ONCE DAILY DOSAGE FORM OF BENZIMIDAZOLE
COMPOUND

FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition of benzmidazole compound. Particularly the present invention relates to pharmaceutical composition of pantoprazole or pharmaceutically acceptable salts thereof. More particularly, the present invention relates to once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Acid labile H+K+-ATPase inhibitors, known as gastric proton pump inhibitors (PPI), are
known and include the generic compounds such as omeprazole, lansoprazole, pantoprazole, pariprazole, rabiprazole and leminoprazole as disclosed for example in U.S. Pat. Nos. 4,045,563; 4,255,431; 4,628,098; 4,686,230; 4,758,579; 4,965,269; 5,021,433; 5,430,042 5,045,552 and 5,708,017.

In general, the proton pump inhibitors of gastric acid secretion work by undergoing a rearrangement to form a thiophilic species which then covalently binds to gastric H+K+ATPase, the enzyme involved in the final step of proton production in the parietal cells, and thereby inhibits the enzyme.

Proton pump inhibitors are commonly used to treat gastric acid related conditions such as
ulcers, gastritis, GERD (Gastroesophageal Reflux Disease), including erosive and non-erosive reflux desease, dyspepsia, with or without heartburn, and Barretts esophogeus. Proton pump inhibitors (PPI) are commonly used as monotherapy, either as once-daily or twice daily dosing. Proton pump inhibitors are also used in combination with H2RA (histamine2 receptor antagonists) and antibiotics, particularly in helicobacter positive patients. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent acid aspiration of gastric add and to prevent and treat stress ulceration. Further, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.

Proton pump inhibitor compounds are susceptible to degradation or transformation in acidic media. The degradation is catalyzed by acidic compounds and is more stabilized in mixtures with alkaline compounds. The stability of proton pump inhibitor compounds may also be affected by moisture, heat, organic solvents and to some degree by light. For example, proton pump inhibitor compounds such as pyridyl methyl sulfmyl benzimidazoles (having a pKa of 4.0 to 5.0) have a mechanism of action requiring accumulation in the acidic space of the parietal cell (secretory canaliculus, pH ca. 1.0) followed by subsequent hydrogen ion catalyzed conversion to the reactive thiophilic species that is capable of inhibiting the gastric ATPase enzyme resulting in effective inhibition of gastric secretion. Due to this mechanism this compound requires specialized gastro protection to remain active for duodenal absorption. For this reason, and due to sensitivity to degradation in the acid milieu of the stomach, oral formulations of proton pump inhibitor compounds are usually enteric coated.

Despite their success, proton pump inhibitors have not been wholly effective in treating all patients and there is, in particular, a significant number of patients on proton pump inhibitors (up to about 73%) who experience nocturnal acid breakthrough (NAB). Nocturnal acid breakthrough is defined as a gastric pH of less than 4 for any 1 hour period between 10:00 PM and 8:00 AM, which is contrasted with daytime acid breakthrough (DAB) which is defined as a gastric pH of less than 4 for any 1 hour period between 8:00 AM and 10:00 PM. See, for example, Nzeako et al, Aliment. Pharmacol. Ther., "An Evaluation of the Clinical Implications of Acid Breakthrough in Patients on Proton Pump Inhibitor Therapy", 2002: 16,1309-1316.

The pattern of NAB is consistent with a "circadian" pattern, i.e., NAB occurs typically at about 1:00 AM, and extends until approximately 5:00 AM (Katz et al., Curr. Gastroenterol., "The Pharmacology and Clinical Relevance of Proton Pump Inhibitors", 2002:4,459-462 and Peghini et al., Gastroenterology, "Ranitidine Controls Nocturnal Gastric Acid Breakthrough on Omeprazole: A Controlled Study in Normal Subjects", 1998:115, 1335-1339. While the exact basis of this pattern is unclear it has been proposed that it reflects a circadian rhythm in terms of synthesis and processing of the proton pump with the appearance of new pumps at night (Hirschowitz et al., Digestive Diseases and Sciences, Vol. 40, No. 2 (February 1995 Supplement), pp.3S-23S).

