dioxide particles. In another embodiment, the coating layer of the active on the inert core comprises in addition to the proton pump inhibitor, a pharmaceutically acceptable stabilizer. The term stabilizer refers to a pharmaceutically acceptable alkaline or basic substance. Such alkaline substances or stabilizers include, but are not limited to, weak inorganic or organic acids, antacids, organic amines, basic amino acids, organic buffers, N-amino sugars, inorganic basic salts, or combinations thereof. Suitable weak inorganic or organic acids include, but are not limited to, sodium, calcium, potassium, magnesium and aluminium salts of citric acid, tartaric acid, phosphoric acid, carbonic acid or the like or combinations thereof. Suitable antacids include, but are not limited to, aluminium, calcium and magnesium hydroxides, magnesium oxide, aluminium hydroxide/sodium bicarbonate coprecipitate or the like or combinations thereof. Organic amines such as, but not limited to, ethylamine, dicyclohexylamine, triethanolamine or the like or combinations thereof can be employed. Suitable basic amino acids include, but are not limited to, lysine, hydroxylysine, arginine, histidine, tryptophane or the like or combinations thereof. Alkaline ammonium salts or organic buffering compounds such as, but not limited to, tri(hydroxymethyl)aminomethane (i.e., Tris-buffer) or the like or combinations thereof can be employed. Suitable N-amino sugars include, but are not limited to, N-methyl-D- glucamine (i.e., Meglumine), N-ethyl-D- glucamine (i.e., Eglumine) or the like or combinations thereof. Suitable inorganic basic salts such as, but not limited to, magnesium carbonate, magnesium hydroxide, magnesium silicate aluminate, magnesium oxide, magnesium silicate, calcium carbonate, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or the like or combinations thereof can be employed. The term stabilizer also includes non-alkaline compounds such as sugar alcohols including, but not limited to, mannitol; or TiO2 and the like known to enhance the stability of proton pump inhibitors. The coating of the active on inert core or the active core may contain a proton pump inhibitor or a combination of proton pump inhibitors.

Further, coating is performed by loading on an inert core an organic, aqueous or hydroalcoholic solution or dispersion comprising a proton pump inhibitor, a pharmaceutically acceptable stabilizer and optionally a binder and/or a plasticizer or other pharmaceutically acceptable excipients such as anti-tacking agents. The binder employed is selected from, but not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose or polyvinyl alcohol or combinations thereof. The plasticizer employed for the purpose of the present invention includes, but is not limited to, triethyl citrate, acetyl triethyl citrate, propylene glycol, polyethylene glycol or a combination thereof. The anti-tacking agent is selected from, but not limited to, talc, or glyceryl monostearate or combinations thereof.

In another embodiment, a proton pump inhibitor and a pharmaceutically acceptable stabilizer, formulated into a core, is employed rather than loading the active on an inert core. Such a core of proton pump inhibitor and pharmaceutically acceptable stabilizer can be prepared by various processes known to a person skilled in the art including, but not limited to, wet granulation, melt granulation, extrusion spheronization, spray drying, direct compression, pelletization, dry granulation or roll compaction. Optionally, such a core may also comprise, in addition to the active agent and stabilizer, other pharmaceutically acceptable excipients, such as diluents, binders, disintegrating agents or lubricants known to a person skilled in the art.

According to the present invention, the active core may comprise a proton pump inhibitor either in or on the core. In a further embodiment, a core of proton pump inhibitor comprises, in addition to the active, a stabilizer and/or other pharmaceutically acceptable excipients, ion exchange resins or cyclodextrins.

In another embodiment, the active cores are in the form of, but not limited to, granules, beads, pellets, minitablets, tablets or the like. In yet another embodiment, the active cores are compressed into tablets or minitablets prior to application of the intermediate and enteric layer. In another embodiment, the active core is in the form of a tablet on which the intermediate and enteric coat is applied.

Intermediate layer of lipophilic substances The active core/s of the present invention are further coated with an intermediate layer of at least one lipophilic substance, before applying an enteric coat. This intermediate layer serves as a barrier to moisture and to the permeation of gastric fluids, thereby protecting the active core against degradation. Moreover, the non-swellable nature of this layer does not create any undue pressure on the outer enteric coat, thereby preventing rupture of the coat and failure of enteric functionality. This, in turn, maintains the desired drug release profile and bioavailability. The intermediate layer also prevents the degradative interaction of acidic functionalities of the enteric polymer with the proton pump inhibitor.

