WO2010117756A2

WO2010117756A2 - Substituted benzimidazole pharmaceutical formulations

Info

Publication number: WO2010117756A2
Application number: PCT/US2010/029145
Authority: WO
Inventors: Vishal Lad; Ajmal Shareef; Vinay Muley; Sushant Dube; Ashwini Rewatkar; Rahul Sudhakar Gawande; Srinivas Irukulla; Suryakumar Jayanthi
Original assignee: Dr. Reddy's Laboratories Ltd; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-03-31
Filing date: 2010-03-30
Publication date: 2010-10-14
Also published as: WO2010117756A3

Abstract

Stable pharmaceutical compositions of dexlansoprazole with pharmaceutical excipients, processes for preparing the stable compositions, packaging and their use in treatment of erosive esophagitis and heartburn associated with non-erosive gastroesophageal reflux disease.

Description

SUBSTITUTED BENZIMIDAZOLE PHARMACEUTICAL FORMULATIONS

INTRODUCTION

Aspects of the present invention relate to formulations comprising at least one substituted benzimidazole derivative, such as lansoprazole or a single enantiomer thereof, and processes for preparing the same. In particular aspects, the present invention relates to formulations comprising a single enantiomer of lansoprazole, which is dexlansoprazole, and processes for preparing the same. In aspects, the invention further relates to therapeutic uses and methods of treatment employing formulations comprising lansoprazole or a single enantiomer thereof.

Embodiments of formulations of the present invention are in the form of multiparticulates, in instances made into a unit dosage form such as a capsule.

Embodiments of the present invention also relate to stable dexlansoprazole modified release formulations which comprise at least two fractions of multiparticulates, wherein one or more of the fractions are in the form of immediate release, delayed release, extended release, sustained release, timed release, pulsatile release, or prolonged release.

Several substituted benzimidazole derivatives including rabeprazole, ^ omeprazole, esomeprazole, lansoprazole, leminoprazole, pantoprazole, and mixtures thereof, are known to be useful for inhibiting gastric acid secretion in mammals and man by controlling gastric acid secretion at the final step of the acid secretory pathway. These active ingredients are acid-labile, creating several problems in formulating the compounds into oral dosage forms because of the acidic environment of the stomach, generally resulting in poor stability. In particular, the compounds are rapidly decomposed and change color under moist conditions or in an acidic to neutral aqueous media.

When these compounds are formulated into pharmaceutical preparations for oral administration, they require special techniques to avoid contact of drug with gastric acid of the stomach. One technique that is commonly used is to coat the acid-labile compound, or its granules or pellets, with an enteric coating, which is insoluble in water under acidic conditions and soluble in water under neutral to alkaline conditions. However, the polymeric materials used in enteric coatings are acidic, and can cause the decomposition of the acid-labile compound. Such decomposition occurs even during the enteric coating process, which results in the coloration of the surface of a drug-containing core. In order to avoid such problems, an inert subcoating, which is not acidic, is often required between the core and the enteric coating.

For substances that are labile in acid media, but have better stability in neutral to alkaline media, it is often advantageous to add alkaline inactive excipients to increase the stability of the active compound during manufacturing and storage. In particular, substituted benzimidazole derivatives such as omeprazole, esomeprazole, and dexlansoprazole are not only unstable in acidic conditions but also are not stable in the neutral solid state. Thus, in order to enhance the storage stability, an alkaline base such as sodium bicarbonate is added to the formulations, and/or the substituted benzimidazole derivatives are converted to their alkaline salts, which are usually more stable than the free species.

In embodiments, the active compound of the compositions and methods of the present invention is an optical isomer of lansoprazole. Chemically, it is the (R)- enantiomer of lansoprazole (having the adopted name "dexlansoprazole") and has structural Formula I. Dexlansoprazole can be referred to by the chemical name (+)-2-[R-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfinyl]-1 H- benzimidazole.

Formula I

Dexlansoprazole is presently commercially available in products sold as KAPIDEX® in the form of 30 mg and 60 mg delayed release capsules, marketed by Takeda. The inactive excipients of KAPIDEX products include sugar spheres, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose, titanium dioxide, hydroxypropyl cellulose, hypromellose 2910, talc, methacrylic acid copolymer, polyethylene glycol 8000, triethyl citrate, polysorbate 80, and colloidal silicon dioxide. The capsule shell is made of hypromellose, carrageenan and potassium chloride. Based on the capsule shell color, blue contains FD&C Blue No.2 and aluminum lake, gray contains ferric oxide and aluminum lake, and both contain titanium dioxide. U.S. Patent Nos. 6,462,058 and 6,664,276 disclose crystalline forms of dexlansoprazole or a salt thereof. U.S. Patent Nos. 4,628,098, 4,786,505, 4,853,230, 5,689,333, 5,045,321 , 5,093,132, and 5,433,959 teach various stabilizing agents for their disclosed benzimidazole derivatives in core tablets. These patents also show that the derivatives are stable in the presence of basic inorganic salts of magnesium, calcium, potassium and sodium. The stability is further enhanced by separating acid labile benzimidazoles from the acidic components of the enteric coating by interposing an intermediate coating (subcoating). U.S. Patent No. 6,939,971 discloses methods of treating Zollinger- Ellison syndrome, reflux esophagitis and Helicobacter pylori infections, by administering compositions containing crystalline dexlansoprazole.

U.S. Patent No. 6,013,281 , of which the entire content is incorporated by reference, also discloses that a separating layer is formed in situ by direct application of an acidic enteric material onto an alkaline core containing benzimidazoles. U.S. Patent Application Publication No. 2006/0057195 A1 describes stable solid preparations for medicinal use containing amorphous benzimidazole compounds including dexlansoprazole, which are produced by blending an amorphous benzimidazole compound with a nontoxic base such as a basic inorganic salt. U.S. Patent Application Publication No. 2006/0013868 A1 discloses a capsule comprising a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. U.S. Patent Application Publication No. 2007/0141137 A1 describes a capsule preparation, which comprises a medicine unstable to moisture, is stable in a low moisture state, and has pH-independent disintegration properties.

There remains a need for providing stable pharmaceutical formulations comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, for providing effective plasma concentrations of the active agent over extended durations of time. SUMMARY

Aspects of the present invention relate to stable modified release formulations comprising at least one substituted benzimidazole derivative, such as lansoprazole or a single enantiomer thereof, for oral administration, and processes of preparation.

In embodiments, the present invention provides stable formulations comprising a single enantiomer of lansoprazole, which is dexlansoprazole, together with one or more excipients.

Embodiments of the present invention provide stable pharmaceutical formulations of dexlansoprazole, comprising crystalline dexlansoprazole having a mean particle size in the range of about 1 to about 500 μm.

In embodiments, stable dexlansoprazole formulations of the present invention are in the form of multiparticulates.

In embodiments, stable dexlansoprazole formulations of the present invention are in the form of multiparticulates, and these can be made into unit dosage forms such as capsules.

In embodiments, stable pharmaceutical formulations of the present invention are in the form of capsules filled with multi-particulates, wherein a particle comprises: a) a core, comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; b) optionally, an intermediate coating surrounding the core; and c) an enteric coating surrounding the core of a) or intermediate layer of ^• b). In embodiments, the present invention provides stable dexlansoprazole modified release formulations comprising at least two fractions of multi- particulates, wherein one or more of the fractions are in the form of immediate release, delayed release, extended release, sustained release, pulsatile release, or prolonged release. In embodiments, the present invention provides stable dexlansoprazole modified release formulations comprising at least two fractions, wherein weight ratios between the first and second fractions of multi-particulates vary from about 10:90 to about 90:10. An aspect of the present invention provides pharmaceutical compositions of dexlansoprazole wherein the polymorphic stability of dexlansoprazole is maintained during processing and storage.

In an embodiment, the dexlansoprazole used as the input active agent is in a substantially amorphous form, wherein said form is substantially retained during the manufacturing of the composition and also during storage for commercially relevant periods.

In an embodiment, the dexlansoprazole used as the input active agent is in a substantially crystalline form, wherein said form is substantially retained during the manufacturing of the composition and also during storage for commercially relevant periods.

In yet another embodiment, the dexlansoprazole used as the input active agent is in a substantially crystalline form, wherein said form is partially or completely converted into amorphous form during the manufacturing of the composition and/or during storage for commercially relevant periods.

In another embodiment, the dexlansoprazole used as the input active agent is in a substantially amorphous form, wherein said form is partially or completely converted into crystalline form during the manufacturing of the composition and/or during storage for commercially relevant periods. In embodiments, the partial or complete form conversion of the input active agent dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the stability of the composition.

In another embodiment, the partial or complete form conversion of the input active agent dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the physico-chemical properties of the composition.

In yet another embodiment, the partial or complete form conversion of the input active agent dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the drug release from the composition.

In embodiments, multi-particulates of the present invention that contain a benzimidazole compound further comprise a pharmaceutically acceptable alkaline compound, which can act as a stabilizer for the drug.

In embodiments, the invention includes methods of preparing a stable formulation of dexlansoprazole, comprising: a) applying a layer of a powder, suspension, dispersion, or solution comprising dexlansoprazole and at least one stabilizer, together with at least one pharmaceutically acceptable excipient, onto pharmacologically inert particles, and drying; b) optionally, applying an intermediate coating; c) applying an enteric coating over particles of a) or the intermediate coating of b); and d) mixing coated particles with one or more pharmaceutically acceptable excipients. In embodiments, the invention relates to stable formulations of dexlansoprazole, wherein concentrations of stabilizer are in the range of about 0.1 % to 10%, by weight of the total composition.

In embodiments, the invention relates to stable formulations of dexlansoprazole, wherein weight ratios of dexlansoprazole to stabilizer are in the range of about 1 :0.01 to about 1 :20.

In embodiments, enteric coatings for multiparticulates of the present invention containing a benzimidazole compound further comprise a pore forming excipient.

In embodiments, the amount of pore former in formulations ranges from about 0.001 to 10 weight percent, with respect to the active agent content.

In embodiments, the present invention provides stable formulations of dexlansoprazole, which are substantially free of degradation impurities.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity A (2-mercaptobenzimidazole) are less than about 2% of label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity B (N-oxide) are less than about 2% of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity C (nitrosulphoxide) are less than about 2% of the label content of dexlansoprazole. In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity D (sulphone) are less than about 2% of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity E (sulphide) are less than about 2% of the label content of dexlansoprazole.

In embodiments, formulations of the present invention may contain any one or more of impurities A, B, C, D, E, or any other drug-related impurity.

In embodiments, the invention relates to stable compositions and/or formulations wherein total impurities are less than about 5% of the label content of dexlansoprazole.

In embodiments, the present invention includes delayed release solid oral dosage forms comprising dexlansoprazole or pharmaceutically acceptable salts thereof, wherein the dosage forms release less than about 10% of contained active ingredient within about the first 120 minutes after immersion into 0.1 N hydrochloric acid (HCI) dissolution medium. The dissolution medium is then changed to pH 6.8 phosphate buffer and release of the drug continues, in the range of about 15% to about 25% of drug released within about an additional 90 minutes, and about 90% to about 100% released within about an additional 300 minutes.

In embodiments, the present invention includes delayed release solid oral dosage forms comprising dexlansoprazole or pharmaceutically acceptable salts thereof, wherein the dosage forms release less than about 10% of contained active ingredient within about the first 120 minutes after immersion into 0.1 N hydrochloric acid (HCI) dissolution medium. The dissolution medium is then changed to pH 7 phosphate buffer and release of the drug continues thereafter, in the range of about 30% to about 40% of drug released within about an additional 45 minutes, and about 75% to about 80% released within about an additional 150 minutes. In embodiments, multiparticulates of the present invention have particle sizes in the range of about 100 μm to 2000 μm.

