Claims:1. A pharmaceutical composition for once a day oral administration, comprising:
a. at least one delayed release form of proton pump inhibitor; and
b. at least one immediate release form and/or a sustained release form of prokinetic agent together with the combination of swellable polymer and gas generating agent;
wherein the composition is being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged period.

2. Composition according to claim 1 wherein the dosage form is bilayer tablet as tablet in tablet unit dosage form having enteric coated proton pump inhibitor tablet embedded in a bilayer portion having one layer as fast disintegrating layer and the second portion is of a sustained release pro-kinetic agent.

3. Composition according to claim 1 or 2 wherein the delayed release proton pump inhibitor is in the form of enteric coated tablet.

4. Composition according to claim 2 wherein the fast disintegrating layer constitutes about 40% to about 60% of total tablet mass.

5. Composition according to any of claims 1 to 3 wherein the proton pump inhibitor is selected from pantoprazole, omeprazole, lansoprazole, esomeprazole, rabeprazole, pariprazole, tenatoprazole, and leminoprazole.

6. Composition according to any of claims 1 to 3 wherein the proton pump inhibitor is pantoprazole.

7. Composition according to claim 6 wherein therapeutically effective amount of pantoprazole in the composition ranges from 30 to 60 mg per tablet.

8. Composition according to claim 1 or 2 wherein the prokinetic agent is selected from domperidone, cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851, zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP- 1 00, diacol and metocloprarnide.

9. Composition according to claim 1 or 2 wherein the prokinetic agent is domperidone.

10. Composition according to claim 9 wherein therapeutically effective amount of domperidone in the composition ranges from 10 to 40 mg per tablet.

11. Composition according to claim 1 wherein the ratio of swellable polymer to gas generating agent selected is 5: 1 to 2: 1.

12. Composition according to claim 1 or 11 wherein the swellable polymer is selected from hydroxypropyl-methyl cellulose (HPMC), poly(ethylene oxide) (PEO), ethyl-cellulose (EC) or mixture thereof.

13. Composition according to claim 1 or 11 wherein the gas generating agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and or mixture with citric acid, tartaric acid or mixture thereof.
, Description:FIELD OF TECHNOLOGY
Present development relates to a pharmaceutical composition comprising designing a novel pharmaceutical composition particularly “tablet in tablet dosage form” that is characterized to release the active ingredients at different site of action in a predictable manner to maximise the bioavailability.

The present novel pharmaceutical composition provides a gastric retention control drug delivery system comprising controlled release core of prokinetic agent, highly swellable polymer & gas generating agent. The said layer formulation is characterized of being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged period.

In the novel pharmaceutical composition of present development; the proton pump inhibitor is enteric coated and is embedded in a rapid disintegrating layer of the bilayer outer tablet which upon contact with the GI fluids rapidly disintegrates and separates the delayed release proton pump inhibitor tablet which releases its contents into the intestine only.
Upon separation from the rapidly disintegrating layer, the specially designed sustained release prokinetic agent layer floats in the gastric medium whereby the release of the prokinetic agent gets restricted into the stomach area which is its desired site of absorption.
The figure 1 represents the disclosure. In the figure 1 represents sustained release layer of prokinetic agent with gas generating agent of present pharmaceutical composition;
2 represents enteric coated tablet of proton pump inhibitor of present pharmaceutical composition;
3 represents rapidly disintegrating layer of present pharmaceutical composition.
The process for the preparation of said novel pharmaceutical composition comprises three major unit operations as described herein below:
A. Manufacturing of rapid disintegrating layer which may or may not contain an active first component
B. Manufacturing of enteric coated proton pump inhibitor – second component

C. Manufacturing of pro kinetic agent layer – third component

Finally three components are compressed resulting into “tablet in tablet dosage form”.

