The following specification describes the nature of the invention and the manner in which it has to be performed.
PHARMACEUTICAL FORMULATIONS COMPRISING PANTOPRAZOLE AND DOMPERIDONE
INTRODUCTION
Aspects of the present invention relate to pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof  and domperidone.
Aspects of the present invention relate to processes for preparing pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone.
Aspects of the application further relate to therapeutic uses and methods of treatment employing such formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone.
Pantoprazole sodium is chemically 5-(difluoromethoxy)-2-[[(3  4-dimethoxy-2-pyridinyl) methyl] sulfinyl] 1 H-benzimidazole sesquihydrate and is represented by structural Formula A. It is commercially available in the form of oral tablets of 20 and 40 mg strengths under the brand name of Protonix® manufactured by Wyeth. Pantoprazole is indicated for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD)  maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome.

Formula A

The domperidone is an antidopaminergic drug chemically known as 5-chloro-1-(1-[3-(2-oxo-2  3-dihydro-1H-benzo[d]imidazol-1-yl) propyl] piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one  and represented as formula B. Domperidone is a medicine that increases the movements or contractions of the stomach and bowel. Domperidone is also used to treat nausea and vomiting caused by other drugs used to treat Parkinson""s disease. Domperidone is a prokinetic agent which enhances gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger  but without disrupting their rhythm. They are used to relieve gastrointestinal symptoms such as abdominal discomfort  bloating  constipation  heart burn  nausea  and vomiting. They are used to treat a number of gastrointestinal disorders  including irritable bowel syndrome  gastritis  acid reflux disease  gastroparesis and functional dyspepsia.

Formula B

A combination therapy of a prokinetic agent and a gastric acid lowering compound is rational and has shown more effectiveness than mono-therapy of proton pump inhibitors. Administration of cisapride and ranitidine was shown to further lower the exposure of the oesophagus to acid(s)"(Inauen W et al. Gut 1993; 34: 1025-1031). Such a therapy was also shown to improve healing rates (de Boer WA et al. Aliment Pharmacol Ther 1994; 8: 147-157).
A combination therapy combining an acid-suppressing agent with a prokinetic agent has been described. [Vyneri et al; N. Engl. J Med 1995; 333: 1106-1110].
The International Application Publication No. WO199725065 discloses oral pharmaceutical dosage form comprising an acid susceptible proton pump inhibitor together with at least one prokinetic agent. Further said patent discloses formulation comprising omeprazole/ lansoprazole and prokinetic agent as mosapride in the form of compressed tablet or pellets filled in capsule.
The International Application Publication No. WO2004071374 discloses once-a-day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent  the proton pump inhibitor being in a delayed release form and the prokinetic agent being in a sustained release matrix tablet form. It also discloses process of preparing the compositions.
The WO2005065664 discloses oral pharmaceutical composition comprising at least one gastric acid suppressing agent and one or more prokinetic agent  characterized in that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form with the proviso that the prokinetic agent is not formulated using a rate controlling polymer and is not present in a sustained release form.
The International Application Publication No. WO2005117870 discloses pharmaceutical composition comprising acid labile proton pump inhibitor  buffering agent in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; and a prokinetic agent.
The International Application Publication No. WO2004089414 discloses drug combination comprising one or more drug units containing one or more proton pump inhibitor agents and one or more drug units containing one or more prokinetic agents.
The present invention provides pharmaceutical compositions comprising a combination of a proton pump inhibitor (PPI) and a prokinetic agent wherein the PPI is present in a delayed release form and the prokinetic agent is present in an immediate release form to provide initial loading dose followed by a sustained release form to maintain the steady drug release for a longer period of time which is useful for the treatment of gastro esophageal reflux disease  reflux esophagitis  peptic ulcer  gastric ulcer  and other gastric acid related disorders. Pharmaceutical formulations of pantoprazole and domperidone as described in the context of the present invention would be a significant improvement in the field of pharmaceutical technology.

SUMMARY OF THE INVENTION
The present invention relate to pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone together with one or more pharmaceutically acceptable excipients.
In embodiments  the present invention provides pharmaceutical formulations comprising pantoprazole sodium and domperidone together with one or more pharmaceutically acceptable excipients.
In embodiments  the present invention provides pharmaceutical compositions comprising pantoprazole or a pharmaceutically acceptable salt thereof in delayed release form  and domperidone in an immediate release form and a sustained release form.
In embodiments  the present invention provides pharmaceutical compositions comprising delayed release pantoprazole or a pharmaceutically acceptable salt thereof in the form of tablets or minitablets and sustained release domperidone in the form of powder  pellets or granules.
In embodiments the present invention relate to processes for preparing formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof  and domperidone.
In embodiments  the present invention provides pharmaceutical formulations comprising pantoprazole sodium and domperidone wherein the formulations are useful in treating gastro-esophageal reflux disease  reflux esophagitis  peptic ulcer  gastric ulcer and other gastric acid related disorders.
In embodiments  the present invention provides pharmaceutical formulations that are stable for commercially relevant times and provide the desired therapeutic concentration of the active agents for the intended duration.
In embodiments  the present invention provides pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein polymorphic stability of the pantoprazole sodium or its salt is achieved during the preparation of the formulations and also during the shelf-life of the formulations.
In embodiments  the present invention provides pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein pantoprazole sodium and domperidone are chemically stable during preparation of the formulations and also during the shelf-life of the formulations.
In embodiments  the present invention relates to solid dosage forms comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein the percentage drug release of pantoprazole or its pharmaceutically acceptable salt composition is not more than about 20% in 2 hours and not less than about 40% in 3 hours when subjected to an in vitro dissolution study.
In embodiments  the present invention relates to solid dosage forms comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein the percentage drug release of domperidone composition is more than about 30% in 3 hours and not less than about 60% in 12 hours when subjected to an in vitro dissolution study.

