The following specification describes the nature of the invention.

NON-ENTERIC PHARMACEUTICAL COMPOSITIONS COMPRISING A BENZIMIDAZOLE PROTON PUMP INHIBITOR

INTRODUCTION

The present invention relates to non-enteric pharmaceutical compositions comprising a benzimidazole proton pump inhibitor such as omeprazole or its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof process of preparation of such compositions and method of using the same. The present invention provides non-enteric pharmaceutical compositions comprising omeprazole at least one buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.
Omeprazole (Formula I) is a substituted benzimidazole 5-methoxy-2-[(4-methoxy-3 5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzi midazole that inhibits gastric acid secretion with an empirical formula of C17H19N3O3S and a molecular weight of 345.42.

Omeprazole belongs to a class of antisecretory compounds called proton pump inhibitors ("PPIs") that do not exhibit anti-cholinergic or H2 histamine antagonist properties. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H+ K+ - ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.

Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base freely soluble in ethanol and methanol and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media but has acceptable stability under alkaline conditions.

Typically omeprazole lansoprazole and other proton pump inhibitors are formulated in an enteric-coated solid dosage form (as either a delayed-release capsule or tablet) or as an intravenous solution (or as a product for reconstitution) and are prescribed for short-term treatment of active duodenal ulcers gastric ulcers gastro esophageal reflux disease (GERD) severe erosive esophagitis poorly responsive systematic GERD and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These conditions are caused by an imbalance between acid and pepsin production called aggressive factors and mucous bicarbonate and prostaglandin production called defensive factors. These above-listed conditions commonly arise in healthy or critically ill patients and may be accompanied by significant upper gastrointestinal bleeding.

H2 antagonists antacids and sucralfate are commonly administered to minimize the pain and the complications related to these conditions. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects such as mental confusion constipation diarrhea and thrombocytopenia. H2 antagonists such as ranitidine and cimetidine are relatively costly modes of therapy particularly in NPO patients which frequently require the use of automated infusion pumps for continuous intravenous infusion of the drug.

At neutral pH omeprazole lansoprazole and other PPI’s are chemically stable lipid-soluble weak bases that are devoid of inhibitory activity. These neutral weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi where the drugs become protonated and thereby trapped. The protonated agent rearranges to form a sulfenic acid and a sulfenamide. The sulfenamide interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H+ K+ - ATPase (Hardman et al. Goodman & Gilman""s The Pharmacological Basis of Therapeutics p. 907 (9th edition 1996)). Omeprazole and lansoprazole therefore are prodrugs that must be activated to be effective. The specificity of the effects of PPIs is also dependent upon: (a) the selective distribution of H+ K+ - ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. (Hardman et al. 1996).

Omeprazole and lansoprazole are available for oral administration as enteric-coated granules in gelatin capsules. Other proton pump inhibitors such as rabeprazole and pantoprazole are supplied as enteric-coated dosage forms. The enteric dosage forms of the prior art have been employed because they are acid labile; thus it is important that these drugs are not exposed to low pH gastric acid prior to absorption. Although these drugs are stable at alkaline pH they are destroyed rapidly as pH falls (e.g. by gastric acid). Therefore if the micro-encapsulation or the enteric coating is disrupted (e.g. trituration to compound a liquid or chewing the capsule) the dosage forms of the prior art will be exposed to degradation by the gastric acid in the stomach. Proton pump inhibitors such as omeprazole represent an advantageous alternative to the use of H2-antagonists antacids and sucralfate as a treatment for complications related to stress-related mucosal damage. However in their current form (capsules containing enteric-coated granules or enteric-coated tablets) proton pump inhibitors can be difficult or impossible to administer to patients who are either unwilling or unable to swallow tablets or capsules such as critically ill patients children the elderly and patients suffering from dysphagia. Therefore it would be desirable to formulate a proton pump inhibitor into a composition that can be made into a solution or suspension and which can be then administered to a patient thereby providing the benefits of the proton pump inhibitor without the drawbacks of the current enteric-coated solid dosage forms and are thus patient compliant.

Omeprazole the first proton pump inhibitor introduced into use has been formulated in many different embodiments such as in a mixture of polyethylene glycols adeps solidus and sodium lauryl sulfate in a soluble basic amino acid to yield a formulation designed for administration in the rectum as taught by U.S. Pat. No. 5 219 870.

Maximum daily dose of omeprazole is 120 mg. As per BCS class the 120 mg of omeprazole should be soluble in 250mL i.e. 0.48mg/mL. But as per solubility data in water at different pH conditions from 1 to 10 the solubility of omeprazole is less than 0.48mg/mL. Hence omeprazole is considered as a low soluble drug. Omeprazole is a weak base is freely soluble in ethanol and methanol and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media but has acceptable stability under alkaline conditions.