The lipophilic substances used in the intermediate layer of the present invention are non polymeric, non swelling and substantially insoluble in gastric fluids. The term "substantially insoluble in gastric fluids" intends to encompass those lipophilic substances that are insoluble or not completely soluble or dispersible in water across pH range of 1-8 commonly encountered in gastrointestinal tract or are only partially soluble or dispersible at, at least a particular pH or are insoluble but dispersible in water across pH range of 1-8 commonly encountered in the gastrointestinal tract. The lipophilic substances that may be incorporated in the intermediate layer include, but are not limited to, fats, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols or esters thereof, or any combinations thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof. Waxes are also monoglycerol esters, diglycerol esters, or triglycerol esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate (COMPRITOL^®), polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, and combinations thereof. Fatty acids include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Long chain monohydric alcohols having not less than 6 carbon atoms and their esters include, but are not limited to, cetyl alcohol, and stearyl alcohol, and mixtures thereof. In one embodiment, the lipophilic substances that may be incorporated in the intermediate layer include, but are not limited to, hydrogenated vegetable oils such as hydrogenated cottonseed oil (LUBRITAB^®), hydrogenated soyabean oil (STEROTEX^® HMNF) or the like, carnauba wax, candelilla wax, spermaceti, beeswax, montan wax, microcrystalline wax, lecithin, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, glyceryl behenate, cetyl alcohol, cetostearyl alcohol, precirol, stearic acid and synthetic waxes e.g. polyethylene and the like, or any combinations thereof.

In one embodiment, this intermediate layer of lipophilic substances is applied to the core of proton pump inhibitor in an aqueous emulsified form by a standard coating process.

U.S. Patent Publication 20080096979 (the '979 publication) which is incorporated herein by reference, describes the process of preparing an aqueous emulsified form of these lipophilic substances. Such a lipophilic coating system comprising a wax or any of the non-limiting examples of lipophilic substances described above, an emulsifying agent and a plasticizer is employed in an embodiment of the present invention as an intermediate layer. The aqueous emulsified coating system disclosed in the '979 publication comprises a) emulsified wax or lipophilic substance wherein its content is up to about 9% by weight and an emulsifying agent at about 0.1 to about 10% by weight, and b) a plasticizer at about 5 to about 40% by weight of the wax. Emulsifying agent herein is selected from, but not limited to, one or more of non ionic emulsifiers, such as mono and diglycerides like glyceryl monooleate (Peceol), medium chain glycerides (capmul), glyceryl ricinoleate, glyceryl laurate, glyceryl caprylate; PEG sorbitan fatty acid esters such as PEG-20 sorbitan monolaurate (Tween 20), PEG 20 sorbitan monostearate (Tween 60), PEG sorbitan monooleate (Tween 80); sorbitan fatty acid esters like sorbitan monolaurate (span 20); sugar ester surfactants like sucrose distearate (sucro ester 7); glyceryl monostearate; polyethylene glycol esters; cellulose derivatives like hydroxypropyl methylcellulose, hydroxypropyl cellulose; or ionic emulsifiers such as sodium caprylate sodium lauryl sulphate, phospholipids, alginate salts. Plasticizer herein is a polymeric selected from, but not limited to, one or more of polyvinyl alcohol, mixture of polyvinyl acetate with povidone (Kollidon^® SR) methylcellulose, ethyl cellulose, sodium carboxy methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyethylene glycol, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate) poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terphthalate), poly (vinyl isobutyl ether), poly (vinyl acetate) poly (vinyl chloride), polyurethane or the like.

The level of intermediate coating of lipophilic substances that is applied for the formulations of the present invention is in the range from about 1% to about 90% by weight of the active cores. In one embodiment, the level of intermediate coating of lipophilic substances is from about 2% to about 80% by weight of the active cores. In another embodiment, the level of intermediate coating of lipophilic substances is from about 5% to about 75% by weight of the active cores.

Optionally, the intermediate layer of lipophilic substances further comprises a stabilizer (as described under active cores) or pharmaceutically acceptable excipients such as anti- tacking agents, disintegrants and the like. Suitable anti-tacking agents include, but are not limited to, talc, glyceryl monostearate, silicon dioxide and metallic stearates such as magnesium stearate, or the like. Suitable disintegrants include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium silicate, or the like or any combinations thereof.

The intermediate layer is applied to the core using standard or conventional coating processes such as, but not limited to, fluidized bed coating, wet granulation or spray drying. The intermediate layer is applied to the core material in any suitable equipment where coating of a core can be achieved. Non-limiting examples of such equipments include, coating pan, fluidized bed processor or the like.

In one embodiment, the active cores coated with the intermediate layer of lipophilic substances may be compressed prior to application of the enteric layer.

