DESC:FIELD OF THE INVENTION
[0001] The present disclosure pertains to the technical field of pharmaceuticals. In particular, the present disclosure pertains to stable controlled release unit dose formulation including at least one substituted benzimidazole derivative (preferably, dexlansoprazole) and preparation method thereof.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Substituted benzimidazoles are potent inhibitors of the H+/K+ ATPase parietal cell proton pump. There are number of substituted benzimidazoles available as proton pump inhibitors such as pantoprazole, omeprazole, esomeprazole, rabeprazole, lansoprazole etc. These actives are acid-labile and generally have poor stability. As other benzimidazole compounds, dexlansoprazole is also unstable in acidic medium. The drug will be rapidly decomposed in acidic to neutral aqueous solution and susceptible to moisture. Therefore, formulation containing such actives should be protected both during their passage through the acidic environment of the stomach and during storage. To overcome this, formulation containing the active is enteric coated to avoid contact of drug with gastric acid of the stomach. Dexlansoprazole have better stability in alkaline media, therefore it is often advantageous to add alkaline inactive ingredients to increase the stability of the active during manufacture and storage.
[0004] Dexlansoprazole is chemically known as (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl} sulfinyl]-lH-benzimidazole, and is structurally represented by the formula as shown below:

[0005] Presently, dexlansoprazole is marketed in the United States under the product trade name DEXILANT™ by Takeda in the strengths of 30 and 60 mg. DEXILANT™ is a proton pump inhibitor (PPI) with a dual delayed release formulation designed to provide two separate releases of medication. The product is indicated for heartburn associated with symptomatic non-erosive gastroesophageal reflux disease, the healing of erosive esophagitis and the maintenance of healed EE.
[0006] United States (US) patents 6,462,058 and 6,664,276 disclose crystalline forms of dexlansoprazole and a salt thereof.
[0007] US patent 7,790,755 discloses a capsule comprising two portions of tablet, granule, or fine granule compositions comprising an active ingredient, wherein the first portion comprises a pH-dependent soluble release-controlled coating layer that contains polymer(s) which are soluble in the pH range of 6.0 to 7.5 and second portion comprises an enteric coat that releases the active ingredient in the pH range of no less than 5.0 to no more than 6.0.
[0008] US patent application no. 2009/208575 discloses a pharmaceutical composition for oral use comprising a) a core comprising an effective amount of benzimidazole and an organic stabilizing agent which is present in an amount effective to stabilize the composition, b) an intermediate layer comprising of a water insoluble polymer and an organic stabilizer, and c) an outer enteric coating layer.
[0009] Indian patent application no. 944/MUM/2011 discloses a delayed release capsule comprising a) a core comprising of dexlansoprazole, alkaline agent and at least one pharmaceutically acceptable carrier b) a subcoat c) about 0 to 50 % of the subcoated core, coated with enteric coat that dissolves in the pH range of about 5.0 to about 5.5 c) about 50 to 100% of the subcoated core, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
[0010] PCT application no. PCT/TR2013/000097 discloses a solid pharmaceutical composition comprising a) a core comprising a proton pump inhibitor, an antacid and one or more pharmaceutically acceptable excipients b) an intermediate layer and c) an enteric coating layer.
[0011] However, there still remains an unmet need for an improved controlled release dosage form design that provides specific dissolution profile for dexlansoprazole, yet can be manufactured by a simple and economic method. There is also a need for an improved dexlansoprazole formulation that is stable and provides effective plasma concentration of dexlansoprazole for extended duration of time.
[0012] The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

OBJECTS OF THE INVENTION
[0013] It is an object of the present disclosure to provide a controlled release dosage form comprising at least one substituted benzimidazole derivative, which in operation can provide effective plasma concentration thereof to a subject in need of a treatment over an extended period of time.
[0014] It is a further object of the present disclosure to provide a controlled release formulation of at least one substituted benzimidazole derivative, which can eliminate or minimize the risk of food effects and dose dumping.
[0015] It is another object of the present disclosure to provide an extended release formulation of at least one substituted benzimidazole derivative, which exhibits desirable drug release profile and stability against pH changes.
[0016] It is another object of the present disclosure to provide an oral extended release dosage form comprising dexlansoprazole.