U.S. Pat. No. 4 786 505 (Lovgren et al.) discloses a pharmaceutical preparation containing omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as a core material in a tablet formulation. The use of the alkaline material which can be chosen from such substances as the sodium salt of carbonic acid are used to form a "micro-pH" around each omeprazole particle to protect the omeprazole which is highly sensitive to acid pH. The powder mixture is then formulated into small beads pellets tablets and may be loaded into capsules by conventional pharmaceutical procedures. This formulation of omeprazole does not provide an omeprazole dosage form which can be administered to a patient who may be unable and/or unwilling to swallow capsules tablets or pellets nor does it teach a convenient form which can be used to make an omeprazole or other proton pump inhibitor solution or suspension.

All of the buffered omeprazole solutions described in the references were administered orally and were given to healthy subjects who were able to ingest the oral dose. In all of these studies omeprazole was suspended in a solution including sodium bicarbonate as a pH buffer in order to protect the acid sensitive omeprazole during administration. In all of these studies repeated administration of sodium bicarbonate both prior to during and following omeprazole administration were required in order to prevent acid degradation of the omeprazole given via the oral route of administration.

The buffered omeprazole solutions of the above cited prior art require the ingestion of large amounts of sodium bicarbonate and large volumes of water by repeated administration. This has been considered necessary to prevent acid degradation of the omeprazole. In the above-cited studies basically healthy volunteers rather than sick patients were given dilute buffered omeprazole utilizing pre-dosing and post-dosing with large volumes of sodium bicarbonate.

The administration of large amounts of sodium bicarbonate can produce at least six significant adverse effects which can dramatically reduce the efficacy of the omeprazole in patients and reduce the overall health of the patients. First the fluid volumes of these dosing protocols would not be suitable for sick or critically ill patients who must receive multiple doses of omeprazole. The large volumes would result in the distention of the stomach and increase the likelihood of complications in critically ill patients such as the aspiration of gastric contents.
Second because bicarbonate is usually neutralized in the stomach or is absorbed such that belching results patients with gastroesophageal reflux may exacerbate or worsen their reflux disease as the belching can cause upward movement of stomach acid (Brunton Agents for the Control of Gastric Acidity and Treatment of Peptic Ulcers In Goodman A G et al. The Pharmacologic Basis of Therapeutics (New York p. 907 (1990)).

Third patients with conditions such as hypertension or heart failure are generally advised to avoid the intake of excessive sodium as it can cause aggravation or exacerbation of their hypertensive conditions (Brunton supra). The ingestion of large amounts of sodium bicarbonate is inconsistent with this advice.

Fourth patients with numerous conditions that typically accompany critical illness should avoid the intake of excessive sodium bicarbonate as it can cause metabolic alkalosis that can result in a serious worsening of the patient""s condition.

Fifth excessive antacid (such as sodium bicarbonate) intake can result in drug interactions that produce serious adverse effects. For example by altering gastric and urinary pH antacids can alter rates of drug dissolution and absorption bioavailability and renal elimination (Brunton supra).

Sixth because the buffered omeprazole solutions of the prior art require prolonged administration of sodium bicarbonate it makes it difficult for patients to comply with the regimens of the prior art. For example Pilbrant. et al. disclose an oral omeprazole administration protocol calling for the administration to a subject who has been fasting for at least ten hours a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later the subject ingests a suspension of 60 mg of omeprazole in 50 ml of water that also contains 8 mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of 8 mmoles sodium bicarbonate solution. Ten minutes after the ingestion of the omeprazole dose the subject ingests 50 ml of bicarbonate solution (8 mmoles). This is repeated at twenty minutes and thirty minutes post omeprazole dosing to yield a total of 48 mmoles of sodium bicarbonate and 300 ml of water in total which are ingested by the subject for a single omeprazole dose. Not only does this regimen require the ingestion of excessive amounts of bicarbonate and water which is likely to be dangerous to some patients it is unlikely that even healthy patients would comply with this regimen.

Omeprazole is acid labile and thus rapidly degraded by gastric acid. ZEGERID® capsules and powder for oral suspension are immediate-release formulations that contain sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation.

ZEGERID® (marketed by SANTARUS) is commercially available as both Rx and OTC. This product is available as an immediate-release capsule dosage form for oral administration and as a powder for preparing oral suspension comprising Omeprazole & sodium bicarbonate. ZEGERID® is indicated for use in the treatment of duodenal ulcer gastric ulcer treatment of gastroesophageal reflux disease (GERD) maintenance of healing of erosive esophagitis and reduction of risk of upper gastrointestinal bleeding in critically ill patients (40mg oral suspension only).