Efforts at modifying proton pump inhibitor dosing to control NAB are disclosed in the literature to have only had limited success. Thus, dosing of a proton pump inhibitor at night (either at dinner time—typically 6:00 PM) or at bed-time (typically 10:30 PM) have not eliminated or significantly reduced the incidence of NAB (Ours et al., The American Journal of Gastroenterology, "Nocturnal Acid Breakthrough: Clinical Significance and Correlation With Esophageal Acid Exposure", Vol. 98, No. 3, 2003, pp. 545-550, and Nzeako et al., Aliment. Pharmacol. Then, "An Evaluation of the Clinical Implications of Acid Breakthrough in Patients on Proton Pump Inhibitor Therapy", 2002: 16,1309-1316,). Without wishing to be bound by theory, the reason for this is believed to be related to the short half-life of the proton pump inhibitor (for example, pantorpazole typically has a half-life of approximately 60 minutes), and the need for the proton pump inhibitor to penetrate into the actively secreting parietal cell and acid dependency concentrate in the canaliculus, convert to its active form and bind the proton pump (Hirschowitz et al., Digestive Diseases and Sciences, Vol. 40, No. 2 (February 1995 Supplement), pp.3S-23S,). Thus, the systemic availability of the proton pump
inhibitor after evening or night-time dosing is not aligned to the "circadian" pattern of acid secretion and will be largely metabolized and eliminated prior to the NAB peak.

One suggested manner of treating NAB, such as disclosed by Xue et al., Aliment Pharmacol. Ther. 2001:15:1351-1356, is by adding an H2RA at bedtime to the proton pump inhibitor. It is suggested by Xue et al. that this dual approach can enhance nocturnal gastric acid pH control, decrease nocturnal gastric acid breakthrough, and decrease the duration of oesphageal acid reflux associated with NAB.

As can be seen from the above, pharmaceutical formulation efforts to date have not been directed to achieving a release profile of proton pump inhibitors that align with the NAB pattern. Indeed, pharmaceutical formulations to date have focused on the specific gastric acid labile characteristics of the proton pump inhibitors. Thus, formulations have been described that "protect" the proton pump inhibitor within an enteric coating layer. It appears that many formulations in the prior art consider it necessary to include in proton pump inhibitor dosage forms an enteric coating. In other words, it appears that many current proton pump inhibitor dosage forms include, as a critical element, an enteric polymer system that is triggered to dissolve and release the proton pump inhibitor under intestinal pH conditions.

In particular, many formulations in the prior art include pH control of the release of the proton pump inhibitor in order that the proton pump inhibitor is released under more neutral or alkaline conditions. See, for example, U.S. Pat. No, 4,786,505 to Lovgren et al., U.S. Pat. No. 4,853,230 to Lovgren et al., U.S. Pat. No. 5,690,960 to Bengtsson et al., U.S. Pat. No. 5,817,338 to Bergstrand et al., U.S. Pat. No. 6,207,198 to Seth, U.S. Pat. No. 6,248,810 to St. Clair et al., U.S. Pat. No. 6,248,355 to Seth.

The use of enteric polymers has then also led to the associated need to separate the proton drug inhibitor from the acid moieties of the enteric polymer by the insertion of an intermediate non-enteric "barrier" coating. This barrier layer is critical for shelf-life stability of the enteric based formulations. Most commonly this barrier coat is a water-soluble layer and these formulations are designed to rapidly release the proton pump inhibitor on emptying from the stomach.

In U.S. Pat. Nos. 5,945,124, 6,068,856 and 6,274,173 to Sachs et al., there is disclosed at least one release-slowing, release-controlling intermediate layer. In particular, Sachs et al. is directed to enhancing of the action of an antimicrobially-active ingredient on Helicobacter by administering pantoprazole in slow-release dosage form (extended release form). Sachs et al. disclose that it is surprising that administration of slow-release pantoprazole results in onset of action taking place significantly faster than on administration in a form without retarding such release, and that the duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.