In embodiments, multiparticulates of the present invention have Carr index values in the range of about 1-50%. In embodiments, ratios of organic solvent to water in coating solutions or dispersions for coating of multi-particulates are about 70:30 to about 100:0, or about 85:15 to about 95:5.

In embodiments, the present invention provides processes for producing stable coated multi-particulates, including drying the multi-particulates after applying a layer of a powder, suspension, dispersion, or solution comprising dexlansoprazole and at least one stabilizer, together with at least one pharmaceutically acceptable excipient, onto pharmacologically inert particles, at temperatures about 40 ± 1O⁰C for about 120 minutes. In embodiments, the invention provides processes for producing stable formulations, wherein multi-particulates are processed in an environment where the relative humidity is not more than about 70%.

In embodiments, the invention provides processes for producing stable formulations, wherein multi-particulates have water contents of 0.5-10% by weight, as determined by the Karl Fischer technique.

In embodiments, the invention provides processes for producing stable formulations, wherein multi-particulates have losses on drying at 105⁰C in the range of about 0.25-10%, or about 0.5-5%, by weight of the multiparticulate composition. In embodiments, the invention provides stable pharmaceutical compositions comprising dexlansoprazole and at least one pharmaceutically acceptable carrier, wherein pH values of the compositions are less than about 12, or less than about 11 , or less than about 10.

In embodiments, the present invention provides processes for producing stable coated multi-particulates having residual solvent levels within the ICH permissible limits.

In embodiments, the present invention provides stabilized pharmaceutical compositions by incorporation of at least one antioxidant.

In embodiments, the content of antioxidant in a formulation ranges from about 0.001 to 10 weight percent, with respect to the active agent.

In embodiments, the invention provides pharmaceutical dosage forms that can withstand stress while being transported and can easily be packaged using an automatic dispensing machine. In embodiments, the invention includes forms of packaging for the dexlansoprazole formulations, such that drug release characteristics of the formulations are maintained during storage for commercially relevant times.

In embodiments, the invention provides dexlansoprazole formulations, in packages suitable for commercial sale which provide stability during storage or transportation.

The dexlansoprazole modified release formulations of the present invention are intended to provide effective plasma concentrations of the active agent for extended duration of time. Additional embodiments of the present invention will be apparent from the following description, drawings and examples. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment or aspect. Additional aspects and embodiments are set forth in the following description, particularly when considered in conjunction with the examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows comparative X-ray powder diffraction (XRPD) patterns for the delayed release (DR) portion of the formulation prepared according to Example 2, where A represents the DR portion and P represents a similarly prepared placebo formulation, omitting the drug. Figure 2 shows comparative XRPD patterns for the extended release (ER) portion of the formulation prepared according to Example 2, where A represents ER portion and P represents a similarly prepared placebo formulation, omitting the drug.

Figure 3 shows comparative XRPD patterns for a formulation of Example 2A, where A represents the formulation (DR and ER) and P represents the placebo formulation, after storage at 40⁰C and 75% relative humidity for 3 months.

Figure 4 shows comparative XRPD patterns for the formulation prepared according to Example 8, where A represents the formulation (DR and ER), B represents starting crystalline dexlansoprazole, and P represents a similarly prepared placebo formulation.

Figure 5 shows comparative XRPD patterns for the formulation prepared according to Example 8, where A represents the formulation (DR and ER), B represents crystalline dexlansoprazole, and P represents the placebo formulation, after storage at 4O⁰C and 75% relative humidity ("RH") for 2 months.

Figure 6 shows comparative XRPD patterns for the formulation prepared according to Example 9, where A represents the starting crystalline dexlansoprazole, B represents the formulation (DR and ER), C represents formulation after storage at 40⁰C and 75% RH for 1 month, D represents formulation after storage at 4O⁰C and 75% RH for 2 months, E represents formulation after storage at 4O⁰C and 75% RH for 3 months, and P represents a similarly prepared placebo formulation.

DETAILED DESCRIPTION

As used herein the term "dexlansoprazole" includes the compound known as dexlansoprazole, pharmaceutically acceptable salts, esters, prodrugs thereof, active metabolites of dexlansoprazole and the prodrugs thereof, and any of their polymorphs, solvates and hydrates. The terms "pharmaceutically acceptable salt" as used herein refers to salts which are known to be non-toxic and are commonly used in pharmaceutical practice. Such pharmaceutically acceptable salts include metal salts, salts with organic bases, salts with basic amino acids, etc. Metal salts include, for example, alkali metal salts, such as sodium salt and potassium salts, and alkaline earth metal salts, such as calcium, magnesium and barium salts. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N₁N- dibenzylethylenediamine, etc. Salts with basic amino acids include, for example, salts with arginine, lysine, etc. Acid addition salts such as hydrochloride salts and the like are also included.

In the present invention, dexlansoprazole and its salts can be used in any crystalline form, amorphous form, or combinations thereof. The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical formulation that is not a pharmacologically active ingredient, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing the pharmaceutical formulations are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or "pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipient.

The term "acid-labile compound" means any compound, which is not stable in acidic conditions or which undergoes degradation or hydrolysis via acid or proton catalyzed reactions.

The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance occurs and instances where it does not.

The term "stability" as used in the description refers to "chemical stability" which is considered with respect to the content of impurities and/or drug ^■ degradation products.

In embodiments, the dexlansoprazole used to make the formulations or contained in the formulations is amorphous, crystalline, or mixtures thereof.

In an aspect, the dexlansoprazole used as the active ingredient is in a substantially amorphous form, wherein said form is substantially retained during the manufacturing of the composition and also during storage. In another aspect, the dexlansoprazole used as the active ingredient is in a substantially crystalline form, wherein said form is substantially retained during the manufacturing of the composition and also during storage for commercially relevant periods.

In an aspect, the dexlansoprazole used as the active ingredient is in a substantially crystalline form, wherein said form is partially or completely converted into amorphous form during the manufacturing of the composition and/or during storage. In another aspect, the dexlansoprazole used as the active ingredint is in a substantially amorphous form, wherein said form is partially or completely converted into crystalline form during the manufacturing of the composition, as well as during storage, and during use, for commercially relevant periods.

"Commercially relevant" periods typically are considered to be about 6 months, 1 year, 2 years, etc., or any intermediate times, generally with products packaged in closed containers. For drug products, storage conditions are specified by regulatory authorities, such as 25⁰C, frequently with excursions permitted to 15-3O⁰C. It is common in the industry to simulate long-term storage, using "accelerated" stability testing conditions, such as 4O⁰C and 75% relative humidity (RH), for shorter durations. In an aspect, a partial or complete form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the stability of the composition. In another aspect, the partial or complete form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the physico-chemical properties of the composition. In yet another aspect, the partial or complete form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the drug release from the composition.

The terms 'modified release' (MR) and 'controlled release¹ (CR) according to the present invention imply that the drug release can be delayed release (DR), extended release (ER), sustained release (SR), pulsatile release (PSR) or prolonged release (PR), or a combination of immediate release and one or more of delayed release, extended release, sustained release, pulsatile release or prolonged release. The term 'delayed release' according to the present invention implies that the drug is not substantially released in the stomach region of the gastro-intestinal tract (GIT); instead, drug release takes place substantially in the upper part of the intestines or a later part of the intestinal tract.

The term 'sustained release' according to the present invention implies that the drug is released in varied quantities substantially throughout the GIT, in a controlled manner. The term 'pulsatile release' according to the present invention implies that the drug is released as one or more pulses in any part of the GIT, commencing immediately after administration or in a delayed manner.

The term 'extended release' according to the present invention implies that the drug is not substantially released in the stomach region of the gastro-intestinal tract (GIT); instead, drug release takes place substantially in the upper part of the intestine over an extended duration of time.

The term 'prolonged release' according to the present invention implies that substantially no drug is released immediately after administration, i.e., the initial drug release starts after a delay, followed by release of the drug in a portion of the GIT or varied quantities of drug release throughout the GIT thereafter.

In embodiments, modified release formulations of dexlansoprazole according to the present invention comprise at least two fractions, wherein both fractions provide delayed release of dexlansoprazole. In embodiments, modified release formulations of dexlansoprazole comprise at least two fractions, wherein both fractions provide delayed release of dexlansoprazole, such that the drug release of one delayed release fraction precedes release of the other delayed fraction, while releasing substantial amounts of drug before, at the same time, or after the same substantial amount of drug is released from the other fraction. In embodiments, modified release formulations of dexlansoprazole comprise at least two fractions, wherein both fractions are in the form of enteric coated compositions intended to provide delayed release of dexlansoprazole, and wherein at least one of the delayed release fractions provides drug release almost immediately after administration or in an extended manner. In embodiments, stable dexlansoprazole formulations of the present invention are in the form of multiparticulates. In embodiments, 'multiparticulates' according to the present invention may be in the form of powders, granules, pellets, spheroids, extrudes, mini-tablets, and the like.

In embodiments, stable dexlansoprazole formulations of the present invention are in the form of multiparticulates, made into a unit dosage form such as capsules.

In embodiments, dexlansoprazole formulations of the present invention are in the form of pellets or mini-tablets, filled into capsules. In embodiments, dexlansoprazole formulations of the present invention comprise a single fraction of multiparticulates such as pellets or mini-tablets, filled into capsule, wherein the multiparticulate fraction comprises cores containing the drug for extended release, having applied thereto a layer of drug coating for immediate release. These can be further coated with an enteric polymer, wherein the multiparticulates are optionally coated to form a subcoating layer, prior to enteric coating.

In embodiments, dexlansoprazole formulations of the present invention comprise at least two fractions of multiparticulates, such as mini-tablets or pellets, filled into capsules, wherein one fraction of multiparticulates is coated with an enteric polymer that dissolves at in pH range between about 3 and 7 to release the active agent, and wherein another fraction of multi-particulates is coated with an enteric polymer that dissolves in a pH range between about 4 and 8 to release the active agent, and wherein the multi-particulates in each fraction are optionally coated to form a subcoating layer, prior to enteric coating.

The different physicochemical properties of the active ingredient, and as well as of excipients, are to be considered, as these properties affect the process and formulation properties of the compound. Various important physicochemical properties include, but are not limited to, particle sizes, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc.

Particle sizes of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle sizes and size distribution. This can be critical for low-dose drugs, and satisfactory dosage units of low doses cannot be manufactured from a drug that does not meet certain particle size and size distribution requirements. Also, particle size plays an important role in dissolution of active ingredient form the final dosage form for certain drugs like dexlansoprazole, because of their poor solubility. Hence, these physicochemical properties not only affect the processes of the preparing pharmaceutical compositions, but also affect the performance of pharmaceutical products, both in vitro and in vivo.

The selection of appropriate particles sizes of dexlansoprazole, as well as of excipients, is within the scope of the invention. The Dio, D50, and D90 values are useful ways for indicating a particle size distribution. Dg₀ is the size for which at least 90 volume percent of the particles have sizes smaller than the said value. Likewise Di₀ refers to 10 volume percent of the particles having sizes smaller than the given value. D₅o refers to at least 50 volume percent of the particles having sizes smaller than the given value, and D _[4,_3] refers to the mean particle size. Methods for determining Dio, D₅₀, D₉₀, and D[₄,3] include laser diffraction techniques, such as using equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom, or by Horiba.

In embodiments, the compositions of the present invention comprise dexlansoprazole or a pharmaceutically acceptable form of dexlansoprazole which has a particle size distribution such that: Dg₀ is about 1 μm to about 1000 μm, or about 1 μm to about 500 μm, or about 10 μm to about 250 μm; and D50 is from about 1 μm to about 500 μm, or about 1 μm to about 250 μm, or about 1 μm to about 100 μm. Flowability of materials is measured and represented using the Carr Index.