ZEGERID® is supplied as immediate-release capsules and unit-dose packets as powder for oral suspension. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium bicarbonate with the following excipients: croscarmellose sodium and sodium stearyl fumarate. ZEGERID® OTC contains croscarmellose sodium FD&C blue No.1 gelatin magnesium stearate pharmaceutical Ink polysorbate 80 and titanium dioxide. Packets of powder for oral suspension contain either 40 mg or 20 mg of omeprazole and 1680 mg of sodium bicarbonate with the following excipients: xylitol sucrose sucralose xanthan gum and flavorings.

According to prescription information available for ZEGERID® capsules/powder for oral suspension is indicated for the short-term treatment of active duodenal ulcer short-term treatment of active benign gastric ulcer treatment of gastroesophageal reflux disease (GERD) maintenance of healing of erosive esophagitis & reduction of risk of upper GI bleeding in critically ill patients. ZEGERID® should be taken on an empty stomach at least one hour before a meal.

Furthermore it is known that when ZEGERID® Oral Suspension and Capsules are administered on an empty stomach 1 hour prior to a meal the absorption of omeprazole is rapid with mean peak plasma levels (% CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%) respectively and time to peak of approximately 30 minutes (range 10-90 min) after a single-dose or repeated-dose administration.

U.S. Patent No. 6 489 346 discloses a solid pharmaceutical composition in a dosage form that is not enteric-coated having active ingredients including a non-enteric coated proton pump inhibitor and at least one buffering agent. The dosage form includes a suspension tablet a chewable tablet an effervescent powder or an effervescent tablet and also provides a method for treating an acid-related gastrointestinal disorder in a subject in need thereof by administering to the subject a solid pharmaceutical composition.

U.S. Patent No. 6 645 988 discloses a pharmaceutical preparations comprising substituted benzimidazole proton pump inhibitors. There is provided a liquid or solid pharmaceutical dosage form that is not enteric coated containing a proton pump inhibitor and a Primary Essential Buffer. When the dosage form is placed in a liquid phase the Primary Essential Buffer maintains the pH of the environment at a value greater than the pKa of the proton pump inhibitor for a time sufficient to substantially avoid acid degradation of the proton pump inhibitor in the environment and also provides a method for treating acid-related gastrointestinal disorders by administering a solid pharmaceutical dosage form; and a kit for the preparation of a liquid oral pharmaceutical composition.
U.S. Patent No. 6 699 885 discloses a method of treating a gastric acid related disorder in a subject in need thereof comprising: providing a solid pharmaceutical composition for oral administration to the subject the composition consisting essentially of: (a) a therapeutically effective amount of at least one acid labile substituted benzimidazole H+ K+ - ATPase proton pump inhibitor; (b) at least one buffering agent in an amount of about 0.1 mEq to about 2.5 mEq per mg proton pump inhibitor; and (c) one or more optional pharmaceutically acceptable excipients; and orally administering the pharmaceutical composition to the subject wherein upon oral administration of the pharmaceutical composition to the subject an initial serum concentration of the proton pump inhibitor greater than about 0.1 mu.g/ml is obtained at any time within about 30 minutes after administration of the composition.

U.S. Patent No. 7 399 772 discloses a method for treating an acid-caused gastrointestinal disorder comprising the step of administering to a subject suffering from said disorder a solid pharmaceutical composition comprising: (a) about 10 mg to about 40 mg of non-enteric coated omeprazole; and (b) sodium bicarbonate in an amount of 0.2 mEq to 5 mEq per 2 mg omeprazole; wherein the composition contains no sucralfate.

U.S. Patent Application Publication No. 2006/0147522 discloses a pharmaceutical formulation in a capsule or caplet oral dosage form comprising: (a) about 5 mg to about 200 mg of at least one acid-labile proton pump inhibitor; (b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; wherein the antacid comprises at least about 400 mg of NaHCO3; and (c) greater than about 2 wt% of disintegrant; wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered; and Tmax of the proton pump inhibitor is obtained within about 60 minutes after administration.

U.S. Patent Application Publication No. 2004/0248942 discloses a harmaceutical composition comprising: (a) an amount of at least one acid labile proton pump inhibitor; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor wherein the composition is administered to a subject prior to a meal and is in an amount effective to maintain gastric pH greater than 4.0 for at least about 1 hour following the meal.

U.S. Patent Application Publication No. 2005/0220870 discloses a method of treating or preventing nocturnal GERD symptoms in a patient in need by administering a pharmaceutical composition comprising: (a) a therapeutically effective amount of at least one acid labile proton pump inhibiting agent; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor.

U.S. Patent Application Publication No. 2008/0275091 discloses a method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof the method comprising: administering to the subject a solid pharmaceutical composition comprising an acid labile proton pump inhibitor and a buffering agent wherein: (a) the proton pump inhibitor is not enteric coated; (b) the proton pump inhibitor is present in the composition in an amount of about 5 mg to about 60 mg; (c) the buffering agent is present in the composition in an amount of about 200 mg to about 3500 mg; and (d) the administration step is performed between about 8:00 pm and about 12:00 am inclusive.