Enteric layer

The one or more active cores coated with an intermediate layer are further coated with an enteric layer. The terms "enteric layer" or "enteric coat" have been employed interchangeably for the purpose of the present invention. The enteric layer or coating comprises at least one acid insoluble or acid resistant enteric polymer or substance including, but not limited to, cellulose derivatives such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, ethylhydroxycellulose phthalate; polyvinylacetatephthalate; polyvinylbutyrate acetate; vinyl acetate-maleic anhydride copolymer; styrene-maleic mono-ester copolymer; methacrylate- methacrylic acid-octyl acrylate copolymer; alginate; acrylic copolymer or methacrylic acid copolymer or any combinations thereof. In one embodiment, enteric coating materials are pharmaceutically acceptable methacrylic acid copolymers based on methacrylic acid and methyl methacrylate such as poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S), poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L).

Further, the enteric layer may comprise a plasticizer such as, but not limited to, triethyl citrate, acetyl triethyl citrate, propylene glycol, polyethylene glycol, acetyl tributyl citrate, acetylated monoglycerides, glycerin, triacetin, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate or a combination thereof; an anti- tacking agent such as, but not limited to, talc, or glyceryl monostearate; or a pigment such as, but not limited to, titanium dioxide, iron oxide, or a mixture thereof. The enteric layer may optionally comprise other pharmaceutically acceptable excipients.

The enteric layer may be applied from an aqueous suspension or an organic solvent solution. In one embodiment, the outer enteric layer is layered by an aqueous suspension or solvent solution of an enteric coating agent that does not have any deleterious affect on the properties of the intermediate layer of lipophilic substances. The enteric coatings may be applied onto the active core/s coated with the intermediate layer in any suitable equipment where coating can be achieved, such as, but not limited to, coating pan or a fluidized bed apparatus, or the like.

The enteric coating applied in the formulations of the present invention is in the range of from about 5% to about 200% by weight of the active core. In one embodiment, the enteric coating is about 7.5% to about 150% by weight of the active core. In another embodiment, the enteric coating is about 10% to about 100% by weight of the active core. The amount of enteric coating applied to the active core depends on successful achievement of enteric function. This amount varies depending on the proton pump inhibitor, size of the active cores, desired protection in acidic environment and desired enteric function.

In one embodiment of the present invention, an additional polymeric and/or non-polymeric intermediate layer or seal coat may optionally be present between the intermediate layer of lipophilic substances and the enteric layer. In another embodiment, an additional intermediate layer polymeric and/or non-polymeric in nature may optionally be present between the intermediate layer of lipophilic substances and the active core. In another embodiment a layer of polymeric and/or non-polymeric in nature may optionally be present on the enteric layer. Such a polymeric coating agent includes, but is not limited to, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, ethyl cellulose, polyvinylacetate, copolymers of polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol or combinations thereof. The non-polymeric coating ageYit includes, but is not limited to, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their esters, phospholipids, terpenes or combinations thereof.

The active units of the present invention comprising active cores, intermediate layer of lipophilic substances and enteric layer may be in the form of, for example, granules, beads, pellets, minitablets or the like. In one embodiment size of the active units of the present invention is in the range from about 50 μm to about 4mm, depending on the final dosage, wherein a multitude of these active units need to be incorporated.

The pharmaceutical formulation of the present invention or the active units described herein may be further coated with one or more seal coatings, film coatings, barrier coatings, compression coatings or fast disintegrating coatings. Further, multiple coatings, including multiple enteric coatings, may be applied for desired performance.

The present invention also provides a method of preparing a oral pharmaceutical composition for administration of acid labile compound comprising the steps of: a) preparing an active core comprising acid labile compound and optionally a stabilizer, wherein the acid labile compound is either in or on the core; b) coating the active core of step a) with lipophilic substances to form an intermediate layer coated active core, wherein said lipophilic substances are applied to said active core in an aqueous emulsified form by a standard coating process; and c) coating the intermediate layer coated active core of step b) with an outer enteric layer. In one embodiment the present invention also provides a method of preparing a oral pharmaceutical composition for administration of proton pump inhibitor comprising the steps of: a) preparing an active core comprising proton pump inhibitor and optionally a stabilizer, wherein the acid labile compound is either in or on the core; b) coating the active core of step a) with lipophilic substances to form an intermediate layer coated active core, wherein said lipophilic substances are applied to said active core in an aqueous emulsified form by a standard coating process; and c) coating the intermediate layer coated active core of step b) with an outer enteric layer.