The Carr Index is the percentage ratio of the difference between tapped density and bulk density to tapped density, calculated as:

Carr Index = [(Tapped density-Bulk density) ÷ Tapped density] * 100.

In embodiments, multiparticulates of the present invention have Carr index values in the range of about 1-40%.

The densities can be determined using the standard test method 616 "Bulk Density and Tapped Density" from United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999.

Carr Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties. The dexlansoprazole compositions in the form of multiparticulates such as granules or pellets of the present invention has a Carr Index which is substantially lower than the 40% described for products with poor flow properties. Values for Carr Index for dexlansoprazole multiparticulate compositions of the invention are generally less than about 55%, or less than about 30%, or less than about 25%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms. In embodiments, multi-particulates of the present invention have particle sizes in the range of about 500 μm to about 2000 μm.

In embodiments, the present invention comprises delayed release solid oral dosage forms comprising dexlansoprazole or pharmaceutically acceptable salts thereof, wherein said dosage forms release less than about 20% of contained active ingredient within about the first 120 minutes, when immersed in 750 or 1000 ml_ of a 0.1 N hydrochloric acid (pH 1.2) dissolution medium, according to test method 711 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., 2005 ("USP"), and type Il apparatus. The dissolution medium is then changed to pH 6.8 phosphate buffer and release of the drug occurs thereafter, in the range of about 10% to about 45% of contained drug released within about an additional 90 minutes, and about 50% to about 100% of the drug released within about an additional 300 minutes.

In embodiments, the present invention includes delayed release solid oral dosage forms comprising dexlansoprazole or pharmaceutically acceptable salts thereof, wherein the dosage forms release less than about 10% of contained active ingredient within about the first 120 minutes after immersion into 0.1 N hydrochloric acid (HCI) dissolution medium. The dissolution medium is then changed to pH 7 phosphate buffer and release of the drug continues thereafter, in the range of about 30% to about 40% of the contained dexlansoprazole released within about an additional 45 minutes, and at least about 75% to about 80% released within about an additional 150 minutes.

An environment that a dosage form is likely to encounter when administered to a human (in vivo) can be correlated to in vitro dissolution studies conducted using dissolution media, such as, but not limited to, simulated gastric fluid (SGF) with or without pepsin, simulated intestinal fluid (SIF) with or without pancreatin, 0.01 N hydrochloric acid (HCI) , pH 1.2, 4.5, 5.5, 6.0, 6.8, 7.2, and 7.4 buffers, pH 2.1 SGF, pH 5.0 and 4.5 acetate buffers, pH 4.5 ammonium acetate buffer, pH 5.0 fed state simulated intestinal fluid (FeSSIF), pH 6.5 fasted state simulated intestinal fluid (FASSIF), pH 6.8 phosphate buffer with or without sodium lauryl sulphate (SLS), pH 1.5 HCI buffer, and the like.

Dexlansoprazole is characterized by a benzimidazole moiety. The drug is unstable under oxidative stress conditions and degrades to form sulphone and N- oxide impurities. Dexlansoprazole is a white to nearly white crystalline powder that melts with decomposition about 140⁰C, to form the impurities 2-mercapto-1 H- benzimidazole and an adduct. The drug is stable when exposed to light. Dexlansoprazole is unstable in acidic conditions, as compared to neutral to alkaline conditions. The drug degrades to form a sulphide impurity under acidic conditions. A nitrosulphoxide impurity is a process related impurity. Hence, dexlansoprazole appears to be an unstable molecule.

Among the various dexlansoprazole degradant impurities, impurities have been identified as described below: 1) Impurity A (2-mercaptobenzimidazole). Chemically, impurity A is 2- mercapto-1 H-benzimidazole and is represented by structural Formula II.

Formula Il

2) Impurity B (N-oxide). Chemically, impurity B is 2(((1-H- benzimidazole-2-yl)sulfinyl)methyl)3-methyl-4(2,2,2-trifluroethoxy)-pyridine-1 - oxide and is represented by structural Formula III.

Formula III

3) Impurity C (nitrosulphoxide). Chemically, impurity C is (R)-(+)-2-(4- Nitro-3-methyl-pyridin-2-ylmethanesulfinyl)-1 H-benzimidazole and is represented by structural Formula IV.

Formula IV

4) Impurity D (sulphone). Chemically, impurity D is (2-(((3-Methyl-4- (2,2,2-trifluroethoxy)-2-pyridyl) methyl-4-sulfonyl) benzimidazole) and is represented by structural Formula V.

Formula V

5) Impurity E (sulphide). Chemically, impurity E is 3,2-(((3-methyl-4- (2,2,2-trifluroethoxy)-pyridin-2-yl)methyl)sulfanyl)-1 H-benzimadazole and is represented by structural Formula Vl.

Formula Vl

6) Adduct impurity. Chemically, the adduct impurity is 1-(1 H- Benzoimidazol-2-ylsulfanyl)-1-methyl-2-(2,2,2-trifluoro-ethoxy)-4a,5,9b-triaza- indeno[2,1-a]indene and is represented by structural Formula VII.

Formula VII

In embodiments, the present invention provides stable formulations of dexlansoprazole, which are substantially free of individual degradation impurities. The term "substantially free" means presence of one or more degradation impurities in an amount less than about 5%, or about 4%, or about 3%, or about 2%, or about 1 %, of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations, wherein levels of impurity A (2-mercaptobenzimidazole) are less than about 2% of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity C (nitrosulphoxide) are less than about 2% of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity D (sulphone) are less than about 2% of the label content of dexlansoprazole. In embodiments, the invention relates to stable compositions and/or formulations wherein levels of impurity E (sulphide) are less than about 2% of the label content of dexlansoprazole.

In embodiments, the invention relates to stable compositions and/or formulations wherein levels of the adduct impurity are less than about 2% of the label content of dexlansoprazole.

In embodiments, formulations of the present invention may contain any one or more of impurities A, B₁ C, D, E, the adduct, or any other drug-related impurity. In embodiments, the invention relates to stable compositions and/or formulations wherein total drug-related impurities, e.g., any combinations of impurities A through E, are less than about 5% of the label content of dexlansoprazole. In embodiments, the invention includes methods of stabilizing dexlansoprazole, comprising: a) applying a layer of a suspension, dispersion, or solution of dexlansoprazole and at least one stabilizer, together with one or more pharmaceutically acceptable excipients, onto a pharmacologically inert substance, followed by drying; b) optionally, applying an intermediate coating; and c) mixing the composition of a) or b) with at least one pharmaceutically acceptable excipient.

Dexlansoprazole is stable at pH values about 9, at which the degradation of dexlansoprazole is minimum. Therefore, the use of a basic substance in an amount such that the environment of dosage form becomes about pH 9 has proven to be effective in stabilizing dexlansoprazole. pH values of about 11 or higher and pH values below about 7 do not provide stabilization as well as that obtained with pH vlaues between about 7 and about 11 , such as pH values about 9.

In embodiments, the invention provides stable pharmaceutical formulations comprising dexlansoprazole and at least one pharmaceutically acceptable carrier, wherein pH values obtained from mixing a formulation in water are less than about 12, or less than about 11 , or less than about 10. The pH of a pharmaceutical formulation can be measured by crushing 5 unit dosage forms in a mortar. For encapsulated products, the capsules are emptied and the contents crushed. The weight equivalent to one dosage form is mixed with 50 mL of purified water and the pH of the solution or suspension is measured.

Various stabilizers for use in the formulations of the invention, to reduce the degradation of dexlansoprazole during storage, etc., include organic and inorganic bases and alkaline substances. Various useful basic inorganic salts include, but are not limited to, basic inorganic salts of sodium, potassium, magnesium, calcium, and mixtures of any two or more thereof. Examples of basic inorganic salt of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, the like and mixtures of any two or more thereof. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, the like and mixtures of any two or more thereof. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al₂(OH)i₆Cθ₃-4H₂θ], aluminum hydroxide-magnesium [2.5MgO AI₂Oa XH₂O], and the like, and mixtures of any two or more thereof. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, the like and mixtures of any two or more thereof. .

Organic bases that may be used in the present invention are pharmaceutically acceptable organic bases, including, but not limited to, meglumine, lysine, N,N'-dibenzylethylenediamine, chloroprocain, choline, diethanolamine, ethylenediamine, procaine, and mixtures of any two or more thereof.

In embodiments, the invention relates to stable formulations of dexlansoprazole wherein concentrations of stabilizer are in the range of about 0.1 % to about 10%, by weight of the total composition. In embodiments, the invention relates to stable formulations of dexlansoprazole wherein weight ratios of dexlansoprazole to stabilizer are in the range of about 1 :0.01 to 1 :5.

An aspect of the present invention provides pharmaceutical compositions of dexlansoprazole wherein the polymorphic stability of dexlansoprazole is maintained during processing and storage.

In an embodiment, the dexlansoprazole used as the active ingredient is in a substantially amorphous form, which form is substantially retained during the manufacturing of the composition and also during storage for commercially relevant periods. In an embodiment, the dexlansoprazole used as the active ingredient is in a substantially crystalline form, which form is substantially retained during the manufacturing of the composition and also during storage for commercially relevant periods. In an embodiment, the dexlansoprazole used as the active ingredient is in a substantially crystalline form, which form is partially or completely converted into amorphous form during the manufacturing of the composition and/or during storage for commercially relevant periods. In an embodiment, the dexlansoprazole used as the active ingredient is in a substantially amorphous form, which form is partially or completely converted into crystalline form during the manufacturing of the composition and/or during storage for commercially relevant periods.

In embodiments, the partial or complete physical form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the stability of the composition.

In an embodiment, the partial or complete form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the physico-chemical properties of the composition. In an embodiment, the partial or complete form conversion of the active ingredient dexlansoprazole during the manufacturing of the composition and/or during storage does not affect the drug release from the composition.

Dexlansoprazole is sensitive to moisture and tends to degrade in the presence of water. Therefore, in order to produce a stabilized pharmaceutical formulation, a non-aqueous process, i.e., dry powder layering combined with minimizing water quantities in coating solutions have been used. The volume ratios of organic solvent to water in the coating solutions for the multiparticulates are about 85:15 to 95:5.

Dexlansoprazole is sensitive to heat and undergoes charring at temperatures about 60⁰C or more, or if exposed to a higher temperature for a longer duration of time. Under the influence of heat, the adduct and benzimidazole impurities are formed. In embodiments, the present invention provides processes for producing stable coated multiparticulates comprising drying the multiparticulates at temperatures below about 6O⁰C, such as 40 ± 10⁰C for about 120 minutes, or 40 ± 5°C, for about 120 minutes.

In embodiments, the invention provides processes for producing stable formulations, wherein multiparticulates are processed in an environment where the relative humidity is not more than about 70%. In embodiments, the invention provides processes for producing stable formulations, wherein multiparticulates have water content about 0.5-10% by weight, as determined using Karl Fischer techniques.

In embodiments, the invention provides processes for producing stable formulations, wherein multiparticulates have a loss on drying at 105⁰C in the range of about 0.25-10%, or about 0.5-5%, by weight of the multiparticulate composition.

In embodiments, the present invention provides processes for producing stable coated multiparticulates having residual solvent levels within the ICH permissible limits. ICH guidelines for residual solvents classify residual solvents into three classes based on possible risk to human health. The three classes are:

1. Class I solvents: solvents to be avoided

Known human carcinogens, strongly suspected human carcinogens, and environmental hazards. 2. Class Il solvents: solvents to be limited

Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.