U.S. Patent Application Publication Nos. 2005/0031700 & 2010/0297220 disclose method of making a pharmaceutical formulation for oral administration comprising: a) making a first blend by dry blending at least one acid-labile substituted bicyclic aryl-imidazole proton pump inhibitor in micronized form with at least one bicarbonate salt of a group 1A metal wherein (i) atleast 80% of micronized proton pump inhibitor is less than 40 µm in diameter; and (ii) the dry blending coats at least some of the bicarbonate salt with at least some of the micronized proton pump inhibitor; and b) blending the first blend with atleast one other excipient.

It is evident that omeprazole has low solubility and is acid labile and thus rapidly degraded by gastric acid upon oral administration. Therefore omeprazole in ZEGERID® capsules and powder for oral suspension has a time to peak of approximately 30 minutes (range 10-90 minutes) after a single-dose or repeated-dose administration.

Hence it is difficult to prepare a non-enteric coated omeprazole composition with an initial quick drug release and optimum drug stability of omeprazole in gastric pH considering the low solubility characteristics and shorter Tmax of ZEGERID® capsules and powder for oral suspension.

The prior art provides several options for the improvement of omeprazole solubility in non-enteric coated compositions comprising benzimidazole proton pump inhibitors viz. increase in disintegrant concentration use of micronized proton pump inhibitors and micronization of buffering agent in the process of making the compositions. However none of these attempts are beneficial; moreover it is cumbersome to a formulation scientist as it requires more number of lab-scale trials and troublesome manufacturing steps and it may not be feasible to scale-up the lab-scale batch formula to a commercial scale batch formula.

Therefore still there is a need for an improved non-enteric pharmaceutical composition comprising benzimidazole proton pump inhibitors which exhibit a quick drug release initially upon administration to a subject and which is comparable in terms of bioequivalence to that of ZEGERID® capsules.

SUMMARY

The present invention relates to non-enteric pharmaceutical compositions comprising a benzimidazole proton pump inhibitor (PPI) such as omeprazole or its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof.
The present invention provides a non-enteric pharmaceutical composition comprising a benzimidazole proton pump inhibitor at least one buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

The present invention provides non-enteric coated omeprazole composition with an initial quick drug release and optimum drug stability.

The compositions of the present invention are easy to formulate and are highly patient-compliant.

The compositions of the present invention can be formulated as multiparticulates such as powder granules or pellets. The multiparticulate compositions can be filled into a sachet or made into a capsule dosage form.

In aspects the compositions of the present invention are advantageously devoid of any enteric coating or delayed or sustained-release delivery mechanisms and comprise a PPI and at least one buffering agent to protect the PPI against acid degradation and a wicking agent to aid in providing an initial quick release of the PPI upon administration.

Aspects of the present invention relate to a non-enteric capsule comprising benzimidazole proton pump inhibitor a buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof a buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

In embodiment the compositions of the present invention comprise a wicking agent such as colloidal silicon dioxide which aids in providing an initial quick drug release when subjected to an in vitro dissolution study or administered in vivo to a subject in need thereof.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent a disintegrant and a lubricant.

Aspects of the present invention relate to processes for preparing a non-enteric pharmaceutical composition comprising omeprazole a buffering agent a wicking agent and optionally other pharmaceutically acceptable excipients.
Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent and optionally other pharmaceutically acceptable excipients; said composition being useful for treating or preventing gastrointestinal disease or disorder.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent and one or more other excipients wherein the percentage of omeprazole or its salt released is not less than (NLT) about 50% in about 45 minutes when subjected to an in vitro dissolution study in phosphate buffer pH 7.4 media.
Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole which remains physically and chemically stable when stored at accelerated storage conditions i.e. temperature of about 40ºC and relative humidity (RH) of about 75%.

An aspect of the present invention relates to a non-enteric capsule comprising omeprazole or its salt wherein the said capsule dosage form is packaged into a HDPE container or laminated aluminium foil pouch.

An aspect of the present invention relates to non-enteric pharmaceutical composition that is physically and chemically stable and provides the desired therapeutic concentration of the active agent for the intended duration.
In aspects the stable non-enteric coated compositions of omeprazole can be used for treating gastrointestinal diseases and/or disorders.

DETAILED DESCRIPTION

Aspects of the present invention relates to non-enteric pharmaceutical compositions comprising a benzimidazole proton pump inhibitor or its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof.

