FIELD OF INVENTION

The invention relates to stable oral pharmaceutical compositions comprising dexlansoprazole or their pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof.

Particularly, the invention relates to stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

The invention also relates to the process of preparing a stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of R-and S- enantiomers) and belong to the class of substituted benzimidazoles. Chemically it is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yI] methyl} sulfinyi]-lH-benzimidazole, having the structure (I) as presented below. It is indicated for healing of all grades of erosive esophagitis for upto 8 weeks, maintenance of healed erosive esophagitis for upto 6 months and for treatment of heartburn with non-erosive gastroesophageal reflux disease for 4 weeks.

(I)

Dexlansoprazole is a pale yellowish white crystalline powder. It is freely soluble in polar organic solvent but practically insoluble in non-polar organic solvent. The solubility of dexlansoprazole in aqueous solution increases with the pH value. It is slightly soluble in water (0.16mg/mL), but becomes soluble (58mg/mL) at the pH value of 10.9.

Apart from having poor solubility, benzimidazole derivatives are known to have poor stability. In particular, they would be rapidly decomposed and colored under moist conditions or in an acidic to neutral aqueous solution. Further, these class of compounds are also known to possess solid-state instability; for example conversion of one polymorphic form to the other, conversion of amorphous form to crystalline form and the like.

Dexlansoprazole is known to exist in different crystalline forms. Different polymorphic forms of the same compound may have completely different properties, especially when compared with an amorphous form of the same active. Amorphous materials have properties that can be of advantage in the preparation of pharmaceutical compositions, such as solubility/dissolution rate, and bioavailability. However, the increased reactivity of an amorphous solid, with a consequent high propensity to spontaneously transform to the crystalline state at a certain conditions such as for example relative humidity, force and temperature among others, may negatively affect the physical and chemical stability of the pharmaceutical composition.

Thus there has always been a need to produce pharmaceutical compositions wherein the drug is retained in the amorphous form, either during formulation processing or during the shelf-life of the formulation. Various approaches used for the formulation of an amorphous material include the use of dry granulation techniques for tableting, complexation, dry mixing, melt-extrusion, co-precipitation, spray drying, and co-milling, to name a few. Compositions comprising amorphous actives suffer from problems of form conversion either during processing or upon stability.

The development of pharmaceutical compositions comprising the amorphous form of dexlansoprazole, which do not show change in XRD pattern of the compositions during manufacturing and upon storage, would be a significant improvement in the delivery of the same.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to stable oral pharmaceutical compositions comprising dexlansoprazole or their pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof.

Particularly, the invention relates to stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

The invention also relates to the process of preparing a stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.

In one embodiment, the invention provides a stable amorphous dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients; wherein dexlansoprazole or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form.

In another embodiment, the invention provides a method of preparing a stable amorphous dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients; which includes forming a mixture comprising dexlansoprazole, a dispersing agent(s), optionally other pharmaceutically acceptable excipients and a solvent; and spray drying the mixture to result in an amorphous dispersion, wherein the dexlansoprazole or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form.

Yet in another embodiment, the invention provides a method of preparing a stable amorphous dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients; which includes forming a mixture comprising dexlansoprazole, a dispersing agent(s), optionally other pharmaceutically acceptable excipients and a solvent; and subjecting to vacuum distillation followed by filtration and drying, wherein the dexlansoprazole or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form.

In yet another embodiment, the invention provides a pharmaceutical composition comprising a stable amorphous dexlansoprazole dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof and a dispersing agent(s),wherein dexlansoprazole or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form; and atleast one pharmaceutically acceptable excipient.

In still another embodiment, the invention provides a use of pharmaceutical compositions comprising stable amorphous dexlansoprazole dispersion for the treatment of all grades of erosive esophagitis and heartburn with non-erosive gastroesophageal reflux disease, by administering orally a therapeutically effective amount of pharmaceutical composition comprising a stable amorphous dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates an XRPD pattern of spray-dried amorphous dispersion comprising dexlansoprazole, polyvinylpyrrolidone and meglumine (Table-1; S. No. 1).