DETAILED DESCRIPTION OF THE INVENTION
In embodiments the present invention relate to pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone together with one or more pharmaceutically acceptable excipients.
In embodiments the present invention provides pharmaceutical compositions of present invention comprising pantoprazole sodium or a pharmaceutically acceptable salt thereof in delayed release form and domperidone in an immediate release form followed by sustained release form.
In embodiments the present invention provides pharmaceutical formulations in the form of a solid oral dosage forms comprising pantoprazole or a pharmaceutically acceptable salt thereof  and domperidone  and one or more pharmaceutically acceptable excipients.
In embodiments the present invention provides pharmaceutical formulations comprising pantoprazole or a pharmaceutically acceptable salt thereof in delayed release form  and domperidone in an immediate release form and a sustained release form.
In embodiments the present invention provides pharmaceutical compositions comprising delayed release pantoprazole or a pharmaceutically acceptable salt thereof in the form of tablets or minitablets and sustained release domperidone in the form of pellets.
In embodiments the present invention relates to solid dosage forms comprising pantoprazole sodium or its pharmaceutically acceptable salt and domperidone  wherein pantoprazole sodium is present in an amount of about 10 mg to about 100 mg and domperidone is present in an amount of about 10 mg to about 100 mg.
In embodiments  the present invention provides pharmaceutical formulations wherein the said domperidone is present in an amount not less than about 5% and not more than 60% as immediate release form and not less than about 40% and not more than about 95% as sustained release form by weight of the total amount of domperidone present in the formulation. Preferably  the formulations contain about 26% as immediate release and about 74% as sustained release of the total amount of domperidone.
In the context of the present invention  the terms “pellets” or “beads” or “spheres” or “granules” or “pellet” or “inert particles” or “particles” or “nucleus” are used synonymously.
As used herein  the terms “delayed release” according to the present invention shall be construed as release of pantoprazole substantially in the intestinal region of the gastro-intestinal tract and is interchangeable with enteric release.
The term “sustained release” according to the present invention shall be construed as a release other than immediate release  such as for example  extended release of active agent  or a combination of immediate release and extended release  or a combination of immediate release and sustained release  or the like.
In embodiments  formulations of the present invention are highly stable chemically and also exhibit appreciable physical and polymorphic stability during the preparation of the formulations and also during their shelf life.
The term ‘shelf life’ is the time that finished products can be stored after manufacturing  during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution  storage  and display.
In embodiments  the present invention provides pharmaceutical formulation in the form of a capsule comprising a tablet composition of pantoprazole or its pharmaceutically acceptable salt  wherein the said pantoprazole tablet contains a core comprising pantoprazole or its pharmaceutically acceptable salt and disintegrant; swellable coating comprising one or more hydrocolloid-formers selected from zein  crospovidone and a hydroxypropyl cellulose surrounding the core; and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate surrounding the swellable coating.
In embodiments  the present invention provides pharmaceutical formulation in the form of a capsule comprising domperidone pellets wherein the said domperidone pellets are prepared by layering onto seal coated non-pareil seeds and then further coating the drug layered pellets with one or more coating layers such that the pellets provide a sustained release of domperidone.
In embodiments  the present invention provides pharmaceutical formulation in the form of a capsule comprising:
(i) a tablet composition of pantoprazole or its pharmaceutically acceptable salt  wherein the said pantoprazole tablet contains a core comprising pantoprazole or its pharmaceutically acceptable salt and disintegrant; swellable coating comprising one or more hydrocolloid-formers selected from zein  crospovidone and a hydroxypropyl cellulose surrounding the core; and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate surrounding the swellable coating  and
(ii) domperidone pellets wherein the said domperidone pellets are prepared by layering onto seal coated non-pareil seeds and then further coating the drug layered pellets with one or more coating layers such that the pellets provide a sustained release of domperidone.
In embodiments  the present invention provides pharmaceutical formulations comprising pantoprazole sodium in delayed release form comprising a core comprising pantoprazole sodium and disintegrant; swellable coating comprising one or more hydrocolloid-formers selected from zein  crospovidone and a hydroxypropyl cellulose surrounding the core and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate surrounding the swellable coating  and the domperidone is present in sustained release form comprising one or more pharmaceutically acceptable excipients.
As contemplated herein  a "swellable coating" is a coating that increases in volume upon contact with aqueous fluids. This swelling usually occurs through imbibition of water. The swellable coating adds 0.1-10% to the weight of the core.
Generally  the swellable coating  upon wetting  becomes a hydrocolloid  which is a gelatinous suspension of microscopic particles in water. Preferably  the hydrocolloid is formed from a prolamine  such as gliadan  hordein or more preferably zein. Zein is extracted from corn as a granular  straw to pale yellow colored amorphous powder or fine flakes and various commercial extracts have molecular weights in the range of 25 000-35 000. Zein is insoluble in water and insoluble in alcohols  but soluble in aqueous alcohol solutions. Chemically  zein is fairly abundant in glutamine and devoid of lysine and tryptophan. Zein comprises about 20-22% glutamic acid and glutamine  17-20% leucine  5-9% proline  8-10% alanine  4-7% phenylalanine  3-7% isoleucine  4-6% serine  4-5% asparginine and 3-5% tyrosine. All of the other amino acids in zein each comprise less than 3%. Zein has been generally recognized as safe (GRAS) by the United States Food and Drug Administration since March  1985 for use in food and pharmaceutical products. Zein is available commercially from several sources  including Freeman Industries LLC  Tuckahoe  New York USA. Among the commercial zein products sold by this company are those designated as Zein F4000  Zein 4400  Zein F6000  Zein G-10  Aqua Zein  and Aqua Zein Neutral.
In embodiments  the present invention relates to solid dosage forms comprising pantoprazole or its pharmaceutically acceptable salt and domperidone  wherein pantoprazole or its pharmaceutically acceptable salt is present in an amount of about 5 mg to about 100 mg and domperidone is present in an amount of about 5 mg to about 100 mg.
In embodiments the present invention provides pharmaceutical formulations comprising pantoprazole sodium in delayed release form and the domperidone in sustained release form wherein domperidone is coated onto non-pareil seeds which are further coated with one or more seal coatings  and wherein domperidone is layered in between one or more of the seal coatings.
In embodiments the present invention provides pharmaceutical formulations comprising pantoprazole sodium in delayed release form comprising a core comprising pantoprazole sodium and disintegrant; swellable coating comprising one or more hydrocolloid-formers selected from zein  crospovidone and a hydroxypropyl cellulose surrounding the core and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate surrounding the swellable coating; and the domperidone is present in sustained release form wherein domperidone is coated onto non-pareil seeds which are further coated with one or more seal coatings and wherein domperidone is layered in between one or more of the seal coatings.
In embodiments the present invention relates to solid dosage forms comprising pantoprazole or its pharmaceutically acceptable salt and domperidone  wherein methods for preparing said dosage forms include one or more of the steps of mixing  dry granulation  wet granulation  fluidized bed granulation  drying  sifting  blending  compaction  compression  polishing  and coating.