BACKGROUND OF THE PRESENT INVENTION
Proton Pump Inhibitors
Proton pump inhibitors (PPIs) are a class of acid-labile pharmaceutical compounds that block gastric acid secretion pathways. Exemplary proton pump inhibitors include, omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. The drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H+/K+- ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to acid degradation and, as such, are rapidly destroyed in an acidic pH environment in the stomach. Therefore, proton pump inhibitors are often administered as enteric-coated dosage forms in order to permit release of the drug in the duodenum after having passed through the stomach. If the enteric-coating of these formulated products is disrupted (e.g., during trituration to compound a liquid dosage form, or by chewing an enteric-coated granular capsule or tablet), or if a co-administered buffering agent fails to sufficiently neutralize the gastrointestinal pH, the uncoated drug is exposed to stomach acid and may be degraded. Use of non-enteric coated compositions involves the administration of one or more buffering agents with an acid labile proton pump inhibitor. The buffering agent is thought to prevent substantial degradation of the acid labile pharmaceutical agent in the acidic environment of the stomach by raising the stomach pH. As disclosed in U.S5840737; US6489346, US6645998 and US6699885.
Proton pump inhibitors are typically prescribed for short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastro-esophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hyper secretory conditions such as Zollinger Ellison syndrome. These above-listed conditions commonly arise in healthy or critically ill patients of all ages, and may be accompanied by significant upper gastrointestinal bleeding. It is believed that proton pump inhibiting agents reduce gastrointestinal acid production by inhibiting H+/K+-ATPase of the parietal cell, which is the final common pathway for gastrointestinal acid secretion. Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion by Blocking H7K+-ATPase.Proton pump inhibitors act as weak bases which reach parietal cells from the blood and diffuse into the secretory canaliculi. There the drugs become protonated and thereby trapped. The protonated compound can then rearrange to form a sulfenamide which can covalently interact with sulfhydryl groups at critical sites in the extra cellular (luminal) domain of the membrane-spanning H+/K+- ATPase. See, e.g., Hardman et al, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 907 (9th ed. 1996). As such, proton pump inhibitors are pro-drugs that must be activated within parietal cells to be effective. The specificity of the effects of proton pump inhibiting agents is also dependent upon: (a) the selective distribution of HNK+-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme.
In respect to the stability properties of proton pump inhibitors, it is desirable that the proton pump inhibitors in an oral solid dosage form must be protected from contact with the acidic gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of proton pump inhibitors can occur.
Prokinetic Agents
Prokinetic agents are prescribed for the treatment of various gastrointestinal diseases, such as gastro-esophageal reflux disease (GERD), inflammatory bowel disease, or to treat primary gastrointestinal motility disorders, such as diffuse esophageal spasm or irritable bowel syndrome. Motility disorders of the gastrointestinal tract may be caused by neural, muscular or receptor damage dysfunction. Examples of neural, muscular, and receptor damage or dysfunction include (but are not limited to) diabetic gastroparesis, scleroderma, or the carcinoid syndrome. Prokinetic agent enhances peristaltic efficiency thus enhancing gastrointestinal motility and gastric emptying. Thus, it is used for treating non-ulcer dyspepsia, gastroparesis, and gastric stasis.
Prokinetic agents would be useful in concomitant therapy with proton pump inhibitors to treat patients with GERD, erosive esophagitis or functional dyspepsia. PPI and prokinetic agent combinations increase the tone of the lower esophageal sphincter, decrease the number of transient lower esophageal relaxations, and increase gastric emptying while the proton pump inhibitor is administered which decreases the volume of gastric juice available for reflux into the esophagus and increases the pH so that refluxed gastric contents are much less injurious to the esophageal mucosa.
As per the current state of the art; combination formulation of prokinetic agent and proton pump inhibitors are generally available in pellets filled in capsules or combination of tablet with tablet and / or pellets in filled hard gelatin capsules.
Proton pump inhibitors and prokinetic agents are commonly used and co- prescribed in the treatment of gastroesophageal reflux diseases and various other gastrointestinal conditions including erosive esophagitis, pathological hypersecretory conditions, gastrointestinal ulcers, dyspepsia, gastroparesis, intestinal pseudo- obstruction and post-operative ileus. Proton pump inhibitors are, however, susceptible to degradation/transformation in acidic and neutral media.
WO97/25065 (hereinafter referred as ‘065) discloses the oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent. Various examples of dosage forms are given in which the proton pump inhibitor is in the form of delayed release and the prokinetic agent is in the form of immediate release. The said ‘065 patent, though indicates (line no. 12 to 19) that" administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results", the number of tablets that has to be given are more than one, for the simple reason that the pro-kinetic agent in the formulation is in conventional form. The pro-kinetic agent, for example, mosapride has elimination half- life of 1.4 to 2 hours. Hence, the unit dosage given to the patient will not be sufficient for once a day regimen i. e. mosapride has to be given to the patient for two times even after the original unit dosage. Thus, the patient at the end of the day would have to take three tablets (first of unit dosage, second of conventional mosapride and third again for conventional mosapride).
196/MUM/2004 discloses a pharmaceutical composition for once a day oral administration, comprising: A) proton pump inhibitor in a delayed release form; and B) prokinetic agent, selected from mosapride and domperidone, in a sustained release dosage form. The invention disclosed in 196/MUM/2004 does not use the combination of swellable polymer and gas generating agent together with prokinetic agent nor gives such teaching to a petson skilled in the art.
WO2005065664A1 discloses a pharmaceutical compositions comprising a proton pump inhibitor and a 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 such as an immediate release form to provide an initial loading dose, and a delayed release form to provide a dose with a lag time with the provision that the prokinetic agent is not present in a sustained release form; moreover the pharmaceutical composition is in the form of tablets filled into hard gelatin capsule (i.e. in simple words two or more tablets are filled in a hard gelatin capsule).
WO2004071374 discloses formulation comprising prokinetic agent as sustained release tablet embedded in delayed release pellets of proton pump inhibitor such that it is covered partially as in inlay tablet or wholly as in tablet in tablet. The release pattern of the prokinetic agent from the inside sustained release portion will largely depend upon the wetting of this inside tablet by the selected dissolution medium in vitro or the surrounding gastro-intestinal fluids in vivo and the overall release pattern of the embedded core tablet will depend upon the disintegration of the outer delayed release pellets portion. Hence the described formulation can be considered as difficult formulation from the manufacturing point of view as well as from the practical situation where it has to undergo disintegration to release the inside tablet to the outer environment so as further release the drug. The disintegration of compressed tablet obtained from compression of a delayed release multiparticulate system cannot be controlled properly. However difficulties associated with the dosage comprising the use of pellets is that pellets cannot be pressed into tablets because they are too rigid and the production of pellets is quite expensive process due to the requirement of highly specialized equipments. Moreover disintegration of delayed release multi unit pellets system is difficult.