The one or more active units of the present invention may be in the form of, but not limited to, granules, pellets, beads, minitablets, tablets or the like. The present invention provides oral pharmaceutical compositions of acid labile substances in the form of orally disintegrating tablets, swallow tablets, bite-dispersion tablets, capsules, granules, dispersible tablets, dry suspensions or the like. In one embodiment these active units are suitable for incorporation into various oral dosage forms, such as swallow tablets, capsules, dry suspensions/powder for suspension, orally disintegrating tablets, dispersible tablets, bite-dispersion tablets, effervescent tablets, chewable tablets, sprinkle granules, quick melt wafers, lozenges or the like. In yet another embodiment the active unit can be formed in the form of a suitable dosage form such as but not limited to swallow tablets or the like. These oral formulations may contain from about 5% to about 100% of the active unit/s of proton pump inhibitor. The compositions of the present invention may further optionally comprise at least one pharmaceutically acceptable excipient. At least one pharmaceutically acceptable excipient present in the pharmaceutical composition of the present invention depends on the final dosage form.

In one embodiment, active units of proton pump inhibitor are incorporated in an orally disintegrating tablet. Orally disintegrating tablets (ODTs) disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation.

The orally disintegrating tablets comprising active units of a proton pump inhibitor further comprise directly compressible co-processed excipient. PCT Application WO2007052289 describes directly compressible co-processed excipient comprising at least one water soluble excipient and water insoluble inorganic excipient such as calcium silicate. The water soluble excipient may be a carbohydrate. The carbohydrate may be a monosaccharide, disaccharide, oligosaccharide or polysaccharide. Examples of carbohydrates include, but are not limited to, monosaccharides, such as sorbitol, glucose, dextrose, fructose, maltose or xylitol, disaccharides such as sucrose, trehalose, lactose, glucose, galactose or mannitol, and oligosaccharides and polysaccharides such as dextrates and maltodextrins. In one embodiment of the present invention, the water soluble and water insoluble excipients in the directly compressible co-processed excipient are in a ratio of water-soluble excipient to water insoluble excipient of from about 50:1 to about 1 :50. In another embodiment this ratio is from about 30:1 to about 1 :30. In a further embodiment this ratio is from about 20:1 to about 1 :20. The amount of directly compressible co-processed excipient employed in the orally disintegrating tablet compositions comprising active units of proton pump inhibitor is about 5% to about 95 % by weight of the dosage form.

The formulations of the present invention may include, in addition to the active units of proton pump inhibitor and directly compressible co-processed excipient, one or more binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, viscolizers, glidants or lubricants, solubilizers, or stabilizers. The formulations of the present invention include at least one superdisintegrant such as, but not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems. In one embodiment, the disintegrants include crospovidone, calcium silicate and starch. The amount of superdisintegrant employed in the composition is about 2% to about 30 % by weight of the dosage form. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinyl pyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate and the like, or any combinations thereof. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. The tablet compositions of the invention may also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. The formulations of the present invention may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the formulations of the invention. Examples of solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof. Formulations of the present invention may also include stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like. Examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof. Souring agents include, but are not limited to, monosodium fumarate and/or citric acid. Formulations of the present invention may optionally include viscolizers agents such as polyalkylene oxides; polyols; starch and starch-based polymers; chitosan; polysaccharide gums; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, poly acrylic acid, gum acacia, gum tragacanth, xanthan gum, guar gum and polyvinyl alcohol and copolymers and mixtures thereof. Sweetening agents include, but are not limited to, aspartame, stevia extract, glycyrrhiza, saccharin, saccharin sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and one or more flavors, e.g., mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty frutty flavor.magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts.

These orally disintegrating tablets may be prepared by any of the known non-limiting techniques such as freeze-drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or with use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like.

The orally disintegrating tablet formulations based on active units of a proton pump inhibitor dissolve or disintegrate in the oral cavity. In one embodiment, the orally disintegrating tablet formulations of the invention dissolve or disintegrate within about 60 seconds.

In another embodiment of the present invention, active units of a proton pump inhibitor are incorporated in bite-dispersion tablets. Bite-dispersion tablets are meant to be taken without water and disperse easily and quickly after a gentle bite when taken orally enabling the active units of the proton pump inhibitor to be orally administered. These tablets comprise various pharmaceutically acceptable excipients as have been discussed under orally disintegrating tablets in addition to excipients which may be specifically employed for bite- dispersion tablets.