3. Class III solvents: solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.

It was observed that during manufacturing of finished products using amorphous dexlansoprazole, the level of residual solvents can be higher than ICH limits. Various techniques involving variation of one or more of the parameters such as processing temperatures, drying times and temperatures, intermittent drying, ratios of drug and binder, concentrations of drug solution, multiple solvent systems (isopropyl alcohol, dichloromethane, methanol, acetone, and their mixtures), effective drying surface areas, and humidification can be used to minimize residual solvent concentrations. In embodiments, a high residual solvent content is prevented by preparation of a premix of dexlansoprazole and at least one pharmaceutically acceptable carrier. Suitable carriers include, but are not limited to, polyvinylpyrrolidones, hydroxypropyl methylcelluloses, basic substances such as magnesium carbonate, meglumine, etc., sugars such as mannitol, sorbitol, etc. and the like. X-ray diffraction patterns of premix samples have been generated at the time of preparation and after 20 hours of storage. The patterns indicate no change in polymorphic form, indicating that premixes are more physically stable. Further, the levels of residual solvent are much lower than the permissible levels, i.e., 3000 ppm. Hence, polymorphic conversion of amorphous to crystalline form and high residual solvent content during processing can be prevented by preparing premixes of dexlansoprazole.

The compositions of the invention can be further processed into various pharmaceutical dosage forms as prepared, or can be combined with one or more pharmaceutically acceptable excipients. The different pharmaceutical dosage forms which comprise the pharmaceutical compositions of the present invention include solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules. The modified release compositions may comprise hydrophilic, lipophilic, or hydrophobic release rate controlling substances, or their combinations, to form matrix or reservoir, or combinations of matrix and reservoir systems. The compositions may be prepared by any techniques, including direct blending, dry granulation, wet granulation (aqueous or non-aqueous, or partly aqueous and partly non-aqueous or aqueous-alcoholic), and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, compression-coated, powder coated, enteric coated, or modified release coated forms.

In embodiments, the invention includes oral pharmaceutical compositions in solid dosage forms, comprising: (a) a core containing dexlansoprazole, which is substantially free of basic substances; (b) a subcoating coated onto the core; and (c) an enteric coating coated onto the subcoating. In certain embodiments, the subcoating is chemically inert.

In embodiments, the invention includes oral pharmaceutical compositions in solid dosage forms, comprising: (a) a core containing dexlansoprazole, including a basic stabilizer; (b) optionally, a subcoating coated onto the core; and (c) an enteric coating. In an embodiment, an enteric coating is coated directly onto the core. In another embodiment, the oral pharmaceutical compositions further include a subcoating coated onto the core, with the enteric coating being coated onto the subcoating.

The cores may also include one or more pharmaceutically acceptable excipients such as surfactants, disintegrants, stabilizers, pH dependent or pH independent polymers, and/or binders. The cores of the present invention may be prepared by homogenously mixing dexlansoprazole and one or more pharmaceutically acceptable excipients, such as those mentioned hereinabove. In embodiments, the cores of the present invention comprise pharmacologically inert materials such as a diluent or sugar spheres, onto which a fluid containing dexlansoprazole is sprayed or layered. The mixture is then formulated into small beads, pellets, granules, fine granules, or mini-tablets, and filled into hard gelatin or soft gelatin capsules using conventional procedures.

In embodiments, formulations of dexlansoprazole are in the form of capsules containing two fractions of coated mini-tablets, A and B₁ wherein each of the fractions form about 5-98% by weight of the total weight of mini-tablets filled into the capsule, and wherein: (a) one fraction of mini-tablets comprises dexlansoprazole and at least one stabilizer in the core, an optional subcoating, and at least one coating comprising at least one pH dependent polymer that dissolves in a pH range about 5-6 to release the active agent; and (b) the other fraction of mini-tablets comprises dexlansoprazole and at least one stabilizer in the core, an optional subcoating, and at least one coating comprising at least one pH dependent polymer which dissolves in a pH range about 6-8 to release the active agent, the coating including at least one pore former.

The pore formers that may be used in the present invention are pharmaceutically acceptable excipients that are water soluble. They dissolve and diffuse out of the coating when they come in contact with aqueous surroundings forming a network of channels. Non-limiting examples include mannitol, dextrose, sucrose, lactose, the like and mixtures of any two or more thereof.

In embodiments, the formulations of dexlansoprazole are in the form of capsules containing two fractions of coated pellets or mini-tablets A and B, wherein each of the fractions forms about 5-98% by weight of the total weight of pellets or mini-tablets filled into the capsule, and wherein: (a) one fraction of pellets or mini-tablets comprises dexlansoprazole and at least one stabilizer in the core, an optional subcoating, and at least one coating comprising at least one pH dependent polymer that can dissolve in a pH range about 5-6, to release the active agent; and (b) the other fraction of pellets or mini-tablets comprises dexlansoprazole and at least one stabilizer in the core, an optional subcoating, and at least one coating comprising at least one pH dependent polymer that can dissolve in a pH range above 6 to about 8, to release the active agent, and wherein the fraction (a) does not completely release the active agent in pH 5-6 media, but about 10% to about 90% of the active agent in fraction (a) is released in a pH range about 6-8. An inert subcoating separates a core from an enteric coating polymer that contains free carboxyl groups, which could cause drug degradation and/or discoloration. The inert subcoating may also serve as a pH-buffering zone, in which hydrogen ions diffusing from the outside toward an alkaline core can react with hydroxyl ions diffusing from the alkaline core toward the surface of the coated articles. A subcoating may comprise one or more layers.

An inert subcoating can be applied to core pellets or mini-tablets by conventional coating procedures in a suitable coating pan or in a fluidized bed apparatus, using water and/or organic solvents for the coating solutions or dispersions. Water soluble or insoluble polymers that can be used for an inert subcoating include, but are not limited to, sugars, zein, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxyethyl celluloses, polyvinyl alcohols, polyethylene glycols, poloxamers (Pluronics™), ethyl celluloses, gelatin, polyarginines, polyglycines, polyvinylpyrrolidones, vinyl acetate copolymers, and mixtures thereof. In the case of mini-tablets, a coating may also be applied using a dry coating technique. The inert subcoating may also include pharmaceutically acceptable water-soluble or tablet excipients that rapidly disintegrate in water. Ordinary plasticizers, pigments, titanium dioxide, talc and other additives may also be included into an inert subcoating. In the case of gelatin capsules, the gelatin capsule itself serves as a subcoating. The quantity of the inert subcoating of the present invention may vary from about 0.1% to 10%, or about 0.5% to 4%, of the total weight of a core. The enteric coating can be applied either directly onto the core or onto the subcoated cores, using conventional coating techniques such as, for instance, pan coating or fluidized bed coating using solutions of pH dependent polymers in water and/or suitable organic solvents, or by using latex suspensions of polymers to provide a modified release of the active agent. Enteric coating polymers that can be used, for example, include cellulose acetate phthalates (CAP), hydroxypropyl methylcellulose phthalates (HPMCP), polyvinyl acetate phthalates (PVAP), hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate trimellitates, hydroxypropyl methylcellulose succinates, cellulose acetate succinates, cellulose acetate hexahydrophthalates, cellulose propionate phthalates, copolymers of methylmethacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methylmethacrylate, and methacrylic acid, copolymers of methylvinyl ether and maleic anhydride (Gantrez™ ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymers, natural resins such as zein, shellac and copal collophorium, carboxymethyl ethylcelluloses, co-polymerized methacrylic acid/methacrylic acid methyl esters, such as, for instance, materials sold as Eudragit^® L12.5, L100, or Eudragit^® S12.5, S100, and several commercially available enteric dispersion systems, e.g., Eudragit^® L30D55, Eudragit^® FS30D, Eudragit^® L100-55, Eudragit^® S100 (all from Evinik Industries), Kollicoat^® MAE30D and 30DP (from BASF),

Estacryl^® 3OD (from Eastman Chemical), Aquateric^® and Aquacoat^® CPD30 (from FMC), and mixtures thereof.

The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer such as, for instance, cetanol, triacetin, citric acid esters such as, for instance, triethyl citrate and products sold as Citroflex^® (from Pfizer), phthalic acid esters, dibutyl succinate, and similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer and is usually in the range of about 1-40% of the enteric coating polymer. Dispersants such as talc, colorants and pigments may also be included in the enteric coating layer. The weight of enteric coating applied is about 0.5-20%, or about 2-10%, of the weight of core material or the subcoated core material.

In embodiments, a coating is applied either directly onto the core or onto the subcoated cores using conventional coating techniques such as, for instance, pan coating or fluidized bed coating, using pH independent polymers dissolved or dispersed in water and/or suitable organic solvents, to provide a modified release of the active agent.

In embodiments, the cores contain one or more release modifying polymers in admixture with dexlansoprazole to form a matrix. In certain embodiments, a modified release matrix is further coated with pH dependent polymer or pH independent polymer, or combinations thereof.

One or more polymers that can be used in the invention for modified release include hydrophilic, hydrophobic, and lipophilic substances, and combinations thereof. Examples of polymers include, without limitation thereto, cellulose ethers, e.g., hydroxypropyl methylcelluloses (hypromelloses or HPMC), hydroxypropylcelluloses (HPC), hydroxyethylcelluloses, ethylcelluloses, and carboxymethylcellulose sodium, polyvinylpyrrolidones, including non-crosslinked polyvinylpyrrolidone, carboxymethylstarch, polyethylene glycols, polyoxyethylenes, poloxamers (polyoxyethylene-polyoxypropylene copolymers), polyvinylalcohols, glucanes (glucans), carrageenans, scleroglucanes (scleroglucans), mannans, galactomannans, gellans, alginic acid and derivatives (e.g., sodium or calcium alginate, propylene glycol alginate), polyaminoacids (e.g. gelatin), methyl vinyl ether/maleic anhydride copolymers, polysaccharides (e.g. carageenan, guar gum, xanthan gum, tragacanth and ceratonia), alpha-, beta- or gamma-cyclodextrins, dextrin derivatives (e.g. dextrin), polymethacrylates (e.g. copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups), acrylic acid polymers (e.g., carbomers), shellac and derivatives thereof, cellulose acetate, cellulose butyrate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate and other acetylated cellulose derivatives, and the like, including any mixtures thereof.

Examples of lipophilic or hydrophobic substances that can be used in the present invention include, without limitation thereto, waxes (e.g., camauba wax , microcrystalline wax, beeswax, and polyethoxylated beeswax), natural fats (coconut, soya, cocoa) including modified forms such as totally or partially hydrogenated, hydrogenated castor oil, hydrogenated vegetable oil, and fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylate fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and derivatives thereof, sphingolipids, sterols such as cholesterol and its substituted derivatives, etc.

In an aspect of the invention, dexlansoprazole is used for preparing inclusion complexes of drug with cyclodextrins. In an aspect of the invention, an amorphous form of dexlansoprazole is used for preparing inclusion complexes with cyclodextrins.

As used herein,' "cyclodextrin" refers to any of the natural cyclodextrins, α- cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and their respective derivatives or analogs. Cyclodextrins (sometimes called cycloamyloses) make up a family of cyclic oligosaccharides, composed of 5 or more α-D-glucopyranoside units linked 1— »4, as in amylose (a fragment of starch). The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecules (such as dexlansoprazole in the present invention), mostly in terms of water/aqueous solubility. An inclusion complex of dexlansoprazole with cyclodextrins also aids in penetration of the drug into body tissues.

Any cyclodextrin, which enhances the aqueous solubility and/or provides for effective delivery of dexlansoprazole, may be used in the present invention. The cyclodextrins of the present invention can include the natural occurring cyclodextrins and their derivatives. The natural cyclodextrins include α- cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Derivatives are typically prepared by modifying the hydroxyl groups located on the exterior or hydrophilic side of the cyclodextrin. The modifications can be made to increase the aqueous solubility and the stability of the complexes and can modify the physical characteristics of the complexes, including the formation and dissociation of the complex. The types and degrees of modification, as well as their preparation, are well-known in the art.