Excipients present in pharmaceutical formulations according to the present invention include but not limited to diluents  binders  stabilizers  lubricants  glidants  disintegrating agents  anti-oxidants  alkalizing agents  surfactants  film coating materials  plasticizers  pigments  opacifiers and coloring agents and any other additives that are commonly used in solid pharmaceutical dosage form preparations.
The diluents present in the pharmaceutical composition according to the application can be one or more of calcium sulfate  cellulose acetate  dextrates  dextrin  dextrose  fructose  kaolin  lactitol  maltitol  maltodextrin  maltose  polymethacrylates  sodium chloride  sucrose  starches  lactose  cellulose derivatives and the like. Different grades of lactose include but are not limited to lactose monohydrate  lactose DT (direct tableting)  lactose anhydrous  Flowlac™  Pharmatose™ and others. Different grades of starches included but are not limited to maize starch  potato starch  rice starch  wheat starch  pregelatinized starch and Starch 1500  Starch 1500 LM grade (low moisture content grade)  fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose  cellulose acetate. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801   Avicel™ PH 101  PH102  PH301  PH302 and PH-F20  microcrystalline cellulose 114  silicified microcrystalline cellulose and microcrystalline cellulose 112. Other useful diluents include but are not limited to one or more of carmellose  sugar alcohols such as mannitol  sorbitol and xylitol  calcium carbonate  magnesium carbonate  sodium carbonate  sodium bicarbonate  light magnesium oxide  heavy magnesium oxide  sodium hydrogen phosphate  calcium sulfate  Disodium hydrogen phosphate basic calcium phosphate  and tribasic calcium phosphate.
The pharmaceutical composition according to the present invention can also comprise binders  such as carboxymethylcellulose  hydroxyethyl cellulose  dextrin  gelatin  maltodextrin  polyethylene oxide  sodium alginate  hydroxypropylcellulose  hydroxypropyl methylcellulose  polyvinylpyrrolidone or povidone (PVP-K25  PVP-K29  PVP-K30  PVP- K90D)  powdered acacia  gelatin  guar gum  carbomer (e.g. carbopol)  methylcellulose  polymethacrylates  and starch.
Excipients present in pharmaceutical formulations according to the application include disintegrant selected from one or more of starches such as potato or tapioca starch  modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500); polyvinylpyrrolidones  including modified polyvinylpyrrolidones (such as crospovidone  polymerized under conditions that promote crosslinking); celluloses such as microcrystalline cellulose  modified celluloses (such as low substituted hydroxypropyl cellulose  croscarmellose sodium and calcium carboxymethyl cellulose); formaldehyde-casein compounds (such as Esma-Spreng.RTM); resins  such as the polacrilin potassium sold by Rohm and Haas Company  Philadelphia  Pennsylvania U.S.A.  using the trademark AMBERLITE IRP88; defatted soybean extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; and sodium carbonate.
The lubricants can also be present as excipients  selected from one or more of stearic acid  magnesium stearate  calcium stearate  sodium laurylsulphate  hydrogenated vegetable oil  hydrogenated castor oil  sodium stearyl fumarate  talc  glyceryl behenate  glyceryl monostearates  palmitic acid  talc  carnauba wax  calcium soaps  zinc stearate  polyoxyethylene monostearates  calcium silicate  silicon dioxide  and macrogols.
The alkanizing agents that are useful in the present invention include alkaline earth metal salt additives and/or alkali metal salt additives and/or organic alkalizing agents. Alkaline earth metal salt additives can include  for example  calcium carbonate  calcium hydroxide  magnesium carbonate  magnesium hydroxide  magnesium silicate  magnesium aluminate  or aluminum magnesium hydroxide and most preferable calcium carbonate. Alkali metal salt additives can be  for example  disodium hydrogen orthophosphate  sodium silicate  sodium carbonate  sodium bicarbonate  sodium hydroxide  sodium aluminate and sodium or potassium citrate  carbonate  bicarbonate  phosphate  sulfate  benzoate and ascorbate and other suitable alkali metal salts most preferable sodium bicarbonate. Examples of organic alkalizing agents include amines. Specific examples of amines include N- methylglucamine  guanine and arginine.
Various pharmaceutically acceptable excipients that may be used as drug release modifying substances in the formulation of the present invention include but are not limited to cellulosic polymers such as hydroxypropylmethyl cellulose phthalate  hydroxypropylcellulose phthalate  hydroxypropyl methylcellulose hexahydrophthalate  cellulose acetate phthalate  cellulose ester-ether phthalate  alkali salts of cellulose acetate phthalate  alkaline earth salts of cellulose acetate phthalate  cellulose acetate hexahydrophthalate  acrylic acid polymers and copolymers such as methacrylic acid  acrylic acid alkyl esters  methacrylic acid alkyl esters; copolymers of acrylic acid  methacrylic acid  methyl acrylate  ethyl acrylate  methyl methacrylate and/or ethyl methacrylate with a terpolymer of ethyl acrylate  methyl methacrylate and trimethylammonioethyl methacrylate chloride (Eudragit RS); vinyl polymers and copolymers such as polyvinyl acetate  polyvinylacetate phthalate  vinylacetate crotonic acid copolymer and ethylene-vinyl acetate copolymers  shellac  ammoniated shellac  shellac-acetyl alcohol and shellac n-butyl stearate and the like. Other classes of polymers  copolymers of these polymers or their mixtures in various ratios as required are within the scope of this invention without limitation.
Many of the drug release modifying substances are generally insoluble in acidic environment such as gastric fluids  but are soluble in higher-pH environment such as the duodenum and lower areas of the gastrointestinal tract. These “enteric polymers” thus delay release of the drug substance contained inside a dosage form  by preventing contact of the drug and fluids until a higher-pH condition is encountered. By selecting appropriate polymers  drug release from a dosage form can be obtained in a desired part of the digestive system.
The term "enteric coating" is a coating that is substantially insoluble at the acidic pH conditions of the stomach but is substantially soluble or water-permeable at the higher pH conditions of the intestines. In this invention  the enteric coating protects the swellable coating against contact with the acidic stomach environment but permits contact of the swellable coating with the more alkaline intestinal fluid. The enteric coating can be chosen to provide targeted release to a particular section of the intestine. For instance  an enteric coating can provide delivery to the duodenum (pH > 5.5)  to the jejunum (pH 6-7)  or to the ileum (pH up to 7.5). Intermediate delivery points can be achieved by combining different coating materials or varying the thickness of the coating. Enteric coating materials include cellulose-based coatings  such as cellulose acetate phthalate and hydroxypropylmethyl cellulose phthalate  methacrylate-based coatings  polyvinyl acetate phthalate-based coatings  and shellac-based coatings.
In the present invention  methacrylate-based coatings are preferred and several useful products are commercially available from Rohm GmbH & Co.  Darmstadt  Germany under the trademark EUDRAGIT®. Eudragit L100-55 is especially preferred.
The descriptions of excipients are illustrative and are not intended to be exhaustive or limiting. Those skilled in the art will be aware of many other substances that are useful in the practice of the application  and the use of such substances is specifically included in this application.
Embodiments of the present invention provide formulations comprising delayed release pantoprazole sodium and sustained release domperidone  having particle size distribution such that 90% of the particles of pantoprazole sodium sesquihydrate are smaller than 200 microns and 90% of the particles of domperidone are smaller than 15 microns.
Pharmaceutical formulations of the present invention may further include any one or more of pharmaceutically acceptable glidants  lubricants  opacifiers  colorants and other commonly used excipients.
The term ‘related substances’ or ‘impurities’ mean the degradation impurities or active ingredient process related impurities. Various degradants and impurities that may be present in a Pantoprazole sodium containing formulation have been identified as the compounds having Formula I to Formula VI.