Aspects of the present application provides a non-enteric pharmaceutical composition comprising a benzimidazole proton pump inhibitor at least one buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof a buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

The present invention provides non-enteric coated omeprazole composition with an initial quick drug release and optimum drug stability. The compositions of the present invention are easy to formulate and are highly patient-compliant.
Preferably a ‘benzimidazole proton pump inhibitor’ is selected from a group comprising omeprazole esomeprazole pantoprazole rabeprazole lansoprazole and dexlansoprazole including its pharmaceutically acceptable salts polymorphs isomers enantiomers prodrugs or derivatives thereof.

For convenience the discussion herein uses omeprazole or its salt as a representative of the entire class of drugs but it is to be understood that the scope of the disclosure is not limited to this particular compound.

As used herein ‘omeprazole’ refers to all compounds of omeprazole including pharmaceutically acceptable salts polymorphs enantiomers prodrugs esters hydrates solvates derivatives or single enantiomers thereof.

As used herein “non-enteric pharmaceutical composition” refers to a composition which does not comprise an enteric polymer known in the art in an amount sufficient to prevent the benzimidazole compound from degradation in the acidic pH of the stomach.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent and optionally other pharmaceutically acceptable excipients.
Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent a disintegrant and a lubricant.

The term "buffering agent" or "buffer" shall mean any pharmaceutically appropriate weak base or strong base (and mixtures thereof) that when formulated or delivered with (e.g. before during and/or after) the PPI functions to substantially prevent or inhibit the acid degradation of the PPI by gastric acid sufficient to preserve the bioavailability of the PPI administered. The buffering agent is administered in an amount sufficient to substantially achieve the above functionality. Therefore the buffering agent of the present invention when in the presence of gastric acid must only elevate the pH of the stomach sufficiently to achieve adequate bioavailability of the drug to effect therapeutic action.

The term "about" refers to quantitative terms plus or minus 20% more preferably plus or minus 10%.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent such as colloidal silicon dioxide and optionally other pharmaceutically acceptable excipients.

Surprisingly the inventors of the present application have found that the addition of a wicking agent such as colloidal silicon dioxide into the composition provides an initial quick drug release of the active agent when subjected to an in vitro dissolution study or administered in vivo.

The term “wicking agent” shall mean any agent that draws water into the interior of product i.e. easily wetted and swell faster (such as a disintegrant) and helps in quick release of the active ingredient. For the purposes of the present invention these wicking agents swell to an appreciable degree.

In aspects the compositions of the present invention can be formulated as multiparticulates such as powder granules or pellets. The multiparticulate compositions can be made into a suitable dosage form such as by filling into a sachet or making into a capsule dosage form.

Further the inventors have also found that the addition of a wicking agent such as colloidal silicon dioxide helps in improving the processability of the multiparticulates for making into a suitable dosage form.

In aspects the compositions of the present invention are advantageously devoid of any enteric coating or delayed or sustained-release delivery mechanisms and comprise a PPI and at least one buffering agent to protect the PPI against acid degradation and a wicking agent to aid in providing an initial quick release of the PPI upon administration.

Aspects of the present invention relate to a non-enteric capsule comprising benzimidazole proton pump inhibitor a buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients.

Useful pharmaceutically acceptable excipients include for example any one or more of diluents binders stabilizers lubricants glidants disintegrating agents anti-oxidants alkalizing agents surfactants and coloring agents and any other materials that are commonly used in solid pharmaceutical dosage form preparations.

Examples of buffering agents include but are not limited to sodium bicarbonate potassium bicarbonate magnesium hydroxide magnesium lactate magnesium glucomate aluminum hydroxide aluminum hydroxide/sodium bicarbonate coprecipitate a mixture of an amino acid and a buffer a mixture of aluminum glycinate and a buffer a mixture of an acid salt of an amino acid and a buffer and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate sodium tartarate sodium acetate sodium carbonate sodium bicarbonate sodium polyphosphate potassium polyphosphate sodium pyrophosphate potassium pyrophosphate disodium hydrogenphosphate dipotassium hydrogenphosphate trisodium phosphate tripotassium phosphate sodium acetate potassium metaphosphate magnesium oxide magnesium hydroxide magnesium carbonate magnesium silicate calcium acetate calcium glycerophosphate calcium cholride calcium hydroxide calcium lactate calcium carbonate calcium bicarbonate and other calcium salts.
Examples of wicking agents include but are not limited to colloidal silicon dioxide kaolin titanium dioxide fumed silicon dioxide alumina niacinamide sodium lauryl sulfate low molecular weight polyvinyl pyrrolidone m-pyrol bentonite magnesium aluminum silicate polyester polyethylene. Materials particularly suitable for the purpose of this invention include the non-swellable wicking agent examples of which are sodium lauryl sulfate colloidal silicon dioxide and low molecular weight polyvinylpyrrolidone.