Sachs et al. disclose that their invention relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for treatment of disorders caused by Helicobacter, wherein pantoprazole is present at least partly in slow-release form. Moreover, Sachs et al. disclose that their invention also relates to an oral pharmaceutical composition in pellet or tablet form for acid-labile irreversible proton pump inhibitors comprising an alkaline pellet or tablet core, at least one release-slowing, release- controlling intermediate layer and an outer enteric layer which is soluble in the small intestine, wherein the intermediate layer for the pharmaceutical composition is formed from a water-insoluble film former, the film former being applied from anhydrous solution or aqueous dispersion.

The goal of the system of Sachs et al. is not directed to treating NAB and is not directed to any time-course and release profile to align proton pump inhibitor release to optimal treatment of NAB. As noted above, Sachs et al. is directed to optimizing combination therapy with an antibiotic for Helicobacter eradication and potential stability advantages of a non-water soluble barrier given the enteric aspect of this formulation.

WO 01/24777 patent publication is directed to pharmaceutical compositions, which includes pharmaceutical compositions for multiphase delivery of proton pump inhibitors. WO 01/24777 discusses that current immediate release dosing regimes often result in periods during the day where the intragastric pH is maintained above 3.0, preferably above 4.0, preferably over a 24 hour period is not achieved, and this may become particularly acute during the night where "breakthrough pH" occurs. WO 01/24777 discloses that there is not a constant requirement for the inhibitor because it is postulated that the initial dose inhibits the receptors and it is only when the receptors begin to regenerate that further inhibitor is required. WO 01/24777 discloses that the use of sustained release formulations therefore involves the use of more inhibitor than necessary. Therefore, it is disclosed that it is desirable to provide pulsed release formulations capable of releasing a second dose of inhibitor when the effects of the first dose begin to diminish. WO 01/24777 broadly discloses delayed release of drugs in anticipation of symptoms. However, the only disclosure relative to release of proton pump inhibitor drugs appears to be a delayed release of the proton pump inhibitor in order to delay the release of the proton pump inhibitor for a lengthy period of time, such as 5 or 6 hours or longer (Examples 1 and 3) for apparently release of the active ingredient upon waking* or an immediate release of proton pump inhibitor in a two population formulation (Example 2). Also, WO 01/24777 discloses the use of disintegrants which result in swelling and disintergration of the dosage unit.

US 2002/0160046 Al discloses stabilized formulations containing omeprazole, or a salt thereof, wherein the formulation does not require a separating layer or an enteric release coating. US 2002/0160046 Al discloses that instead of an enteric coating, the inventive formulation includes a non-enteric time-release (TR) coating applied directly over the omeprazole-containing core. This coating is disclosed to be designed such that the core of the dosage form will rapidly (immediately or catastrophically) disintegrate into an aqueous environment of use when non-acidic media or digestive juice in the environment come into contact with the core. Thus, while US 2002/0160046 Al discloses that the TR coating generally possesses erosion and/or diffusion properties that are essentially independent of the pH of the external aqueous medium and of the enzymes and bile salts present in the GI tract, it also discloses that the active ingredient is immediately released, and does not appear to disclose sustained release.

WO 00/78293, is directed to a dosage form which is prepared without an enteric coating, and which comprises a core material containing an active ingredient selected from omeprazole, an alkaline salt thereof, S-omeprazole or an alkaline salt thereof, one or more alkaline additives which are alkalizing agents having a pH of not less than 8.5 when measured in a 2% w/w water solution/dispersion with a pH-measuring electrode, and one or more swelling agents. The core is coated with a semi permeable membrane that is able to disrupt or may change its permeability after a predetermined time. WO 00/78293 does not appear to teach or suggest any specific desirable dissolution profile, but appears to indicate that after the pellet formulations have left the stomach, generally within 2-4 hours, the semi permeable membrane covering the individual pellets disrupts and/or starts to release the active ingredient in the small intestine. The sole dissolution profile disclosed in WO 00/78293 is in Example 4 wherein dissolution is measured for 2 hours using 0.1 M HC1 and then at pH 6.8. The dissolution profile appears to exemplify a low initial release followed by a rapid release of active ingredient when exposed to the pH 6.8 environment.

Hammer et al (Alimentary Pharmacol Ther 2004; 19 (19): 1105-10) discloses that nocturnal gastric acid suppression can be significantly improved by splitting a 40 mg esomeprazole dose into 20 mg bid. This treatment regimen provides both rapid and sustained acid suppression.