Figure 2 illustrates an XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising dexlansoprazole, polyvinylpyrrolidone and potassium hydroxide (Table-2; S. No. 1).

Figure 3 illustrates an overlaid XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising dexlansoprazole, polyvinylpyrrolidone and potassium hydroxide and its placebo (Table-2; S. No. 1).

Figure 4 illustrates an XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising dexlansoprazole, polyvinylpyrrolidone and potassium hydroxide after 4 week (Table-2; S. No. 1).

Figure 5 illustrates an overlaid XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising dexlansoprazole, polyvinylpyrrolidone and potassium hydroxide after 4 week and its placebo (Table-2; S. No. 1).

Figure 6 illustrates an XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising dexlansoprazole, polyvinylpyrrolidone and potassium hydroxide after 12 week (Table-2; S. No. 1).

Figure 7 illustrates an overlaid XRPD pattern of amorphous dispersion prepared by vacuum distillation comprising Dexlansoprazole, Polyvinylpyrrolidone and potassium hydroxide after 12 week and its placebo (Table-2; S. No. 1).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to stable oral pharmaceutical compositions comprising dexlansoprazole or their pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof.

Particularly, the invention relates to stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

The invention also relates to the process of preparing a stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.

The invention also relates to pharmaceutical composition comprising a stable amorphous dexlansoprazole dispersion comprising dexlansoprazole or a pharmaceutically acceptable salt thereof and a dispersing agent(s), wherein dexlansoprazole or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form; and atleast one pharmaceutically acceptable excipient.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for dexlansoprazole or a pharmaceutically acceptable salt thereof and the amorphous dispersion comprising dexlansoprazole or its salt, a dispersing agent (s) and optionally other pharmaceutically acceptable excipients.

The term "dispersion" as used herein refers generally to solid dispersion, unless specified otherwise. It may be used interchangeably and synonymously for "pre-mix" or "admixture" to name a few. It consists of at least two different components, generally a hydrophilic matrix comprising a dispersing agent(s) and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles.

"Substantially amorphous form" according to the invention refers that no recognizable characteristic crystalline dexlansoprazole peaks or excipient peaks are present in an X-ray powder diffraction pattern of the material.

"Stable" according to the invention refers to the ability of the amorphous dexlansoprazole dispersion as well as the compositions comprising it, to resist changes against physical, chemical as well as solid-state instability.

The "dispersing agent(s)" according to the invention can be any pharmaceutically acceptable excipient that once co-processed with dexlansoprazole or a salt thereof, functions to maintain dexlansoprazole in a substantially amorphous form. The dispersing agent(s) to be combined with dexlansoprazole can be crystalline or amorphous. Non-limiting examples of such dispersing agent(s) include cellulosic polymers such as an alkyl celluloses (e.g., methylcellulose, ethyl cellulose, and the like); modified celluloses such as carboxymethylcellulose, hydroxypropyl methyl cellulose, cross-linked sodium carboxymethylcellulose, hydroxyl alkyl cellulose (e.g., hydroxypropyl cellulose); polyvinylpyrrolidone; cross-linked homopolymer of N-vinyl-2-pyrrolidone; polyvinylpyrrolidone-vinyl acetate copolymer; polyvinyl alcohol; polysaccharides; a mono or disaccharides (e.g., lactose); sugar alcohol; or a combination comprising at least one of the foregoing dispersing agent.

Dexlansoprazole or its pharmaceutically acceptable salt used in the preparation of the dispersion can be either pure crystalline or pure amorphous form. It further includes dexlansoprazole or its salt in either partially crystalline or partially amorphous form. It also includes dexlansoprazole or its salt comprising a mixture of both crystalline and amorphous form in any ratio.