The pharmaceutical formulations according to the application can also include disintegrating agents such as carmellose calcium carboxymethylstarch sodium croscarmellose sodium crospovidone and colloidal silicon dioxide.
Alkalizing agents as used herein can include alkaline earth metal salt additives and/or alkali metal salt additives and/or organic alkalizing agents. Alkaline earth metal salt additives can include for example calcium carbonate calcium hydroxide magnesium carbonate magnesium hydroxide magnesium silicate magnesium aluminate or aluminum magnesium hydroxide and most preferable calcium carbonate. Alkali metal salt additives can be for example disodium hydrogen orthophosphate sodium silicate sodium carbonate sodium bicarbonate sodium hydroxide sodium aluminate and sodium or potassium citrate carbonate bicarbonate phosphate sulfate benzoate and ascorbate and other suitable alkali metal salts most preferable sodium bicarbonate. Examples of organic alkalizing agents include amines. Specific examples of amines include N- methylglucamine guanine and arginine.

One or more glidant materials which improve the flow of powder blends pellets or mini-tablets and minimize dosage form weight variations can be present as excipients such as colloidal silicon dioxide silica derivatives and talc.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent a disintegrant and a lubricant.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts sodium bicarbonate colloidal silicon dioxide and croscarmellose sodium and sodium stearyl fumarate or magnesium stearate.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising 20-40 mg of omeprazole or its salts about 200-1500 mg of sodium bicarbonate and between about 0.5-5.0 mg of colloidal silicon dioxide; and optionally other pharmaceutically acceptable excipients.

Aspects of the present application relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts sodium bicarbonate about 0.01%w.w to about 0.6%w/w of colloidal silicon dioxide croscarmellose sodium and magnesium stearate.

Aspects of the present invention provide processes for the preparation of non-enteric pharmaceutical formulations comprising a benzimidazole PPI such as omeprazole or its salts a buffering agent a wicking agent and one or more other pharmaceutically acceptable excipients.

An aspect of the present application provides a process for the preparation of non-enteric pharmaceutical formulations comprising omeprazole wherein the said process comprises:

(i) Sifting all the ingredients through appropriate sieve
(ii) Blending the sifted material in a blender and
(iii) Filling the blended material into a suitable sized capsule.

An aspect of the present application provides a process for the preparation of non-enteric pharmaceutical formulations which comprises the following steps:

1. Sifting:
1.1 Part-I: Omeprazole 10-50% of ‘buffering agent’ and disintegrant were sifted.
1.2 Part-II: The ‘wicking agent’ and 5-30% of ‘buffering agent’ were weighed.
1.3 The above material of step 1.1 and step 1.2 were again sifted together.
1.4 Part-III: 10-50% of ‘buffering agent’ was sifted and collected separately.
1.5 Part-IV: 10-50% of ‘buffering agent’ was sifted collected separately.
1.6 Lubricant was sifted and collected separately.

2. Blending:
2.1 Sifted material of step 1.4 (part-III) was loaded in a double cone blender followed by step 1.3 and 1.5 material and were blended for 20 minutes.
2.2 Sifted material of step 1.6 was added to the blend of step 2.1 and lubricated for 5 minutes.

3. Capsule Filling:
3.1 The resultant mixture of step 2.3 was filled in empty hard gelatin capsule shell size ‘00’ by using Automated Capsule filling machine.

4.0 Packaging:
4.1 The filled capsules were packed in HDPE containers and in laminated aluminium foil pouch.

The dosage forms can be subjected to in vitro dissolution testing such as according to Test 711 “Dissolution” in United States Pharmacopeia 29 United States Pharmacopeial Convention Inc. Rockville Maryland 2005 (“USP”) to determine the rate at which the active agents are released from the dosage forms and content of active agents can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).
Aspects of the present application relates to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent and optionally one or more other pharmaceutically acceptable excipients wherein the percentage of omeprazole or its salts released is not less than about 40% within about 45 minutes when subjected to an in vitro dissolution study in phosphate buffer having a pH of about 7.4.

Aspects of the present application relates to pharmaceutical composition comprising omeprazole remains physically and chemically stable when stored at accelerated storage conditions (i.e. temperature of about 40ºC and relative humidity of about 75%) for at least three months. For example the maximum unspecified degradation impurities and total omeprazole-related impurities formed in the stable formulations upon such storage do not exceed 0.5% & 5% w/w of the label content of the drug respectively.

The term ‘stability’ is the propensity of a drug substance or formulated drug product to remain within established specifications to maintain its identity strength quality and purity during manufacturing and in storage at normal ambient conditions in original packaging until its expiration date. The term ‘chemical stability’ means the tendency of drug to resist degradation or decomposition due to internal reactions or due to the effects of external conditions such as oxygen heat light pressure etc. and includes maintaining acceptable concentrations of drug-related impurities.