CN102125689A discloses a product comprising a proton pump inhibitor and prokinetic agent bilayer tablet, characterized in that the proton pump inhibitor and prokinetic agent are at different layers i.e. both the active ingredients are present in a different release unit, preferably two lamellar (meaning alternating layers of different materials in the form of lamellae) bilayer tablets.
WO1997025065A1/ US6132771 discloses an oral, fixed unit dosage forms, i.e. a multiple unit tableted dosage forms, multilayered tablets or a capsule filled with more than one pharmaceutically active compound. The active compounds present in the dosage form are preferably an acid susceptible proton pump inhibitor which is protected by an enteric coating layer, and one or more prokinetic agents.
Presently combination formulation of prokinetic agent and proton pump inhibitor is generally available in pellets filled in capsules or combination of tablet with tablet and / or pellets in filled hard gelatin capsules. However none is available as tablet in tablets dosage form.
None of the prior art disclosed herein above discloses about the incorporation of a gas generating agent contained in the sustained release layer which not only helps in formulating the product as a floating sustained release layer in acidic environment but also helps in detaching the enteric coated tablet from sustained release layer. Nor there is any indication or teaching which motivates a person skilled in the art to incorporate gas generating agent which addresses the problem associated with such pharmaceutical compositions disclosed therein in the prior art.
Disclosed herein is a bilayer tablet in tablet formulation, upper layer comprising of modified/sustained release part of prokinetic agent along with gas generating agent which will help to get floated in gastric medium and providing sustained action of prokinetic agent over long period. Upon separation from the rapidly disintegrating layer, the specially designed sustained release prokinetic agent layer floats in the gastric medium whereby the release of the prokinetic agent is then restricted into the stomach area which is its desired site of absorption.
Thus the release of each active layer can be predicted in vitro and vivo thus assuring that the release occurs at the site of action.

Advantages of “Tablet in Tablet” technology that is used in the present invention which does not comprise pellets filled in capsules or combination of tablet with tablet and / or pellets in filled hard gelatin capsules.
1. Tablet in tablet system provides the ability to prevent interactions between drugs and excipients; and by providing an array of release profiles in one delivery system of either the same or different drugs, treatment for conditions that require a regimen of more than one drug.
2. By using “tablet in tablet” system dosage form comprising of an active ingredient as modified release and an active ingredient as immediate release is prepared.
3. “Tablet in tablet” system provides immediate drug release using a disintegrating monolithic matrix in order to achieve an initial peak in plasma drug level, delayed drug release using an eroding monolithic matrix which delivers another active drug to a different part of the gastrointestinal tract, providing controlled drug release instituting as well able monolithic matrix and better control and regulation of release profiles by retarding initial burst release and achieving zero-order kinetics.
4. Controlled-release profile is achieved by using “tablet in tablet” that typically involves a drug core layer that is surrounded by barrier layers that is made up of hydrophilic swellable polymers such as Hydroxypropyl-methyl cellulose (HPMC) and poly(ethylene oxide) (PEO) or hydrophobic polymers such as ethyl-cellulose (EC) and the likes. The barrier layers minimize and therefore delay the interaction of the gastrointestinal environment with the active core, by decreasing the surface area available for drug release or by controlling the rate, at which the solvent penetrates the layers allowing the initial burst release to be minimized and therefore the drug release is controlled at a near constant.
5. “Tablet in tablet” has ability to release soluble and insoluble drugs at a zero-order rate of release in dissolution media. Dosage frequency of highly water soluble drugs can be reduced providing same efficacy.
6. Adverse effects due to sub therapeutic plasma concentration are avoided by using Tablet in tablet technology.
7. The burst effect, namely, large release within a short period of time, is common in highly soluble drugs, and is avoided, as it leads to high concentration of active ingredients in the blood stream.
8. A novel and robust controlled release formulation of Domperidone to reduce the dosing frequency.
9. Composition of Domperidone & Pantoprazole exhibit controlled release in-vitro behavior with a release profile of less than 10% for initial two hours (retarding initial burst) followed by a controlled complete release in controlled manner.
OBJECT OF THE INVENTION:
The first aspect of the present invention is to provide a new oral dosage form comprising two or more different active substance combined in one fixed unit dosage form of bilayer tablet in tablet.

The second aspect of the present invention is to provide a once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, which provides an improved pharmacokinetic profile. An improved pharmacokinetic profile here means that the formulation provides a more constant blood level of drug and shows less fluctuation between the maximum and minimum plasma drug concentration than once or repeated doses of regular/immediate release drug formulation containing equal amounts of active ingredients administered per day.

The third aspect of the present invention is to provide an oral solid dosage form bilayer tablet in tablet having pharmaceutical composition of Pantoprazole & Domperidone as active Pharmaceutical and acceptable excipients.

The fourth aspect of the present invention is to provide a pharmaceutical dosage form prepared in tablet in tablet bilayer dosage form having controlled release layer of Domperidone, enteric coated of Pantoprazole which embedded in same tablet and second layer is rapid disintegrating layer to support inner embedded tablet of Pantoprazole.