Formula I: [5-(difluoromethoxy)-2-[[3  4-dimethoxypyridin-2-yl) methyl] sulfonyl] 1H-benzimidazole] (Sulfone impurity)

Formula II: 5-(difluoromethoxy)-2-[[3  4-dimethoxypyridin-2- yl)methyl]sulphanyl]-1H- benzimidazole (Impurity B)

Formula III: 5-(difluoromethoxy)-1H-benzimidazole-2-thiol (Impurity C)

Formula IV: 5-(difluoromethoxy)-2-[(RS)-[(3 4-dimethoxypyridin-2-yl)methyl]
(Impurity D)

Formula V: 6-(difluoromethoxy)-2-[(RS)-[(3 4-dimethoxypyridin-2-yl)methyl]
sulphinyl]-1-methyl-1H-benzimidazole (Impurity E)

Formula VI: Mixture of the stereoisomers of 6  6""-bis(difluoromethoxy)-2 2""-
bis [[(3 4-dimethoxypyridin-2-yl)methyl]sulphinyl]-1H 1""H-5 5""-bibenz imidazolyl (Impurity F)
Various degradants and impurities that may be present in domperidone containing formulation have been identified as the compounds having Formula I-V.

Formula I: 5-choloro-1-(piperidin-4-yl)-1  3-dihydro-2H-benzimidazole-2-one (Impurity A)

Formula II: 4-(5-chloro-2-oxo-2  3-dihydro-1H- benzimidazole-1-yl)-1-formylpiperi dine (Impurity B)

Formula III: Cis-4-(5-chloro-2-oxo-2 3-dihydro-1H-benzimidazol-1-yl)-yl)-1-[3-(2-oxo-2 3-dihydr-1H-benzimidazol-1-yl)propyl]piperidine 1-oxide (Impurity C)

Formula IV: 5-chloro-3-[3-(2-oxo-2  3-dihydro-1H-benzimidazol-1-yl) propyl]-1-[1-[3-(2-oxo-2 3-dihydro-1H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1 3-dihydro-2H-benzimidazol-2-one (Impurity D)