U.S. Pat. No. 5,885,616 discloses a single bead drug delivery system which can provide a two-step release of active agent to facilitate an immediate yet sustained drug delivery. It does not disclose a lag time controlling layer comprising a high viscosity water soluble polymer as the only or the essential polymer. Neither does it disclose or suggest this delivery system for PPI's.

WO 98/19668 is directed to a multicompartment delayed release drug delivery system for acid sensitive drugs like omeprazole. The delayed release is related to a delayed release enteric barrier providing gastro-resistant behaviour for delivering omeprazole in the proximal segment (pH 5-6) of the gastrointestinal tract. This enteric barrier comprises enteric coating polymers as material of this layer.

EP 1194131 B1 discloses a controlled release dosage form producing at least a timed pulse. The delayed release is achieved with a coating comprising one or more ammonio methacrylate copolymers (water insoluble polymers).

WO 01/24777 discloses a pharmaceutical formulation for once daily administration
providing a phased release of a drug or particularly multiphase delivery of PPI's such as perprazole (nowadays known as Esomeprazole). The core is surrounded by an outer semi-permeable membrane comprising a permeable water insoluble polymer and at least 50% by weight of glidant.

U.S. Pat. No. 6,749,867 presents a time-release dosage form for acid-sensitive drugs or more particularly omeprazole, including a drug-containing core surrounded by an inert time-release coating, being water soluble or water erodible, delaying release to generally 0.5-5.0 hours after administration.

WO 2000/078293 presents a dosage form for omeprazole or an alkaline salt thereof, S-omeprazole or an alkaline salt thereof, as active ingredient in a core together with alkaline additive(s) and swelling agent(s). The core is coated with a semipermeable membrane, achieving a delayed release starting when the membrane disrupts.

EP 1086694 presents a solid oral pharmaceutical formulation for acid sensitive benzimidazoles in the form of pellets. The pellets have at least a system for modified release that achieve slow release profiles by an intermediate layer comprising a combination of an inert, noalkaline polymer insoluble in water (ethylcellulose) and an inert, nonalkaline polymer soluble in water (hydroxypropyl methyl cellulose). The slow release pellets can be mixed with fast release pellets and formulated into capsules or tablets.

WO 2002/053097 presents a nonenteric coated carrier for a proton pump inhibitor, including a bicarbonate or a carbonate salt of a Group IA metal.

The United States of Food and Drug Administration recently approved Santarus's Zeregid® an immediate release of omeprazole formulation without use of enteric coat, which contains sodium bicarbonate for stabilizing omeprazole in the stomach, thus gives immediate effect by reaching peak plasma concentration in 30 minutes, thus giving immediate control of acid.

But this is contraindicated to for patients who require sodium restriction, such as those with ascites, renal impairment, congestive heart failure, or difficult-to-control
hypertension.

Castell et al, (Aliment Pharmacol Ther 2005;21:1467-1474) discloses the comparison of the median percentage of time that gastric pH stayed above 4 during night- time interval (10 p.m. to 6 a.m.) between omeprazole immediate release dosage form and pantoprazole delayed release dosage form and concluded that omeprazole 40mg immediate release dosage once daily or twice daily maintains gastric pH above 4 more time when compared with pantoprazole 40mg delayed release dosage form once daily or twice daily.

In view of the above, there is still an existing need for development of proton pump inhibitor formulation that controls the acid secretion whole 24-hour period including in night time for treating Nocturnal acid breakthrough with out use of twice daily dosing of PP1 or intravenous infusion of proton pump inhibitors or co administration of proton pump inhibitors with H2 receptor antagonist or immediate release dosage forms containing sodium bi carbonate. The present inventors during their continuous efforts have developed once daily dosage form of Pantoprazole and pharmaceutically acceptable salts thereof, which provides acid control for about 18-24-hours especially at night time (NAB), thus removing the necessity of twice daily dosing or intravenous infusion of proton pump inhibitors or co administration of proton pump inhibitors with H2 receptor antagonist or immediate release dosage form.