In addition to the dispersing agent, the amorphous dispersion can optionally further comprise other pharmaceutically acceptable excipient such as alkalinizing agents, stabilizing agents, surfactants, plasticizers, fillers, and the like.

The amorphous state in the dispersion is stabilized by a stabilizing agent, providing a suitable shelf life. The stabilized composition also provides an increased solubility of the active substance. The stabilizing agent prevents, inhibits or delays recrystallisation of the less soluble, crystalline form of the active substance.

Suitable "stabilizing agents" used according to the invention include both inorganic and organic compounds.

Examples of inorganic compounds include, but not limited to sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate precipitated calcium carbonate, calcium hydroxide and the like or combinations thereof.

Examples of organic compounds include, but not limited to meglumine, lysine, N, N'-dibenzylethylenediamine, chloroprocain, choline, diethanolamine, ethylenediamine, procaine and the like or combinations thereof.

Various methods of preparing amorphous dispersion known in the art include spray drying; freeze drying (lyophilization); crash cooling from supercritical fluids, solution enhanced dispersion by supercritical fluids; rapid expansion of supercritical solution; vacuum distillation followed by drying and co-precipitation with suitable excipients.

In one embodiment, the dispersion is prepared by spray-drying a solution or a suspension comprising dexlansoprazole or its salt, a dispersing agent(s) and optionally other pharmaceutically acceptable excipient in a suitable solvent.

In one embodiment, the dispersion is prepared by freeze-drying a solution or a suspension comprising dexlansoprazole or its salt, a dispersing agent(s) and optionally other pharmaceutically acceptable excipient in a suitable solvent.

Alternatively, the dispersion may also be prepared by Fluid-Bed Drying technique, wherein a solution or a suspension comprising dexlansoprazole or its salt, a dispersing agent(s) and optionally other pharmaceutically acceptable excipient in a suitable solvent in dried at atmospheric conditions.

Yet, in another embodiment the amorphous dispersion of dexlansoprazole may also be prepared comprising the steps of:

(a) Dissolving dexlansopraozle, dispersing agent and one or more pharmaceutically acceptable excipient in a suitable solvent followed by stirring to get a clear solution.

(b) Filtering the solution of step (a) through hyflow bed to remove all undissolved particulate.

(c) Subjecting the clear filtrate to vacuum distillation followed by drying to get the amorphous dispersion of dexlansoprazole.

Suitable solvents that may be used for preparing the amorphous dispersion include those that do not adversely affect the stability of dexlansoprazole, and are preferably inert. Such solvents may be organic, aqueous, or a mixture thereof. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethyl sulfoxide; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Specifically aqueous solvents are used, that is, a solvent comprising water and/or a water-miscible organic solvent such as a lower alcohol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethyl formamide, and the like. Combination of various solvents can also be used.

The solvent can be removed by any variety of methods as discussed previously such as evaporation optionally under reduced pressure or under heat or vacuum, precipitation by a non-solvent, freeze drying, spray drying, and the like.

The mixture comprising of dexlansoprazole, dispersing agent(s), and optionally other pharmaceutically acceptable excipient, in a suitable solvent can by spray dried using techniques and equipment known in the art. The spray drier atomizes the solution in a stream of air or other gas resulting in rapid evaporation of the solvent leaving behind a dispersion of amorphous dexlansoprazole and dispersing agent.

Determination of the solid-state stability and extent of conversion of the crystalline form of dexlansoprazole to amorphous form in the dispersion and pharmaceutical compositions comprising such dispersions can be determined using analytical techniques known in the art, including x-ray diffraction analysis, differential scanning calorimetry, optical microscopy, and the like.

In one embodiment, the invention provides for pharmaceutical compositions comprising the stable amorphous dispersion of dexlansoprazole. Such compositions are preferably in the form of oral solid dosage forms. The term "solid dosage" defines a system in a solid state in the form of a tablet, mini-tablet, pellet, powder or granule or a micro-granule comprising a core containing the active ingredient along with other suitable pharmaceutical excipients.