In yet another embodiment, active units of a proton pump inhibitor are incorporated in dispersible tablets. Dispersible tablet refers to a tablet which disperses in aqueous phase, e.g., in water before administration. A water-dispersible tablet, according to the British Pharmacopoeia and European Pharmacopoeia, should meet the requirements of the test for dispersible tablets as regards dispersion time (<3 minutes) and dispersion quality (i.e., to pass through a 710 μm sieve).

The dispersible tablet compositions comprising active units of proton pump inhibitor can further comprise, in addition to pharmaceutically acceptable excipients as disclosed under orally disintegrating tablets, one or more viscolizers and one or more pH-modifiers. Examples of viscolizers which can be used include, but are not limited to, polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, microcrystalline cellulose; gums such as gum arabic alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, karaya, whelan; polyols such as dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; carbopol, starch and starch-based polymers such as pregelatinized starch, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyl lactams); polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; povidone vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, chitosan, and combinations thereof. In one embodiment, viscolizers are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene oxide, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof. The weight percent of the viscolizer in the dosage form is about 2 to about 75 weight percent. In one embodiment, the weight percent of the viscolizer in the dosage form is about 10 to about 70 weight percent. In another embodiment, the weight percent of the viscolizer in the dosage form is about 5 to about 50 weight percent. The viscolizers act to control the sedimentation rate of dispersed active agent, thereby producing homogeneous dispersions when the dispersible tablets are dispersed in water before administration thus ensuring substantially uniform dosing. They rapidly generate viscosity when the dispersible tablets come in contact with water and a homogenous suspension is formed, which can be easily swallowed by children and the elderly, with minimal effect of the release properties of the biologically active ingredient.

Dispersible tablets of the present invention may comprise pH-modifiers, which are substances that maintain the pH of the aqueous dispersion produced upon dispersion of the tablets in water in the range from about 3 to about 5. Such pH-modifiers include, but are not limited to, citric acid, tartaric acid or malic acid or buffers such as sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen phosphate, calcium tartrate, magnesium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, magnesium tartrate, potassium citrate, potassium tartrate, sodium citrate, sodium tartrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate or the like, or any combinations thereof.

In another embodiment the active unit of a proton pump inhibitor is in the form of a swallow tablet. Furthermore, formulations or dosage forms of the present invention may be designed for immediate release, intermediate release, pulsatile release, controlled release, sustained release, modified release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release, in the desired environment of use, such as the neutral to alkaline environment of the gastrointestinal tract. Levels or amounts of coating may be varied to achieve the desired release profile. Optionally, a proton pump inhibitor, same or different than the one present in the active core, may also be present in the intermediate layer or layers.

The terms "tablet" and "tablet formulations" are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation, extrusion or melt granulation. In one embodiment, the process is direct compression which involves compression of active unit-excipient blend after mixing them for a definite time period. The tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal and trapezoidal. In one embodiment, the tablet has a round shape. In another embodiment, the tablet has an oval shape. In yet another embodiment, the tablet is in the form of a parallelogram.

The formulations of the present invention may be used to treat erosive esophagitis (chronic and/or inflammation of the esophagus) or gastroesophageal reflux (heartburn), Zollinger- Ellison syndrome or other acid-related gastric conditions. They may also be used individually or in combination with antibiotics such as clarithromycin and amoxicillin to treat duodenal (intestinal) ulcers caused by the bacteria Helicobacter pylori. The present invention further provides method of treating or preventing gastric acid related conditions by administering to a patient in need thereof a formulation comprising one or more active units, wherein each active unit comprises a core of an acid labile compound, an intermediate layer of lipophilic substances and an enteric layer. In another embodiment the present invention provides method of treating or preventing gastric acid related conditions by administering to a patient in need thereof a formulation comprising one or more active units, wherein each active unit comprises a core of proton pump inhibitor, an intermediate layer of lipophilic substances and an enteric layer. The proton pump inhibitor in the active core is in an amount effective to produce the desired therapeutic or prophylactic effect.

Formulations of the present invention may be adapted to deliver one or more active agents in addition to a proton pump inhibitor. The active agent includes, but is not limited to, domperidone, mosapride, cisapride, galantamine hydrobromide, carrageenan, itopride hydrochloride, mosapride citrate dehydrate, metaxalone, bismuth subcitrate, metronidazole, tetracycline, ranitidine, cimetidine, etidronate, nifedipine, glipizide, misoprostol, vitamin B12, clarithromycin, diphenhydramine, acetaminophen, ibuprofen, aspirin, naproxen, tegaserod, simethicone, colesevelam hydrochloride, ursodeoxycholic acid, colestipol, sevelamer, vitamin D, pentoxifylline or licofelone.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Details of the present invention, including its objects and advantages, are provided in the non-limiting exemplary illustrations below.