The fifth aspect of the present invention is to provide gastric retention control drug delivery system comprising controlled release core of Domperidone drug, highly swellable polymer & gas generating agent and said layer formulation being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged periods.

The sixth aspect of the present invention is to provide a process for preparing a combined one fixed unit dosage form in the form of a tablet in tablet comprising delayed release Pantoprazole or a pharmaceutically acceptable salt thereof and sustained or modified release form of Domperidone

SALIENT FEATURES OF THE PRESENT INVENTION

The aim of the present invention is to deliver the medicament to the site of action or absorption.

On contact with gastric medium, the one of the layer which is designed to disintegrate rapidly disintegrates within 2 to 3 minutes. This is followed by separation of the inside tablet containing Pantoprazole in an enteric coated form. After the tablet is dislodged, the sustained release part of Domperidone starts floating in the stomach.

The sustained release Domperidone is designed in such a way that the layer immediately floats in the gastric medium there by release the medicaments in stomach area for longer duration where it is mostly absorbed.

Immediate dislocation of the Pantoprazole tablet in tablet is of prime importance as if it is embedded in the SR layer, then it will not be easy to separate the same due to rapid swelling of the matrix where it gets firmly attached to the polymer.

If the tablet is not embedded in the SR layer, it is likely to stick to the polymer matrix during the course of transit in the GI tract if the separation does not happen in first few minutes. As a result the release of Pantoprazole will be delayed considerably in the intestine.

Incorporation of a gas forming agent completely prevents the adhesion of the tablet in tablet to the SR layer. On immediate contact with acidic fluid in gastric region, the gas bubbles push the tablet so much so that it helps in dislodging the same which due to the heavy nature will sink to the bottom while the SR layer starts floating in the acidic medium there by sustaining the release of the Domperidone from the polymer matrix.
STATEMENT OF THE INVNEION
A pharmaceutical composition for once a day oral administration, comprising:
a) at least one delayed release form of proton pump inhibitor; and
b) at least one immediate release form and/or a sustained release form of prokinetic agent together with the combination of swellable polymer and gas generating agent;
wherein the composition is being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged period.
The dosage form is bilayer tablet as tablet in tablet unit dosage form having enteric coated proton pump inhibitor tablet embedded in a bilayer portion having one layer as fast disintegrating layer and the second portion is of a sustained release pro-kinetic agent. The delayed release proton pump inhibitor is in the form of enteric coated tablet. The fast disintegrating layer constitutes about 40% to about 60% of total tablet mass. The proton pump inhibitor is selected from pantoprazole, omeprazole, lansoprazole, esomeprazole, rabeprazole, pariprazole, tenatoprazole, and leminoprazole. The proton pump inhibitor selected is pantoprazole in the composition ranges from 30 to 60 mg per tablet. The prokinetic agent is selected from domperidone, cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851, zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP- 1 00, diacol and metocloprarnide. The prokinetic agent selected is Domperidone in the composition ranges from 10 to 40 mg per tablet. The ratio of swellable polymer to gas generating agent selected is 5: 1 to 2: 1. The swellable polymer is selected from hydroxypropyl-methyl cellulose (HPMC), poly(ethylene oxide) (PEO), ethyl-cellulose (EC) or mixture thereof. The gas generating agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and or mixture with citric acid, tartaric acid or mixture thereof.
SUMMARY OF THE INVENTION
The present invention relates to a novel pharmaceutical composition as tablet in tablet unit dosage form comprising proton pump inhibitor in combination with prokinetic agent in a sustained released form.
The proton pump inhibitor is enteric coated and is embedded in a rapid disintegrating layer of the bilayer outer tablet which upon contact with the GI fluids rapidly disintegrates and separates the delayed release proton pump inhibitor tablet which releases its contents into the intestine only.
Further, the present invention relates to a pharmaceutical composition comprising Pantoprazole in the form of enteric coated tablet in combination with Domperidone in the form of sustained release tablet, highly swellable polymer & gas generating agent and said layer formulation being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged periods.
The present invention provides a use of the said formulation for the treatment and prevention of acid related gastrointestinal disorders, preferably gastroesophageal reflux disorders.
The present invention also discloses the process for the preparation of said pharmaceutical preparation.
GLOSSARY OF TERMS: To more readily facilitate an understanding of the invention and its preferred embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.
As used herein, the terms "comprising," "including," and "such as" are used in their open, non-limiting sense.
The term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" indicates that values slightly outside the cited values, i.e., plus or minus 0.1 % to 10%, which are also effective and safe. Such dosages are thus encompassed by the scope of the claims reciting the terms "about" and "approximately."
"Binders" impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL- 10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.
"Carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like.
"Diffusion facilitators" and "dispersing agents" include materials that control the diffusion of an aqueous fluid through a coating. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG and the like.
Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present invention.
"Diluents" increase bulk of the composition to facilitate compression. Such compounds include e.g., lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinzed starch; compressible sugar, such as Di-Pac® (Amstar); mannitol; hydroxypropylmethylsellulose; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite; and the like.
The term "disintegrate" includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
"Disintegration agents" facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.
"Drug absorption" or "absorption" refers to the process of movement from the site of administration of a drag toward the systemic circulation, e.g., into the bloodstream of a subject.
An "enteric coating" is a substance that remains substantially intact in the stomach but dissolves and releases the drug once the small intestine is reached. Generally, the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a slightly higer pH, typically a pH of 4 or 5, and thus dissolves sufficiently in the small intestines to gradually release the active agent therein.
"Erosion facilitators" include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.
"Filling agents" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose; dextrates; dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
"Gastrointestinal fluid" is the fluid of stomach secretions of a subject or the saliva of a subject after oral administration of a composition of the present invention, or the equivalent thereof. An "equivalent of stomach secretion" includes, e.g., an in vitro fluid having similar content and/or pH as stomach secretions such as a 1% sodium dodecyl sulfate solution or 0.1N HCl solution in water.
"Lubricants" are compounds which prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid; calcium hydroxide; talc; sodium stearylfumerate; a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®); higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, glycerylbehenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Carb-O-Sil®, a starch such as corn starch, silicone oil, a surfactant, and the like.
"Pharmacodynamics" refers to the factors which determine the biologic response observed relative to the concentration of drag at a site of action. "Pharmacokinetics" refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
"Plasticizers" are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin.
"Solubilizers" include compounds such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate and the like.
"Stabilizers" include compounds such as any antioxidation agents, buffers, acids, and the like.
"Surfactants" include compounds such as sodium lauryl sulfate, sorbitanmonooleate, polyoxyethylenesorbitanmonooleate, polysorbates, polaxomers, bile salts, glycerylmonostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF); and the like.
A "therapeutically effective amount" or "effective amount" is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a proton pump inhibitor is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. For example, an effective amount of a proton pump inhibitor refers to an amount of proton pump inhibitor that reduces acid secretion, or raises gastrointestinal fluid pH, or reduces gastrointestinal bleeding, or reduces the need for blood transfusion, or improves survival rate, or provides for a more rapid recovery from a gastric acid related disorder. An "effective amount" of a prokinetic agent is an amount effective to achieve a desired pharmacological effect on the subject's condition, without undue adverse side effects. The effective amount of a pharmaceutical agent will be selected by those skilled in the art depending on the particular patient and the disease level. It is understood that "an effect amount" or "a therapeutically effective amount" can vary from subject to subject, due to variation in metabolism of therapeutic agents such as proton pump inbhibitors and/or prokinetic agents, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
"Treat" or "treatment" as used in the context of a gastric acid related disorder refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, such as preventing the disorder or disease from occurring in a subject which may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. "Treat" or "treatment" as used in the context of a prokinetic agent refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, such as preventing the disorder or disease from occurring in a subject which may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., anesting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. Thus, as used herein, the term "treat" is used synonymously with the term "prevent."
"Wetting agents" include compounds such as oleic acid, glycerylmonostearate, sorbitanmonooleate, sorbitanmonolaurate, triethanolamineoleate, polyoxyethylenesorbitanmonooleate, polyoxyethylenesorbitanmonolaurate, sodium oleate, sodium lauryl sulfate, and the like.