Formula V: 1  3-bis[3-[4-(5-chloro-2-oxo-2 3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]propyl]-1 3-dihydro-2H- benzimidazol-2-one (Impurity F)
The percentage of each of various degradants and impurities generated in the formulations of the present invention relating to pantoprazole or domperidone during stability study of the product at 40°C/75% RH for at least 6 months or at 25°C/60% RH for at least 12 months are not more than 2% w/w of the labeled amount of the particular active agent.
The dosage forms can be subjected to in vitro dissolution testing  such as according to Test 711 “Dissolution” in United States Pharmacopeia 29  United States Pharmacopeial Convention  Inc.  Rockville  Maryland  2005 (“USP”)  to determine the rate at which the active agents are released from the dosage forms  and content of active agents can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).
In embodiments  the dosage form of the present invention comprising delayed release pantoprazole sodium tablet and sustained release domperidone pellets was subjected to in-vitro dissolution using 0.1 N hydrochloric acid (HCl) for 2 hour followed by 900mL of pH 6.8 phosphate buffer and 0.1 N hydrochloric acid (HCl) for 2 hour followed by 900mL of pH 6.5 FASSIF at 100 rpm for pantoprazole sodium and 900mL of 0.1 N hydrochloric acid (HCl) for 1 h followed by 900mL of pH 5.8 acetate buffer+0.25% SLS at 100rpm for sustained release domperidone pellets.
In embodiments  the present invention provides solid dosage forms comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein the percentage drug release of pantoprazole or its pharmaceutically acceptable salt is not more than about 20% in 2 hours and not less than about 40% in 3 hours when subjected to an in vitro dissolution study.
In embodiments  the present invention provides solid dosage forms comprising pantoprazole or a pharmaceutically acceptable salt thereof and domperidone  wherein the percentage drug release of domperidone is more than about 30% in 3 hours and not less than about 60% in 12 hours when subjected to an in vitro dissolution study.
In embodiments the present invention relates to processes for preparing pharmaceutical formulations comprising pantoprazole sodium or a pharmaceutically acceptable salt thereof and domperidone.
Aspects of the present invention include method of preparing pharmaceutical dosage forms comprising pantoprazole sodium or a pharmaceutically acceptable salt thereof in delayed release form and domperidone in sustained release form.
In embodiments  pharmaceutical formulations of the present invention comprising pantoprazole or its salt and domperidone is prepared by the following process:
(i) Preparing an enteric coated tablet of pantoprazole or its salt 
(ii) Preparing sustained release pellets or granules of domperidone  and
(iii) Preparing a capsule dosage form by filling the tablet of pantoprazole prepared in step (i) and sustained release pellets or granules of domperidone prepared in step (ii).
In embodiments  compositions of pantoprazole sodium are prepared as follows:
Part I. Preparation of core tablets:
1. Sifting: Sift Pantoprazole sodium  mannitol  crospovidone through # 30 mesh
sieve and milled Sodium carbonate anhydrous  Crospovidone  purified talc and Calcium stearate through # 60 mesh sieve.
2. Dry mixing: Load the sifted intra granular materials of step 1 into rapid mixer
granulator (RMG).and mix for 5 minutes.
3. Binder and Sodium Carbonate solution preparation: Dissolve Hydroxypropyl
cellulose (binder) and Sodium Carbonate separately in required quantity of
purified water.
4. Granulation: Add binder solution of step 3 to dry mix of step 2 followed by
addition of sodium carbonate solution of step 3 and granulate the wet mass..
5. Drying: Dry the granules of step 4 in the fluid bed dryer at inlet temp of 50°C
to 60°C to get LOD in between 1.0 to 2.0 % w/w at 85°C.
6. Milling: Sift the dried granules of step 5 through #25 mesh and mill the
retained granules through comminuting mill with knifes forward  at medium speed using 1.0 mm mesh followed by passing through #25 mesh.
7. Blending and Lubrication: Blend Crospovidone and talc were mixed with
milled granules of step 6 in octagonal blender and lubricate with calcium stearate.
8. Compression: Compress the blend of step 7 using suitable toolings.
Part II. Barrier coating or seal coating:
1. Coating solution preparation: Dissolve Zein F 4000 and Eudragit L100 55
sequentially in a mixture of isopropyl alcohol and purified water to get a clear solution.
2. Coating: Coat the core tablets of Part I with seal coating solution of step 1 in
pan coater up to 2.0% weight build up.
Part III. Enteric coating:
1. Dissolve Eudragit L100 55 into appropriate quantity of isopropyl alcohol
and add triethyl citrate to this solution with continuous stirring.
2. Disperse talc and titanium oxide appropriate quantity of isopropyl alcohol and
pass through the colloidal mill.
3. Mix the dispersion of step 2 with Eudragit L100 55 solution of step 1and then
passed through nylon cloth.
4. Coat the seal coated tablets of Part II with enteric coating dispersion of
step 3.
In embodiments  compositions of domperidone are prepared
as follows:
Part I: Seal Coating I
1. Dissolve ethylcellulose 10 cps & HPMC 3 cps in the ratio of 1:1 in a solvent
mixture having appropriate ratio of isopropyl alcohol  dichloromethane and purified water.
2. Coat Tartaric acid spheres with the coating solution of step 1.
3. Dry the seal coated pellets of step 2 and sift through suitable mesh #sieve.
Part II: Drug Loading I:
1. Dissolve the HPMC in water followed by addition of domperidone under
stirring and filter the resulting suspension.
2. Spray the drug suspension of step 1 on the seal coated pellets of Part I.
3. Dry the drug coated pellets of step 2 and sift through suitable mesh #sieve.
Part III: Sub Coating I:
1. Dissolve the HPMC in water and filter the resulting solution.
2. Spray the solution of step 1 on the drug coated pellets of Part II.
3. Dry the sub-coated pellets of step 2 and sift through suitable mesh #sieve.
Part IV: Sustained Release Coating:
1. Dissolve Eudragit RLPO  Eudragit RSPO & Eudragit L 100-55 in isopropyl
alcohol and water and add PEG 8000 and talc to this solution.
2. Spray the solution of step 1 on the sub coated pellets of Part III to get desired
weight build up
3. Dry the coated pellets of step 2 and sift through suitable mesh #sieve.
Part V: Sub Coating II:
1. Dissolve HPMC in water and filter the resulting solution.
2. Spray the solution of step 1 on the sustained release coated drug loaded
pellets of Part IV to get desired weight build up.
3. Dry the coated pellets of step 2 and sift through suitable mesh #sieve.
Part VI: Drug Loading II:
1. Dissolve the HPMC in water followed by addition of domperidone under
stirring and filter the resulting suspension.
2. Spray the drug suspension of step 1 on the sub coated pellets of Part V.
3. Dry the drug coated pellets of step 2 and sift through suitable mesh #sieve.
Part VII: Seal Coating II:
1. Dissolve HPMC 3 cps in water and filter the resulting solution.
2. Coat the drug coated pellets of Part VI with the coating solution of step 1.
3. Dry the seal coated pellets of step 2 and sift through suitable mesh #sieve.
Part VIII: Polishing:
1. Load the seal coated pellets of Part VII in a blender and mix with pre-sifted
talc for suitable period of time.
In embodiments  a pantoprazole sodium delayed release tablet and domperidone sustained release pellets were filled into a capsule.
In embodiments  compositions of the present invention are made into suitable pharmaceutical dosage forms. The different pharmaceutical dosage forms include solid oral dosage forms such as  but not limited to  tablets  capsules  and sachets.
In embodiments  formulations of the present invention are in the form of multi-particulates filled into capsules.
In embodiments  formulations of the present invention are in the form of multiple particles such as powder  granules or pellets or mini-tablets that are further made into suitable dosage forms  such as capsules  tablets  and the like.
In embodiments the present invention provides pharmaceutical formulations of the invention comprising pantoprazole sodium and domperidone wherein the formulations are useful in treating gastro esophageal reflux disease  reflux esophagitis  peptic ulcer  gastric ulcer and other gastric acid related disorders..
The following examples further describe certain specific aspects and embodiments of the invention. The examples are provided solely for the purpose of illustration  and should not be construed as limiting the scope of the invention in any manner.
Examples 1: Pantoprazole sodium 40 mg delayed release and domperidone 30 mg sustained release capsules.
A. Pantoprazole delayed release tablet
Ingredient Qty/ Tablet (mg)
Core Tablet
Pantoprazole Sodium Sesquihydrate 45.1
Mannitol (Pearlitol® SD 200) 77.9
Sodium Carbonate Anhydrous 4
Crospovidone Type A 6
Hydroxy propyl cellulose (Klucel® LF) 3.5
Sodium Carbonate Anhydrous 4
Purified water* q.s.
Crospovidone Type A 6
Purified Talc 1.5
Calcium Stearate 2
Total 150 mg
Seal coating
Zein F4000 Regular 2.5
Methacrylic acid Ethyl acrylate copolymer
(Eudragit® L100 55) 0.5
Isopropyl Alcohol* q.s.
Purified Water* q.s.
Enteric Coating
Eudragit® L100 55 20
Triethyl Citrate 2
Purified Talc 3
Titanium Dioxide 4
Isopropyl Alcohol* q.s.
Total 182 mg