EXAMPLES

Example 1) Orally Disintegrating Tablet Formulation of Esomeprazole

Table 1 : Preparation of active cores

Esomeprazole magnesium trihydrate, mannitol, lactose, microcrystalline cellulose and disodium hydrogen phosphate were dry mixed. Hydroxypropyl methyl cellulose and sodium lauryl sulphate were dissolved in purified water to form the granulation solution, which was added to the powder mixture to form wet mass. The mass was extruded and spheronized. The pellets were then dried and sifted.

Table 2: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl mono- & dicaprate in molten wax. Hydroxy propyl methyl cellulose was dissolved in water and this aqueous phase was added to oily phase. Talc was added to the emulsion, homogenized well and cooled to room temperature.

Esomeprazole active cores prepared as per peptization procedure described in Table 1 were then coated with aqueous coating emulsion of lipophilic substance to 20% weight gain using bottom spray assembly.

Table 3: Preparation of coating solution for enteric layer

Esomeprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 50% weight gain using this enteric coating composition.

Table 4: Preparation of orally disintegrating tablets of Esomeprazole

All the ingredients except colloidal silicon dioxide and magnesium stearate were added to the enteric coated active units and blended well. The blend was lubricated and compressed into tablets having following parameters:

Hardness (N) : 50-80

Friability (%) : 0.48

Disintegration time (sec) : 15-25

Disintegration time in oral cavity (sec) : 35-45

The compressed tablets had pleasant taste and mouth feel.

Example 2) Capsule Formulation of Esomeprazole

Table 5: Preparation of active cores

Aqueous dispersion of esomeprazole magnesium trihydrate, hydroxy propyl methyl cellulose and disodium hydrogen phosphate was prepared to which talc was further added. This coating solution was sprayed on 105 mg microcrystalline cellulose beads. Table 6: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl mono- & dicaprate in molten wax. Hydroxy propyl methyl cellulose was dissolved in water and this aqueous phase was added to oily phase. Talc and titanium dioxide was added to the emulsion, homogenized well and cooled to room temperature.

Esomeprazole active cores prepared as per drug layering procedure described in Table 5 were then coated with aqueous coating emulsion of lipophilic substance to 25% weight gain using bottom spray assembly.

Table 7: Preparation of coating solution for enteric layer

Esomeprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 80% weight gain using this enteric coating composition. Table 8: Preparation of capsules of Esomeprazole

Esomeprazole enteric coated granules were blended with microcrystalline cellulose, sodium stearyl fumarate and filled into capsules.

Example 3) Bite-dispersion Tablet Formulation of Esomeprazole

Table 9: Preparation of active cores

Esomeprazole magnesium trihydrate was mixed with microcrystalline cellulose, mannitol, L- arginine and copovidone. The dry blend was then subjected to roll compaction followed by sifting to get active cores. Table 10: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl mono- & dicaprate in molten wax. Aqueous dispersion of ethyl cellulose was added to oily phase. Talc was added to the emulsion, homogenized well and cooled to room temperature to get a coating emulsion.

The active cores of Table 9 were coated to the weight gain of 20 % by using above coating solution.

Table 11 : Preparation of coating solution for enteric layer

Esomeprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 40% weight gain using the enteric coating composition of Table 11.

Table 12: Preparation of bite-dispersion tablets of Esomeprazole

All the ingredients except colloidal silicon dioxide and magnesium stearate were added to the enteric coated active units of Esomeprazole and blended well. The blend was lubricated and compressed into tablets. The tablets had pleasant taste and mouth feel.

Example 4) Dispersible tablet formulation of Esomeprazole

Table 13: Preparation of active cores

Aqueous dispersion of esomeprazole magnesium trihydrate, hydroxy propyl methyl cellulose and magnesium oxide was prepared to which talc was further added. This coating solution was sprayed on 115 mg non-pareil sugar spheres.

Table 14: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl mono- & dicaprate in molten wax. Hydroxy propyl methyl cellulose and triethyl acetate was dissolved in water and this aqueous phase was added to oily phase. Talc was added to the emulsion, homogenized well and cooled to room temperature.

Esomeprazole active cores prepared as per drug layering procedure described in Table 13 were then coated with aqueous emulsion of lipophilic substances to 20% weight gain using bottom spray assembly.

Table 15: Preparation of coating solution for subcoat between intermediate layer of lipophilic substance and enteric layer

Esomeprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 5% weight gain using the coating composition described in Table 15.