The term ‘related substances’ or ‘impurities’ mean the degradation impurities and/or active ingredient process related impurities of drug materials.
The related substance i.e. Omeprazole or its salt thereof include the following: omeprazole N-oxide omeprazole sulphone omeprazole sulphide Impurity A: 1-(5-methoxy-1H-benzo[d]imidazol-2-yl)-3 5dimethyl-4-oxo-1 4-dihydropyridine-2-carboxylic acid Impurity C: 6-Methoxy-2-(4-methoxy-3 5-dimethyl-pyridin-2-yl methanesulfinyl)-1-methyl-1H-benzimidazole desulphur and desoxy desmethyl impurities.

In aspects the stable non-enteric coated compositions of omeprazole can be used for treating gastrointestinal diseases and/or disorders.

Aspects of the present invention relate to a non-enteric pharmaceutical composition comprising omeprazole or its salts a buffering agent a wicking agent and optionally other pharmaceutically acceptable excipients; said composition being useful for treating or preventing gastrointestinal disease or disorder.

The term ‘gastrointestinal disorder’ shall mean any disorder relates to duodenal ulcer disease gastric ulcer disease gastroesophageal reflux disease erosive esophagitis poorly responsive symptomatic gastroesophageal reflux disease pathological gastrointestinal hypersecretory disease Zollinger Ellison Syndrome and acid dyspepsia.

The term ‘shelf life’ is the time that finished products can be stored after manufacturing during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution storage and display. The shelf life is established by the manufacturer of a product.

An aspect of the present invention relates to a non-enteric capsule comprising omeprazole or its salt wherein the said capsule dosage form is packaged into a HDPE container or laminated aluminium foil pouch.

An aspect of the present invention relates to non-enteric pharmaceutical composition that is stable and provides the desired therapeutic concentration of the active agent for the intended duration.

The selection of appropriate particles sizes of the active agents as well as of excipients is within the scope of the application. D10 D50 D90 and D95 values are useful ways for indicating a particle size distribution. D95 is the size value where at least 95 volume percent of the particles have sizes smaller than the value. Methods for determining D95 include laser diffraction techniques such as using equipment from Malvern Instruments Ltd. Malvern Worcestershire United Kingdom or from Horiba.

Aspects of the present invention relate to pharmaceutical composition are prepared by using an active agent which is omeprazole or its salts having average particle size of about 0.1 µm to about 200 µm or about 1 µm to about 50 µm.

“Initial quick drug release” means the release of proton pump inhibitor (PPI) compound from non-enteric coated compositions of the present invention such that not less than about 60% of the PPI is released in 900 ml phosphate buffer having a pH of 7.4 at 5 minutes and not less than 30% of PPI released in 500 ml of dissolution media (prepared using 0.1N HCl and Water in a ratio of 0.2:1) at 5 minutes.

An aspect of the present application relates to a non-enteric capsule comprising omeprazole or its salt wherein the said capsule dosage form is packaged into a HDPE container and laminated aluminium foil pouch.

It is known that the amount of a drug released at a particular target site plays a role in its dissolution absorption and/or bioavailability. Therefore definite amounts of the PPI such as omeprazole should be released at a specific site or pH in order to provide the desired dissolution absorption and/or bioavailability. The compositions of the present application comprising omeprazole is designed to provide desired release of the omeprazole as required for providing a pharmacological effect without substantial toxicity when administered to a subject.

The following examples further describe certain specific aspects and embodiments of the application. These examples are provided solely for the purpose of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

EXAMPLE 1 (without wicking agent):

Manufacturing process:

1. Sifting:

1.1 Part-I: Omeprazole 40% of sodium bicarbonate and croscarmellose sodium were sifted through #40 mesh (ASTM) in a container.

1.2 The above material of step 1.1 was again sifted through #40 mesh (ASTM)

1.3 Part-II: 30% of sodium bicarbonate was sifted through #40 mesh (ASTM)
and collected separately.

1.4 Part-III: 30% of sodium bicarbonate was sifted through #40 mesh (ASTM) and collected separately.

1.5 Sodium stearyl fumarate was sifted through #40 mesh (ASTM) and collected separately.

2. Blending:

2.1 Sifted material of step 1.3 (part-II) was loaded in a double cone blender followed by step 1.2 material.

2.2 Sifted material of step 1.4 (part-III) and the material of step 2.1 were blended in a double cone blender for 20 minutes.

2.3 Sifted material of step 1.5 was added to the blend of step 2.2 and lubricated for 5 minutes.

3. Capsule Filling:

The resultant mixture of step 2.3 was filled in empty hard gelatin capsule shell size ‘00’ by using automated capsule filling machine.