SUMMARY OF THE INVENTION

The present invention meets unmet medical need for the treatment of nocturnal acid breakthrough (NAB) and the unfulfilled needs of the pharmaceutical industry.

The present invention provides once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof.

The present invention also provides once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, for acid control in both day time and night time.

The present invention provides once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, for providing release of pantoprazole or pharmaceutically acceptable salts thereof, for about 18-24 hours.

The present invention also provides once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form provides any one of the following in-vivo plasma profile:

a) two mean t max 's first at about 1-4 hour and the second at about 10-20 hours
b) mean area under the curve more than 5.0g.hr/ml
c) two mean C max'
s first at about 500 ng/ml to 3500ng/ml and second at about 750
ng/ml to 4000ng/ml.

The present invention also provides once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form provides mean plasma concentration of pantoprazole more than about l00ng/ml for about 18-24hrs.
The present invention also provides process for preparing once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof for providing release of pantoprazole for about 18-24 hours.

The present invention meets unfulfilled needs of the pharmaceutical industry for controlling nocturnal acid breakthrough (NAB).

The once daily dosage form according to the present invention may be in the form of tablets, minitablets or capsules or pellets or granules or spheroids or microparticles.

In an another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof for providing release of pantoprazole or pharmaceutically acceptable salts thereof, for about 18- 24-hrs, wherein the dosage form comprises two portions, one is delayed release portion and the second portion is lag-time controlled.

Delayed release portion according to the present invention comprises inert core, drug coat, an optional separating layer, and enteric coating layer,

Lag-time controlled portion according to the present invention comprises an inert core, drug coat, an optional separating layer, modified release coating layer, lag time controlled coating layer and enteric coating layer.

The above two portions may be filled into capsules or compressed into tablets.

In an another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form is in the form of enteric coated tablet comprises two portions: first portion contains core coated with pantoprazole sodium, optional finishing layer and second portion is lag-time controlled.

Lag-time controlled release portion according to the present invention comprises an inert core, drug coat, an optional separating layer, modified release coat, and lag time controlling coating layer.

In an another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form in the form of enteric coated tablet comprising pantoprazole or pharmaceutically acceptable salts thereof, diluents, binders, disintegrants, alkaline substances, lubricants and lag-time controlled portion as mentioned above.

In another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises:

i) core comprising pantoprazole sodium, alkaline substance, diluents,
disintegrants, binders and lubricants
ii) optional separating layer
iii) modified release coating layer
iv) lag-time controlled coating layer
v) second drug layer comprising pantoprazole sodium, alkaline substance, binders, plasticizers
vi) separating layer
vii) enteric coating layer.

The core may be in the form of tablet, minitablet or pellets. The final enteric coated minitablets or pellets may be filled into capsules or compressed into tablets.

In another embodiment of the present invention is once daily dosage form of
pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises;

i) core comprising pantoprazole sodium, alkaline substance, modified
release polymer, diluents, disintegrants, binders and lubricants
ii) optional separating layer
iii) lag-time controlled coating layer
iv) second drug layer comprising pantoprazole sodium, alkaline substance, binders, plasticizers
v) optional separating layer
vi) enteric coating layer.

The core may be in the form of tablet or minitablet

In another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises:

i) inert core
ii) first drug layer comprising pantoprazole sodium, alkaline substance, diluents, and binders
iii) optional seal coating layer
iv) modified release coating layer
v) lag-time controlled layer
vi) second drug layer comprising pantoprazole sodium, alkaline substance, and binders
vii) seal coating layer
viii) enteric coating layer.

The core may be in the form of spheroid or pellets. The filial enteric coated spheroids or pellets are compressed into tablets or filled into capsules,

The inert core may be water soluble core such as Sugar seeds (USP), also known as nonpareils, salt crystals, etc, or water insoluble core such as silicon dioxide, glass or plastic particles, microcrystalline cellulose etc.

Suitable alkaline substance(s) used according to the present invention is any substance(s) which protect pantoprazole or its salts from acid degradation or which creates a "micro-pH" around each pantoprazole particle of not less than pH=7, may be selected but are not restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances; organic pH-buffering substances such as trihydroxymethylaminomethane or other similar, pharmaceutically acceptable pH-buffering substances or meglumine.

