WO2013088272A1

WO2013088272A1 - Pharmaceutical composition comprising esomeprazole magnesium dihydrate

Info

Publication number: WO2013088272A1
Application number: PCT/IB2012/056089
Authority: WO
Inventors: Vivek Dubey; Rahul Dabre; Girish Kumar Jain
Original assignee: Wockhardt Ltd
Current assignee: Wockhardt Ltd
Priority date: 2011-12-14
Filing date: 2012-11-01
Publication date: 2013-06-20
Anticipated expiration: 2014-06-14

Abstract

The present invention relates to a wet granulated pharmaceutical composition comprising esomeprazole magnesium dihydrate with one or more pharmaceutical excipients, wherein the dosage form is essentially free of esomeprazole magnesium trihydrate.

Description

PHARMACEUTICAL COMPOSITION COMPRISING ESOMEPRAZOLE MAGNESIUM DIHYDRATE

Field Of The Invention

Background Of The Invention

Esomeprazole is the S-isomer of omeprazole Esomeprazole magnesium is a proton pump inhibitor used for the treatment of conditions where a reduction in gastric acid secretion is required. The conditions requiring reduction of gastric acid secretion may comprise, but not limited to treatment of gastroesophageal reflux disease, maintenance treatment of patients with reflux esophagitis, nonerosive reflux disease (NERD) (i.e. heartburn and regurgitation), healing of Nonsteroidal anti-inflammatory drug (NSAID) -associated gastric ulcers, reduction of risk of NSAID-associated gastric ulcers treatment of pathological hypersecretory conditions, including Zollinger-Ellison, Syndrome, Helicobacter pylori (H. pylori) eradication.

The magnesium salt is a white to slightly colored crystalline powder. It is marketed under trade name of Nexium® delayed release dosage form and contains esomeprazole magnesium trihydrate. Esomeprazole magnesium trihydrate contains 3 moles of water of solvation and is slightly soluble in water. The structural formula of esomeprazole magnesium trihydrate is:

Esomeprazole magnesium dihydrate is a moisture sensitive drug. Presence of moisture leads to conversion of esomeprazole magnesium dihydrate form to esomeprazole magnesium trihydrate form during storage or shelf life of the pharmaceutical dosage form. It is understood that for the development of formulation of any active pharmaceutical ingredient, the chemical stability, solid- state stability, and shelf life of the active pharmaceutical ingredient are important properties. The compositions containing active pharmaceutical ingredient, should be capable of being effectively stored over appreciable period of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient.

The inventors of the present invention have found that when esomeprazole magnesium dihydrate is processed or formulated in presence of water, it gets converted to esomeprazole magnesium trihydrate. Further, use of alcoholic solvents lead to conversion of esomeprazole magnesium dihydrate to amorphous form or exhibited discoloration due to degradation of esomeprazole magnesium dihydrate.

U.S. Patent No. 7,41 1 ,070 discloses magnesium salt of S-omeprazole trihydrate.

The prior art discloses several processes for preparing pure and stable form of esomeprazole magnesium dihydrate essentially free of esomeprazole magnesium trihydrate.

Thus, there existed a continuing need to develop new compositions with improved stability of the active ingredient, wherein the active ingredient is esomeprazole magnesium dihydrate which will not get convert to esomeprazole trihydrate in composition throughout the shelf life of the product.

None of the prior art however discloses a pharmaceutical composition comprising esomeprazole magnesium dihydrate, which is substantially free of esomeprazole magnesium trihydrate, which is safe and has an enhanced therapeutic effect over the existing individual drug therapy. Summary of The Invention

In one general aspect of the invention, there is provided a wet granulated pharmaceutical dosage form comprising esomeprazole magnesium dihydrate with one or more pharmaceutical excipients, wherein the dosage form is substantially free of esomeprazole magnesium trihydrate.

