DESC:FIELD OF THE INVENTION
The present invention relates to a tablet dosage form for release of a first fraction of a proton pump inhibitor at about a first pH and a second fraction of the proton pump inhibitor at about a second pH.
BACKGROUND OF THE INVENTION
Proton pump inhibitors are a class of pharmaceutical compounds that inhibit gastric acid secretions by inhibiting H+/K+ adenosine triphosphatase. The proton pump inhibitors are prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. Chemically, the proton pump inhibitors are substituted benzimidazole derivatives. These active pharmaceutical ingredients are acid-labile and have poor stability under moist conditions or in an acidic to neutral aqueous solution. The target site in the gastro intestinal (GI) tract from where maximum absorption of the proton pump inhibitors takes place include the proximal and distal parts of the small intestine such as duodenum and jejunum. Therefore, it’s a challenge for a formulator to develop an oral pharmaceutical dosage form that is, on one hand, stable in acidic environment of the stomach, and, on the other hand, delivers the drug in a targeted fashion to the desired sites of the small intestine such that higher absorption with reduced degradation takes place, thus resulting in increased overall bioavailability. The present invention provides such a dosage form.
SUMMARY OF THE INVENTION
The present invention provides a tablet dosage form comprising a core comprising a first fraction of proton pump inhibitor, the core being surrounded by concentric coatings comprising:
i. a first seal coat,
ii. a first delayed release coating comprising one or more enteric polymers wherein the coating is soluble at a pH in the range of about 6 to 6.5,
iii. a second seal coat,
iv. a coating comprising a second fraction of the proton pump inhibitor,
v. a third seal coat and
vi. a second delayed release coating comprising an enteric polymer soluble at a pH of about 5.5.
The present invention further provides a tablet dosage form comprising a core comprising a first fraction of proton pump inhibitor, the core being surrounded by concentric coatings comprising:
i. a first seal coat,
ii. a first delayed release coating comprising a mixture of an enteric polymer soluble at a first pH and an enteric polymer soluble at a second pH wherein the coating is soluble at a pH in the range of about 6 to 6.5,
iii. a second seal coat,
iv. a coating comprising a second fraction of the proton pump inhibitor,
v. a third seal coat and
a second delayed release coating comprising an enteric polymer soluble at a pH of about 5.5.

BRIEF DESCRIPTION OF FIGURE
Figure 1: The figure 1 represents a graph showing plasma concentration – time profile of pantoprazole upon oral administration of the tablet dosage form of the present invention (example 1) to a human subject.
DETAILED DESCRIPTION OF THE INVENTION
The proton pump inhibitors used according to the present invention include, but are not limited to pantoprazole, rabeprazole, lansoprazole, omeprazole, esomeprazole, dexlansoprazole, leminoprazole or pharmaceutically acceptable salts, enantiomers and hydrates thereof. In one preferred embodiment, the proton pump inhibitor is pantoprazole sodium. In another preferred embodiment, the proton pump inhibitor is rabeprazole sodium.
The terms "pharmaceutically acceptable salt" as used herein refers to salts that are known to be non-toxic and are commonly used in pharmaceutical practice.
The term “tablet” as used herein refers to the single monolithic solid pharmaceutical dosage form containing the active medicament and pharmaceutically acceptable excipients, and is prepared by compression. Suitably, the tablet is a compact single unit, solid pharmaceutical dosage form comprising unit dose of drug and may have a core with one or more coatings. It differs from multiparticulate dosage forms which have multiplicity of small discrete units such as pellets, each unit constituting a fraction of drug.
The term "acid-labile compound" means a compound, which is not stable in acidic conditions or which undergoes degradation or hydrolysis in acidic conditions.
The term ‘delayed release’ according to the present disclosure implies that the drug is not released in the stomach region of the gastrointestinal tract (GIT); instead, drug release is delayed until the tablet dosage form reaches the small intestinal region, wherein release takes place in the proximal or distal part of the intestine depending upon the pH of the environment of the intestinal tract.
The term ‘delayed release coating’ according to the present invention implies a coating of enteric polymers that do not dissolve in the acidic pH of the stomach but dissolves at pH of about 5.5 or above, the pH present in the small intestine region of the GIT.
The term ‘about’ in ‘pH of about’ or ‘pH about’ as used herein covers pH values which are within ±0.2 of the stated pH.
As used herein about 5.5 encompasses 5.3-5.7, such as 5.4, 5.5 and 5.6. As used herein about 6 to about 6.5 encompasses 5.8 to 6.7, such as 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5 and 6.6. As used herein about 7 encompasses 6.8 to 7.2, such as 6.9, 7.0, and 7.1.
The present invention provides a tablet comprising a core comprising a first fraction of proton pump inhibitor, the core being surrounded by concentric coatings comprising:
i. a first seal coat,
ii. a first delayed release coating comprising one or more enteric polymers wherein the coating is soluble at a pH in the range of about 6 to 6.5,
iii. a second seal coat,
iv. a coating comprising a second fraction of the proton pump inhibitor,
v. a third seal coat and
i. a second delayed release coating comprising an enteric polymer soluble at a pH of about 5.5.