Table 16: Preparation of coating solution for enteric layer

Esomeprazole active cores coated with the intermediate layer of lipophilic substance and subcoat were further coated to 30% weight gain using this enteric coating composition.

Table 17: Preparation of dispersible tablets of Esomeprazole

All the ingredients were sifted and blended with enteric coated active units equivalent to 20mg Esomeprazole. The blend was lubricated with magnesium stearate. The mixture was compressed as dispersible tablets. The dispersible tablets had excellent palatability and passed the disintegration and dispersibility tests as per Ph. Eur. (4^th Edition).

Example 5) Swallow tablet formulation of Lansoprazole

Table 18: Preparation of active core

Ingredients mg/tab

Lansoprazole 15

Mannitol, USP 120.3

Lansoprazole was mixed well with mannitol, lactose monohydrate, microcrystalline cellulose, disodium hydrogen phosphate and hydroxypropyl cellulose. Sodium lauryl sulfate dissolved in purified water, was used to granulate the above blend. The granules were then dried and sieved and blended with lubricants and compressed into tablets to get the active core.

Table 19: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared by melting hydrogenated vegetable oil in water bath and adding Tween 80 in molten wax. Hydroxy propyl methyl cellulose was dissolved in water and this aqueous phase was added to oily phase. Talc was added to the mixture, homogenized well and cooled to room temperature. The active core of Table 18 was coated to the weight gain of 20 % by using above coating solution.

Table 20: Preparation of coating solution for enteric layer

Lansoprazole active core coated with the intermediate layer of lipophilic substance was further coated to 20% weight gain using this enteric coating composition.

Example 6) Orally Disintegrating Tablet Formulation of Lansoprazole

Table 21: Preparation of active cores

Lansoprazole, mannitol, lactose, microcrystalline cellulose and disodium hydrogen phosphate were dry mixed. Hydroxypropyl methyl cellulose and sodium lauryl sulphate were dissolved in purified water to form the granulation solution, which was added to the powder mixture to form wet mass. The mass was extruded and spheronized. The pellets were then dried and sifted.

Table 22: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared as mentioned in Example 1 - Table 2.

Lansoprazole active cores prepared as per peptization procedure described in Table 21 were then coated with aqueous emulsion of lipophilic substance to 20% weight gain using bottom spray assembly.

Table 23: Preparation of coating solution for enteric layer

Lansoprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 50% weight gain using this enteric coating composition. Table 24: Preparation of orally disintegrating tablets of Lansoprazole

All the ingredients except colloidal silicon dioxide and magnesium stearate were added to the enteric coated active units and blended well. The blend was lubricated and compressed into tablets. The compressed tablets had pleasant taste and mouth feel.

Example 7) Bite-dispersion tablet formulation of Pantoprazole

Table 25: Preparation of active cores

Aqueous dispersion of pantoprazole sodium sesquihydrate, hydroxy propyl methyl cellulose and magnesium oxide was prepared to which talc was further added. This coating solution was sprayed on 85 mg non-pareil sugar spheres.

Table 26: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Pantoprazole active cores prepared as per drug layering procedure described in Table 13 were then coated with aqueous coating emulsion of lipophilic substance to 25% weight gain using bottom spray assembly.

Table 27: Preparation of coating solution for enteric layer

Pantoprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 50% weight gain using this enteric coating composition.

Table 28: Preparation of bite-dispersion tablets of pantoprazole

All the ingredients except colloidal silicon dioxide and magnesium stearate were added to the enteric coated active units of pantoprazole and blended well. The blend was lubricated and compressed into tablets. The tablets had pleasant taste and mouth feel.

Example 8) Orally Disintegrating Tablet Formulation of Esomeprazole

Table 29: Preparation of active cores

D.M.Water q.s.

Aqueous dispersion of esomeprazole magnesium trihydrate and hydroxy propyl methyl cellulose was prepared to which talc was further added. This coating solution was sprayed on 65 mg microcrystalline cellulose beads.

Table 30: Preparation of aqueous coating system of lipophilic substance for intermediate layer

Coating emulsion was prepared as mentioned in Example 1 - Table 2.

Esomeprazole active cores prepared as described in Table 29 were then coated with aqueous emulsion of lipophilic substance to 20% weight gain using bottom spray assembly.

Table 31 : Preparation of coating solution for enteric layer

Ingredients %w/w

Methacrylic acid copolymer Type A, USP/NF 12.5

Triethyl citrate, USP 6.3

Talc, USP 6.2

0.1 N Ammonia solution 7

D.M Water q.s

Esomeprazole active cores coated with the intermediate layer of lipophilic substance were further coated to 50% weight gain using this enteric coating composition. Table 32: Preparation of orally disintegrating tablets of Esomeprazole

Claims

1) An oral pharmaceutical composition for administration of acid labile compounds comprising one or more active units, wherein each active unit comprises a core of at least one acid labile compound, an intermediate layer of at least one lipophilic substance and an enteric layer.