4.0 Packaging:

4.1 The filled capsules were packed in HDPE containers and in laminated aluminium foil pouch.

Table-2: Comparative dissolution profile of Zegerid 40mg/1.1gm capsules Vs capsules of Example-1 in phosphate buffer pH 7.4; 900mL; 75rpm USP Type-II (Paddles):

Table-3: Comparative dissolution profile of Zegerid 40mg/1.1gm Vs capsules of Example-1 in 500 ml of dissolution media (prepared using 0.1N HCl and Water in a ratio of 0.2:1); 100rpm; USP Apparatus Type-I (Basket)

40mg Capsules of Example-1

EXAMPLE 2 (with wicking agent):

Capsule Filling

Empty hard gelatin capsule shell size ‘00’ with opaque white coloured body and opaque blue coloured cap imprinted ‘364’ on body with blue ink and ‘RDY’ on cap with white ink
01 No

Manufacturing process:

1. Sifting:

1.1 Part-I: Omeprazole 30% of sodium bicarbonate and croscarmellose sodium were sifted through #40 mesh (ASTM) in a container.

1.2 Colloidal silicon dioxide and 10% of sodium bicarbonate were weighed and taken as required.

1.3 The above material of step 1.1 and step 1.2 were sifted through #40 mesh (ASTM).

1.4 Part-II: 30% of sodium bicarbonate was sifted through #40 mesh (ASTM) and collected separately.

1.5 Part-III: 30% of sodium bicarbonate was sifted through #40 mesh (ASTM) and collected separately.

1.6 Sodium stearyl fumarate was sifted through #40 mesh (ASTM) and collected
separately.

2. Blending:

2.1 Sifted material of step 1.4 (part-II) was loaded in a double cone blender followed by step 1.3 material.
2.2 Sifted material of step 1.5 (part-III) and the material of step 2.1 were blended in a double cone blender for 20 minutes.

2.3 Sifted material of step 1.6 was added to the blend of step 2.2 and lubricated for 5 minutes.

3. Capsule Filling:

3.1 The resultant mixture of step 2.3 was filled in empty hard gelatin capsule shell size ‘00’ by using automated capsule filling machine.
4.0 Packaging:

4.1 The filled capsules were packed in HDPE containers and in laminated aluminium foil pouch.

Table-5: Comparative dissolution profile of Zegerid 40mg/1.1gm Vs Example-2 formulations A B & C in phosphate buffer pH 7.4; 900mL; 75rpm USP Apparatus Type-II (Paddles).

Table-6: Comparative dissolution profile of Zegerid 40mg/1.1gm Vs capsules of Example-2 formulations A B & C in 500 ml of dissolution media (prepared using 0.1N HCl and Water in a ratio of 0.2:1); 100rpm; USP Apparatus Type-I (Basket)

The capsules prepared in Example-2 were subjected to accelerated stability study for 3 Months at 40ºC/75%RH. The results are provided in Table-7.

Table-7: “Related substances” of omeprazole of Example 2

EXAMPLE 3 (with wicking agent):

Empty hard gelatin capsule shell size ‘00’ with opaque white coloured body and cap imprinted ‘363’ on body and ‘RDY’ on cap with blue ink
01 No

Manufacturing process: Same as Example 2.

Table-9: Comparative dissolution profile of Zegerid 20mg/1.1gm Vs Example-3 formulations A B & C in phosphate buffer pH 7.4; 900mL; 75rpm USP Type-II (Paddles).

We Claim:

1. A non-enteric pharmaceutical composition comprising a benzimidazole proton pump inhibitor (PPI) buffering agent, wicking agent and one or more other pharmaceutically acceptable excipients.

2. The non-enteric pharmaceutical compositions as claimed in claim 1 wherein the composition is a multiparticulate composition.

3. The non-enteric pharmaceutical compositions as claimed in claim 2 wherein the multiparticulate composition is in the form of granules or pellets that can be filled into a sachet or made into a capsule dosage form.

4. The non-enteric pharmaceutical compositions as claimed in claim 1 wherein the wicking agent is colloidal silicon dioxide.

5. The non-enteric pharmaceutical compositions as claimed in claim 1 where is the benzimidazole proton pump inhibitor (PPI) is omeprazole or its pharmaceutically acceptable salt thereof.

6. The non-enteric pharmaceutical composition of as claimed in claim 5 wherein the omeprazole released from the composition is not less than (NLT) about 50% in about 45 minutes when subjected to in vitro dissolution in phosphate buffer pH 7.4 media.

7. A process for preparing a non-enteric pharmaceutical composition comprising omeprazole, or its pharmaceutically acceptable salts a buffering agent, a wicking agent and optionally other pharmaceutically acceptable excipients.

8. A method of treating gastrointestinal diseases and/or disorders by a non-enteric pharmaceutical composition comprising omeprazole, or its pharmaceutically acceptable salts.

9. A non-enteric pharmaceutical composition comprising a benzimidazole proton pump inhibitor (PPI) and process of preparation thereof, as described and illustrated in the examples herein.