B. Domperidone sustained release pellets
Ingredients Qty/capsule (mg)
Seal coat - I
Tartaric acid pellets (#25/#30) 90.5
Ethyl Cellulose 10 cps 2.3
Hypromellose 3 cps (Methocel® E3LV) 2.3
Acetyl tributylcitrate 0.5
Isopropyl Alcohol q.s.
Dichloromethane* q.s.
Purified water* q.s.
Total 95.8
Drug load - I
Domperidone 21
Hypromellose 3 cps (Methocel® E3LV) 5.3
Purified water* q.s.
Total 121.7
Sub Coat - I
Hypromellose 3 cps (Methocel® E3LV) 6.1
Purified water* q.s.
Total 127.8
Sustained Release Coat
Ammonio Methacrylate Copolymer 
Type A (Eudragit® RLPO) 5.4
Ammino Methacrylate Copolymer
Type B (Eudragit® RSPO) 5.4
Methacrylic Acid Copolymer (Type C)
(Eudragit® L 100-55) 16.2
Polyethylene glycol 8000 1.4
Talc 2.7
Isopropyl Alcohol q.s.
Purified water q.s.
Total 158.9
Sub Coat - II
Hypromellose 3 cps (Methocel® E3LV) 8
Purified water* q.s.
Total 166.9
Drug load - II
Domperidone 9
Hypromellose 3 cps (Methocel® E3LV) 2.3
Purified water* q.s.
Total 178.1
Seal Coat - III
Hypromellose 3 cps (Methocel® E3LV) 8.9
Purified water* q.s.
Purified Talc 1
Total 188
*lost during processing
Manufacturing process of pantoprazole sodium delayed release tablet:
Part I. Preparation of core tablets:
1. Sift pantoprazole sodium  mannitol  crospovidone through # 30 mesh
and sodium carbonate anhydrous  crospovidone  purified talc and calcium stearate through # 60 mesh.
2. Mix thoroughly pantoprazole sodium  mannitol and crospovidone using a
rapid mixer granulator (RMG).
3. Dissolve hydroxypropyl cellulose (binder) and sodium carbonate
separately in required quantity of purified water.
4. Granulate the dry mix of step 2 by adding the binder solution of step 3
followed by addition of sodium carbonate solution of step 3 and additional quantity of water as required to get good granules.
5. Dry the granules of step 4 in the fluid bed dryer at inlet temperature of 50°C to
60oC to get LOD in between 1.0 to 2.0 % w/w at 85°C.
6. Sift the dried granules of step 5 through #25 mesh and mill the retains through
comminuting mill with knifes forward  at medium speed using 1.0 mm mesh followed by passing through #25 mesh.
7. Mix Crospovidone and talc to the blend of step 6 in octagonal blender and
lubricate the granules with calcium stearate.
8. Compress the blend of step 7 using 10.0 x 5.0 mm modified capsule shaped
punches with beveled edges and dies using a suitable compression machine.

Part II. Barrier coating or seal coating:
1. Dissolve Zein F 4000 and Eudragit L100 55 sequentially in a mixture of
isopropyl alcohol and purified water to get a clear solution.
2. Coat the core tablets of Part I with seal coating solution of step 1 in
pan coater up to 2.0% weight build up.