SUMMARY OF THE INVENTION
[0017] Aspects of the present disclosure relate to controlled release dosage form(s) comprising at least one substituted benzimidazole derivative, which in operation can provide effective plasma concentration thereof to a subject in need of a treatment over an extended period of time. According to embodiments, the controlled release dosage form can include at least three functional coating layers such as an intermediate layer, an enteric layer and a lag time controlling layer.
[0018] In an aspect, the present disclosure provides a controlled release pharmaceutical composition including: an inner inert core; a drug layer surrounding the inner inert core containing a substituted benzimidazole derivative, and one or more pharmaceutically acceptable excipients; a barrier layer surrounding the drug layer, wherein the barrier layer can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients; a first bioadhesive layer surrounding the barrier layer, wherein the first bioadhesive layer includes a natural polymer and one or more pharmaceutically acceptable excipients; an enteric layer surrounding the first bioadhesive layer, wherein the enteric layer includes an enteric polymer and one or more pharmaceutically acceptable excipients; and a second bio-adhesive layer surrounding the enteric layer, wherein the second bioadhesive layer includes a natural polymer and one or more pharmaceutically acceptable excipients.
[0019] In an embodiment, the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof. In an embodiment, the drug layer surrounding the inert core further includes an alkaline compound. In an embodiment, the alkaline compound includes one or more of magnesium carbonate, magnesium hydroxide, sodium hydroxide, sodium chloride, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, or any combination thereof. In an embodiment, the pH-independent water soluble polymer includes cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and/or mixtures thereof. In an embodiment, the bioadhesive polymer includes shellac. In an embodiment, the enteric layer includes a methacrylic acid copolymer. In an embodiment, the controlled release pharmaceutical formulation is in form selected from a group consisting of a tablet, a capsule and multilayered pellets.
[0020] According to embodiments of the present disclosure, the controlled release pharmaceutical formulation has an in vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released within about 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; and (b) not more than 20% of the dexlansoprazole or a salt thereof is released in a time of 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 20% and not more than 80% of the dexlansoprazole or a salt thereof is released in 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released in 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS.
[0021] In another aspect, the present disclosure provides a controlled release pharmaceutical composition, comprising: (a) first coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer and a bioadhesive coating; and one or more pharmaceutically acceptable excipients; and (b) second coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer, an enteric coating and one or more pharmaceutically acceptable excipients.
[0022] In an embodiment, the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof. In an embodiment, the first coated pellets comprises from about 10% to about 90% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 10% to about 90% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition. In an embodiment, the first coated pellets comprises from about 40% to about 60% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 40% to about 60% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition. In an embodiment, the barrier layer comprises cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and/or mixtures thereof. In an embodiment, the bioadhesive coating comprises shellac. In an embodiment, the enteric layer comprises a methacrylic acid copolymer.
[0023] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The presently disclosed embodiments will be further explained with reference to the drawings. The drawings are not necessarily in scale, with emphasis instead generally placed upon illustrating the principles of the presently disclosed embodiments.
[0025] The appended Fig. 1 illustrates the pellet realized in accordance with an embodiment of the present disclosure. Said pellet comprises of an inert core 1 which can be selected from microcrystalline cellulose beads, starch beads, sugar beads, inert organic and inorganic material beads or any other beadlets or commercially available non-peril seeds, granules, particles and micropellets. The inert core 1 is further coated with a drug layer 2, wherein the drug layer 2 can include dexlansoprazole or a salt thereof and one or more pharmaceutically acceptable excipients. The drug layer 2 is further coated with a barrier layer 3 surrounding the drug layer, wherein the barrier layer 3 can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients. The barrier layer 3 is further coated with a first bio-adhesive layer 4 surrounding the barrier layer, wherein the bioadhesive layer 4 can include a natural polymer and one or more pharmaceutically acceptable excipients. The bioadhesive layer 4 is further coated with an enteric layer 5 surrounding the first bioadhesive layer, wherein the enteric layer 5 can include an enteric polymer and one or more pharmaceutically acceptable excipients. The enteric layer 5 is further coated with a second bio-adhesive layer 6 surrounding the enteric layer 5, wherein the second bioadhesive layer 6 can include a natural polymer and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION
[0026] For those skilled in the art, numerous embodiments described below are for illustration purpose only, which do not limit the scope of the present disclosure in any manner.