DETAILED DESCREPTION OF THE INVENTION
The present invention relates to a novel pharmaceutical composition as tablet in tablet unit dosage form comprising proton pump inhibitor in combination with prokinetic agent in a sustained released form, highly swellable polymer & gas generating agent. The proton pump inhibitor is enteric coated and is embedded in a rapid disintegrating layer of the bilayer outer tablet which upon contact with the GI fluids rapidly disintegrates and separates the delayed release proton pump inhibitor tablet which releases its contents into the intestine only.
Further, the present invention relates to a pharmaceutical composition comprising Pantoprazole in the form of enteric coated tablet in combination with Domperidone in the form of sustained release tablet, highly swellable polymer & gas generating agent and said layer formulation being capable of swelling and achieving rapid floating while maintaining its physical integrity in gastrointestinal fluids for prolonged periods.

On contact with gastric medium, the one of the layer which is designed to disintegrate rapidly disintegrates within 2 to 3 minutes. This is followed by separation of the inside tablet containing Pantoprazole in an enteric coated form. After the tablet is dislodged, the sustained release part of Domperidone starts floating in the stomach.

It further relate to method or process for preparing a combined one fixed unit dosage form in the form of a tablet comprising delayed release Pantoprazole or a pharmaceutically acceptable salt thereof and sustained or modified release form of Domperidone.
In the present invention the gas generating agent contained in the sustained release layer not only helps in formulating the product as a floating sustained release layer in acidic environment but also helps in detaching the enteric coated tablet from sustained release layer. The floating layer remains in the stomach or upper part of GIT for prolonged period of time, therefore, maximum drug release is obtained at desired site where it is more soluble. Thereafter the detached enteric coated tablet of acid unstable Pantoprazole drug will be free to move towards intestine to release the contents in intestine as designed.
Pantoprazole sodium, a proton pump inhibitor, is chemically 5-(difluoromethoxy)-2-[[(3, 4-dimethoxy-2-pyridinyl) methyl] sulfinyl] 1 H-benzimidazolesesquihydrate and is represented by structural Formula A. It is commercially available in the form of oral tablets of 20 and 40 mg strengths. 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 prokinetic agents are domperidone, cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851, zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP- 1 00, diacol and metocloprarnide.
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 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