Any of the natural cyclodextrins can be derivatized, such as derivatives of β-cyclodextrin. Cyclodextrin derivatives include alkylated cyclodextrins, comprising methyl-, dimethyl-, trimethyl- and ethyl-β-cyclodextrins; hydroxyalkylated cyclodextrins, including hydroxyethyl-, hydroxypropyl-, and dihydroxypropyl-β-cyclodextrin; ethylcarboxymethyl cyclodextrins; sulfate, sulfonate and sulfoalkyl cyclodextrins, such as β-cyclodextrin sulfate, β- cyclodextrin sulfonate, and β-cyclodextrin sulfobutyl ether; as well as polymeric cyclodextrins. Other cyclodextrin derivatives can be made by substitution of the hydroxy groups with saccharides, such as glucosyl- and maltosyl-β-cyclodextrin.

Other cyclodextrins include the naturally occurring cyclodextrins, methyl-β- cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2-hydroxymethyl-β- cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3- hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, or β-cyclodextrin sulfobutyl ether. Any of the above cyclodextrins or their derivatives or polymers prepared from them can be used for preparation of the compositions of the invention, either alone or in the form of mixtures of one or more cyclodextrins.

In an aspect, pharmaceutical compositions of the present invention comprise dexlansoprazole, adsorbed onto at least one pharmaceutically acceptable carrier. Carriers according to the present invention include, but are not limited to, polyvinylpyrrolidones, hydroxypropyl methylcelluloses, sugars such as mannitol, sorbitol, and the like.

In embodiments, the invention includes modified release pharmaceutical compositions comprising dexlansoprazole, optionally together with one or more pharmaceutically acceptable excipients, wherein said compositions are in multiparticulate form. In embodiments, the invention includes modified release pharmaceutical compositions comprising cores containing dexlansoprazole, optionally together with one or more pharmaceutically acceptable excipients, and a coating comprising one or more polymers, wherein the said compositions are in multiparticulate form. In embodiments, modified release multiparticulates of dexlansoprazole comprise non-pariel cores such as sugar or similar substances, upon which dexlansoprazole is loaded, optionally together with one or more pharmaceutically acceptable excipients, using any technique such as powder layering, solution spraying, suspension spraying, or any other technique known to the art.

In embodiments, modified release compositions of the invention comprise dexlansoprazole loaded onto non-pariel cores having a coating comprising one or more pH independent polymers, pH dependent polymers, or combinations thereof.

In embodiments, the invention includes pharmaceutical compositions comprising modified release multi-particulates comprising dexlansoprazole, comprising dexlansoprazole-containing cores and a coating comprising one or more polymers, and optionally having one or more further coatings. In embodiments, multi-particulates comprising dexlansoprazole further comprise one or more non-functional coatings or functional coatings, to provide modified release of the active agent.

The multiparticulate formulations of the invention can be prepared using the techniques described herein, as well as other methods known to those having skill in the art.

In embodiments, multi-particulates comprising dexlansoprazole are coated with different concentrations of polymers, giving portions having different release profiles, and these can be combined to form a pharmaceutical composition or dosage form to achieve desired modified release profiles. In embodiments, multi-particulates comprising dexlansoprazole are coated with different types of polymers, either enteric polymers (pH dependent polymers) or modified release polymers (pH independent polymers) giving different release profiles, and these can be combined to form a pharmaceutical composition or dosage form to achieve desired modified release profiles. In embodiments, multi-particulates comprising dexlansoprazole can be combined with pharmaceutically acceptable excipients and compounded to form a pharmaceutical composition, which can be compressed into tablets or placed into suitable capsule shells, using techniques known to those having skill in the art. In embodiments, the compositions of the present invention are filled into hard gelatin capsules, wherein hard gelatin capsule shells comprise one or more of hydroxymethyl cellulose, carrangeenan, potassium chloride, polyvinyl polymers such as polyvinyl acetate and polyvinyl alcohol, and the like. Pharmaceutically acceptable excipients according to the present invention include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, anti-oxidants, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations. Various useful fillers or diluents according to the present invention include, but are not limited to, starches, lactose, mannitol (Pearlitol™ SD200), cellulose derivatives, confectioner's sugar, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV), and others. Different starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products), and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include, but are not limited to, Ceolus™ KG801 , Avicel™ PH 101 , PH102, PH301 , PH302 and PH-F20, PH-112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders according to the present invention include but are not limited to hydroxypropylcelluloses, also called HPC (Klucel™ LF, Klucel™ EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP- K30, and PVP-K90), Plasdone™ S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol^®), methylcelluloses, polymethacrylates, starches, and mixtures thereof.

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di- sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including, but not limited to, crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XMO, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include, but are not limited to, low-substituted hydroxypropylcellulose LH11 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal (or fumed) silicon dioxide, starches and mixtures thereof.

Useful surface-active agents according to the present invention include non-ionic, cationic or anionic or zwitterionic surface-active agents. Useful non- ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (Span™) and polyhydroxyethylenically treated sorbitan esters (Tween™), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface- active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as, for example, soybean lecithin, egg yolk and mixtures thereof.

In embodiments, the stabilized compositions of the present invention contain at least one antioxidant. The antioxidant may be present either as a part of the composition or as a packaging component. Thus, in a particular embodiment of a process according to the present invention, antioxidants are introduced into the formulation during the drug loading stage over inert cores. The antioxidants are present in an amount effective to retard decomposition of dexlansoprazole, as it is susceptible to oxidation. In embodiments, the content of antioxidant in the formulation ranges from about 0.001 to 10 weight percent, with respect to the active agent.

Among the antioxidants, non-limiting examples include ascorbic acid and its salts, tocopherols, and sulfite salts, such as sodium metabisulfite or sodium sulfite, sodium sulfide, dl-alpha-tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propyl gallate. Other suitable antioxidants will be readily recognized by those skilled in the art. In embodiments, sodium metabisulfite, sodium sulfite, sodium sulfide, and their mixtures are useful as antioxidants. Useful lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, camauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof. One or more glidant materials, which improve the flow of powder blends, pellets, and mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and combinations thereof.

Colouring agents can be used to colour code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein.

Colouring agents can also be used to differentiate the varied fractions of multiparticulates contained in a unit dosage form such as a capsule. Suitable colouring agents include, without limitation, natural and/or artificial compounds such as FD&C colouring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like.

Various solvents can be used in the processes of preparation of pharmaceutical compositions of the present invention include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, and any mixtures thereof. pH independent polymers according to the present invention include, but are not limited to, carbomers, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyvinyl acetates, polyvinyl alcohols, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, methyl celluloses, ethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxybutyl methyl celluloses, natural polymers such as alginates and other polysaccharides that include but are not limited to arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans (such as, for example, inulin), levan, fucoidan, carrageenan, galatocarolose, pectic acid, pectin, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, keratan, chondroitan, dermatan, hyaluronic acid, alginic acid, xanthan gum, starch, and various other natural homopolymer or heteropolymers such as those containing one or more of the following, viz., aldoses, ketoses, acids or amines, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, mannitol, sorbitol, lactose, sucrose, trehalose, maltose, cellobiose, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid, and naturally occurring derivatives thereof, and including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly (ortho) esters, polyurethanes, poly (butyric acid), poly (valeric acid), poly (caprolactone), poly (hydroxybutyrate), poly (lactide-co-glycolide) and poly (lactide-co-caprolactone) copolymers and mixtures thereof. Various pH dependent polymers according to the present invention include, but are not limited to, Eudragit^® 100, Eudragit^® RSPO & RLPO, Eudragit^® ND 40, polymers and copolymers of acrylic and methacrylic acids, cellulose acetate butyrates, cellulose acetate phthalates, hydroxypropyl methyl cellulose phthalates, poly(methyl methacrylate)s, poly(ethylmethacrylate)s, poly(butylmethacrylate)s, poly(isobutylmethacrylate)s, poly(hexlmethacrylate)s, poly(isodecylmethacrylate)s, poly(laurylmethacrylate)s, poly(phenyl methacrylate)s, poly(methyl acrylate)s, poly(isopropyl acrylate)s, poly(isobutyl acrylate)s, poly(octadecyl acrylate)s, and any mixtures thereof. In embodiments, one or more pH independent or pH dependent polymers are used for coating the compositions of the present invention.

Other useful additives for coating include, but are not limited to, plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents. Various useful plasticizers include, but are not limited to, substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titanium dioxide may also be present in an amount ranging from about 0.5% to about 20%, based on the total weight of the coating.

Antiadhesives are frequently used in the film coating process to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The antiadhesive is frequently present in the film coating in an amount of about 0.5% to 15%, based upon the total weight of the coating.

The foregoing descriptions of excipients are not intended to be exhaustive. Those skilled in the art will be aware of many other substances that are useful in the practice of the invention, and the use of such substances is specifically included in this invention.

In embodiments, the invention includes methods of preparing the pharmaceutical compositions of the present invention. In embodiments, the invention includes stabilized pharmaceutical compositions of dexlansoprazole that may be prepared by spray drying a suspension or solution of dexlansoprazole and a water soluble sugar derivative, with or without an organic base, and optionally together with one or more pharmaceutically acceptable excipients. Alternatively, dexlansoprazole compositions may also be prepared using fluid bed granulation techniques, where a solution of dexlansoprazole, with or without a stabilizer, and optionally together with one or more pharmaceutically acceptable excipients, is sprayed onto inert cores or layered on inert cores. In a specific embodiment, a composition of the present invention may be prepared by a process including: (a) dissolving dexlansoprazole or a pharmaceutically acceptable salt thereof in an organic solvent; (b) optionally, adding one or more pharmaceutically acceptable excipients such as a stabilizer, a binder, polymer and/or a disintegrant to the solution; (c) spraying the solution onto a substrate comprising at least one diluent, optionally together with a disintegrant, to obtain granules; (d) drying the granules; (e) optionally milling the granules; (f) mixing one or more excipients such as diluent, disintegrant, lubricant and/or glidant with the dried granules of (d) or milled granules of (e); (g) compressing the material of (f) to form mini-tablets; (h) optionally subcoating the mini-tablets; (i) coating the mini-tablets of (g) or (h) with a pH dependent polymer or a pH independent polymer; and (j) filling the coated mini-tablets into a capsule. In embodiments, the capsule comprises at least two fractions of coated mini-tablets, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In embodiments, the capsule comprises at least two fractions of coated mini-tablets, wherein both fractions are coated with one or more pH independent polymers or one or more pH dependent polymers.

In embodiments, dexlansoprazole compositions may be prepared using powder layering techniques, wherein a drug layering powder containing dexlansoprazole, with or without a stabilizer, optionally together with one or more pharmaceutically acceptable excipients, is layered onto inert cores while being sprayed with a binder solution. In a specific embodiment, a composition of the present invention may be prepared by a process including: (a) preparing a drug layering powder by mixing a diluent, optionally together with one or more pharmaceutically acceptable excipients, such as a stabilizer and/or a disintegrant; (b) preparing a binder solution; (c) coating sugar spheres with drug layering powder, while being sprayed with the binder solution, to obtain drug layered pellets; (d) drying the pellets; (e) optionally subcoating the drug layered pellets; (f) coating the pellets of (d) or (e) with a pH dependent polymer or a pH independent polymer; and (g) filling the coated pellets into a capsule. In embodiments, the capsule contains at least two fractions of coated pellets, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In embodiments, the capsule comprises at least two fractions of coated pellets, wherein both fractions are coated with one or more pH independent polymers or one or more pH dependent polymers.