[0027] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0028] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0029] As used in this specification, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0030] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.”
[0031] Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0032] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0033] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0034] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0035] Aspects of the present disclosure relate to controlled release dosage form comprising at least one substituted benzimidazole derivative, which in operation can provide effective plasma concentration thereof to a subject in need of a treatment over an extended period of time. According to embodiments, the controlled release dosage form can include at least three functional coating layers such as an intermediate layer, an enteric layer and a lag time controlling layer. The functional coating layers can protect the active ingredient in acid environment and retard the release in proximal region of small intestine. The functional coating layers can also control the release of active ingredient independent of food intake, thereby eliminating or minimizing the risk of food related dose dumping.
[0036] As used herein, the terms “granule” and “pellet” can be used interchangeably. For the purpose of this description, the terms “release modifying agent”, “release controlling agent”, and “controlled release agent”, relate to any material, used for controlling the release of an active ingredient from the formulation.
[0037] The claimed formulation composition is efficacious as compared to the formulation known in the art. The release of drug from the claimed composition is controlled by a combination of erosion and diffusion. The novelty aspect of the controlled release pharmaceutical composition resides in the composition with specific release rate of the active drug as stated in claim.
[0038] Aspects of the present disclosure relate to controlled release dosage form comprising at least one substituted benzimidazole derivative, which in operation can provide effective plasma concentration thereof to a subject in need of a treatment over an extended period of time. According to embodiments, the controlled release dosage form can include at least three functional coating layers such as an intermediate layer, an enteric layer and a lag time controlling layer.
[0039] In an aspect, the present disclosure provides a controlled release pharmaceutical composition including: an inner inert core; a drug layer surrounding the inner inert core containing a substituted benzimidazole derivative, and one or more pharmaceutically acceptable excipients; a barrier layer surrounding the drug layer, wherein the barrier layer can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients; a first bioadhesive layer surrounding the barrier layer, wherein the first bioadhesive layer includes a natural polymer and one or more pharmaceutically acceptable excipients; an enteric layer surrounding the first bioadhesive layer, wherein the enteric layer includes an enteric polymer and one or more pharmaceutically acceptable excipients; and a second bio-adhesive layer surrounding the enteric layer, wherein the second bioadhesive layer includes a natural polymer and one or more pharmaceutically acceptable excipients.
[0040] In an embodiment, the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof. In an embodiment, the drug layer surrounding the inert core further includes an alkaline compound. In an embodiment, the alkaline compound includes one or more of magnesium carbonate, magnesium hydroxide, sodium hydroxide, sodium chloride, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, or any combination thereof. In an embodiment, the pH-independent water soluble polymer includes cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and/or mixtures thereof. In an embodiment, the bioadhesive polymer includes shellac. In an embodiment, the enteric layer includes a methacrylic acid copolymer. In an embodiment, the controlled release pharmaceutical formulation is in form selected from a group consisting of a tablet, a capsule and multilayered pellets.
[0041] According to embodiments of the present disclosure, the controlled release pharmaceutical formulation has an in-vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released within about 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; and (b) not more than 20% of the dexlansoprazole or a salt thereof is released in a time of 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 20% and not more than 80% of the dexlansoprazole or a salt thereof is released in 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released in 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS.
[0042] In another aspect, the present disclosure provides a controlled release pharmaceutical composition, comprising: (a) first coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer and a bioadhesive coating; and one or more pharmaceutically acceptable excipients; and (b) second coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer, an enteric coating and one or more pharmaceutically acceptable excipients.
[0043] In an embodiment, the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof. In an embodiment, the first coated pellets comprises from about 10% to about 90% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 10% to about 90% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition. In an embodiment, the first coated pellets comprises from about 40% to about 60% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 40% to about 60% of Dexlansoprazole of the total weight of Dexlansoprazole present in said composition. In an embodiment, the barrier layer comprises cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and/or mixtures thereof. In an embodiment, the bioadhesive coating comprises shellac. In an embodiment, the enteric layer comprises a methacrylic acid copolymer.