Part III. Enteric coating:
1. Dissolve Eudragit L100 55 into appropriate quantity of isopropyl alcohol
and add triethyl citrate to this solution with continuous stirring.
2. Disperse talc and titanium oxide appropriate quantity of isopropyl alcohol and
pass through the colloidal mill.
3. Mix the dispersion of step 2 with Eudragit L100 55 solution of step 1and then
pass through nylon cloth.
4. Coat the seal coated tablets of Part II with enteric coating dispersion of
step 3 up to 19.0 % weight build up.

Manufacturing Process of domperidone sustained release pellets:
Part I: Seal Coating I:
1. Dissolve ethylcellulose 10 cps & HPMC 3 cps in the ratio of 1:1 in a solvent
mixture having appropriate ratio of isopropyl alcohol  dichloromethane and purified water.
2. Coat Tartaric acid spheres with the coating solution of step 1.
3. Dry the seal coated pellets of step 2 and sift through suitable mesh sieve.

Part II: Drug Loading I:
1. Dissolve the HPMC in water followed by addition of domperidone under
stirring and filter the resulting suspension.
2. Spray the drug suspension of step 1 on the seal coated pellets of Part I to get
desired build up of about 27.5 ± 1.0% w/w.
3. Dry the drug coated pellets of step 2 and sift through suitable mesh sieve.

Part III: Sub Coating I:
1. Dissolve the HPMC in water and filter the resulting solution.
2. Spray the solution of step 1 on the drug coated pellets of Part II.
3. Dry the sub-coated pellets of step 2 and sift through suitable mesh sieve.

Part IV: Sustained Release Coating:
1. Dissolve Eudragit RLPO  Eudragit RSPO & Eudragit L 100-55 in isopropyl
alcohol and water and add PEG 8000 and talc to this solution.
2. Spray the solution of step 1 on the subcoated pellets of Part III to get desired
weight build up of 24.3 ± 1.0% w/w.
3. Dry the coated pellets of step 2 and sift through suitable mesh sieve.

Part V: Sub Coating II:
1. Dissolve HPMC in water and filter the resulting solution.
2. Spray the solution of step 1 on the sustained release coated drug loaded
pellets of Part IV to get desired weight build up of about 5 ± 1.0% w/w.
3. Dry the coated pellets of step 2 and sift through suitable mesh sieve.

Part VI: Drug Loading II:
1. Dissolve the HPMC in water followed by addition of domperidone under
stirring and filter the resulting suspension.
2. Spray the drug suspension of step 1 on the subcoated pellets of Part V to get
desired build up of about 6.75 ± 1.0% w/w.
3. Dry the drug coated pellets of step 2 and sift through suitable mesh sieve.
Part VII: Seal Coating II
1. Dissolve HPMC 3 cps in water and filter the resulting solution.
2. Coat the drug coated pellets of Part VI with the coating solution of step 1 to
get desired build up of about 5 ± 1.0% w/w.
3. Dry the seal coated pellets of step 2 and sift through suitable mesh sieve.
Part VIII: Polishing:
1. Load the seal coated pellets of Part VII in a blender and mix with pre-sifted
talc for suitable period of time.
The pantoprazole sodium tablets of example 1 were subjected to in-vitro dissolution test using 0.1 N hydrochloric acid (HCl) for 2 hour followed by 900mL of pH 6.8 phosphate buffer and 0.1 N hydrochloric acid (HCl) for 2 hour followed by 900mL of pH 6.5 FASSIF at 100 rpm as dissolution media. The in-vitro data was compared with marketed Reference product Stomac® 40. Results are shown in the table-1. Domperidone sustained release pellets of example 1 were subjected to in-vitro dissolution test 900mL of 0.1 N hydrochloric acid (HCl)  followed by 900mL of pH 5.8 acetate buffer+0.25% SLS at 50 rpm. Results are shown in table-2.

Manufacturing Process of capsule containing pantoprazole sodium delayed release tablet and domperidone sustained release pellets:
1. Domperidone pellets assay is calculated and the required amounts of pellets are taken to get 30 mg of Domperidone/capsule.
2. Pantoprazole tablet and Domperidone sustained release pellets are filled in capsules (size 1) using capsule filling machine.

Table-1:

Time (Minutes) Cumulative percentage (%) release of pantoprazole
0.1N HCl for 2 hours followed by Ph 6.8 phosphate buffer 0.1N HCl for 2 hours followed by pH 6.5 FASSIF
Example 1 Reference Example 1 Reference
125 0 0 0 0
130 0 0 0 0
135 3 2 4 4
140 21 12 41 40
150 72 52 95 90
165 99 95 98 100
Table-2:
Time (hours) Cumulative percentage (%) release of domperidone
0.5 31
1 48
0.5 70
2 77
3 82
4 88
6 94
8 95
12 97

Example 2:
Pantoprazole sodium 40 mg delayed release tablet:
Ingredient Qty/ Tablet (mg)
2A 2B 2C 2D
Core tablet
Pantoprazole Sodium Sesquihydrate 45.1 45.1 45.1 45.1
Mannitol (Pearlitol® SD 200) 83.3 83.3 83.3 83.3
Sodium Carbonate Anhydrous 4 4 4 4
Crospovidone Type A 6 6 6 6
Hydroxy propyl cellulose (Klucel® LF) 3.5 3.5 3.5 3.5
Sodium Carbonate Anhydrous 4.0 4.0 4.0 4.0
Purified water* q.s. q.s. q.s. q.s.
Crospovidone Type A 1.7 1.7 1.7 1.7
Purified Talc 0.4 0.4 0.4 0.4
Calcium Stearate 2.0 2.0 2.0 2.0
Total 150 mg 150 mg 150 mg 150 mg
Seal coating
Zein F4000 Regular 1.8 1.8 1.8 1.8
Methacrylic acid Ethyl acrylate copolymer (Eudragit® L100 55) 0.4 0.4 0.4 0.4
Isopropyl Alcohol* q.s. q.s. q.s. q.s.
Purified Water* q.s. q.s. q.s. q.s.
Enteric Coating
Methacrylic acid Ethyl acrylate copolymer (Eudragit® L100 55) 15.7 17.8 22.1 19.9
Triethyl Citrate 1.6 1.8 2.2 2.1
Purified Talc 2.4 2.7 3.3 3.0
Titanium dioxide 3.1 3.5 4.6 3.9
Isopropyl Alcohol* q.s. q.s. q.s. q.s.
Total (mg) 175.1 178.1 184.2 181.1
*lost during processing
Manufacturing processes for pantoprazole delayed release tablets for Examples 2A-2D are similar to process as described in Example 1.