The present invention further provides a tablet dosage form comprising a core comprising a first fraction of proton pump inhibitor, the core being surrounded by concentric coatings comprising:
i. a first seal coat,
ii. a first delayed release coating comprising a mixture of an enteric polymer soluble at a first pH and an enteric polymer soluble at a second pH wherein the coating is soluble at a pH in the range of about 6 to 6.5,
iii. a second seal coat,
iv. a coating comprising a second fraction of the proton pump inhibitor,
v. a third seal coat and
a second delayed release coating comprising an enteric polymer soluble at a pH of about 5.5
Advantageously, the tablet dosage form of the present invention provides a dual drug release behavior. Significantly, it allows for controlled drug release both in terms of spatial and temporal control of drug release. In one or more embodiments, the tablet dosage form of the present invention comprises at least two fractions of proton pump inhibitor, present in the single tablet dosage form, wherein the two fractions are designed such that there occurs delayed release of the proton pump inhibitor based on specific pH of the environment in the gastrointestinal tract. The drug release of one delayed release fraction precedes the other delayed release fraction thus giving a dual release behavior. This is accomplished by concentric coatings of specific enteric polymers, i.e. the delayed release coatings, according to the present invention.
There is provided one delayed release coating comprising an enteric polymer soluble at a pH of about 5.5, covering one fraction of the drug as well as another delayed release coating comprising another enteric polymer or a mixture of two enteric polymers soluble at a pH in the range of about 6 to 6.5, covering another fraction of the drug.
The tablet dosage form according to one embodiment of the present invention shows pH based dual release of proton pump inhibitor. Such that the second (outer concentric) fraction of proton pump inhibitor present in an outer concentric coating gets released in the region of small intestine which has a pH of about 5.5, suitably the duodenum region. The first (inner concentric) fraction of proton pump inhibitor present in tablet core gets released in the region of small intestine which has a pH of about 6.5 (6 – 6.8), suitably the distal part of the small intestine such as jejunum. This signifies the spatial control of drug release.
Suitably, the dosage form allows for spatial control of drug release whereby first fraction of the total dose is released in the duodenum region of the GIT, which has a pH of about 5.5 and second fraction of the total dose is released in the jejunum region of the GIT, which has a pH of about 6.0 to 6.8. The release is further controlled such that there occurs no release of the drug in the stomach region where it is not desired.
The tablet dosage form of the present invention also provides a temporal control over the drug release. The first portion of the total dose is released at a time as soon as the tablet gets emptied from the stomach and reaches the duodenum. Generally, this varies from 1-3 hours post ingestion, depending upon the gastric emptying time. The second fraction of the total dose gets released during the course of transit of the tablet from the distal part of the upper intestine, i.e. jejunum region of the GIT which has a pH of around 6.0 -6.8. (Gut, 1988, 29, 1035-1041). The intestinal transit takes place in around 2-4 hours. Thus, there occurs dual release of drug at desired sites of absorption leading to maximum utilization of the drug and improved efficacy. Suitably the novel design of the tablet dosage form of the present invention provides for the spatial and temporal control of drug release.
Suitably, the ratio of first fraction of proton pump inhibitor to the second fraction of the proton pump inhibitor present in the tablet dosage form according to the present invention may range from about 4:1 (about 80/20%) to about 3:2 (about 60/40%). In one preferred embodiment, ratio of first fraction to the second fraction of the proton pump inhibitor is 3:1, wherein the first fraction comprises about 75% of the proton pump inhibitor and the second fraction comprises about 25% of the proton pump inhibitor. Wherein the first fraction comprises about 60% to about 80% of the proton pump inhibitor, such as 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 or 79%. And wherein the second fraction comprises the remainder of the proton pump inhibitor.
The tablet core according to the present invention comprises first fraction of proton pump inhibitor. It further comprises a stabilizer and other pharmaceutically acceptable excipients. Suitably, the stabilizers according to the present invention include, but are not limited to water soluble polymers, sugar or sugar alcohols and alkalizers. Suitably, the water soluble polymers that can be used as a stabilizer includes, but are not limited to polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), hydroxypropyl celluloses, hydroxyethyl celluloses, hydroxypropyl methylcelluloses, polyvinyl alcohols, carboxymethylcellulose sodium, and any mixtures thereof. Suitably, sugar or sugar alcohols that can be used as a stabilizer includes, but are not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, and mixtures thereof. Suitably, the alkalizers that can be used as a stabilizer includes, but are not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, magnesium carbonate and the like. Alternatively, the proton pump inhibitors can be stabilized in the form of their alkaline salts such as basic inorganic salts including, but are not limited to, basic inorganic salts of sodium, potassium, magnesium, and calcium. Examples of the basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.
Suitably, the pharmaceutically acceptable excipients include one or more of diluents, binders, alkalizers, dissolution enhancers, lubricants, glidants, disintegrating agents, antioxidants, surfactants, plasticizers, antiadherents, opacifiers, solvents, colorants, pigments, antifoam agents, or any other suitable agents known to formulate a tablet dosage form.
The first, second and third seal coat according to the present invention comprises a suitable coating material, preferably a coating polymer and other suitable coating excipients. The seal coats are inert layers i.e. they do not contain the active pharmaceutical ingredient or drug (proton pump inhibitors).
Suitably, the coating materials that can be used for the seal coating layers include the following without any limitations thereto - polymeric materials such as hydroxypropyl methylcelluloses {for example, Hypromellose (E-15 LV); Hypromellose 2910 (Methocel E-3 LV); and the like}, polyvinylpyrrolidone (povidones, available grades), polyvinyl alcohol, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose; saccharides such as sucrose, lactose, corn starch, zein, gelatin and the like and mixtures thereof.
The excipients that may be used in the seal coats include, but are not limited to plasticizers such as polyethylene glycol, polyethylene glycol derivatives (polyethylene glycol/Macrogol 6000); triacetin, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, propylene glycol, glycerin, liquid paraffin, triethyl citrate, and the like and mixtures thereof, pigments or colourants (for example ferric oxide and the like), masking agents (for example titanium dioxide and the like), antistatic agents (for example titanium oxide, light magnesium oxide, talc and the like). In some embodiments, these coating excipients like plasticizers, pigments, colourants, masking agents, antistatic agents and any other suitable coating excipients are also present in the first and second delayed release coating and in the coating comprising the second fraction of the proton pump inhibitor.