Gastroesophageal reflux diseases (GERD) are the term applied to the symptoms or tissue damage caused by the reflux of gastric content (usually acidic) into the esophagus. It is extremely common with one third of adult reporting occasional heartburn and 10 % complaining of daily symptoms. Some patients may develop esophageal mucosal damage causing oesophagitis more severe complications.
Similarly, dyspepsia is also very common medical complaint comprising symptoms such as regurgitation, heartburn, abdominal discomfort and bloating. GERD and peptic ulcers are one of the most common causes of dyspepsia.
Several factors like incompetent lower esophageal sphincter, acidic nature of refluxate, abnormal oesophageal clearance and delayed gastric emptying either alone or in combination may contribute to GERD.
GERD is predominantly result of the problem with gastrointestinal motility. However, most of the symptoms of GERD are due to injurious effects of acid peptic refluxate on the esophageal epithelium .The goals of treatment of GERD are to decrease gastroesophageal reflux to render the reflux harmless to improve esophageal clearance and to protect the esophageal mucosa. Hence the combination of drugs one of which suppresses acid and the other improves gastrointestinal motility is effective in treating GERD.
Hence the combination of drugs one of which suppressing the acid secretion and the other improving gastrointestinal motility is an effective therapeutic option for treating such diseases.
Pantoprazole, a proton pump inhibitor has showed greater clinical efficacy than the other classes of acid suppressing agents in various clinical studies.
Domperidone, a prokinetic agent also been shown in various clinical trials as an effective and safe agent to improve gastrointestinal motility. Domperidone increases LES pressure and enhances the upper gastrointestinal motility and thus treats the underlying pathophysiology of dyspepsia & GERD.
Thus, the combination of Pantoprazole and Domperidone helps in GERD to decrease gastroesophageal reflux, to render the reflux harmless, to improve esophageal clearance and to protect the esophageal mucosa.
The advantage of the said novel pharmaceutical composition is the maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuation, predictable and reproducible release rates for extended durations, enhancement of activity duration for short half-life drugs, the elimination of side effects, frequent dosing, optimized therapy and better patient compliance.
Hence this combination of Pantoprazole with Domperidone in sustained release form, is feasible to be given once a day. This helps to improve patient compliance in the treatment of GERD to decrease gastroesophageal reflux, to render the reflux harmless, to improve esophageal clearance and to protect the esophageal mucosa.

In the present novel pharmaceutical composition the sustained release layer contains gas generating agent which helps in detaching enteric coated tablet from sustained release layer and get buoyant which would remain in stomach or upper part of GIT for prolonged period of time, therefore, the maximum drug release occurs at desired site. At the other end detached enteric coated tablets moves towards intestine and further releases the contents as the desired site of action.

The preparation of pharmaceutical composition of the present invention comprises four phases:

Bi-layer oral dosage forms are made in according to conventional manufacturing process known in the art. The whole tablet comprises three different components prepared separately. It comprises a fast disintegrating layer which may or may not contain an active pharmaceutical ingredient, second component is the enteric coated tablets of Pantoprazole, and third component is the Domperidone sustained release layer with a gas generating agent

A. MANUFACTURING OF RAPID DISINTEGRATING LAYER – FIRST COMPONENT
First component which is a fast disintegrating layer is manufactured by sifting and blending the excipients in a suitable blender. This layer may or may not contain a part of the prokinetic agent to release a initial loading dose rapidly.

B. MANUFACTURING OF ENTERIC COATED PANTOPRAZOLE TABLET – SECOND COMPONENT
Enteric coated tablets are prepared in accordance with conventional manufacturing process briefly described as follows. Pantoprazole, mannitol, sodium carbonate and crospovidone are mixed in suitable granulating equipment such as rapid mixer granulator, and granulated with binder solution prepared by dissolving hydroxypropyl cellulose in isopropyl Alcohol. The wet mass is dried in suitable dryer such as fluid bed dryer, after sizing the dried granules were lubricated with calcium stearate & compressed into tablets by using 5.5 mm standard concave punch die set on a rotary compression machine. Compressed tablet were seal coated with HPMC E-5 followed by enteric coating using methacrylic acid.

C. MANUFACTURING OF DOMPERIDONESR LAYER – THIRD COMPONENT
Sustained release component layer containing Effective and therapeutically effective amount of Domperidone, HPMC K – 4M, HPMC K - 15M and remaining quantity of microcrystalline cellulose into a suitable rapid mixer granulator, further granulated with binder solution prepared by dissolving HPMC E-5 in isopropyl alcohol and purified water mixture. The wet mass was dried in suitable dryers such as fluid bed dryer. The dried granules were suitably sized using suitable sizing equipment such as multi mill. Extra-granular materials such as potassium bicarbonate, HPMC K-4M, HPMC K-15M sifted and blended with the dried sized granules in a suitable blender followed by lubrication with colorant, magnesium stearate, purified talc.

D. COMPRESSION OF THREE COMPONENTS:
Three components obtained hereinabove are compressed by using special machines supplied for manufacturing these types of special tablets such as by Cadmach Machineries, India and the likes. The machines have a suitable change parts or device to insert or place the tablet on to the first layer of the tablet followed by placement of the second layer, thus sandwiching the inner tablet between two powder layers.