[0044] In an embodiment, the controlled release formulation of dexlansoprazole can be multilayered pellets, wherein the multilayered pellets can include: an inner inert core; a drug layer surrounding the inert core, wherein the drug layer can include a substituted benzimidazole derivative (preferably, Dexlansoprazole or a salt thereof but not limited thereto) and one or more pharmaceutically acceptable excipients; a barrier layer surrounding the drug layer, wherein the barrier layer can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients; a first bio-adhesive layer surrounding the barrier layer, wherein the bioadhesive layer can include a natural polymer and one or more pharmaceutically acceptable excipients; an enteric layer surrounding the first bioadhesive layer, wherein the enteric layer can include an enteric polymer and one or more pharmaceutically acceptable excipients; and a second bio-adhesive layer surrounding the enteric layer, wherein the second bioadhesive layer can include a natural polymer and one or more pharmaceutically acceptable excipients.
[0045] The appended Fig. 1 illustrates the pellet realized in accordance with an embodiment of the present disclosure. Said pellet comprises of an inert core 1 which can be selected from microcrystalline cellulose beads, starch beads, sugar beads, inert organic and inorganic material beads or any other beadlets or commercially available non-peril seeds, granules, particles and micropellets. The inert core 1 is further coated with a drug layer 2, wherein the drug layer 2 can include dexlansoprazole or a salt thereof and one or more pharmaceutically acceptable excipients. The drug layer 2 is further coated with a barrier layer 3 surrounding the drug layer, wherein the barrier layer 3 can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients. The barrier layer 3 is further coated with a first bio-adhesive layer 4 surrounding the barrier layer, wherein the bioadhesive layer 4 can include a natural polymer and one or more pharmaceutically acceptable excipients. The bioadhesive layer 4 is further coated with an enteric layer 5 surrounding the first bioadhesive layer, wherein the enteric layer 5 can include an enteric polymer and one or more pharmaceutically acceptable excipients. The enteric layer 5 is further coated with a second bio-adhesive layer 6 surrounding the enteric layer 5, wherein the second bioadhesive layer 6 can include a natural polymer and one or more pharmaceutically acceptable excipients.
[0046] According to embodiments of the present disclosure, the inner inert core or seed core can be any conventional seed material, including but not limited to water soluble or insoluble seed selected from microcrystalline cellulose beads, starch beads, sugar beads, inert organic or inorganic material beads, or any other beadlets, non-peril seeds, granules, particles and micropellets.
[0047] In an embodiment, the first and second bio-adhesive layers of the controlled release formulation can be formed of a natural polymer that can preferably be selected from the group consisting of acacia gum, alginic acid, pectin, tragacanth, chitosan and shellac. However, is should be appreciated that any other material, as known to or appreciated by a person skilled in the pertinent art, can be utilized to serve its intended purpose as laid down in the present disclosure without departing from the spirit and scope of the present invention.
[0048] The first and second bio-adhesive layers can control the release of the active ingredient to provide an improved and pre-determined in-vitro release rate. The unique configuration of the bio-adhesive layers can facilitate release of the drug at different pH levels, thereby providing an improved in-vitro release profile. The bio-adhesive layer is capable of substantially maintaining its integrity in varying pH conditions of stomach depending on presence or absence of food, and can resist release of active ingredient in acidic environment of stomach. Desirable drug release rates can be achieved by changing the composition and/or configuration of the various layers of the controlled release formulation.
[0049] None of the cited prior art disclose the key feature of the present invention, which is the two coated layer of substantially water insoluble shellac applied to the intermediate layer, nor do they suggest providing such a layer. These two layers assist the release of drug from the claimed composition by diffusion. The dexlansoprazole (or any other substituted benzimidazole derivative formulated in accordance with embodiments of the present disclosure) is released in the gastrointestinal tract over a long period of time.
[0050] According to embodiments of the present disclosure, the multilayered pellets including dexlansoprazole can exhibit an in vitro dissolution profile, wherein (a) not less than 10% and not more than 30% of dexlansoprazole or a salt thereof is released within a time period ranging from 10 to 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 50% and not more than 80% of the dexlansoprazole or a salt thereof is released within a time period ranging from 50 to 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released within a time period ranging from 105 to 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS. In a preferred embodiment, the multilayered pellets including dexlansoprazole can exhibit an in-vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released within about 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; and (b) not more than 20% of the dexlansoprazole or a salt thereof is released in a time of 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 20% and not more than 80% of the dexlansoprazole or a salt thereof is released in 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released in 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS.