In preferred embodiments, the coating comprising the second fraction of the proton pump inhibitor as well as the third seal coat, may include, water soluble excipients, such as for example, sucrose, mannitol, glucose, xylitol, sorbitol, sodium chloride, potassium chloride, calcium chloride and the like. Further, it may include water insoluble but swellable polymers like low substituted hydroxypropyl cellulose (for example marketed under the tradename L-Hydroxypropyl cellulose LH-32); crosslinked polyvinyl pyrrolidone (such as marketed under the trade name Kollidon CL and Kollidon CL-F). In one specific embodiment, a combination of sucrose and L-Hydroxypropyl cellulose LH-32 is used. In preferred embodiments, the coating comprising the second fraction of the proton pump inhibitor further comprise a stabilizer as used in the core.
Suitably, the first delayed release coating according to the present invention may comprise one or more enteric polymers in suitable amounts such that the coating is soluble at a pH of 6.0 to 6.5. In one embodiment, the first delayed release coating comprises a single enteric polymer which is soluble at a pH of 6.0 to 6.5. In another embodiment, the first delayed release coating comprises a mixture of an enteric polymer soluble at a first pH and an enteric polymer soluble at a second pH such that the mixed polymer coating is soluble at a pH in the range of about 6 to 6.5. In one preferred embodiment, the first delayed release coating according to the present invention comprise a mixture of two enteric polymers, first being soluble at a first pH of about 5.5 and second being soluble at a second pH of about 7 and the polymers are selected and used in such amounts that the overall coating is soluble at a pH in the range of about 6 to 6.5. In one preferred embodiment, the ratio of the first enteric polymer (soluble at a pH about 5.5) and second enteric polymer (soluble at a pH about 7) present in the first delayed release coating, may range from about 4:1 to 3:2, preferably from about 3:1 to 2:1, more preferably from about 3:1 to 2.5:1, more preferably about 2.3:1 in one particularly preferred embodiment. In one embodiment, wherein the first delayed release coating comprises a mixture of two enteric polymers, first being soluble at a first pH of about 5.5 and second being soluble at a second pH of about 7 it was observed that when first polymer soluble at pH 5.5 was 80%, the tablet disintegrated at pH 6.0 phosphate buffer and gave complete release, while in other case when the first polymer soluble at pH 5.5 was 60%, the tablet did not got disintegrated at a pH of 6.8, with no drug release, while when first polymer soluble at pH 5.5 was 75% to 67%, desired drug release at pH 6 – 6.5 was observed.
The enteric polymer soluble at a pH about 6.5 that may be used in the first delayed release coating may be selected from, but not limited to Hypromellose acetate succinates such as those marketed under the trade name Aqoat®AS-HF. The enteric polymers soluble at a pH about 5.5 that may be used in the first delayed release coating include, but are not limited to polymethacrylates or methacrylic acid copolymers, such as Poly(methacrylic acid, ethyl acrylate) 1:1, marketed under the trade name EUDRAGIT® L30 D-55; EUDRAGIT®L100-55 by Rohm GmbH or Evonik Industries; Eastacryl® 30D by Eastman Chemical company; Kollicoat® MAE 30 D and Kollicoat® MAE 30 DP by BASF Fine Chemicals; Acryl-EZE® and Acryl-EZE® MP by Colorcon company.; polyvinyl acetate phthalate; hypromellose phthalate (marketed under the trade name HP-50; HP-55 and HP-55S). (Ref: Handbook of Pharmaceutical Excipients, fifth edition, 2006).
The enteric polymer soluble at a pH about 7 that may be used in the first delayed release coating include, but are not limited to methacrylic acid copolymer such as Poly (methacrylic acid, methyl methacrylate) 1:2, marketed under the trade name EUDRAGIT® S-100, EUDRAGIT® S 12.5; EUDRAGIT® S 12.5 P; Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3:1, marketed under the trade name EUDRAGIT FS 30D, by Rohm GmbH or Evonik Industries. (Ref: Handbook of Pharmaceutical Excipients, fifth edition, 2006).
According to the present invention, the second delayed release coating comprise an enteric polymer soluble at a pH of about 5.5. The enteric polymers soluble at a pH about 5.5 that may be used in the second delayed release coating include, but are not limited to hydroxypropyl methyl cellulose acetate succinate’ grades LF and LG that have succinoyl content of 14-18% and are marketed under the trade name Aqoat® AS-LF and Aqoat® AS-LG; polymethacrylates or methacrylic acid copolymers, such as Poly(methacrylic acid, ethyl acrylate) 1:1, marketed under the trade name EUDRAGIT® L30 D-55; EUDRAGIT®L100-55 by Rohm GmbH or Evonik Industries; Eastacryl® 30D by Eastman Chemical company; Kollicoat® MAE 30 D and Kollicoat® MAE 30 DP by BASF Fine Chemicals; Acryl-EZE® and Acryl-EZE® MP by Colorcon company; polyvinyl acetate phthalate, hypromellose phthalate (marketed under the trade name HP-50; HP-55 and HP-55S). (Ref: Handbook of Pharmaceutical Excipients, fifth edition, 2006).