In another general aspect of the invention, there is provided a process of preparing a pharmaceutical composition of esomeprazole magnesium dihydrate, which process comprises steps of:

(a) mixing esomeprazole magnesium dihydrate with a binder soluble in non aqueous non-alcoholic solvent for granulation, optionally along with one or more pharmaceutically acceptable excipients;

(b) granulating the mixture prepared in step (a) by wet granulation process using a non-aqueous, non-alcoholic solvent as granulating liquid;

(c) optionally, formulating the granules in a desired dosage form,

wherein the composition is substantially free of esomeprazole magnesium trihydrate.

(c) drying the granules prepared in step (b); and

(d) optionally formulating the granules in a desired dosage form,

wherein the composition is substantially free of esomeprazole magnesium trihydrate. In another general aspect of the invention, there is provided a process of preparing a pharmaceutical composition of esomeprazole magnesium dihydrate, which process comprises a step of coating esomeprazole magnesium dihydrate on an inert core, wherein the composition is substantially free of esomeprazole magnesium trihydrate.

In another general aspect of the invention, there is provided a wet granulated, pharmaceutical composition comprising esomeprazole magnesium dihydrate with one or more pharmaceutical excipients, wherein the composition exhibits controlled release, extended release, delayed release of esomeprazole magnesium dihydrate, and characterized in that the composition is substantially free of esomeprazole magnesium trihydrate.

Brief Description of the Drawings

Figure 1 : XRD of Esomeprazole magnesium trihydrate.

Figure 2: XRD of Esomeprazole magnesium dihydrate.

Figure 3: XRD of Esomeprazole magnesium dihydrate composition of Example 1 . Figure 3(A): XRD of Esomeprazole magnesium dihydrate composition of Example 1 after storage at 40°C at 75% RH for 3 months in 60cc HDPE container with CRC & 2 silica gel canister.

Figure 3(B): XRD of Esomeprazole Magnesium Dihydrate composition of Examplel after storage at 40 °C at 75% RH for 3 months in Alu-Alu Blister pack.

Detailed Description of The Invention

The present inventors while formulating compositions comprising esomeprazole magnesium dihydrate by wet granulation technique discovered that esomeprazole magnesium dihydrate is highly unstable and readily converts to esomeprazole magnesium trihydrate when water or water like aqueous based solvents are used during formulation process. The present inventors surprisingly found that when non-aqueous, non-alcoholic solvents were used for wet granulation process, the granules obtained had improved the stability of esomeprazole magnesium dihydrate during formulation and shelf life of dosage form. Further the compositions so obtained are essentially free of esomeprazole trihydrate throughout the shelf life of the composition.

Thus, the composition of the present invention not only prevents the physical transformation of esomeprazole magnesium dihydrate to esomeprazole magnesium trihydrate during formulation process but also maintains its stability during storage.

Solvents suitable for the process of the present invention are those known to ordinary skilled in the art and includes but not limited to one or more di-lower alkyl ketone, example acetone, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether etc.

In an embodiment, the composition comprises one or more layers of esomeprazole magnesium dihydrate coated on cores.

The core material used is water-soluble inert core comprises of sugar spheres. The water-soluble inert core can comprise hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixtures thereof.

In a further embodiment the composition exhibits extended release, modified release, controlled release or delayed release of esomeprazole magnesium dihydrate.

In a further embodiment, the composition is further coated with one or more functional (e.g. enteric coating) or non-functional layers (barrier or film-coating).

In another embodiment, the coating layer can be a film coat, seal coat, sub-coat, delayed release coat or an enteric release coat. In another embodiment, the coating can be carried out by using fluidized bed processor, glatt, spray dryer, or any other suitable coating techniques known in the art.

In another embodiment, the pharmaceutical compositions may be formulated in the form of pellets, tablets, capsules, granules, beads, caplets, disc, pills, sachet, spheroids, mini-tablets, granules in a capsule, and beads and/or mini-tablets in a capsule.

The pharmaceutical composition of the invention further may comprise pharmaceutically acceptable excipients selected from one or more of binders, glidants, lubricants, fillers, plasticizers, lubricants, etc.