[0051] For determination of in vitro release rate, 0.1N HCl (500 ml) can be used as acid stage medium, and phosphate buffer (900 ml) having a pH of about 7 can be used as intestinal stage medium. The present formulation can release drug in the same manner as reference formulation.
[0052] The shellac coating layer of the invention is not affected by the fluctuations in the pH of the stomach environment due to presence or absence of food. Dexlansoprazole is released in a prolonged way from the oral tablet composition in small intestine.
[0053] According to embodiments of the present disclosure, a controlled release dosage form can be formulated in such a manner that a first portion of active ingredient is released either immediately or after a delay time to provide a pulse of drug release, and one or more additional portions of the active ingredient is released, each after a respective lag time, to provide additional pulses of drug release during a period of time.
[0054] In an exemplary embodiment, the present disclosure provides a controlled release pharmaceutical formulation comprising: (a) first coated pellets, comprising: an inner inert core; a drug layer surrounding the inert core, wherein the drug layer can include dexlansoprazole or a salt thereof and one or more pharmaceutically acceptable excipients; a barrier layer surrounding the drug layer, wherein the barrier layer can include a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients; a first bio-adhesive layer surrounding the barrier layer, wherein the bioadhesive layer can include a natural polymer and one or more pharmaceutically acceptable excipients; an enteric layer surrounding the first bioadhesive layer, wherein the enteric layer can include an enteric polymer and one or more pharmaceutically acceptable excipients; a second bio-adhesive layer surrounding the enteric layer, wherein the second bioadhesive layer can include a natural polymer and one or more pharmaceutically acceptable excipients; and (b) second coated pellets comprising dexlansoprazole or a salt thereof, a barrier layer, an enteric coating and one or more pharmaceutically acceptable excipients.
[0055] In an embodiment, the controlled release formulation including dexlansoprazole exhibits an in-vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released from the pellets within first 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; then (b) not less than 10% and not more than 30% of the dexlansoprazole or a salt thereof is released within a time period ranging from 10 to 20 minutes subsequent to the first 120 minutes; not less than 50% and not more than 80% of the dexlansoprazole or a salt thereof is released within a time period ranging from 50 to 60 minutes; not less than 80% of the dexlansoprazole or a salt thereof is released within a time period ranging from 105 to 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS. In a preferred embodiment, the controlled release formulation including dexlansoprazole exhibits an in-vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released within about 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; and (b) not more than 20% of the dexlansoprazole or a salt thereof is released in a time of 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 20% and not more than 80% of the dexlansoprazole or a salt thereof is released in 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released in 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS.
[0056] According to embodiments of the present disclosure, the controlled release formulation can be constructed as multilayered pellets with desirable dissolution profile. The pellets can be further filled in hard gelatin capsules or it can be further formulated in the form of tablets, disintegrating tablets, suspensions, etc. as required.
[0057] In another aspect, the present disclosure provides a method for producing a controlled release dosage form for oral administration, wherein the method can include the steps of: providing an aqueous binder solution comprising one or more pharmaceutically acceptable excipients; providing a blend comprising dexlansoprazole (or any other substituted benzimidazole derivative) and one or more pharmaceutically acceptable excipients; coating an inert core (non-pareil seeds or pellets or beads) with the blend while spraying the binder solution to provide a drug layer over the inert core; applying an aqueous hydroxypropylmethyl cellulose solution over the drug layer to provide a barrier layer; applying a bio-adhesive coating dispersion over the barrier layer to provide a first bio-adhesive layer; applying an enteric coating solution over the first bio-adhesive layer to provide an enteric layer; and applying a bio-adhesive coating dispersion over the enteric layer to provide a second bio-adhesive layer over the enteric layer.