In one embodiment according to the present invention, the first delayed release coating is applied to a weight gain of about 4% to 10% w/w of the tablet, such as about 5, 6, 7, 8, or 9% w/w of the tablet, preferably about 5% to about 9% w/w of the tablet. In one embodiment according to the present invention, the second delayed release coating is applied to a weight gain of about 4% to 14% w/w of the tablet, such as about 5, 6, 7, 8, 9, 10, 11, 12 or 13% w/w of the tablet, preferably about 8% to about 12% w/w of the tablet.
The concentric coatings according to the present invention can be applied using conventional coating procedures such as in a suitable coating pan or in fluidized bed apparatus, using water and/or organic solvents for the coating solutions or dispersions.
The tablet dosage form according to the present invention is physically and chemically stable upon storage and in the acidic environment of the stomach upon delivery, such that there occurs no substantial degradation of the drug (proton pump inhibitor). The tablet dosage form according to the present invention suitably delivers the drug in a targeted fashion to the desired sites of the small intestine such that higher absorption with reduced degradation in-transit takes place, resulting in increased overall bioavailability of the proton pump inhibitor.
The tablet dosage form of the present invention is a compact single solid dosage form and offers several advantages as compared to the multiparticulate dosage form such as multiple coated pellets filled in a capsule. The tablet dosage form show better stability as compared to pellets filled capsules. The processing time, the amount of coating excipients required and therefore the overall cost of coating/processing is much lower in case of tablet dosage form compared to the multiparticulate dosage forms such as pellets filled capsules. The multiparticulate dosage forms such as pellets filled in capsule, show non-uniform distribution throughout the GIT upon administration.
Once the capsule filled with enteric coated granules is ingested, the capsule shell dissolves immediately and the pellets get emptied into the stomach. During the subsequent gastrointestinal transit process, the pellets do not travel as a unit dosage, rather spreads randomly over a large surface area at different sites in the GIT. The pellets do not reach the duodenum simultaneously, neither do the pellets reach the jejunum simultaneously. This leads to release of drug at different locations and at different time points, thus causing uneven and non-uniform release of the active ingredient at different locations in the GIT. Exact temporal release of drug could not take place. Even if the pellets are coated with a specific pH enteric polymer, the pellets do not release the drug at a particular site at the same time, due to scattering of the pellets over different sites. Thus, spatial and temporal control of drug release could not take place in case of multiparticulate dosage forms.
Unlike these multiparticulate dosage forms, the tablet dosage form of the present invention, which is a monolithic single unit tablet, upon oral administration is present at a single location in the GIT at one point in time and releases the drug at one particular location, based on the pH of the GI environment, thus allowing for both spatial and temporal control of drug release. This is evident from Figure 1, which illustrates the plasma concentration –time profile post oral ingestion of the tablet dosage form of the present invention. Two sharp peaks are observed at two different time points. The first sharp peak in Figure 1 is seen at around 2-3 hours post ingestion, which corresponds to the first fraction of dose being released and absorbed. The second sharp peak is seen at a time period of about 3-5 hours post dosing, which corresponds to second fraction (larger fraction) of dose being released and absorbed. Thus, the drug release proceeds in a controlled dual release fashion. A portion of the drug (about 25%) gets released/absorbed at a time period of about 1.5- 3.0 hours post dosing, when the tablet dosage form encounters a pH of about 5.5-6.0, pH similar to that in the duodenum region of GIT. Another portion (about 75%) gets released/absorbed at a time period of about 3-5 hours, post dosing when the tablet dosage form encounters a pH of about 6.5 (pH 6.0 – 6.8), pH similar to that in the jejunum/upper small intestine region of GIT. (Gut, 1988, 29, 1035-1041). The delayed dual release and absorption provides an extended T max, enhanced bioavailability and prolonged drug action.
Another advantage of the tablet dosage form of the present invention as compared to the multiparticulate dosage forms such as pellets (pellets filled capsule) is that the tablet dosage form can be administered irrespective of food intake while the multiparticulate dosage forms are indicated to be administered after overnight fasting, because if administered with food, the food transit movements can adversely affect distribution of pellets, some may remain in the stomach and some in the intestine, resulting from multiple waves of gastric emptying. This can further cause incomplete and non-uniform release and absorption of drug.
In the context of this specification "comprising" is to be interpreted as "including".
Aspects of the invention comprising certain elements are also intended to extend to alternative embodiments "consisting" or "consisting essentially" of the relevant elements.
Where technically appropriate, embodiments of the invention may be combined.
Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
Technical references such as patents and applications are incorporated herein by reference.
Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.
Hereinafter, the invention is more specifically described by way of examples. The examples are not intended to limit the scope of the invention and are merely used as illustrations.

Example 1:

The tablet dosage form according to one embodiment of the present invention is given below in Table 1:
Table 1: Tablet dosage form of pantoprazole sodium.