The examples of suitable binders include, starch, gums, pregelatinized starch, povidone, povidone derivatives, crospovidone, copolymer of N-vinyl-2- pyrrolidone and vinyl acetate, stearic acid, polyvinyl pyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC) and their salts.

Suitable binder for the present invention includes copolymer of N-vinyl-2- pyrrolidone and vinyl acetate or povidone derivatives.

Suitable fillers may include one or more of saccharose, glucose, fructose, maltose, maltitol, mannitol, dextrins such as maltodextrins; xylitol, sorbitol, microcrystalline cellulose, titanium dioxide, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, or silicates such as magnesium aluminium silicate.

Suitable pharmaceutically acceptable plasticizers comprise of dioctylphthalate, dibutyl phthalate, benzylptyl phthalate, triethylcitrate or polyethelene glycol. Suitable lubricant may include one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate, talc, etc.

Suitable disintegrant may include one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate, etc.

Suitable glidant may include one or more of, colloidal silicon dioxide, talc or cornstarch, etc.

Suitable coating polymers selected from the group consisting of one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof.

Cellulose derivatives include, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.

Polyhydric alcohols include, polyethylene glycol (PEG) or polypropylene glycol or any combinations thereof.

Saccharides, gums and their derivatives include, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan gum, karaya gum, tragacanth, carrageenan, acacia gum, arabic gum or gellan gum or the like; or any combinations thereof.

Vinyl derivatives, polymers, copolymers or mixtures thereof include, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations thereof.

Polyalkylene oxides or copolymers thereof include, polyethylene oxide, polypropylene oxide, poly (oxyethylene)-poly (oxypropylene) block copolymers (poloxamers) or combinations thereof.

Maleic acid copolymers include, vinylacetate, maleic acid anhydride copolymer, styrene, maleic acid anhydride copolymer, styrene, maleic acid monoester copolymer, vinylmethylether, maleic acid anhydride copolymer, ethylene, maleic acid anhydride copolymer, vinylbutyiether, maleic acid anhydride copolymer, acrylonitrile, methyl acrylate, ethyl acrylate, maleic acid anhydride copolymer, butyl acrylate, styrene, maleic acid anhydride copolymer or the like or any combinations thereof.

Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol, Eudagrit. Pharmaceutically acceptable acrylic polymer may include one or more, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate. Non-polymeric rate controlling excipient is selected from the group consisting of fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or any combinations thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes employed in the present invention include, but are not limited to, natural waxes (such as animal waxes, vegetable waxes, and petroleum waxes, paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof.

Also some other type of waxes are monoglyceryl esters, diglyceryl esters, or glyceryl esters (glycerides) and derivatives or mixtures thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate (compritol), polyglyceryl diisostearate, lauroyl macrogolglycerides (Gelucire), oleoyl macrogolglycerides, stearoyl macrogolglycerides, mixtures of monoglycerides and diglycerides of oleic acid (Peceol), or combinations thereof.

Fatty acids include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil (Lubritab), hydrogenated cottonseed oil, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, etc. or mixtures thereof.

Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, or stearyl alcohol or mixtures thereof.

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.

The term "wet granulation" refers to process involving introduction of binder and solvent to the pharmaceutical powder.

The term "esomeprazole magnesium dihydrate" refers to magnesium salt of esomeprazole having molecular formula C₃₄H36MgN6O6S₂-2H₂O and comprises 2 moles of water of solvation.

The term "esomeprazole magnesium trihydrate" refers to magnesium salt of esomeprazole having molecular formula C₃₄H36MgN6O6S₂-3H₂O and comprises 3 moles of water of solvation.

The term "essentially free of esomeprazole magnesium trihydrate" means that there is presence less than 0.001 %w/w of trihydrate form of esomeprazole magnesium.