Example 3: Domperidone 30 mg sustained release pellets
Ingredients Qty/capsule (mg)
3A 3B 3C 3D
Seal coat - I
Tartaric acid pellets (#25/#30) 43.6 136 89.8 100
Ethyl Cellulose 10 cps 1.1 3.4 2.2 2.5
Hypromellose 3 cps (Methocel® E3LV) 1.1 3.4 2.2 2.5
Acetyl tributylcitrate 0.2 0.7 0.5 0.5
Isopropyl Alcohol* q.s. q.s. q.s. q.s.
Dichloromethane* q.s. q.s. q.s. q.s.
Purified water* q.s. q.s. q.s. q.s.
Total 46 143.5 94.7 105.5
Drug load - I
Domperidone 24 30 20 22
Hypromellose 3 cps (Methocel® E3LV) 6 7.5 5 5.5
Purified water* q.s. q.s. q.s. q.s.
Total 76 181 119.7 133
Subcoat- I
Hypromellose 3 cps (Methocel® E3LV) - 9.1 6.0 6.6
Purified water* - q.s. q.s. q.s.
Total - 190.1 125.7 139.6
Sustained Release coat
Ammonio Methacrylate Copolymer 
Type A (Eudragit® RLPO) 2.7 6.7 4.4 4.9
Ammino Methacrylate Copolymer
Type B (Eudragit® RSPO) 1.1 6.7 4.4 4.9
Methacrylic Acid Copolymer
(Type C) (Eudragit® L 100-55) - 20 13.2 14.6
Polyethylene glycol 8000 0.2 1.7 1.1 1.2
Talc -- - 1.1 1.2
Isopropyl Alcohol q.s. q.s. q.s. q.s.
Purified water q.s. q.s. q.s. q.s.
Total 80 225.2 149.9 166.4
Subcoat- II
Hypromellose 3 cps (Methocel® E3LV) - - 7.5 8.3
Purified water* - - q.s. q.s.
Total - - 157.4 174.7
Drug load -II
Domperidone 6 - 10 8
Hypromellose 3 cps (Methocel® E3LV) 1.5 - 2.5 2
Purified water* q.s. - q.s. q.s.
Total 87.5 - 169.9 184.7
Seal coat - III
Hypromellose 3 cps (Methocel® E3LV) 4.4 - 8.5 9.2
Purified water* q.s. - q.s. q.s.
Total 91.9 - 178.4 194

Manufacturing processes for Domperidone sustained release pellets for Examples 3A-3D is similar to process as described in Example 1.
One tablet of Example 2A-2C and pellets equivalent to 30 mg of domperidone of Example 3A-3D is filled into a suitable size capsule.

CLAIMS:

1. A pharmaceutical formulation comprising combination of pantoprazole or its pharmaceutically acceptable salt in a delayed release form and domperidone in a sustained release form together with one or more pharmaceutically acceptable excipients.
2. A pharmaceutical formulation of claim 1 comprising pantoprazole or a pharmaceutically acceptable salt thereof in delayed release form  and domperidone in an immediate release form and a sustained release form.
3. A pharmaceutical formulation according to any of the claims 1 and 2 wherein delayed release pantoprazole or its pharmaceutically acceptable salt is in the form of tablets or minitablets  and domperidone is in the form of powder  pellets or granules.
4. A pharmaceutical formulation according to any of the claims 1-3 wherein the formulation of pantoprazole provides a release of pantoprazole or its pharmaceutically acceptable salt of not more than about 20% in 2 hours and not less than about 40% in 3 hours when subjected to an in vitro dissolution study.
5. A pharmaceutical formulation according to any of the claims 1-3 wherein the formulation of domperidone provides a release of domperidone of not more than about 30% in 3 hours and not less than about 60% in 12 hours when subjected to an in vitro dissolution study.
6. A pharmaceutical formulation according to any of the claims 1-5 wherein each of pantoprazole or its pharmaceutically acceptable salt and domperidone is present in an amount of about 10 mg to about 100 mg.
7. A pharmaceutical formulation according to any of the preceding claims 1-6 in the form of a capsule comprising a tablet composition of pantoprazole or its pharmaceutically acceptable salt  wherein the said pantoprazole tablet contains a core comprising pantoprazole or its pharmaceutically acceptable salt and disintegrant; swellable coating comprising one or more hydrocolloid-formers selected from zein  crospovidone and a hydroxypropyl cellulose surrounding the core; and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate surrounding the swellable coating.
8. A pharmaceutical formulation according to any of the preceding claims 1-7 in the form of a capsule comprising domperidone pellets wherein the said domperidone pellets are prepared by layering onto seal coated non-pareil seeds and then further coating the drug layered pellets with one or more coating layers such that the pellets provide a sustained release of domperidone.
9. A pharmaceutical formulation according to any of the claims 1-8 wherein the formulations are useful in treating gastro-esophageal reflux disease  reflux esophagitis  peptic ulcer  gastric ulcer and other gastric acid related disorders.
10. A pharmaceutical formulation of claim 1 prepared by the following process:
(i) Preparing an enteric coated tablet of pantoprazole 
(ii) Preparing sustained release pellets or granules of domperidone  and
(iii) Preparing a capsule dosage form by filling the tablet of pantoprazole prepared in step (i) and sustained release pellets or granules of domperidone prepared in step (ii).