S.No. Ingredients Quantity (mg/tablet)
Core comprising a first fraction of the proton pump inhibitor
1. Pantoprazole Sodium 68.50
2. Mannitol (Pearlitol SD200) 54.50
3. Anhydrous Lactose (SuperTab 21 AN) 5.00
4. Crosslinked Polyvinyl pyrrolidone (Kollidon CL Type A) 67.76
5. Anhydrous sodium carbonate 16.30
6 Polyvinylpyrrolidone (K-90) 2.00
7 Purified water * 55.00
9 Calcium stearate 1.94
First Seal Coating
1. Hydroxypropyl methyl cellulose (Hypromellose E-15 LV) 10.95
2. Polyethylene glycol 6000(Macrogol 6000) 2.19
3. Light Magnesium dioxide 0.84
4. Ferric oxide Red 0.68
5. Titanium dioxide 0.34
6. Purified water* 161.47
First Delayed Release Coating
1 Methacrylic acid copolymer NF Type C (Kollicoat MAE 30DP) 15.91$
2 Methacrylic acid copolymer NF (Eudragit FS 30D) 6.82$
3 Triethyl citrate 2.27
4 Purified water* 46.43
Second Seal Coating
1. Sucrose (Pharma grade sugar) 6.80
2. Hydroxypropyl methyl cellulose 2910 (Methocel E-3 LV) 3.00
3. Corn starch 5.00
4. L-Hydroxypropyl cellulose LH-32 5.00
5. Titanium dioxide 0.20
6. Purified water* 80.00
Coating comprising a second fraction of the proton pump inhibitor
1. Pantoprazole Sodium 22.90
2. Anhydrous sodium carbonate 2.50
3. Sucrose (Pharma grade sugar) 16.30
4. Polyvinylpyrrolidone (K-30) 2.30
5. Purified water* 125.23
Third Seal Coating
1. Hydroxypropyl methyl cellulose 2910 (Methocel E-3 LV) 2.10
2. Sucrose (Pharma grade sugar) 5.10
3. Corn starch 3.75
4. L-Hydroxypropyl cellulose LH-32 3.75
5. Titanium dioxide 0.30
6. Purified water* 60.00
Second delayed release coating
1. Hydroxypropyl methyl cellulose acetate succinate (Aqoat AS-LF) 24.56
2. Triethyl citrate 3.40
3. Talc 9.64
4. Titanium dioxide 1.20
5. Ferric oxide yellow 1.20
6. Isopropyl alcohol* 205.33
7. Purified water* 88.00
*Evaporated/removed during drying /processing
$ Solid content present in dispersion
Process-
Preparation of Core Tablet of Pantoprazole Sodium -The drug pantoprazole sodium and excipients (mannitol, lactose, anhydrous sodium carbonate, part of crosspovidone) were shifted through a suitable sieve and mixed in a mixer-cum granulator. Aqueous solution of povidone (K-90) was prepared and used to granulate the powder mix. The wet mass was milled through a suitable S.S. screen. The granules were dried in a fluid bed dryer (FBD) for required LOD (loss on drying). The dried granules were shifted through suitable sieve and the dried oversize granules were milled through a suitable S.S. screen. The sifted and milled granules were blended with lubricant (calcium acetate and a part of crosspovidone) and were compressed into tablet.
First Seal Coating - An aqueous solution of hypromellose (E-15LV) and macrogol 6000 was prepared in water. Magnesium oxide, ferric oxide red and titanium dioxide were dispersed in the above solution. This was used to apply a seal coating over the core tablet of pantoprazole.
First Delayed Release Coating - A coating dispersion comprising of Eudragit FS30D and Kollicoat MAE 30DP was prepared with triethyl citrate as plasticizer and water as the vehicle and it was applied as a coat over the first seal coated core tablet of pantoprazole.
Second Seal Coating - A coating dispersion comprising of sucrose, hypromellose 2910 (Methocel E-3 LV), corn starch, L-hydroxypropyl cellulose LH-32 and titanium dioxide was prepared in water and it was applied as a coat over first delayed release coated pantoprazole tablet.

Coating comprising a second fraction of the proton pump inhibitor - Aqueous drug solution containing pantoprazole sodium, sodium carbonate, sucrose and povidone (K-30) was prepared in water and it was applied as a coat over the second seal coated pantoprazole tablet.
Third Seal Coating - A coating dispersion comprising of sucrose, hypromellose 2910, corn starch, hydroxyl propyl cellulose LH32 and titanium dioxide was prepared in water and it was applied as a third seal coating over the pantoprazole tablet comprising the second fraction of the proton pump inhibitor.
Second Delayed Release Coating - A coating dispersion comprising of hypromellose acetate succinate (Aqoat AS-LF) was prepared with triethyl citrate, talc, titanium dioxide and ferric oxide yellow using water-isopropyl alcohol mixture as the vehicle. The coating dispersion was applied as a second delayed release coating on third seal coated pantoprazole tablet.
The tablet dosage form so prepared packaged in Alu-Alu strip package and were subjected to storage stability testing under various storage conditions, including room temperature storage at 25°C/60% relative humidity and 30°C/65% relative humidity; and accelerated storage conditions, i.e. 40°C/75% relative humidity. The tablet dosage form was found to be stable upon storage. The values for assay of drug, % impurity C (5-(difluoromethoxy)-1Hbenzimidazole-2-thiol), highest unknown impurity and total impurity were analyzed by HPLC technique and were found to be within limit after 9 month storage at room temperature and 6 month storage at accelerated storage conditions. The assay of drug was found to be within range of specification of 90-110% of label claim; the impurity C and highest unknown impurity was found to be not more than 1.0%; the total impurity was found to be not more than 3.0% and the loss on drying was found to be within specification range of not more than 10%w/w. Based on these observations it can be concluded that the tablet dosage form will remain stable at room temperature for the shelf life of 24 months.