Equipment suitable for processing the pharmaceutical compositions of the present invention include any one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multi-mills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

In embodiments, the invention includes packaging for the dexlansoprazole compositions which maintain stability during storage and transportation. The stabilization of the dexlansoprazole composition of the present invention can be improved by using packaging inhibiting the permeation of oxygen and moisture, packaging having inert gases (namely, packages with air replaced with gases other than oxygen), vacuum packaging and packages contianing a deoxidizer. The stabilization is improved by reducing oxygen with which the solid preparation is directly brought in contact, using these package forms. When a deoxidizer is enclosed, the pharmaceutical solid preparation can be packed with an oxygen permeating material, and then this is enclosed within other packaging.

In embodiments, stable compositions of the present invention include a desiccant and/or an oxygen absorbant as a component of packaging. A desiccant is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately well-sealed container. Commonly encountered pre-packaged desiccants are solids, and work through absorption or adsorption of water, or a combination of the two. Desiccants for specialized purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules. Pre-packaged desiccants are most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Non-limiting examples of various desiccants are anhydrous calcium sulfate (Drierite^®), silica gel, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves. Commercially available oxygen absorbant products such as StabilOx® are useful in minimizing the degradation of active agent due to oxidation.

In embodiments, the invention includes the use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, and blisters or strips composed of moisture resistant aluminum, high-density polypropylene, or polyvinyl chloride and/or polyvinylidene dichloride.

In embodiments, the invention includes forms of packaging for formulations of dexlansoprazole, such that retardation of drug release from the formulations is prevented. In embodiments, the invention provides a package suitable for commercial sale, which provides stability during storage, transportation, and use. In embodiments, the pharmaceutical dosage forms of the present invention are orally administered to a patient in need thereof.

In an aspect, the invention also provides methods of treating gastrointestinal inflammatory diseases and gastric acid-related diseases in mammals and man including reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer, using the formulations and pharmaceutical compositions of the present invention. The compounds and compositions of this invention may be administered to a subject in a therapeutically effective amount. The dosage forms can be subjected to in-vitro dissolution testing according to Test 711 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, to determine the rate at which the active substance is released from the dosage forms, and content of active substance can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).

A useful HPLC analytical method for determining dexlansoprazole concentrations and impurity content is one using a C-18 column (Xterra RP-18, 150x4.6 mm, 5 μm) and the following parameters:

Flow: 0.8 mL/minute.

Detector wavelength: 285 nm.

Column temperature: 30±2°C.

Injection volume: 40 μL

Run time: 60 minutes.

Mobile phase A: Water.

Mobile phase B: A mixture of acetonitrile, water and triethylamine in the volume ratio of 160:40:1 , respectively.

Program: Gradient, as shown in Table 1.

Table 1

A 200 ppm test solution is prepared in pH 11.0 borate buffer and 40 μL is injected into a reversed-phase C-18 column (Xterra RP-18,150x4.6 mm, 5 μm) of a gradient high performance liquid chromatograph. Absorbance is monitored at 285 nm. Borate buffer of pH 11.0 is used as a blank.

For the analysis, a blank is injected, followed by two injections of diluted standard, then a sample. Among the observed peaks are those having the relative retention times and relative response factors (dexlansoprazole = 1), as shown in Table 2. Table 2

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

EXAMPLES 1-2: Formulations for dexlansoprazole 60 mg and 30 mg capsules.

^* Evaporates during processing. ** Solid content of the dispersion Manufacturing process: A. Seal coating of sugar spheres

1. Hydroxypropyl methylcellulose (5 cps) is dissolved in a mixture of methanol and methylene chloride.

2. The solution is sprayed onto sugar spheres using a fluid bed processor (FBP)₁ to achieve a weight gain after drying of 5%. B. Drug loading onto sugar spheres

2. Meglumine is added to the solution and stirred to dissolve completely.

3. Dexlansoprazole is dissolved in the solution to form a drug solution, and the temperature of this solution is maintained at 2-15°C throughout the process.

4. The drug solution is sprayed onto seal coated sugar spheres from step A2.

5. Coated particles are dried at 40⁰C until loss on drying (LOD) is less than 2% w/w, measured at 105⁰C.

C. Subcoating

1. Hydroxypropyl methylcellulose (5 cps) is dissolved in a mixture of isopropyl alcohol and methylene chloride.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve.

3. Talc and titanium dioxide are combined with a mixture of isopropyl alcohol and methylene chloride, and colloid milled.

4. Dispersion from step 3 is added to polymer solution of step 1 and stirred.

5. The dispersion of step 4 is applied to drug coated sugar spheres from step B5, using a fluid bed processor.

D. Enteric Coating of delayed release portion

1. Dissolve Eudragit^® L100-55 in isopropyl alcohol with stirring. 2. Water and triethyl citrate are added to the solution with stirring.

3. Talc is added to the solution with stirring.

4. The dispersion of step 3 is sprayed onto 25% of the subcoated pellets from step C5, to achieve a weight gain after drying of 15% ± 3% w/w, using a FBP with bottom spray. 5. Coated pellets are dried in the FBP until LOD is between 1-3% w/w at 105⁰C, measured using a halogen moisture balance.

6. The pellets are cured in the FBP for 2 hours at 40⁰C.

E. Enteric coating of extended release portion 1. Eudragit^® S100 and Eudragit^® L100 are dissolved in a mixture of 92 parts isopropyl alcohol and 8 parts water.

2. Triethyl citrate is dissolved in water.

3. The solution of step 2 is added slowly to the solution of step 1 with continuous stirring.

4. Talc is added to solution of step 3, with stirring, and stirring is continued during the subsequent coating operation.

5. The dispersion from step 4 is sprayed onto 75% of the subcoated pellets from step C5, to achieve a weight gain after drying of 50% ± 5% w/w, using a FBP with bottom spray.

6. Coated pellets are dried in the FBP until LOD of the tablets is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

7. The pellets are cured in the FBP for 2 hours at 40⁰C. F. Encapsulation

1. Enteric coated pellets (DR and ER) are filled into capsules.

The capsules of Example 2 are packaged in a closed HDPE container with a 3 g molecular sieve pouch (Example 2A) or a 3 g silica gel pouch (Example 2B) as desiccants, and stored at accelerated stability testing conditions 40⁰C and 75% relative humidity (RH) for 3 months. Samples are analyzed for impurities before and after the storage, and data are tabulated in Table 3, where the values are expressed as percentages of the label dexlansoprazole content.

Table 3

ND: Not detected.

Samples are analyzed using XRPD. Figures 1 and 2, respectively represent XRPD patterns for the DR and ER portions of the Example 2 product ("A") and a pattern is also shown for a similarly prepared placebo formulation without any dexlansoprazole ("P"). Figure 3 shows XRPD patterns for the contents of Example 2A capsules ("A") and a similarly prepared placebo formulation without any dexlansoprazole ("P"), after storage at 4O⁰C and 75% RH for 3 months. The patterns indicate that dexlansoprazole retains its polymorphic form during the storage.

Physical characteristics of coated pellets prepared according to Example 2, such as particle size, bulk density and tapped density, are measured. The pellets are subjected to bulk and tapped density testing according to Test 616 "Bulk Density and Tapped Density," Method I, in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, to determine the flow properties of the pellets. Data are shown in Table 4.

Table 4

EXAMPLE 3: Formulation for dexlansoprazole 60 mg capsules.

* Evaporates during processing. ** Solid content of the dispersion. Manufacturing process: A. Seal coating of sugar spheres

1. Hydroxypropyl methylcellulose (HPMC 5 cps) is dissolved in a mixture of isopropyl alcohol and dichloromethane.

2. The solution is sprayed onto sugar spheres using a FBP, to achieve a weight gain of 5%. B. Drug loading on sugar spheres

1. Polyvinylpyrrollidone (K30) is dissolved in methanol.

2. Meglumine is added to the solution and stirred to disperse it.

3. Sodium sulphite is dissolved in water and added to the dispersion. 4. Dexlansoprazole is dissolved in the dispersionand the temperature of the dispersion is maintained at 2-15°C throughout the remaining process.

5. The dispersion is sprayed onto seal coated sugar spheres from step A2, and pellets are dried at 40⁰C until LOD is less than 2% w/w, measured at 105⁰C. C. Subcoating

1. Hydroxypropyl methylcellulose is dissolved in a mixture of isopropyl alcohol and dichloromethane.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve, mixed with isopropyl alcohol and dichloromethane, and colloid milled. 3. The solution from step 1 and the dispersion from step 3 are combined and stirred.

4. The mixture from step 4 is coated onto the pellets from step B5, using a FBP.

D. Enteric coating of delayed release portion 1. Eudragit^® L100-55 is dissolved in isopropyl alcohol.

2. Water (5% of the isopropanol volume in step 1) and triethyl citrate are added to the solution with stirring.

3. Talc is added to the solution with stirring.

4. The dispersion from step 3 is sprayed onto 25% of the subcoated pellets from step C5, to achieve a weight gain of 15 ± 3% w/w, using a FBP with bottom spray.

5. Coated pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

6. The pellets are cured in the FBP for 2 hours at 4O⁰C. E. Enteric coating of extended release portion

The process for enteric coating of extended release pellets is similar to the process described for Examples 1 and 2. F. Encapsulation 1. Enteric coated pellets (DR and ER) are filled into capsules.

The capsules of Example 3 are analyzed for impurities, and the results are in Table 5, where the values are expressed as percentages of the label dexlansoprazole content.

Table 5

EXAMPLES 4-5: Formulation for dexlansoprazole 60 mg and 30 mg capsules. A. Delayed release (DR) pellets

* Evaporates during processing.

# Solid content of the dispersion.

Particle size distribution of dexlansoprazole used in the formulations:

Manufacturing process: Steps for DR and ER portions are the same, through the 'subcoating' stage.

A. Drug layering

1. Dexlansoprazole, powdered sucrose, magnesium carbonate, and low-substituted hydroxypropyl cellulose are mixed together, to produce a drug layering powder.

2. Hydroxypropyl cellulose is dissolved in water.

3. Sugar spheres are coated with drug layering powder, while being sprayed with the solution of step 2, in powder layering equipment.

4. Drug layered pellets are dried in a FBP at 40 ± 5⁰C, until LOD₁ measured at 105⁰C, is 2% w/w or less.

B. Subcoating

1. Hydroxypropyl cellulose is dissolved in water.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve. 3. Talc and titanium dioxide are mixed with water and colloid milled.

4. Dispersion of step 3 is added to polymer solution of step 1 and stirred.

5. Dispersion of step 4 is coated onto the drug layered pellets from step A4, using a FBP.

C. 1. Enteric Coating of DR portion

1. Methacrylic acid copolymer type C, Eudragit^® L30D-55 is mixed with water.

2. Polyethylene glycol 6000 is dissolved in water and combined with the dispersion of step 1.

3. Polysorbate 80 is dissolved in warm water, then cooled. Talc and titanium dioxide are dispersed in the solution and homogenized for 15 minutes.

4. Dispersion of step 3 is added to the solution of step 2 and stirred.

5. The dispersion of step 4 is sprayed onto subcoated pellets to achieve a weight gain of 20 ± 3%, using a FBP with bottom spray.

6. Coated pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105^cC using a halogen moisture balance.

7. The pellets are cured in the FBP at 40⁰C for 2 hours.

8. Talc is added to enteric coated pellets in the FBP and fluidized for 10 minutes.

C. 2. Enteric coating of ER portion

1. Eudragit^® S100 and Eudragit^® L100 are dissolved in isopropyl alcohol.

2. Triethyl citrate is dissolved in water. 3. Solution of step 2 is added slowly to the solution of step 1 with continuous stirring.

4. Talc (first quantity) is added to the solution of step 3 with stirring, and the stirring is continued throughout the coating operation.

5. The dispersion is sprayed onto subcoated pellets, to achieve a weight gain of 50 ± 5% w/w, using a FBP with bottom spray.

6. Coated pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

7. The pellets are cured in the FBP at 4O⁰C for 2 hours. 8. Talc is added to enteric coated pellets in the FBP and fluidized for 10 minutes.