In such solid dosage forms, the amorphous dispersion may be admixed with suitable pharmaceutical excipient to form the core. The pharmaceutical compositions comprising amorphous dexlansoprazole dispersion involves the steps to prepare: a) a core comprising drug premix along with at least one disintegrant, binder, an alkaline reacting agent and optionally other excipients b) a membrane surrounding the core, which comprises of a water-insoluble, water-permeable rate-controlling polymer, c) a drug coating layer comprising said amorphous dispersion over the membrane layer and d) an another membrane coating comprising of biodegradable pharmaceutically acceptable excipients, surrounding said drug layer.

The core may be formulated into a tablet, mini-tablet, pellet, granule or a micro-granule by approaches known in the prior art. The amorphous drug dispersion with or without disintegrant(s) and binder may be incorporated in the core by coating over non¬pareil seeds or granulating the mixture with a binder solution, which is followed by extrusion-spheronization. The drug, binder and disintegrant may be applied as a mixture over the core or may be incorporated in the core as separate layers. The core may optionally also contain an alkaline reacting agent and other suitable pharmaceutical excipients.

The core may by prepared as pellets by using amorphous dexlansoprazole dispersion along with various pharmaceutically acceptable excipients which further coated with various enteric polymer to form enteric coated pellets.

Yet in another embodiment, the core may also be produced by mixing drug along with disintegrant, dry binder, alkaline reacting agent, lubricant etc. and then compressing into mini-tablets of 1 mm to 3 mm diameter.

The release of drug from the core can be controlled by a water-insoluble water-permeable rate controlling polymer alone or a mixture thereof with or without a plasticizer and other pharmaceutically acceptable excipients.

The enteric polymer may be selected from the group comprising copolymer of methacrylic acid-methyl acrylate, (Eudragit®), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and hydroxymethylcellulose acetate succinate and the like or combinations thereof.

The water-insoluble water-permeable rate-controlling polymer may be selected from the group comprising ethyl cellulose, cellulose acetate, ammonio methacrylate copolymers, neutral copolymer consisting of polymethracrylic acid esters, polyethylene oxide, polyvinyl pyrrolidine and its copolymers, polyvinyl acetate.

Suitable plasticizers may be selected from the group comprising of triethyl citrate, triacetin, acetyl triethyl citrate, dibutyl sebacate, dibutyl phthalate, soybean oil, olive oil, propylene glycol, glycerin, polyethylene glycol etc.

The biodegradable pharmaceutically acceptable excipients that form the coating membrane may be selected from a prolamine, such as gliadan, hordein or more preferably zein.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof.

It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

A. Dexlansoprazole Dispersion

Dexlansoprazole amorphous dispersions are prepared by spray-drying solutions of dexlansoprazole, dispersing agent(s) and stabilizer in a hydro-alcoholic / alcoholic solution as disclosed in the Table 1.

Table 1

Dispersing Active Other
S. Agent Ingredient Excipient
No. Name Quantity Dex- Name Quantity
(mg) lansoprazole (mg)
{mg)
1 Polyvinylpyrrolidone 120 60 Meglumine 24 (Povidone K-30)
2 Polyvinylpyrrolidone 120 60 Meglumine 24 (Povidone K-25)
3 Polyvinylpyrrolidone 120 60 Meglumine 24 (Povidone K-60)

4 Hydroxypropyl methyl 120 60 Meglumine 24 cellulose
5 Hydroxypropyl methyl 120 60 Meglumine 24 cellulose phthalate
6 Cross-linked homopolymer 120 60 Meglumine 24
ofN-vinyl-2-pyrrolidone
(Crospovidone)
7 Polyvinylpyrrolidone-vinyl 120 60 Meglumine 24
acetate copolymer
(Copovidone S-630)
8 Polyvinylpyrrolidone 20 10 Potassium 2.28.
1 (Povidone K-30) hydroxide

Brief Manufacturing Procedure for S. No. 1

1. Dexlansoprazole was dissolved in Ethanol (230mL).
2. Povidone K-30 was added to the above solution.
3. Meglumine was dissolved in water (12mL).
4. Meglumine solution was added to solution of step 2.
5. Solution of step 4 was spray-dried to get the solid dispersion.