Example 2:
The tablet dosage form according to another embodiment of the present invention is given below in Table 2:
Table 2:

S.No Ingredients Quantity (mg/tab)
Core comprising a first fraction of the proton pump inhibitor
1. Pantoprazole Sodium 68.50
2. Mannitol (Pearlitol SD200) 54.50
3. Anhydrous Lactose (SuperTab 21 AN) 5.00
4. Crosslinked polyvinyl pyrrolidone (Kollidon CL Type A) 67.76
5. Anhydrous sodium carbonate 16.30
6. Povidone (K-90) 2.00
7. Purified water * 55.00
8. Calcium stearate 1.94
First Seal Coat
1 Hydroxypropyl methyl cellulose (E-15 LV) 10.95
2 Polyethylene glycol/Macrogol 6000 (PEG6000) 2.19
3 Light Magnesium dioxide 0.84
4 Red oxide of iron 0.68
5 Titanium dioxide 0.34
6 Purified water* 161.47
First Delayed Release Coating
1 Methacrylic acid copolymer NF Type C (Kollicoat MAE30DP) 15.91$
2 Methacrylic acid copolymer NF (Eudragit FS 30D) 6.82$
3 Triethyl citrate 2.27
4 Purified water* 46.43
Second Seal Coat
1 Povidone 1.95
2 Calcium Carbonate 6.525
3 Corn starch 6.525
4 Iron oxide yellow 0.1
5 Titanium dioxide 0.1
6 Purified water* 22.80
Coating comprising a second fraction of the proton pump inhibitor
6. Pantoprazole Sodium 22.90
7. Anhydrous sodium carbonate 2.50
8. Sucrose (Pharma grade sugar) 16.30
9. Povidone (K-30) 2.30
10. Purified water* 125.23
Third Seal Coat
1. Sucrose (Pharma grade sugar) 5.10
2. Hydroxypropyl methyl cellulose (E-3) 2.10
3. Corn starch 3.75
4. L-Hydroxypropyl cellulose LH-32 3.75
5. Titanium dioxide 0.30
6. Purified water* 60.00
Second Delayed Release Coat
1. Hypromellose acetate succinate (Aqoat AS-LF) 24.56
2. Triethyl citrate 3.40
3. Talc 9.64
4. Titanium dioxide 1.20
5. Yellow oxide of iron 1.20
6. Isopropyl alcohol* 205.33
7. Purified water* 88.000
*Evaporated/removed during drying /processing
$ Solid content present in dispersion
The tablet was prepared following a similar process as described in Example 1, with minor variations in accordance with varying ingredients.
Example 3:
The tablet dosage form according to another embodiment of the present invention is given below in Table 3:
Table 3:

Sr.No Ingredients Quantity (mg/tab)
Core comprising a first fraction of the proton pump inhibitor
1 Pantoprazole Sodium 68.50
2 Mannitol (Pearlitol SD200) 54.50
3 Anhydrous Lactose (SuperTab 21 AN) 5.00
4 Crosslinked polyvinyl pyrrolidone (Kollidon CL Type A) 67.76
5 Anhydrous sodium carbonate 16.30
6 Povidone (K-90) 2.00
7 Purified water * 55.00
8 Calcium stearate 1.94
First Seal Coat
1 Hydroxypropyl methyl cellulose (E-15 LV) 10.95
2 Polyethylene glycol/Macrogol 6000 (PEG6000) 2.19
3 Light Magnesium dioxide 0.84
4 Red oxide of iron 0.68
5 Titanium dioxide 0.34
6 Purified water* 161.47
First Delayed Release Coating
1 Methacrylic acid copolymer NF Type C (Kollicoat MAE30DP) 15.91$
2 Methacrylic acid copolymer NF (Eudragit FS 30D) 6.82$
3 Triethyl citrate 2.27
4 Purified water* 46.43
Second Seal Coat
1 Sucrose (Pharma grade sugar) 6.80
2 Hydroxypropyl methyl cellulose (E-3) 3.00
3 Corn starch 5.00
4 L-Hydroxypropyl cellulose LH-32 5.00
5 Titanium dioxide 0.20
6 Purified water* 80.00
Coating comprising a second fraction of the proton pump inhibitor
1 Pantoprazole Sodium 22.90
2 Anhydrous sodium carbonate 2.50
3 Sucrose (Pharma grade sugar) 16.30
4 Povidone (K-30) 2.30
5 Purified water* 125.23
Third Seal Coat
1 Sucrose (Pharma grade sugar) 5.10
2 Hydroxypropyl methyl cellulose (E-3) 2.10
3 Corn starch 3.75
4 L-Hydroxypropyl cellulose LH-32 3.75
5 Titanium dioxide 0.30
6 Purified water* 60.00
Second Delayed Release Coat
1 Kollicoat MAE -30 DP 22.73
2 PEG 6000 2.27
3 Purified water 46.97
*Evaporated/removed during drying /processing
$ Solid content present in dispersion
The tablet was prepared following a similar process as described in Example 1, with minor variations in accordance with varying ingredients.