The term "pharmaceutical excipients" refers to binders, plasticizer, fillers, lubricants, disintegrants, surfactants and glidants. The term "pharmaceutical dosage form" or "pharmaceutical composition" refers to tablets, capsules, granules, beads, caplets, disc, pills, sachet, spheroids, minitablets, granules in a capsule, beads in a capsule and mini-tablets in a capsule.

The phrase "inert core," as used herein, includes core that water soluble or water-swellable inert core.

The term 'inlayed tablet' as used herein refers to a type of a layered tablet in which instead of the core tablet being completely surrounded by a coating, the top surface is completely exposed.

The composition of the present invention may be used for the treatment of various conditions requiring reduction in gastric acid secretion. Such conditions includes, but are not limited to gastroesophageal reflux disease, maintenance treatment of patients with reflux esophagitis, non-erosive reflux disease (NERD) (i.e. heartburn and regurgitation), Nonsteroidal anti-inflammatory drug (NSAID) associated gastric ulcers, risk of NSAID-associated gastric ulcers treatment of pathological hypersecretory conditions (including Zollinger-Ellison Syndrome), Helicobacter pylori (H. pylori) infection.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

Example 1 : Esomeprazole magnesium dihydrate granules

Table 1

Procedure: Polethylene glycol and acetone were mixed with gentle heating. Esomeprazole was dispersed in the above mixture. The dispersion was then sprayed on the sugar sphere. The drug coated sugar spheres were then given seal coat of HPMC followed by enteric coat comprising of Eudagrit and plasticizers TEC (triethyl citrate) and PlasACRYL (glyceryl monostearate and triethyl citrate).

Example 2: Esomeprazole magnesium dihydrate mini-tablet

Table 2

Procedure:

Esomeprazole magnesium was sifted along with mannitol. PEG 6000 was melted by gentle, heating and acetone was added to it followed by addition of Plasdone S 630. Spray the molten mixture on the powder mixture to get granules. Granules were lubricated sodium stearyl fumarate. Granules were coated with seal coat. Further, enteric coat was applied.

Example 3: Esomeprazole magnesium dihydrate tablet

Table 3

Procedure:

Esomeprazole magnesium was sifted along with mannitol. PEG 6000 was melted by gentle, heating and Acetone was added to it followed by addition of Plasdone S 630. The molten mixture was sprayed on the powder mixture to get granules. Granules were lubricated with sodium stearyl fumarate and were coated with seal coat. Further, enteric coat was applied. Further granules were lubricated with talc before compression into tablet dosage form.

Example 4: Characterization of Esomeprazole magnesium dihydrate formulation of Example 1 using X-ray powder diffraction.

Table 4

Some additional very weak peaks found in the diffractogram have been omitted from Table 5 & 6.

Table 5

Positions and intensities of the major peaks in the XRP- diffractogram Of the formulation of magnesium salt of esomeprazole dihydrate after storage at 40 °C at 75% RH for 3 months in 60cc HDPE with CRC & 2 silica gel canister

d-value/°A Relative Intensity

15.3 vs

9.3 vs

7.6 vs

7.0 vs

6.8 vs

4.7 vs

4.5 vs

4.3 vs

3.6 vs

3.5 vs

3.1 vs

2.9 s

2.8 s

2.4 s Table 6

Example 5: Stability study (Effect of Packaging)

Table 7: Esomeprazole magnesium dihydrate formulation of Example 1 packed in 60cc HDPE container with CRC & 2 silica gel canisters

Impurity (%)

Related Substances 40^/75%ΒΗ

Initial

1 M 2M 3M

Citizen Impurity A 0.003 0.019 0.025 0.025

Omprazole N-Oxide 0.000 0.007 0.01 1 0.000

Omeprazole Related Compound A 0.052 0.066 0.075 0.066

D-Methoxy Omeprazole 0.000 0.002 0.002 0.000

Omeprazole Related Compound-C 0.018 0.01 1 0.015 0.017

Highest Unknown 0.026 0.048 0.066 0.071 Total Unknown 0.175 0.346 0.460 0.394

Total RS 0.248 0.451 0.588 0.502

Table 8: Esomeprazole magnesium dihyc rate formulation o f Examp e 1 packed in Alu-Alu cold form Blister

The stability study results of the formulation of Example 1 indicates that, the it remains stable for a period of at least 3 months at 40 °C at 75% relative humidity, independent of the packaging. Further, total related substances were within the specified limits.