Suitable binders used according to the present invention may be selected from povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose or combinations thereof.

Suitable disintegrants used according to the present invention may be selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, and combinations thereof.

Suitable diluents used according to the present invention may selected from microcrystalline cellulose, lactose, starch, sorbitol, sucrose, dicalcium phosphate or combinations thereof.

Suitable lubricants used according to the present invention may be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like.
Suitable plasticizers used according to the present invention may be selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin and the like.

The separating layer(s) or seal coating layer can be applied by coating procedures in suitable equipment such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. The materials for separating layers are pharmaceutically acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carragenan, microcrystalline cellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer(s).

Enteric coating layers may be applied on pantoprazole or its salt layer of which may be optionally covered with separating layer using a suitable coating technique as is understood by one of skill in the art. The enteric coating material may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating polymers one or more, separately or in combination, of the following can be used; e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac, zein, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters or other suitable enteric coating polymer(s).

The enteric coating layers contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and combinations thereof.

Suitable modified release polymers used according to the present invention may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof

Modified release coating layer may be applied on pantoprazole or its salt layer of which may be optionally covered with separating layer using a suitable coating technique as is understood by one of skill in the art. The modified release coating layer may contain pharmaceutically acceptable plasticizers, hydrophobic substances and ami tackifiers like talc, magnesium stearate, sodium stearate fumarate to obtain the desired modified release properties. Plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and combinations thereof.

Suitable hydrophobic substances talc, magnesium stearatc, sodium stearate fumarate.

The modified release coating material/s as mentioned above may be dispersed or dissolved in either water or in suitable organic solvents.

Lag-time controlled coat may delay the release of the drug from about 05-12 hours.

Suitable lag time controlled release polymers used according to the present invention may be selected from high viscosity polymers like ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum, guar gum, gum Arabic, tragacanth, carregenan and combinations thereof.

Pharmaceutically acceptable salts selected from sodium, potassium, magnesium etc. Preferably, the pantoprazole is in the form of sodium salt.

The dosage of pantoprazole or its salts may be from about 20mg to 120mg.

In another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof for providing release of pantoprazole for about 18-24 hours, wherein the dosage form provides any one of the following in-vivo plasma profile:

d) two mean Ws first at about 1-4 hour and the second at about 10-20 hours
e) mean area under the curve more than 5.0ug.hr/ml
f) two mean C max 's first at about 500 ng/ml to 3500ng/ml and second at about 750 ng/ml to 4000ng/ml.

In yet another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, for providing for mean plasma concentration of pantoprazole more than about l00ng/ml for about 18-24hrs.

In yet another embodiment of the present invention provides process for preparing controlled dosage form of pantoprazole or pharmaceutically acceptable salts thereof comprising two portions, one is delayed release portion and the second portion is lag-time controlled.

Delayed release portion may be prepared by:

i) applying drug layer comprising pantoprazole sodium, alkaline
substance, binder, disintegrant over inert core;
ii) applying an optional separating layer over drug layer;
iii) applying enteric coating over optional separating layer/drug layer.

Lag-time controlled portion may be prepared by:

i) applying drug layer comprising pantoprazole sodium, alkaline
substance, binder, disintegrant over inert core;
ii) applying an optional separating layer on drug layer;
iii) applying modified release layer over separating layer/drug layer;
iv) applying lag-time controlled layer over modified release layer;
v) applying enteric coating layer over lag-time controlled layer.

The above two portions may be filled into capsules or compressed into tablets.
In an another embodiment of the present invention provides process for preparing once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the process comprises:
i) first portion contains core coated with pantoprazole sodium, optional finishing layer;

ii) second portion is lag-time controlled is prepared by the same process as mentioned above except enteric coating.

The first and second portions are mixed with tableting excipients like diluents binders, disintegrants, lubricants, and compressed into tablets and finally enteric coated with enteric polymers.