Example 4:
The tablet dosage form according to another embodiment of the present invention is given below in Table 4:
Table 4:

Sr.No Ingredients Quantity (mg/tab)
Core comprising a first fraction of the proton pump inhibitor
1 Pantoprazole Sodium 68.50
2 Mannitol (Pearlitol SD200) 54.50
3 Anhydrous Lactose (SuperTab 21 AN) 5.00
4 Crosslinked polyvinyl pyrrolidone (Kollidon CL Type A) 67.76
5 Anhydrous sodium carbonate 16.30
6 Povidone (K-90) 2.00
7 Purified water * 55.00
8 Calcium stearate 1.94
First Seal Coat
1 Hydroxypropyl methyl cellulose (E-15 LV) 10.95
2 Polyethylene glycol/Macrogol 6000 (PEG6000) 2.19
3 Light Magnesium dioxide 0.84
4 Red oxide of iron 0.68
5 Titanium dioxide 0.34
6 Purified water* 161.47
First Delayed Release Coating
1 Methacrylic acid copolymer NF Type C (Kollicoat MAE30DP) 15.91$
2 Methacrylic acid copolymer NF (Eudragit FS 30D) 6.82$
3 Triethyl citrate 2.27
4 Purified water* 46.43
Second Seal Coat
1 Mannitol 11.80
2 Hydroxypropyl methyl cellulose (E-3) 3.00
3 L-Hydroxypropyl cellulose LH-32 5.00
4 Titanium dioxide 0.20
5 Purified water* 80.00
Coating comprising a second fraction of the proton pump inhibitor
1 Pantoprazole Sodium 22.90
2 Anhydrous sodium carbonate 2.50
3 Sucrose (Pharma grade sugar) 16.30
4 Povidone (K-30) 2.30
5 Purified water* 125.23
Third Seal Coat
1 Sucrose (Pharma grade sugar) 5.10
2 Hydroxypropyl methyl cellulose (E-3) 2.10
3 Corn starch 3.75
4 L-Hydroxypropyl cellulose LH-32 3.75
5 Titanium dioxide 0.30
6 Purified water* 60.00
Second Delayed Release Coat
1 Hypromellose acetate succinate (Aqoat AS-LF) 24.56
2 Triethyl citrate 3.40
3 Talc 9.64
4 Titanium dioxide 1.20
5 Yellow oxide of iron 1.20
6 Isopropyl alcohol* 205.33
7 Purified water* 88.000
*Evaporated/removed during drying /processing
$ Solid content present in dispersion
The tablet was prepared following a similar process as described in Example 1, with minor variations in accordance with varying ingredients.
Example 5:
The tablet dosage form according to another embodiment of the present invention is given below in Table 5:
Table 5:

Sr.No Ingredients Quantity (mg/tab)
Core comprising a first fraction of the proton pump inhibitor
1 Pantoprazole Sodium 68.50
2 Mannitol (Pearlitol SD200) 54.50
3 Anhydrous Lactose (SuperTab 21 AN) 5.00
4 Crosslinked polyvinyl pyrrolidone (Kollidon CL Type A) 67.76
5 Anhydrous sodium carbonate 16.30
6 Povidone (K-90) 2.00
7 Purified water * 55.00
8 Calcium stearate 1.94
First Seal Coat
1 Hydroxypropyl methyl cellulose (E-15 LV) 10.95
2 Polyethylene glycol/Macrogol 6000 (PEG6000) 2.19
3 Light Magnesium dioxide 0.84
4 Red oxide of iron 0.68
5 Titanium dioxide 0.34
6 Purified water* 161.47
First Delayed Release Coating
1 Hypromellose acetate succinate (Aqoat AS-HF) 15.91$
2 Triethyl citrate 1.591
3 Isopropyl alcohol* 110.25
4 Purified water* 47.25
Second Seal Coat
1 Sucrose (Pharma grade sugar) 6.80
2 Hydroxypropyl methyl cellulose (E-3) 3.00
3 Corn starch 5.00
4 L-Hydroxypropyl cellulose LH-32 5.00
5 Titanium dioxide 0.20
6 Purified water* 80.00
Coating comprising a second fraction of the proton pump inhibitor
1 Pantoprazole Sodium 22.90
2 Anhydrous sodium carbonate 2.50
3 Sucrose (Pharma grade sugar) 16.30
4 Povidone (K-30) 2.30
5 Purified water* 125.23
Third Seal Coat
1 Sucrose (Pharma grade sugar) 5.10
2 Hydroxypropyl methyl cellulose (E-3) 2.10
3 Corn starch 3.75
4 L-Hydroxypropyl cellulose LH-32 3.75
5 Titanium dioxide 0.30
6 Purified water* 60.00
Second Delayed Release Coat
1 Hypromellose acetate succinate (Aqoat AS-LF) 24.56
2 Triethyl citrate 3.40
3 Talc 9.64
4 Titanium dioxide 1.20
5 Yellow oxide of iron 1.20
6 Isopropyl alcohol* 205.33
7 Purified water* 88.000

*Evaporated/removed during drying /processing
$ Solid content present in dispersion
The tablet was prepared following a similar process as described in Example 1, with minor variations in accordance with varying ingredients.
Example 6:
The tablet dosage form was subjected to Acid Resistance Testing and drug dissolution tessting:
Acid resistant testing was carried out using USP dissolution apparatus II (Paddle):- One tablet was placed in each of six bowls containing 500 ml, 0.1 N hydrochloric acid maintained at 37 ± 0.5°C and the apparatus was operated at 100 RPM. The apparatus was stopped after 2 hours and the entire dissolution media was carefully decanted from all the six bowls. The tablets were carefully dried with tissue paper. The % acid resistance value was determined as = % label claim of pantoprazole from assay test - % of label claim of pantoprazole in 0.1N HCl in residue (insoluble form). The amount of drug was analyzed by HPLC technique.
Drug dissolution testing was carried out using USP dissolution apparatus II (Paddle) (100rpm). The dissolution apparatus was initially run with 500 ml, 0.1 N hydrochloric acid for 2 hours. At the end of 2 hours the entire 0.1 N hydrochloric acid media was carefully decanted and the tablets were carefully wiped with tissue paper and the bowls were replaced with 900 ml phosphate buffer (pH 6.0) which is preheated at 37°C. The tablets were dropped in the respective bowls and the dissolution apparatus was run for 1 hour (i.e. 2-3 hours cumulatively). The buffer sample was collected after 1 hour (i.e. 2-3 hours cumulatively) and analyzed for drug dissolution (at pH 6.0).
After 1 hour (i.e. 2-3 hours cumulatively), the entire phosphate buffer pH 6.0 was decanted carefully and replaced with 1000 ml of phosphate buffer pH 6.8 and dissolution was continued till 4 hour. The sample was collected and analyzed for drug dissolution (pH 6.8) at 4 hour, by HPLC technique.