Dispersions given in S. No. 2 to 7 (Table -1) were prepared by using similar procedure as described in S. No. 1 (Table-1).

Brief Manufacturing Procedure for S. No. 8

1. Dexlansoprazole was dissolved in a mixture of methanol (l00mL) and Potassium hydroxide (2.28gm) at 25-30°C under nitrogen atmosphere followed by stirring for about 5-10mins.

2. Povidone K-30 (20gm) was added to the solution of step 1 at 25-30°C and stirred for about 5-10mins to get clear solution.

3. Solution of step 1 was spray-dried to get the solid dispersion.

Alternatively, dexlansoprazole amorphous dispersions are also prepared by vacuum distilling followed by filtration and drying solutions containing dexlansoprazole, dispersing agent(s) and potassium hydroxide in various type of alcoholic solution as disclosed in the Table 2.

Table-2

Dispersing Active Other
S. Agent Ingredient Excipient
No. Name Quantity Dex- Name Quantity
(mg) lansoprazole (mg)
(Sg)
1 Polyvinylpyrrolidone 20 10 Potassium 1.52 (Povidone K-30) hydroxide
2 Polyvinylpyrrolidone 20 10 Potassium 1.52 (Povidone K-30) hydroxide
3 Polyvinylpyrrolidone 20 10 Potassium 1.52 (Povidone K-30) hydroxide
4 Polyvinylpyrrolidone 20 10 Potassium 1.52 (Povidone K-30) hydroxide
5 Polyvinylpyrrolidone 20 10 Potassium 1.52 (Povidone K-30) hydroxide

Brief Manufacturing Procedure for S. No. 1

1. Dexlansoprazole was dissolved in a mixture of methanol (150mL) and Potassium hydroxide (1.52gm) at 25-30°C under nitrogen atmosphere followed by stirring for about 10-15mins.

2. Povidone K-30 (20gm) was added to the solution of step 1 at 25-30°C and stirred for about 5-10mins to get clear solution.

3. The solution of step 2 was filtered through hyflow bed to remove any undissolved particulate.

4. The clear filtrate of step 3 was then subjected to vacuum distillation at about 35-38°C for 4-5 hrs to remove solvent completely and to get foamy solid.

5. The foamy solid of step 4 was then grinded and dried over vacuum at about 40°C for 12-15hrs to get stable amorphous dexlansoprazole.

Dispersions given in S. No. 2 to 5 (Table- 2) were prepared by using similar procedure as described in S. No. 1 (Table-2).

Dried solid dispersion obtained above is analyzed by x-ray powder diffraction (XRPD). XRPD patterns (Figure 1 & 2) indicate the dried solid dispersions according to S. No. 1 in the table 1 and 2 are amorphous.

B. Enteric coated pellets compositions comprising Dexlansoprazole Dispersion/ Premix.

Example 1

Instant release drug cores in the form of pellets with the following composition were prepared by powder drug layering technique.

Core pellet formulation

Ingredients Qty % (w/w)
Non-pareil seeds 40.00
Dexlansoprazole premix 46.00
Hydroxypropyl cellulose (Low-substituted) 10.00
Hydroxypropyl cellulose 4.00

A blend of Dexlansoprazole premix and hyroxypropyl cellulose (low substituted) was prepared by mixing in the bin blender for about 20 minutes. This powdered blend was then charged in the powder feeder of solid powder layering machine. Non-Pareil seeds were loaded in a chamber of powder drug layering machine and were rotated such that bed of non-peril seeds get fluidized. Binder solution of hydropropyl cellulose was then sprayed onto the non-peril seeds and powdered blend of Dexlansoprazole premix and Hydroxypropyl Cellulose (Low-substituted) was sprinkled simultaneously. Wet pellets were then dried in a vacuum tray drier.