[0058] The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1 - For orange coloured pellets

Ingredients Quantity in % (w/w)
Drug Pellets
Dexlansoprazole 22.0
Light Magnesium Oxide 7.2
Mannitol (Pearlitol 160 C) 6.8
Sodium Lauryl sulphate 4.5
Purified Talc 1.2
Croscarmellose Sodium 1.6
Non Pareil Seeds (Inactive core) 27.08
Sodium dihydrogen orthophosphate dihydrate 1.2
Hydroxymellose (Hydroxypropylmethylcellulose E-5) 5 cups 1.2
Isopropyl alcohol q.s.
Purified water q.s.
Seal coating
Hypromellose (Hydroxypropyl methyl cellulose) 4.0
Purified Talc 0.4
Triethyl citrate 0.4
Titanium dioxide 0.4
Sodium hydroxide 0.2
Isopropyl alcohol q.s.
Dichloromethane q.s.
Enteric coating
Eudragit S-100 (Enteric polymer) 21.0
Triethyl citrate 1.7
Lake of sunset yellow 0.3
Purified Talc 0.5
Titanium dioxide 0.5
Isopropyl alcohol q.s.
Acetone q.s
Purified water q.s
Process for preparation of orange coloured pellets:
Sifting process of drug pellets:
[0059] Dexlansoprazole, light magnesium oxide, mannitol, sodium lauryl sulfate, titanium dioxide, purified talc, Croscarmellose sodium were passed through the mesh size of 40 stainless steel sieve for sifting. The above sifted materials were transferred into a blender and mixed at slow speed for 15 minutes for dry mixing.
[0060] The binder solution was prepared by transferring the required quantity of isopropyl alcohol in stainless steel vessel. Dispersing hypromellose 5 cups in small quantities in isopropyl alcohol under stirring. Sodium dihydrogen orthophosphate dihydrate was dissolved in purified water under slow stirring. The stirring was continued till the clear solution was obtained. The above solutions were transferred under stirring to get clear uniform solution and free from lumps.
[0061] The required quantity of Non Pareil seeds were transferred into the conventional coating pan and, layering of the drug powder on the Non Pareil seeds by spraying the binder solution with the help of spray gun and dry mixing of the blend. After completion of drug powder layering, air dry the drug loaded pellets in tray dryer for 2 hours and followed by drying at 40ºC – 45ºC. The dried drug loaded pellets were sifted through the mesh 16 stainless steel sieve and stored in double lined polyethylene bags in HDPE containers.

Process for the formation of first layer on pellets (Seal coating)
[0062] Seal coating suspension was prepared by mixing Isopropyl alcohol and Dichloromethane in a stainless steel tank then HPMC (Hydroxypropyl methyl cellulose) E5 was added under continuous stirring till to get clear solution and free from lumps, Titanium Dioxide, Sodium hydroxide, Triethyl citrate and Talc were added to this solution under stirring till uniform dispersion was obtained and free from lumps. The seal coating suspension was filtered through the mesh of 100 stainless steel sieves.
[0063] The drug loaded pellets were transferred in FBE (Fluid Bed Equipment) bowl and seal coated by continuously spraying of seal coating suspension. The coating suspension was under continuous stirring throughout the coating process. After seal coating, the seal coated pellets were dried at the temperature of 35ºC to 40ºC in FBE. Sifting of the dried seal coated pellets by passing through the mesh 14 stainless steel and mesh size of 20 sieves in a vibratory sifter.
[0064] Enteric coating suspension was prepared by taking Isopropyl alcohol, acetone and purified water in a stainless steel vessel. Eudragit S-100 was added and dissolved under continuous stirring until the solution was clear and free from lumps. Triethyl citrate was added in the solution under continuous stirring until the solution was clear. Lake of sunset yellow, titanium dioxide and purified talc was dispersed into the above solution under stirring until a uniform suspension was obtained and free from lumps.
[0065] The seal coated pellets were transferred in a Fluid Bed Equipment (Bottom Spray) bowl and started enteric coating by continuously spraying of Enteric coating suspension. After enteric coating, the enteric coated pellets were dried at a temperature of 35ºC to 40ºC and further enteric coated pellets were sifted by passing through a mesh 14 and mesh 20 stainless steel sieves in a vibratory sifter.