Effective and therapeutically effective amount of Pantoprazole is about 30-40 mgs.
Effective and therapeutically effective amount of Domperidone is about 10 mgs to about 40 mgs
The ratio of swellable polymer to gas generating agent selected is 5: 1 to 2: 1.
In present invention sustained release layer of tablet in tablet contains alkali metal carbonate or bicarbonate or combination of citric acid with alkali metal carbonate or bicarbonate and the said alkali metal carbonate or bicarbonate is selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixture thereof as a gas generating component or the said sustained release layer of tablet in tablet contains contain gas generating couples like alkali and acid salts that generates gas upon contact with the gastric fluid.

Diluents selected are well excepted pharmaceutical excipients. These include Microcrystalline cellulose, starch, lactose monohydrate, lactopress SD 250, saccharides like mannitol, sorbitol, sucrose, glucose in different concentration and the likes.

Example of suitable binder to the invention without excluding any other selected from povidone or HPMC E-3/5 and hydroxypropyl cellulose low viscosity/ high viscosity and the likes.

Disintegrating agent is selected from croscarmellose sodium, pre-gelatinised starch, crospovidone and the likes which promote rapid disintegration of tablet.

Example of controlled release excipients are hydroxypropyl methylcellulose (hereinbefore and hereinafter also reffered as HPMC), a partially O-methylated and O-(2-hydroxypropalated) cellulose available in different grades that vary in viscosity. It is commercially available as benecel, metolose, methoceletc. In present invention HPMC K4M, K15Mis used as swelling polymer in different concentration.

Example of floating agent used but not limited to potassium or sodium bicarbonate, sodium or potassium carbonate, combination of citric acid and sodium/ potassium carbonate, combination of citric acid and sodium/ potassium bicarbonate. In the present invention may comprise a one or more gas generating component that generates gas upon contact with the gastric fluid, or may include a combination of ingredients that generates gas in presence of gatro-intestinal fluids.

The gas generating agent also referred as effervescent agent is used in an amount ranging from about 1% to about 50% by weight of the core, more preferably from about 1% to about 8% by weight of the core. Alkali metal bicarbonate or carbonates are preferred gas generating agents. Potassium bicarbonate is used as the preferred gas generating agent.

Examples of suitable lubricant to the invention but not limited to are stearic acid, magnesium stearate, calcium stearate, or mixtures thereof and are used to a concentration of about 0.5 to about 4% w/w.

Examples of suitable glidant to the invention are but not limited to purified talc, colloidal silicon dioxide or mixtures thereof and the likes.

Example of suitable coating materials of the invention and its complementary tablet without excluding any other, are hydroxymethyl cellulose, methacrylic acid and co-polymers, triethyl citrate, propylene glycol, dibutylphthtalate and the like.

The invention can be best understood by the following but not limited example.

A. MANUFACTURING OF RAPID DISINTEGRATING LAYER – FIRST COMPONENT

Sr. Item mg/tablet
1 Microcrystalline Cellulose PH 102 145.63 mg
2 Lactopress SD 250 47.08
3 Maize Starch 21.9
4 Croscarmellose sodium 1.00
5 Magnesium Stearate 2.19
6 Purified Talc 1.10
7 Colloidal Silicon Dioxide 1.10
8 Colorant q.s.
Total 220.00

First component which is a fast disintegrating layer is manufactured by sifting and blending the above excipients in a suitable blender. This layer may or may not contain a part of the prokinetic agent to release an initial dose rapidly.

B. MANUFACTURING OF ENTERIC COATED PANTOPRAZOLE TABLET – SECOND COMPONENT:

Sr. Item mg/tablet
Core Tablet
1 Pantoprazole Sodium 42.40
2 Mannitol 15.50
3 Sodium Carbonate (Anhydrous) 3.50
4 Crospovidone 5.00
5 HPC (Klucel-LF) 1.60
6 Calcium Stearate 2.00
7 Isopropyl Alcohol* q.s
70.00
Seal coating
8 HPMC E-5 4.00
9 Isopropyl Alcohol* q.s
10 Methylene Chloride* q.s
11 Purified Talc 1.70
12 Polyethylene Glycol 6000
(Laffcol-6000) 0.70
76.40
Enteric coating
13 Methacrylic Acid Co-polymer Type-C 6.80
14 Dibutyl Phthalate 1.10
15 Titanium Dioxide 0.30
16 Sunset Yellow Lake 1.00
17 Purified Talc 0.40
18 Isopropyl Alcohol* q.s
19 Acetone* q.s
Total 86.00

Enteric coated tablets are prepared in accordance with conventional manufacturing process briefly described as follows. Pantoprazole, mannitol, sodium carbonate and crospovidone are mixed in suitable granulating equipment such as rapid mixer granulator, and granulated with binder solution prepared by dissolving hydroxypropyl cellulose in isopropyl alcohol. The wet mass is dried in suitable dryer such as fluid bed dryer, after sizing the dried granules are lubricated with calcium stearate & compressed into tablets by using 5.5 mm standard concave punch die set on a rotary compression machine. Compressed tablet are seal coated with HPMC E-5 followed by enteric coating using Methacrylic acid.