Example 6: Dissolution Study

The formulation of Example 1 was subjected to dissolution study using USP Type II (Paddle) dissolution apparatus at 100rpm after storing the formulation over 3 months at 40 °C and 75% relative humidity.

Table 9: Esomeprazole magnesium dihydrate formulation of Example 1 packed in 60cc HDPE container with CRC & 2 silica gel canisters

Table 10: Esomeprazole magnesium dihydrate formulation of Example 1 packed in Alu-Alu cold form Blister

Assay

Time

40°C/75%RH

(min) Initial

1 M 2 M 3 M

10 71 96 74 59

15 100 101 96 99

20 99 101 97 100

30 96 100 96 99

45 93 98 93 96

60 91 97 91 94

Claims

WE CLAIM:

1 . A wet granulated pharmaceutical composition comprising esomeprazole magnesium dihydrate with one or more pharmaceutical excipients, wherein the composition is essentially free of esomeprazole magnesium trihydrate.

2. The wet granulated pharmaceutical composition of claim 1 , wherein the wet granulation comprises use of one or more solvents selected from di- lower alkyl ketone, acetone, ether, and diethyl ether.

3. The wet granulated pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipients comprises one or more of binders, plasticizer, fillers, lubricants, disintegrants, surfactants glidants and coating agents.

4. The wet granulated pharmaceutical composition of claim 2, wherein the binder comprise one or more of povidone, crospovidone or copolymer of N-vinyl-2-pyrrolidone and vinyl acetate starch, stearic acid, gums, hydroxypropylmethyl cellulose.

5. The wet granulated pharmaceutical composition of claim 2, wherein the plasticizer comprises one or more of dioctyl phthalate, dibutyl phthalate, benzylptyl phthalate or polyethelene glycol.

6. The wet granulated pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in the form of pellets, a tablet, a capsule, granules, beads, a caplet, disc, pills, a sachet, spheroids, a minitablet, granules in a capsule, beads in a capsule and minitablets in a capsule.

7. The wet granulated pharmaceutical composition of claim 1 , wherein the composition exhibits controlled, extended, or delayed release of esomeprazole magnesium dihydrate.

8. A pharmaceutical composition comprising esomeprazole magnesium dihydrate with one or more pharmaceutical excipients prepared by a process comprising coating a mixture comprised of esomeprazole magnesium dihydrate and non-aqueous, non-alcoholic solvent on an inert core, wherein the composition is substantially free of esomeprazole magnesium trihydrate.

9. The pharmaceutical composition of claim 8, wherein the non-aqueous, non-alcoholic solvent comprises one or more of di-lower alkyl ketone, acetone, ether, and diethyl ether.

10. A process of preparing pharmaceutical composition of esomeprazole magnesium dihydrate, which process comprises of:

(b) granulating the mixture prepared in step (a) by wet granulation process using a non-aqueous, non-alcoholic solvent as granulating liquid; and

(c) optionally, formulating the granules prepared in step (b) in a desired dosage form,

wherein the composition is essentially free of esomeprazole magnesium trihydrate.

1 1 . The process of claim 10, wherein the non-aqueous, non-alcoholic solvent comprises one or more of di-lower alkyl ketone, acetone, ether or diethyl ether.

12. The wet granulated pharmaceutical composition of claim 1 , wherein esomeprazole magnesium dihydrate in the composition provides an X-ray powder diffraction pattern exhibiting substantially the following d-values:

13. A method of treating a gastric acid related conditions which method comprises administering to a subject suffering from said condition the pharmaceutical composition of claim 1 .