Example 2 - For white coloured pellets
Ingredients Quantity in % (w/w)
Drug Pellets
Dexlansoprazole 22.0
Light Magnesium Oxide 8.2
Mannitol (Pearlitol 160 C) 5.8
Sodium Lauryl sulphate 4.0
Titanium dioxide 0.3
Purified Talc 0.5
Croscarmellose Sodium 1.5
Non Pareil Seeds (Inactive core) 24.70
Sodium dihydrogen orthophosphate dihydrate 1.2
PVP K-30 2.5
Isopropyl alcohol q.s.
Purified water q.s.
Seal coating
Hypromellose (Hydroxypropyl methyl cellulose) 12
Purified Talc 0.8
Triethyl citrate 1.2
Titanium dioxide 1.2
Isopropyl alcohol q.s.
Dichloromethane q.s.
Enteric coating
Drug coat L30D55 (Enteric polymer) 45.0
Triethyl citrate 1.7
Sodium hydroxide 0.1
Purified Talc 0.4
Titanium dioxide 0.4
Purified water q.s.
Process for preparation of white coloured pellets:
Sifting process of drug pellets:
[0066] Dexlansoprazole, light magnesium oxide, mannitol, sodium lauryl sulfate, titanium dioxide, purified talc, Croscarmellose sodium were passed through the mesh size of 40 stainless steel sieve for sifting. The above sifted materials were transferred into a blender and mixed at slow speed for 15 minutes for dry mixing.
[0067] The binder solution was prepared by mixing up of the two solutions in which the first solution was prepared by taking isopropyl alcohol and dispersing PVP K 30 (Polyvinylpyrrolidone/ Povidone) into it by stirring and the second solution was prepared by taking purified water and dissolving sodium dihydrogen orthophosphate dihydrate into it by stirring and filtering the solution.
[0068] The required quantity of Non Pareil seeds were transferred into the conventional coating pan and, layering of the drug powder on the Non Pareil seeds by spraying the binder solution with the help of spray gun and dry mixing of the blend. After completion of drug powder layering, air dry the drug loaded pellets in tray dryer for 2 hours and followed by drying at 40ºC – 45ºC. The dried drug loaded pellets were sifted through the mesh 16 stainless steel sieve and stored in double lined polyethylene bags in HDPE containers.

Process for the formation of first layer on pellets (Seal coating)
[0069] Seal coating suspension was prepared by mixing Isopropyl alcohol and methylene dihydrochloride in a stainless steel tank then HPMC (Hydroxypropyl methyl cellulose) E5 was added with constant and continuously stirring till to get clear solution and free from lumps, triethyl citrate was added to this solution under stirring. Titanium dioxide and purified talc were taken and passed through the mesh size of 100 and filtered with isopropyl alcohol and methylene dihydrochloride.
[0070] The drug loaded pellets were transferred in FBE (Fluid Bed Equipment) bowl and seal coated by continuously spraying of seal coating suspension. The coating suspension was under continuous stirring throughout the coating process. After seal coating, the seal coated pellets were dried at the temperature of 35ºC to 40ºC in FBE. Sifting of the dried seal coated pellets by passing through the mesh 14 stainless steel and mesh size of 20 sieves in a vibratory sifter.

Process for the formation of second layer on pellets (Enteric coating)
[0071] Purified water was taken in a stainless steel tank and sodium hydroxide was dissolved uniformly at the room temperature for getting the first solution, dispersion of drug coat L30 D in the purified water in a stainless steel tank under stirring. Titanium dioxide and purified talc were added to the purified water in a stainless steel tank for getting second solution. The Drug coat L30 was dispersed in the first solution by slow stirring for 5 to 10 min. The above solution was filtered and rinsed with purified water.
[0072] The seal coated pellets were transferred in a Fluid Bed Equipment (Bottom Spray) bowl and started enteric coating by continuously spraying of Enteric coating suspension. After enteric coating, the enteric coated pellets were dried at a temperature of 35ºC to 40ºC and further enteric coated pellets were sifted by passing through a mesh 14 and mesh 20 stainless steel sieves in a vibratory sifter.