Example 2

Instant release drug cores in the form of pellets with the following composition were prepared by coating non-pareil seeds by using different compositions of amorphous dexlansoprazole dispersion.

Core pellet formulation

Ingredients Qty % (w/w)
Non-pareil seeds (30-35) 90.00
Dexlansoprazole Premix 66.84
Talc 20.00
Crospovidone 10.00
Methanol q.s

Dexlansoprazole premix was dissolved in the methanol. Crospovidone were further dissolved in the drug solution. Talc was dispersed in the final solution. Finally the resulting drug dispersion was coated over non-pareil seeds in Wurster coater to get the pellets.

Example 3

Drug cores prepared in the Example 2 were further coated using following composition and process.

Seal Coating I

Ingredients Qty % (w/w)
Hypromellose 3cps 90.00
Macrogol 6000 10.00
Methylenedichloride (80%) q.s.
lPA(20%) 1 q.s.

About 400 gms of drug loaded pellets each of Example 2 were loaded in Wurster-coater and coated with solution prepared by dissolving hypromellose and macrogol 6000 in a mixture of methylenedichloride and isopropyl alcohol (in 8:2 ratio). The coating was done till a weight built-up of about 20% w/w was achieved.

Example 4

Seal coated cores of Example 3 were further coated using following composition and process.

Example 3A

Example 3B

Example 3C

Enteric coat I %w/w %w/w %w/w
Eudragit L 100 36.30 27.20 18.20
EudragitS 100 54.50 63.50 72.60
Triethyl citrate 8.30 8.30 8.30
Talc 0.90 0.90 0.90
Ethanol (90%) q.s. q.s. q.s.
Water (10%) q.s. q.s. q.s.

Seal coated cores were coated with different enteric compositions in Example 3A, Example 3B, Example 3C having Eudragit L100: Eudragit S 100 in 40:60, 30:70 and 20:80 ratio. Eudragit LI00 and Eudragit S 100 were dissolved in ethanol. Triethyl citrate was dissolved in water. Both the solutions were mixed and Talc was dispersed to form final dispersion which was coated over the seal coated pellets in Wurster coater. The coating was done till a weight built-up of about 24% w/w was achieved.

Example 5

Enteric coated pellets of Example 3 can be alternatively coated with second enteric coat with the following composition.

Enteric Coat II I %w/w
Eudragit S 100 90.0
Triethyl citrate 9.0
Talc 1.0
Ethanol (90%) q.s
Water (10%) q.s.

Eudragit S 100 was dissolved in ethanol. triethyl citrate was dissolved in water. Both the solutions were mixed and Talc was dispersed to form final dispersion which was coated over the enteric coated pellets of example 3 A, example 3Band example 3C pellets in Wurster coater. The coating was done till a weight built-up of about 15% w/w was achieved.

Example 6

Seal coated pellets of Example 2 can be alternatively coated with Enteric coat with the following composition.

Enteric Coat I %w/w
Eudragit S 100 90.0
Triethyl citrate 9.0
Talc 1.0
Ethanol (90%) q.s.
Water (10%) q.s.

Eudragit S 100 was dissolved in ethanol.

Triethyl citrate was dissolved in water. Both the solutions were mixed and Talc was dispersed to form final dispersion which was coated over the seal coated pellets of example 2 in Wurster coater. The coating was done till a weight built-up of about 5-15% w/w.

Example 7

Enteric coated pellets of Example 6 can be additionally coated with second enteric coat with the following composition.

Enteric Coat I %w/w
Eudragit L 100 55 90.0
Triethyl citrate 9.0
Talc 1.0
Ethanol (90%) q.s
Water (10%) q.s.