D. Encapsulation

1. Enteric coated pellets (DR and ER) are filled into capsules.

The bulk density, tapped density, Carr index, and particles size properties of the pellets are shown in Table 6.

Table 6

The above-prepared ER pellets, filled into six capsule shells, are subjected to dissolution testing with the following conditions:

Medium: 0.1 N HCI (pH 1.2) for the first 2 hours, then in pH

6.8 phosphate buffer with 0.3% SLS.

Volume of medium: 900 mL. Apparatus: USP apparatus Il (paddle). Stirring: 75 rpm. Duration: 150 minutes. The results are shown in Table 7.

Table 7

EXAMPLES 6-7: Dexlansoprazole-loaded pellets.

^* Evaporates during processing. Manufacturing process:

1. Meglumine or magnesium oxide, and polyvinylpyrrolidone K30, are combined with a mixture of dichloromethane and methanol, with stirring.

2. Dexlansoprazole is added to the dispersion of step 1 and the entire dispersion is passed through a sieve. Temperatures of 4-15⁰C are maintained throughout the coating process.

3. The dispersion of step 2 is sprayed onto sugar spheres, in a FBP.

4. Drug layered pellets are dried in the FBP at 40 ± 5⁰C until the LOD, measured at 105⁰C, is 2% w/w or less.

The pellets of Example 6 and 7 are stored at 25°C and 60% RH in a closed HDPE container. Samples are analyzed for impurities before and after storage, and the results are shown in Table 8.

Table 8

ND: Not detected.

EXAMPLE 8: Formulation for dexlansoprazole 60 mg capsules

^* Evaporates during processing.

** Solids content of the dispersion

Manufacturing process for delayed release portion:

A. Seal coating of sugar spheres 1. Polyvinylpyrrollidone K30 is dissolved in water.

2. The solution is sprayed onto sugar spheres using a FBP, to achieve a weight gain of 5% after drying.

B. Drug loading onto seal coated sugar spheres

1. Polyvinylpyrrollidone K30 is dissolved in water. 2. Magnesium carbonate light, sodium lauryl sulphate, and dexlansoprazole are combined with water and homogenized for 30 to 45 minutes.

3. Dispersion of step 2 is added to the solution of step 1 with stirring.

4. The dispersion is passed through a 100 or 80 mesh sieve and is slowly stirred throughout the coating process. 5. Seal coated pellets from step A1 are coated with dispersion from step 4 in a FBP with bottom spray and dried in the FBP until LOD is less than 2% w/w, measured at 105⁰C using a halogen moisture balance.

C. Subcoating of drug loaded pellets

1. Polyvinylpyrrollidone K30 is dissolved in water. 2. Talc and titanium dioxide are combined with water and homogenized for 20 to 30 minutes. 3. Dispersion of step 2 is added to polymer solution of step 1 and stirred.

4. Dispersion is coated onto drug loaded pellets using a FBP.

D. Enteric Coating - The enteric coating process for delayed release portion is similar to the process followed for coating delayed release pellets of Examples 4 and 5.

Manufacturing process for extended release portion:

A. Seal coating of sugar spheres

1. Polyvinylpyrrollidone K30 is dissolved in water. 2. The solution is sprayed onto sugar spheres using a fluid bed processor, to achieve a weight gain of 5% w/w after drying.

B. Drug loading onto seal coated sugar spheres

1. Polyvinylpyrrollidone K30 is dissolved in water.

2. Magnesium carbonate light, sodium lauryl sulphate and dexlansoprazole are combined with water and homogenized for 30 to 45 minutes.

3. The dispersion from step 2 is added to the solution from step 1 and stirred.

4. The dispersion is passed through a 100 or 80 mesh sieve and slowly stirred throughout the coating procedure. 5. Seal coated pellets from step A2 are coated with the dispersion in a

FBP with bottom spray and dried in the FBP until LOD of the pellets is less than 2% w/w, measured at 105⁰C using a halogen moisture balance.

C. Subcoating of drug loaded pellets

1. Polyvinylpyrrollidone K30 is dissolved in water. 2. Talc and titanium dioxide are combined with water and homogenized for 20 to 30 minutes.

3. Dispersion of step 2 is added to the polymer solution of step 1 and stirred.

4. The dispersion is coated onto drug loaded pellets from step B5, using a FBP.

D. Enteric Coating - The enteric coating process for extended release portion is similar to the process followed for coating extended release pellets of Examples 4 and 5. Encapsulation

1. Enteric coated pellets (DR containing 25% of the total dose and ER containing 75% of the total dose) are filled into capsules (HPMC₁ size 1 for 60 mg)-

Capsules of Example 8 are packaged in a closed HDPE container with a 3 g molecular sieve desiccant pouch and stored under accelerated stability testing conditions of 4O⁰C and 75% RH for 2 months. The samples are analyzed for impurities before and after storage, and results are shown in Table 9, where values are percentages of the label dexlansoprazole content.

Table 9

ND: Not detected.

The initial and 2 months stored samples of Example 8 are analyzed by XRPD. Figure 4 shows patterns for the formulation before storage, where A represents the contents of capsules, B represents crystalline dexlansoprazole, and P represents a similarly prepared placebo formulation, without any drug. Figure 5 shows patterns for the formulation after storage, where A represents the contents of capsules, B represents crystalline dexlansoprazole, and P represents a placebo formulation, without any drug. It is observed that dexlansoprazole retains its polymorphic form in the formulation during storage. EXAMPLES 9-10: Formulations for dexlansoprazole 60 mg and 30 mg capsules. A. Delayed release (DR) pellets

B. Extended release (ER) pellets

* Solids content of the dispersion. ** Evaporates during processing. Manufacturing process:

1. Extended Release Portion

A. Seal coating of sugar spheres 1. Hydroxypropyl methylcellulose (HPMC 5 cps) is dissolved in water.

B. Drug Loading

1. Hydroxypropyl methylcellulose is dissolved in water. 2. Magnesium carbonate light and dexlansoprazole are combined with water and homogenized for 30 to 45 minutes.

3. Dispersion of step 2 is added to solution of step 1 with stirring.

4. The dispersion is passed through a 60 or 80 mesh sieve and is slowly stirred throughout the coating procedure. 5. Seal coated pellets from step A2 are coated with the dispersion using a FBP with bottom spray.

C. Subcoating

1. Hydroxypropyl methylcellulose is dissolved in water.

2. Talc and titanium dioxide are combined with water and homogenized for 20 to 30 minutes.

3. Dispersion of step 2 is added to the polymer solution of step 1 with stirring.

4. Dispersion is coated onto drug loaded pellets from step B5 using a FBP. D. Enteric Coating

The enteric coating process for extended release portion is similar to the process followed for coating extended release pellets of Examples 4 and 5.

II. Delayed Release Portion A. Seal Coating

1. Hydroxypropyl methylcellulose is dissolved in water.

2. The solution is coated onto sugar spheres using a FBP to achieve a weight gain of 5% after drying. B. Drug Loading

1. Hydroxypropyl methylcellulose is dissolved in water.

2. Magnesium carbonate light, sodium lauryl sulphate, and dexlansoprazole are combined with water and homogenized for 30 to 45 minutes. 3. Dispersion of step 2 is added to the solution of step 1 with stirring.

4. The dispersion is passed through a 60 or 80 mesh sieve and slowly stirred throughout the coating procedure.

5. Seal coated pellets from step A2 are coated with the dispersion using a FBP with bottom spray. • C. Subcoating

1. Hydroxypropylmethylcellulose is dissolved in water.

3. Dispersion of step 2 is added to polymer solution of step 1 and stirred.

4. Dispersion is coated onto drug loaded pellets from step B5 using a FBP.

D. Enteric Coating

The enteric coating process for delayed release portion is similar to the process followed for coating delayed release pellets of Examples 4 and 5.

E. Encapsulation

1. DR and ER pellets are filled into capsules.

Capsules of Example 9 are packaged in a closed HDPE container with a 3 g molecular sieve desiccant pouch, and stored under accelerated stability testing conditions of 4O⁰C and 75% RH for 3 months. Samples are analyzed for impurities before, during, and after storage, and the results are shown in Table 10. Samples also are subjected to dissolution testing with the following conditions:

Medium: 0.1 N HCI (pH 1.2) for 2 hours, then in pH 7.0 phosphate buffer with 0.3% SLS. Volume of medium: 900 mL. Apparatus: USP apparatus Il (paddle).

Stirring: 75 rpm. Duration: 150 minutes, and the results are shown in Table 1 1.

Table 10

ND: Not detected.

Table 11

The initial, 1 , 2 and 3 months stored samples of Example 9 are analyzed by XRPD. Figure 6 shows comparative XRPD patterns for the formulation prepared according to Example 9, where A represents the starting crystalline dexlansoprazole, B represents the formulation (DR and ER), C represents formulation after storage at 40⁰C and 75% RH for 1 month, D represents formulation after storage at 4O⁰C and 75% RH for 2 months, E represents formulation after storage at 4O⁰C and 75% RH for 3 months, and P represents a similarly prepared placebo formulation. A decrease in the intensity of the characteristic peaks of input crystalline dexlansoprazole has been observed during storage. Hence, it is concluded that initially crystalline dexlansoprazole is substantially converted to amorphous form in the formulation, during storage.

These results indicate that the conversion of the initial crystalline form of dexlansoprazole, substantially to amorphous form, during the manufacturing of the composition and/or during storage does not affect drug release from the formulation.

EXAMPLE 11 : Dexlansoprazole 90 mg, 60 mg, and 30 mg capsules.

^* Evaporates during processing. Manufacturing process:

A. Drug Layering

1. Dexlansoprazole, powdered sucrose, magnesium carbonate, and L- HPC are mixed.

2. HPC is dissolved in methanol.

3. Sugar spheres are coated with the powder mixture, while being sprayed with the solution of step 2, in powder layering equipment.

4. Pellets are dried in a FBP at an inlet temperature of 40 ± 5°C until LOD at 105⁰C is 2% w/w or less.

B. Subcoating

1. Hydroxypropylcellulose is dissolved in a mixture of ethanol and water.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve, combined with ethanol, and colloid milled.

3. Dispersion of step 2 is added to polymer solution of step 1 and stirred.

4. The dispersion is coated onto pellets of step A4, using a FBP.

C. Coating of Part A 1. Eudragit S100 and Eudragit L100 are dissolved in ethanol.

2. Triethyl citrate is dissolved in water.

3. The solution of step 2 is added slowly to the solution of step 1 , with continuous stirring. 4. Talc is added to the solution with continuous stirring, and the dispersion is stirred throughout the coating operation.

5. The dispersion is coated onto subcoated pellets from step B4 using a FBP with bottom spray. 6. Coated pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

7. The pellets are cured in the FBP at 4O⁰C for 2 hours.

8. Talc is added to enteric coated pellets in the FBP and fluidized for 10 minutes. D. Coating of Part B

1. Eudragit L30D55 is diluted with water and mannitol is added to the dispersion.

2. Triethyl citrate is dissolved in water.

3. Solution of step 2 is added slowly to dispersion of step 1 , with continuous stirring.

4. Talc is added to the dispersion, continuous stirring, and the dispersion stirred throughout the coating operation.

5. The dispersion is coated onto subcoated pellets from step B4, using a FBP with bottom spray. 6. Coated pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

7. The pellets are cured in the FBP at 40⁰C for 2 hours.

8. Talc is added to coated pellets in the FBP and fluidized for 10 minutes. E. Encapsulation

1. Parts A and B pellets are filled into capsules.

EXAMPLE 12: Dexlansoprazole 90 mg, 60 mg, and 30 mg capsules.