The specification range for –
Acid resistance (0-2 Hour) is - not more than 10%;
Drug dissolution in 6.0 pH (2-3 hour) is between 10-35%
Drug dissolution in 6.8 pH (3-4 hour) is not less than 70%
Observations: - The acid resistance value (at 2 hour) was zero %; the drug dissolution in pH 6.0 buffer at 3.0 hour was found to be 22 % and the drug dissolution in pH 6.8 buffer at 4.0 hour was found to be 92 %, which was well within the specification ranges. The drug dissolution or release profile at varying pH demonstrates that the tablet dosage form of the present invention show controlled release of proton pump inhibitor, whereby the drug release does not occur in the acidic pH, similar to pH of the stomach, thus protecting the active drug from interacting with acid, and in-turn preventing its degradation. Further the drug release proceeds in a controlled dual release fashion whereby a portion of the drug (about 25%) gets released at pH 6.0 after a period of 3.0 hours (pH similar to that in the duodenum region of GIT), and another portion (about 75%) gets released at a pH of about 6.8 after 4 hours (pH similar to that in the jejunum/upper small intestine region of GIT.)
Example 7: In-vivo plasma pharmacokinetics study:
The tablet dosage form of the present invention (example 1 having 80 mg of pantoprazole) was administered orally to a human subject in the morning with about 240 ml of water. The subject was fasted for at least 10 hours prior to administration of the dosage form and until 4 hours after dosing.
Sampling schedule: 27 blood samples were collected including the pre-dose blood sample. A pre-dose blood sample of 4 mL was collected within 1 hour prior to schedule dosing. Post dose blood samples (4 mL each) were collected at 0.500, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.000, 5.500, 6.000, 6.500, 7.000, 7.500, 8.000, 9.000, 10.000, 12.000, 16.000, 20.000 and 24.000 hours in vacutainers containing K2EDTA as an anticoagulant.
The amount of Pantoprazole in plasma (at different time points) was quantitated using a validated LC/MS/MS method. LLOQ = 24.9 ng/mL. The plasma pantoprazole concentration versus time profile at different time points is represented in Figure 1. Various pharmacokinetic parameters (Cmax, AUC, t1/2, Tmax, Kel etc.) were determined.
The plasma drug concentration time profile as plotted in Figure 1 shows two sharp peaks at two different time points, indicating that the tablet dosage form of the present invention show dual release and absorption of proton pump inhibitor. Almost no drug release and/or absorption takes place until 2 hours post dosing. At a time period of about 1.5 to 3 hours post dosing, a portion of the drug (smaller portion) gets released and absorbed, (indicated by first sharp peak in Figure 1) followed by release and absorption of another portion (larger portion) of the drug, at a time period of about 3-5 hours post dosing (indicated by second sharp peak in Figure 1). The tablet dosage form of the present invention thus advantageously show a controlled dual drug release and absorption, with extended residence time of the drug in plasma (higher Tmax) and thus improving the overall bioavailability of the drug. There occurs both spatial and temporal control of drug release and absorption. The drug release and/or absorption does not occur in the acidic pH, similar to pH of the stomach, thus protecting the active drug from interacting with acid. A portion of the drug (about 25%) gets released/absorbed at a time period of about 1.5- 3.0 hours post dosing, when the tablet dosage form encounters a pH of about 5.5-6.0, pH similar to that in the duodenum region of GIT. Another portion (about 75%) gets released/absorbed at a time period of about 3-5 hours, post dosing when the tablet dosage form encounters a pH of about 6.4 (pH 6.0 – 6.8), pH similar to that in the jejunum/upper small intestine region of GIT.
,CLAIMS:1. A tablet comprising a core comprising a first fraction of proton pump inhibitor, the core being surrounded by concentric coatings comprising:
i. a first seal coat,
ii. a first delayed release coating comprising one or more enteric polymers wherein the coating is soluble at a pH in the range of about 6 to 6.5,
iii. a second seal coat,
iv. a coating comprising a second fraction of the proton pump inhibitor,
ii. a third seal coat and
iii. a second delayed release coating comprising an enteric polymer soluble at a pH of about 5.5.
2. The tablet as claimed in claim 1, wherein the first delayed release coating comprises a mixture of an enteric polymer soluble at a first pH of about 5.5 and an enteric polymer soluble at a second pH of about 7.
3. The tablet as claimed in claim 2, wherein the ratio of the enteric polymer soluble at a first pH of about 5.5 and the enteric polymer soluble at a second pH of about 7 in the first delayed release coating is in the range of 4:1 to 3:2.
4. The tablet as claimed in claim 2, wherein the ratio of the enteric polymer soluble at a first pH of about 5.5 and the enteric polymer soluble at a second pH of about 7 in the first delayed release coating is in the range of 3:1 to 2:1.
5. The tablet as claimed in claim 1, wherein the ratio of first fraction of proton pump inhibitor to the second fraction of the proton pump inhibitor is from 4:1 to 3:2.
6. The tablet as claimed in claim 1, wherein the first delayed release coating is applied to a weight gain of 5% to 9% w/w of the tablet.
7. The tablet as claimed in claim 1, wherein the second delayed release coating is applied to a weight gain of 8% to 12% w/w of the tablet.
8. The tablet as claimed in claim 1, wherein the proton pump inhibitor is selected from pantoprazole, rabeprazole, omeprazole, esomeprazole, lansoprazole, dexlansoprazole or pharmaceutically acceptable salts thereof.

Dated this 14th day of April 2016

(Signature).......................
Dr. RATNESH SHRIVASTAVA
SUN PHARMACEUTICAL INDUSTRIES LTD.