Eudragit L 100 55 was dissolved in ethanol. triethyl citrate was dissolved in water. Both the solutions were mixed and talc was dispersed to form final dispersion which was coated over the enteric coated pellets of example 6 in Wurster-coater. The coating was done till a weight built-up of about 20-40% w/w.

C. Mini-tablets compositions comprising
Dexlansoprazole Dispersion/Premix.

Example 1.

The drug containing cores of dexlansoprazole are also prepared in the form of mini-tablets.

Core tablet formulation

Ingredients Qty % (w/w)
Dexlansoprazole premix 79.00
Mannitol 10.00
Crospovidone 5.00
Hydroxypropyl cellulose (Low-substituted) 5.00
Magnesium stearate 1.00

Dexlansoprazole premix, crospovidone, mannitol and hyroxy propyl cellulose (low-substituted) were mixed and sifted through sieve of mesh# 30 (ASTM). The sifted material was then blended in a bin blender for 30 minutes and then lubricated with magnesium stearate. The lubricated blend was then compressed into mini-tablets of 1.5 mm on rotary compression machine.

Example 2

Drug cores prepared in the Example 2 were further coated using following composition and process.

Coating composition

Ingredients Qty % (w/w)
Cellulose acetate 50.00

Polyethylene glycol 8000 40.00
Triethyl citrate 10.00

About 1200g of dexlansoprazole cores of Example 2 were loaded in Wurster coater and coated with the coating composition of cellulose acetate, polyethylene glycol 8000 and triethyl citrate in solvent system of acetone and water. The coating was done till a weight built-up of about 5-7% w/w was achieved.

Example 3

The coated cores of Example 3 were further coated with the drug and other excipients using solid drug powder layering technique. The detailed composition and process is as follows:

Drug coating composition

Ingredients Qty % (w/w)
Dexlansoprazole premix 80.00
Hydroxypropyl cellulose (Low-substituted) 15.00
Hydroxypropyl cellulose 5.00

A blend (about 1600 g) of dexlansoprazole premix, hyroxy propyl cellulose (low substituted) was prepared by mixing in the bin blender for about 20 minutes. This powdered blend was then charged in the powder feeder of solid powder layering machine. Coated cores of Example 3 (About 1100 g) were loaded in a chamber of powder drug layering machine and were rotated such that bed get fluidized. Binder solution of hydroxy propyl cellulose was then sprayed onto the coated cores of Example 3 and powdered blend of dexlansoprazole and hydroxy propyl cellulose (low-substituted) was sprinkled simultaneously. Wet pellets were then dried in a vacuum tray drier.

Example 4

The formulation mentioned in Example 4 was finally coated with the following coating composition.

Coating composition

Ingredients Qty % (w/w)
Dexlansoprazole cores of Example 4 80.00
Zein 18.00
Polyethylene glycol 400 2.00

The drug loaded cores of Example 4 were further coated with the hydro-alcoholic solution of zein and polyethylene glycol 400 till desired weight built-up was obtained.

Stability Studies

A. Stability Study for amorphous dispersion
The amorphous dispersion prepared according to the Serial No.2 (Table-2) of the invention was subjected to accelerated conditions [40°C/75% RH] for 3 months and related substances were analyzed by HPLC method and X-ray powder diffraction.

The results analyzed by HPLC are summarized in Table 3 and X-ray powder diffraction are summarized in Figure Nos. 2, 3, 4, 5, 6, 7.

Table-3

Related Substance Initial 2 week 4 week 12 week
2-Hydroxy Bezimidazole 0.01 0.02 0.03 0.01
2- Mercapto Benzimidazole NR 0.01 0.02 0.00
MethoxyIMP 0.01 0.01 0.01 0.01
DXL-n Sulphone NR NR 0.00 0.18
Sulphone Impurity 0.13 0.17 0.19 0.18
Sulphide Impurity NR 0.01 0.01 0.01
Highest Unknown 0.01 0.06 0.03 0.02
Total Imp 0.21 0.38 0.41 0.30

B. Stability Study for composition comprising amorphous dispersion

The enteric coated pellets prepared according to the Example 3C of the invention were subjected to accelerated conditions [40°C/75% RH] for 4 weeks and parameters such as related substances, dissolution were analyzed.