2) The composition of claim 1 wherein said acid labile compound is a proton pump inhibitor.

3) The composition of claim 2 wherein said proton pump inhibitor is omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, dontoprazole, habeprazole, ransoprazole, pariprazole, disulprazole, esomeprazole, pumaprazole, AZ0865, CS526, revaprazan, AG-2000, AU-461 , BY112, soraprazan

(BY359), BY841 , BY067, BY574, BY841, CP-113411 , DBM-819, KR-60436, SKF- 96067, SKF- 96356, SKF-97574, T-330, T-776, WY-27198, YH-1885, YH-1238, fpl- 65372-XX, YJA-20379-8, YM-19020, SCH-28080, SCH-32651, AZD-0865, AR- H047108, H-335/25, HN-11203, SK&F-95601, NC-1300 and NC-1300-B, N-2220, Hoe-731 (Saviprazole), IY-81149 (llaprazole); H-405/02 and R-105266, TY-11345 or nepaprazole sodium, TU-199, and 2, 3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo (1 ,2-a) pyridine-6-carboxamide, or a pharmaceutically acceptable salt, hydrate, ester, isomer, enantiomer, tautomer, racemic mixture, prodrug, polymorph, amorphous modification, co-crystal, metabolite, or derivative thereof, or a combination thereof.

4) The composition of claim 2 wherein said proton pump inhibitor is esomeprazole magnesium trihydrate.

5) The composition of claim 1 wherein said core further comprises a stabilizer, said stabilizer being a weak inorganic or organic acid, an antacid, an organic amine, a basic amino acid, an organic buffer, an N-amino sugar, an inorganic basic salt, a sugar alcohol, or a combination thereof. 6) The composition of claim 1 wherein said core is in the form of granule, pellet, bead, minitablet, tablet or a combination thereof.

7) The composition of claim 1 wherein said lipophilic substance of the intermediate layer is a fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol, or an ester thereof, or a combination thereof.

8) The composition of claim 1 wherein said lipophilic substance of the intermediate layer is hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, camauba wax, candelilla wax, spermaceti, beeswax, montan wax, microcrystalline wax, lecithin, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, glyceryl behenate, cetyl alcohol, cetostearyl alcohol, precirol, stearic acid or synthetic wax, or a combination thereof.

9) The composition of claim 1 wherein said intermediate layer of at least one lipophilic substance is applied to the core in an aqueous emulsified form.

10) The composition of claim 9 wherein said intermediate layer when applied to the core in an aqueous emulsified form comprises at least one lipophilic substance, at least one emulsifier and at least one plasticizer.

11) The composition of claim 1 wherein said enteric layer comprises an enteric polymer, said enteric polymer being cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, alginate, acrylic copolymer or methacrylic acid copolymers, or a combination thereof. - 12) The composition of claim 1 wherein said composition further comprises at least one pharmaceutically acceptable excipient, said excipient being a directly compressible excipient, binder, disintegrant, superdisintegrant, diluent, salivating agent, surfactant, flavor, sweetener, colorant, souring agent, viscolizer, glidant, lubricant, solubilizer, or s stabilizer.

13) The composition of claim 1 wherein said composition is in the form of a orally disintegrating tablet, effervescent tablet, dispersible tablet, bite-dispersion tablet, sprinkle granules, suspension, powder for suspension, swallow tablet, capsule, quick0 melt wafers, lozenge, or chewing gum.

14) A method of preparing a oral pharmaceutical composition for administration of acid labile compound comprising the steps of: a) preparing an active core comprising acid labile compound and optionally a5 stabilizer, wherein the acid labile compound is either in or on the core; b) coating the active core of step a) with lipophilic substances to form an intermediate layer coated active core, wherein said lipophilic substances are applied to said active core in an aqueous emulsified form by a standard coating process; and c) coating the intermediate layer coated active core of step b) with an outer enteric0 layer.

15) The method of claim 14 wherein said acid labile compound is a proton pump inhibitor. 5 16) A method of treating or preventing gastric acid related conditions comprising administering to a patient in need thereof a composition comprising one or more active units, wherein each active unit comprises a core of at least one acid labile compound, an intermediate layer of lipophilic substances and an enteric layer.

17) The method of claim 16 wherein said acid labile compound is a proton pump inhibitor.