^* Evaporates during processing. Manufacturing process: A. Drug Layering

1. Dexlansoprazole, powdered sucrose, magnesium carbonate, and L- HPC are mixed. 2. HPC is dissolved in methanol.

3. Sugar spheres are coated with the powder from step 1 , while being sprayed with the solution of step 2, in powder layering equipment.

4. Drug layered pellets are dried in a FBP at 40 ± 5°C until LOD at 105⁰C is 2% w/w or less.

B. Seal Coating

1. Hydroxypropyl methylcellulose is dissolved in a mixture of ethanol and water.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve, combined with an ethanol and water mixture, and colloid milled.

3. Dispersion of step 2 is added to the polymer solution of step 1 and stirred.

4. The dispersion is coated onto drug layered pellets from step A4 using a FBP. C. Part A (enteric coating)

1. Eudragit S100 and Eudragit L100 are dissolved in ethanol.

2. Tritethyl citrate is dissolved in water.

3. Solution of step 2 is added slowly to solution of step 1 , with continuous stirring. 4. Talc (first quantity) is added to the solution, with stirring, and stirring is continued throughout the coating operation. *

5. The dispersion is coated onto seal coated pellets from step B4 using a FBP with bottom spray.

6. The pellets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance.

7. The pellets are cured in the FBP at 4O⁰C for 2 hours.

8. Talc (second quantity) is added to enteric coated pellets in the FBP and fluidized for 10 minutes.

D. Part B (non-enteric coating) 1. HPMC is dissolved in water.

2. Tritethyl citrate is dissolved in water.

3. Solution of step 2 is added slowly to the solution of step 1 , with continuous stirring. 4. Talc (first quantity) is added to the solution with stirring, and stirring is continued throughout the coating operation.

7. The pellets are cured in the FBP at 40⁰C for 2 hours.

8. Talc (second quantity) is added to coated pellets in the FBP and fluidized for 10 minutes.

E. Encapsulation

1. Coated pellets (parts A and B) are filled into capsules.

EXAMPLE 13: Dexlansoprazole 60 mg and 30 mg capsules.

^* Evaporates during processing. *^* Solids content of the dispersion. Manufacturing process: I. Mini-tablets

A. Granules

1. Hydroxypropyl cellulose is dissolved in a mixture of methanol and methylene chloride.

2. Meglumine is dissolved in the solution.

3. Dexlansoprazole is dissolved in the solution, and the temperature of this solution is maintained at 2-15⁰C throughout the process.

4. The drug solution is sprayed onto a blend of mannitol and L-HPC using a FBC with top spray, then the formed granules are dried at 40⁰C until LOD is less than 2% w/w, measured at 105⁰C.

5. The granules are sifted through a 40 mesh sieve, and the retained particles are milled in comminuting mill, passed through the sieve, and combined with the original sieved material.

B. Tableting 1. Milled granules, mannitol, talc, and high-viscosity HPC are mixed in a double cone blender for 20 minutes.

2. Sodium stearyl fumarate is sifted through a 40 mesh sieve and mixed with the blend of step 6 in a double cone blender for 10 minutes. 3. The lubricated blend is compressed into 2 mm mini-tablets having an average weight of 5 mg.

II. Immediate release coating C. Drug Loading

1. Meglumine is dissolved in methanol, then PVP is dissolved with stirring.

2. Dexlansoprazole is dissolved in the solution with stirring, and the temperature is maintained at 4-15°C for coating.

3. Minirtablets from step B3 are coated with the solution of step 2 in a FBP. D. Subcoating

1. Hydroxypropyl cellulose is dissolved in a mixture of isopropyl alcohol and methylene chloride.

2. Talc and titanium dioxide are sifted through a 60 mesh sieve, combined with a mixture of isopropyl alcohol and methylene chloride, and colloid milled..

3. Dispersion of step 2 is added to polymer solution from step 1 and stirred.

4. The dispersion is coated onto the mini tablets from step C3, using a FBP. E. Enteric coating

1. Eudragit L30D-55 is diluted with water.

2. Polyethylene glycol is dissolved in water and added to the dispersion of step 1.

3. Polysorbate 80 is dissolved in warm water, GMS and titanium dioxide are added, and the mixture is homogenized for 45 minutes until room temperature is attained.

4. Dispersion of step 3 is added to the solution of step 2 and stirred. 5. Subcoated mini tablets from step D4 are coated with the dispersion to achieve a weight gain of 14 ± 2%, using a FBP with bottom spray.

6. Coated mini tablets are dried in the FBP until LOD is 1-3% w/w, measured at 105⁰C using a halogen moisture balance. 7. Minitablets are cured in the FBP for 2 hours at 40⁰C.

F. Encapsulation 1. Enteric coated mini-tablets are filled into capsules.

EXAMPLE 14: Dexlansoprazole 60 mg and 30 mg capsules.

* Evaporates during processing. *^* Solids content of the dispersion. Manufacturing process: A. Drug loaded pellets 1. Meglumine is dissolved in methanol, then hydroxypropyl cellulose is dissolved in the solution.

2. Dexlansoprazole is dissolved in the solution, and the temperature is maintained at 4-15⁰C during the coating procedure.

3. Sugar spheres are coated with the solution of step 2 in a FBP. B. Immediate release coating

1. Meglumine is dissolved in methanol, then PVP is dissolved in the solution.

2. Dexlansoprazole is dissolved in the step 1 solution, and the temperature is maintained at 4-15⁰C during the coating procedure. 3. Drug loaded pellets from step A3 are coated with the solution of step 2, in a FBP.

C. Subcoating

The subcoating process is similar to the process mentioned for Example 13. D. Enteric coating

The enteric coating process is similar to the process mentioned for Example 13.

E. Encapsulation

1. Lubricated enteric coated pellets are filled into capsules.

Claims

CLAIMS:

1. A stable pharmaceutical formulation comprising dexlansoprazole, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients, the formulation containing any of impurity compounds A, B, C, D, or E₁ in amounts less than about 2 percent by weight of the label dexlansoprazole content, and containing total dexlansoprazole-related impurities in amounts less than about 5 percent by weight of the label dexlansoprazole content, after storage for three months at 4O⁰C and 75% relative humidity.

D

2. The pharmaceutical formulation according to claim 1 , prepared using dexlansoprazole or a salt thereof having a mean particle size in the range of about 1 to about 500 μm.

3. The pharmaceutical formulation according to claim 1 , prepared using an amorphous form of dexlansoprazole or a salt thereof, which form is substantially retained during manufacturing of the formulation and/or during storage for a commercially relevant period.

4. The pharmaceutical formulation according to claim 1 , prepared using a crystalline form of dexlansoprazole or a salt thereof, which form is substantially retained during manufacturing of the formulation and/or during storage for a commercially relevant period.

5. The pharmaceutical formulation according to claim 1 , prepared using a crystalline form of dexlansoprazole or a salt thereof, which form is partially or completely converted into an amorphous form during manufacturing of the formulation and/or during storage for a commercially relevant period.

6. The pharmaceutical formulation according to claim 1 , prepared using an amorphous form of dexlansoprazole or a salt thereof, which form is partially or completely converted into a crystalline form during manufacturing of the formulation and/or during storage for a commercially relevant period.

7. The pharmaceutical formulation according to claim 1 , in the form of granules, pellets, spherules, micro-tablets, mini-tablets, a tablet, a capsule, or a capsule filled with particles.

8. The pharmaceutical formulation according to claim 1 , in the form of a capsule filled with particles, wherein a particle comprises: a) a core, comprising dexlansoprazole, or a pharmaceutically acceptable salt thereof, and at least one solid pharmaceutically acceptable excipient; b) optionally, an intermediate layer over the core; and c) an enteric coating over the core of a) or intermediate layer of b).

9. The pharmaceutical formulation of claim 1 , wherein a pharmaceutical excipient comprises at least one stabilizer for dexlansoprazole.

10. The pharmaceutical formulation of claim 9, wherein a stabilizer comprises sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, aluminum hydroxide-magnesium, calcium carbonate, calcium hydroxide, meglumine, lysine, N,N'-dibenzylethylenediamine, chloroprocain, choline, diethanolamine, ethylenediamine, procaine, or any mixtures thereof.

11. The pharmaceutical formulation according to claim 9, wherein a stabilizer is present in amounts about 0.1 to about 10 percent by weight of the total composition.

12. The pharmaceutical formulation according to claim 9, wherein weight ratios of dexlansoprazole to stabilizer are in the range of about 1 :0.01 to about 1 :20.

13. The pharmaceutical formulation according to claim 1 , wherein a pharmaceutical excipient comprises a pore former in concentrations about 0.001 to about 10 percent by weight of the dexlansoprazole content.

14. The pharmaceutical formulation of claim 13, wherein a pore former comprises mannitol, dextrose, sucrose, lactose, or any mixtures thereof.

15. The pharmaceutical formulation of claim 1 , wherein a pharmaceutical excipient comprises an anti-oxidant, in concentrations from about 0.001 to about 10 percent by weight of the dexlansoprazole content.

16. The pharmaceutical formulation of claim 15, wherein an anti-oxidant comprises ascorbic acid or any of its salts, a tocopherol, sodium metabisulfite, sodium sulfite, sodium sulfide, dl-alpha-tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, or any mixtures thereof.

17. The pharmaceutical formulation according to claim 1 , wherein no greater than about 10% of contained dexlansoprazole dissolves within about 120 minutes after immersion into a pH 1.2 aqueous medium, then, after immersion into pH 6.8 phosphate buffer, about 15% to about 25% of contained dexlansoprazole is dissolved within about an additional 90 minutes, and about 90% to about 100% is dissolved within about an additional 300 minutes.

18. The pharmaceutical formulation according to claim 1 , wherein no greater than about 10% of contained dexlansoprazole dissolves within about 120 minutes after immersion into a pH 1.2 aqueous medium, then, after immersion into a pH 7 phosphate buffer, about 30% to about 40% of contained dexlansoprazole is dissolved within about an additional 45 minutes, and about 75% to about 80% is dissolved within about an additional 150 minutes.

19. The pharmaceutical formulation according to claim 1 , having a water content about 0.5-10% by weight, as determined using a Karl Fischer technique.

20. The pharmaceutical formulation according to claim 1 , having a loss on drying at 105⁰C in the range of about 0.25 to about 10 percent by weight.

21. The pharmaceutical composition according to claim 1 , wherein pH values of the compositions are less than about 12.

22. The pharmaceutical composition according to claim 1 , wherein pH values of the compositions are less than about 10.

23. A process for preparing a pharmaceutical formulation, comprising: a) applying a layer of a powder, suspension, dispersion, or solution comprising dexlansoprazole or a salt thereof, at least one stabilizer, and one or more pharmaceutically acceptable excipients, onto inert particles, and drying; b) optionally, applying an intermediate coating; c) applying an enteric coating over particles of a) or an intermediate coating of b); d) mixing coated particles of c) and one or more pharmaceutically acceptable excipients, and e) forming the mixture of d) into a dosage form.

24. The process according to claim 23, wherein an enteric coating liquid phase comprises one or more organic solvents and water in volume ratios about 70:30 to about 100:0.

25. The process according to claim 23, wherein an enteric coating liquid phase comprises one or more organic solvents and water in volume ratios about 85:15 to about 95:5.

26. The process according to claim 23, wherein drying in a) is conducted at temperatures about 40 ±10°C.

27. The process according to claim 23, conducted at relative humidity values not higher than about 70%.

28. The pharmaceutical formulation according to claim 1 , packaged in a container that prevents ingress of oxygen and moisture.

29. The pharmaceutical formulation according to claim 28, packaged in a container with a desiccant, oxygen absorbent, or both.

30. A method of treating erosive esophagitis and heartburn associated with non-erosive gastroesophageal reflux disease in a mammal, comprising administering to the mammal an effective amount of the pharmaceutical composition according to claim 1.