Samples were analyzed by HPLC method and results are summarized in Table 4 and 5.

Table-4

Related Substances Initial 4 weeks
2-Hydroxy benzimidazole impurity 0.04 0.13
2-Mercapto benzimidazole impurity 0.00 0.02
Methoxy impurity 0.01 0.01
DX1-1 0.01 0.00
DXL-Sulphone 0.00 0.64
DXL-Sulphide impurity 0.00 0.01
M+467 0.01 0.04
Highest Unkown impurity 0.02 0.06
fotal Impurity 0.56 1.00

Table-5
Dissolution Initial 1 month
Acid Release (0.1N HC1 / lhr) 1.2 2.8
pH 7.2 Phosphate Buffer Release /
Time (min)
10 24.3 29
20 82.0 76.6
30 91.8 85.7
45 94.7 88.3
60 95.1 89.3
90 94.2 89.7
120 92.2 90.1
Infinite 92.4 90.2

WE CLAIM:

1. A stable amorphous dispersion comprising dexlansoprazole, a dispersing agent(s), and optionally other pharmaceutically acceptable excipient.

2. The dispersion according to claim 1, wherein said pharmaceutically acceptable excipient comprises alkalinizing agent, stabilizing agent, surfactant, plasticizer, filler or a combination thereof.

3. The dispersion according to claim 2, wherein said stabilizing agent comprises inorganic or organic compounds.

4. The dispersion according to claim 1, wherein said dispersing agent comprises methylcellulose, ethyl cellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose, cross-linked sodium carboxymethylcellulose, hydroxyl alkyl cellulose, polyvinylpyrrolidone, cross-linked homopolymer of N-vinyl-2-pyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polysaccharides, lactose, sugar alcohol or a combination thereof.

5. The dispersion according to claim 3, wherein said inorganic compound is selected from a group comprising potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, calcium carbonate, calcium hydroxide or a combination thereof.

6. The dispersion according to claim 3, wherein organic compound is selected from a group comprising meglumine, lysine, N, N'-dibenzylethylenediamine, chloroprocain, choline, diethanolamine, ethylenediamine, procaine or a combination thereof.

7. A pharmaceutical composition comprising amorphous dexlansoprazole dispersion as claimed in claim 1 and at least one pharmaceutically acceptable excipient.

8. A stable pharmaceutical composition comprising:

a) a core comprising amorphous dexlansoprazole dispersion, disintegrant, binder, an alkaline reacting agent and optionally other excipients,

b) a membrane surrounding the core, which comprises of a water-insoluble, water-permeable rate-controlling polymer,

c) a drug coating layer comprising said amorphous dispersion over the membrane layer and

d) an outer membrane coating comprising biodegradable pharmaceutically acceptable excipient, surrounding said drug layer.

9. A process for preparing a stable amorphous dispersion comprising dexlansoprazole, wherein said process involves the following steps:

a) preparing a mixture comprising dexlansoprazole, a dispersing agent(s), optionally other pharmaceutically acceptable excipients and a solvent, and;

b) spray-drying the mixture of step (a) to get an amorphous dispersion of dexlansoprazole.

10. A process for preparing a stable amorphous dispersion comprising dexlansoprazole, wherein said process involves the following steps:

a) dissolving dexlansopraozle, dispersing agent(s) and one or more pharmaceutically acceptable excipient in a suitable solvent followed by stirring to get a clear solution;

b) filtering the solution of step (a) to get a clear filtrate;

c) subjecting the clear filtrate of step (b) to vacuum distillation followed by drying to get the amorphous dispersion of dexlansoprazole.