Dissolution study:
Time Dexilant (% Drug release) Composition of the Invention (% Drug release)
10 min 20.6 19.0
20 min 23.0 31.3
50 min 55.61 57.5
60 min 73.6 62.8
75 min 86.7 77.8
105 min 93.9 89.3
120 min 95.5 93.4
sum 448.90 431.10
[0073] Table provides dissolution data for reference formulation (Dexilant®) and the composition according to the invention. For determination of drug release rate, USP Type I apparatus (100 rpm) was used wherein 0.1N HCl (500 ml) was used for acid stage and Phosphate buffer (900 ml) of pH 7.0 was used as an intestinal stage medium. The results indicate that composition of the invention migrates the drug release in equivalent manner or even further relative to that exhibited by reference formulation.
,CLAIMS:1. A controlled release pharmaceutical composition, said composition comprising:
an inner inert core;
a drug layer surrounding the inert core containing a substituted benzimidazole derivative, and one or more pharmaceutically acceptable excipients;
a barrier layer surrounding the drug layer, wherein the barrier layer comprises a pH-independent water soluble polymer and one or more pharmaceutically acceptable excipients;
a first bioadhesive layer surrounding the barrier layer, wherein the first bioadhesive layer comprises a natural polymer and one or more pharmaceutically acceptable excipients;
an enteric layer surrounding the first bioadhesive layer, wherein the enteric layer comprises an enteric polymer and one or more pharmaceutically acceptable excipients; and
a second bio-adhesive layer surrounding the enteric layer, wherein the second bioadhesive layer comprises a natural polymer and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition as claimed in claim 1, wherein the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof.
3. The pharmaceutical composition as claimed in claim 1, wherein the drug layer surrounding the inner inert core further comprises an alkaline compound.
4. The pharmaceutical composition as claimed in claim 3, wherein the alkaline compound comprises any or a combination of magnesium carbonate, magnesium hydroxide, sodium hydroxide, sodium chloride, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate and magnesium aluminate.
5. The pharmaceutical composition as claimed in claim 1, wherein the pH-independent water soluble polymer comprises cellulose derivatives selected from a group consisting of ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and mixture thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein the bioadhesive polymer comprises shellac.
7. The pharmaceutical composition as claimed in claim 1, wherein the enteric layer comprises a methacrylic acid copolymer.
8. The pharmaceutical composition as claimed in claim 1, wherein the composition is in a form selected from a group consisting of a tablet, a capsule and a multilayered pellet(s).
9. The pharmaceutical composition as claimed in claim 1, wherein the composition has an in vitro dissolution profile, wherein (a) not greater than 10% of dexlansoprazole or a salt thereof is released within about 120 minutes after immersion in 500 ml of 0.1 N hydrochloric acid having a pH of 1.2; and (b) not more than 20% of the dexlansoprazole or a salt thereof is released in a time of 20 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; (b) not less than 20% and not more than 80% of the dexlansoprazole or a salt thereof is released in 60 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS; and (c) not less than 80% of the dexlansoprazole or a salt thereof is released in 120 minutes in 900 ml of pH 7 phosphate buffer with 5 mM SLS.
10. A controlled release pharmaceutical composition, said composition comprising:
(a) first coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer and a bioadhesive coating; and one or more pharmaceutically acceptable excipients; and
(b) second coated pellets, wherein said pellets comprises a substituted benzimidazole derivative, a barrier layer, an enteric coating and one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition as claimed in claim 10, wherein the substituted benzimidazole derivative is dexlansoprazole, including pharmaceutically acceptable salts thereof.
12. The pharmaceutical composition as claimed in claim 10, wherein the first coated pellets comprises from about 10% to about 90% of Dexlansoprazole of total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 10% to about 90% of Dexlansoprazole of total weight of Dexlansoprazole present in said composition.
13. The pharmaceutical composition as claimed in claim 10, wherein the first coated pellets comprises from about 40% to about 60% of Dexlansoprazole of total weight of Dexlansoprazole present in said composition and the second coated pellets comprises from about 40% to about 60% of Dexlansoprazole of total weight of Dexlansoprazole present in said composition.
14. The pharmaceutical composition as claimed in claim 10, wherein the barrier layer comprises cellulose derivatives selected from a group consisting of ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, and mixture thereof.
15. The pharmaceutical composition as claimed in claim 10, wherein the bioadhesive coating comprises shellac.
16. The pharmaceutical composition as claimed in claim 10, wherein the enteric layer comprises a methacrylic acid copolymer.