In an another embodiment of the present invention is once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, for providing release of pantoprazole or pharmaceutically acceptable salts thereof for about 18- 24-hrs, wherein the dosage form in the form of enteric coated tablet comprising pantoprazole or pharmaceutically acceptable salts thereof, diluents, binders, disintegrants, alkaline substances, lubricants and lag-time controlled portion, wherein the process comprises:

i) preparing lag-time controlled pellets as the same process mentioned above except enteric coating

ii) lag-time controlled pellets of step i) are mixed with pantoprazole sodium, diluents, binders, disintegrants, alkaline substances, lubricants and compressed into tablets and

iii) enteric coat is applied over the tablets obtained in step ii).

In an another embodiment of the present invention provides process for preparing once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the process comprises:

i) pantoprazole sodium, alkaline substance, diluents, disintegrants, are mixed; granulated with binder solution; dried the wet granules; lubricate the dried granules and compressed into tablets in the diameter of 5mm;
ii) applying optional separating layer over the tablets obtained in step i);
iii) applying modified release coating layer over the tablets obtained in step i) /
separating layer of step ii);
iv) applying lag-time controlled coating layer;
v) applying second drug layer comprising pantoprazole sodium, alkaline
substance, binders;
vi) applying separating layer over second drug layer ;
vii) applying enteric coating layer over the separating layer.

The final enteric coated tablets are filled into capsules into tablets.

In an another embodiment of the present invention provides process for preparing once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the process comprises:

i) pantoprazole sodium, alkaline substance, diluents, modified release polymer
are mixed; granulated with binder solution; dried the wet granules; lubricate the dried granules and compressed into tablets;
ii) applying optional separating layer over the tablets obtained in step i);
iii) applying lag-time controlled coating layer over tablets of step i)/ over
separating layer of step ii) ;
iv) applying second drug layer comprising pantoprazole sodium, alkaline substance, binders over lag-time controlled layer of step iii);
v) applying separating layer over second drug layer of step iv);
vi) applying enteric coating layer over the separating layer of step v).

In an another embodiment of the present invention provides process for preparing once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the process comprises:
i) drug layer comprising pantoprazole sodium, alkaline substance, and
binders on microcrystalline cellulose spheres;
ii) applying optional seal coating layer over drug layer of step i);
iii) applying modified release coating layer over drug layer of step i) / seal coating layer;
iv) applying lag-time controlled coating layer over modified release layer of
step iii);
v) applying second drug layer comprising pantoprazole sodium, alkaline
substance, and binders over lag-time controlled layer of step iv);
vi) applying seal coating layer over second drug layer of step v);

vii) applying enteric coating layer over seal coating layer of step vi)..

The invention is illustrated by the following non limiting examples:

Example 1:

A. Delayed release portion:

B. Lag time controlled release portion:

Batch size- 450 units/capsules.

Brief manufacturing Process:

Delayed release portion:

Step 1: Dissolve pantoprazole sodium in water; add sodium carbonate and HPMC to the
pantoprazole solution under stirring and form drug layering solution.

Step 2: applying step 1 drug solution on to Micro crystal line cellulose spheres in the range of 400 - 600 microns using fluid bed coating apparatus (Wurster process)

Step 3: preparation of seal coating solution: HPMC is dissolved in water and talc is added to the HPMC solution under stirring to form as dispersion.

Step 4: applying step 4 seal coating dispersion over drug loaded pellets obtained in step 2 to form seal coated pellets using fluid bed coating apparatus (Wurster process).

Step 5: Preparation of enteric coat suspension:, triethylcitrate is disolved in water and talc is dispersed in water under stirring then Eudragit L30D55 dispersion was added and formed the enteric coating dispersion.

Step 6: applying enteric coat dispersion over the seal coating layer of step 4 pellets/ on drug coated pellets obtained in step 2 to obtain delayed release portion.

Lag time controlled release portion:

Step 1-2 are same as that of delayed release portion.

Step3: Preparation of modified release layer: HPMC was dissolved in water; magnesium stearate and talc are added to form smooth dispersion.

Step A: Applying step 3 solution over the drug layered pellets obtained step 2 using fluid bed coating apparatus (Wurster process) and the final pellet is called as modified release pellets. Step 5: Preparartion of lag time controlled layer dispersion: Methocel K4M and HPMC 6cps is dispersed in ethanol 90% under stirring.

Step 7: Applying step 5 solution over the modified release layered pellets obtained step 4
using fluid bed coating apparatus (Wurster process) and the final pellet is called as modified

Lag time controlled pellets.

Step 8: applying lag time controlled release suspension of step 7 on controlled release pellets obtained in step 6.

Step 9: Preparation of enteric coat suspension: triethylcitrate is disolved in water and talc is dispersed in water under stirring then Eudragit L30D55 dispersion was added and formed the enteric coating dispersion.

Step 10: applying enteric coat dispersion over the lag time controlled layer of step 8 pellets using fluid bed coating apparatus (Wurster process). J

C. Capsule filling:

The above pellets obtained in step A and B are filled into capsules.

Example 2:

Batch size- 450 units/capsules.

Brief Manufacturing Process:

Step 1 to 8 are same as that of Lag time controlled release portion of example 1
Step 9; Preparation of second drug layer solution: Dissolve pantoprazole sodium in water; add sodium carbonate and HPMC to the pantoprazole solution under stirring and form drug layering solution.

Step 10: preparation of seal coating solution: HPMC is dissolved in water and talc is added to the HPMC solution under stirring to form as dispersion.

Step 11: applying step 10 seal coating dispersion over drug loaded pellets obtained in step 8 to form seal coated pellets using fluid bed coating apparatus (Wurster process).

Step 12: Preparation of enteric coat suspension:, triethylcitrate is disolved in water and talc is dispersed in water under stirring then Eudragit L30D55 dispersion was added and formed the enteric coating dispersion.

Step 13: applying enteric coat dispersion over the seal coating layer of step 11 pellets using fluid bed coating apparatus (Wurster process).

Step 14: The above pellets obtained step 13 are filled into capsules.

We Claim;

1. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form provides any one of the following in-vivo plasma profile:

a) two mean t max 's first at about 1-4 hour and the second at about 10-20 hours

b) mean area under the curve more than 5.0g.hr/ml

c) two mean C max 's first at about 500 ng/ml to 3500ng/ml and second at about 750 ng/ml to 4000ng/ml.

2. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form provides mean plasma concentration of pantoprazole more than about l00ng/ml for about 18-24hrs.

3. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises:

i) core comprising pantoprazole sodium, alkaline substance, diluents,
disintegrants, binders and lubricants

ii) optional separating layer

iii) modified release coating layer

iv) lag-time controlled coating layer

v) second drug layer comprising pantoprazole sodium, alkaline substance,
binders, plasticizers

vi) separating layer vii) enteric coating layer.

4. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises:

i) core comprising pantoprazole sodium, alkaline substance, modified release
polymer, diluents, disintegrants, binders and lubricants

ii) optional separating layer

iii) lag-time controlled coating layer

iv) second drug layer comprising pantoprazole sodium, alkaline substance, binders, plasticizers

v) optional separating layer

vi) enteric coating layer.

5. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, wherein the dosage form comprises:

i) inert core

ii) first drug layer comprising pantoprazole sodium, alkaline substance,
diluents, and binders

iii) optional seal coating layer

iv) modified release coating layer

v) lag-time controlled layer

vi) second drug layer comprising pantoprazole sodium, alkaline substance,
and binders

vii) seal coating layer

viii) enteric coating layer.

6. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, as claimed in Claim 3, 4 and 5 wherein alkaline substances selected from sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances; trihydroxymethylaminomethane, meglumine and combinations thereof.

7. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, as claimed in Claim 3, 4 and 5 wherein lag-time controlled layer polymers selected from ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum, guar gum, gum Arabic, tragacanth, carregenan and combinations thereof.

8. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, as claimed in Claim 3, 4 and 5 wherein separate coating layer or seal coating layer polymers selected from sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carragenan, microcrystalline cellulose, carboxymethylcellulose sodium and combinations thereof.

9. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, as claimed in Claim 3, 4 and 5 wherein modified release polymers selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof.

10. Once daily dosage form of pantoprazole or pharmaceutically acceptable salts thereof, as claimed in Claim 3, 4 and 5 wherein enteric coating polymers selected from
methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac, zein, o-polymerized methacrylic acid, methacrylic acid methyl esters and combinations thereof.