C. MANUFACTURING OF DOMPERIDONESR LAYER – THIRD COMPONENT

Sr. Item mg/tablet
1 Domperidone 30.00
2 Microcrystalline Cellulose Plain 29.50
3 H.P.M.C. K-4 M 16.00
4 H.P.M.C. K-15 M 24.00
5 H.P.M.C. E 5 5.00
6 Potassium Bi-carbonate 10.00
7 Purified Talc 3.00
8 Magnesium Stearate 1.00
9 Isopropyl Alcohol q.s
10 Purified Water q.s
11 Colorant 1.5
Total 120.00

Sustained release component layer containing domperidone, HPMC K – 4M, HPMC K - 15M and remaining quantity of microcrystalline cellulose into a suitable rapid mixer granulator, further granulated with binder solution prepared by dissolving HPMC E-5 in isopropyl alcohol and purified water mixture. The wet mass is dried in suitable dryers such as fluid bed dryer. The dried granules are suitably sized using suitable sizing equipment such as multi mill. Extra-granular materials such as potassium bicarbonate, HPMC K-4M, HPMC K-15M sifted and blended with the dried sized granules in a suitable blender followed by lubrication with colorant, magnesium stearate, purified talc.

COMPRESSION OF THREE COMPONENTS:
Finally three components are compressed by using special machines supplied for manufacturing this type of special tablets such as by Cadmach Machineries, India etc. The machines have a suitable change parts or device to insert or place the tablet on to the first layer of the tablet followed by placement of the second layer, thus sandwiching the inner tablet between two powder layers.

OBSERVATION OF EXAMPLE 1:
Sr. No. Parameter Observation
1 Disintegration time of fast disintegrating layer 20 sec. to 30 sec.
2 Floating lag time of SR part 5 sec. to 30 sec.
3 Duration of floating of SR part More than 12 hrs
4 Time required to detach the embedded enteric coated tablet from the layer 10 to 120 sec.
EXAMPLE 2
A) MANUFACTURING OF RAPID DISINTEGRATING LAYER – FIRST COMPONENT
First component dummy layer is manufactured as per the process and composition given in example 1.

B) MANUFACTURING OF ENTERIC COATED PANTOPRAZOLE TABLET – SECOND COMPONENT:
Enteric coated tablets are manufactured as per the process and composition given in example 1.

C) MANUFACTURING OF DOMPERIDONE SR LAYER – THIRD COMPONANT
Sustained release component layer containing Domperidone is manufactured as per the process and composition given in example 1. However no gas generating agent is included into the layer.

The tablets are compressed as per the process given in the example 1.

OBSERVATION OF EXAMPLE 2:
Sr. Parameter Observation
1 Disintegration time of fast disintegrating layer 10 sec. to 15 sec.
2 Floating lag time of SR part No floating was observed.
3 Duration of floating of SR part No floating was observed.
4 Time required to detach the embedded enteric coated tablet from the layer Variable, 0.5 to 3 hrs.

In such cases, the enteric coated tablet cannot travel to the intestine thus delaying the release of the proton pump inhibitor from the enteric coated tablet as the release of the pantoprazole. Since the SR layer of pro-kinetic agent is not floating type site specific drug delivery will not be achieved.

EXAMPLE 3

In this example a combination of gas generating agents are used: combination citric acid/ tartaric acid and carbonates etc.

A) MANUFACTURING OF RAPID DISINTEGRATING LAYER – FIRST COMPONENT
First component dummy layer is manufactured as per the process and composition given in example 1.

B) MANUFACTURING OF ENTERIC COATED PANTOPRAZOLE TABLET – SECOND COMPONENT:
Enteric coated tablets were manufactured as per the process and composition given in example 1.

C) MANUFACTURING OF DOMPERIDONE SR LAYER – THIRD COMPONANT
Sustained release component layer containing Domperidone is manufactured as per the process and composition given in example 1. However a combination of gas generating agents is used.

Sr. Item mg/tablet
1 Domperidone 30.00
2 Microcrystalline Cellulose Plain 29.50
3 H.P.M.C. K-4 M 16.00
4 H.P.M.C. K-15 M 24.00
5 H.P.M.C. E 5 5.00
6 Potassium/ Sodium Bi-carbonate 10.00
7 Citric Acid/ Tartaric Acid 4.00
8 Purified Talc 3.00
9 Magnesium Stearate 1.00
10 Isopropyl Alcohol q.s
11 Purified Water q.s
12 Colorant 1.50
Total 124.00

COMPRESSION

Finally three components are compressed by using the special compression machine.

OBSERVATION EXAMPLE 3:
Sr. Parameter Observation
1 Disintegration time of fast disintegrating layer 20 sec. to 30 sec.
2 Floating lag time of SR part 5 sec. to 35 sec.
3 Duration of floating of SR part More than 12 hr
4 Time required to detach the embedded enteric coated tablet from the layer 10 – 60 sec.

PHARMACOKINETICS:
The dissolution of the tablets is carried out by the following standard methods. The
whole tablet is placed in the respective media and operated as per the
dissolution conditions mentioned for each API.

PANTOPRAZOLE PART:
Dissolution Parameters
Parameters Acid Stage Buffer Stage
Apparatus Paddle (with sinker) Paddle (with sinker)
Medium 1000 ml 0.1 N HCl 1000 ml 6.8 buffer
Speed 100 rpm 100 rpm
Time Points 2 hrs 45 minutes
Temperature 37±0.50C 37±0.50C
% drug released NMT 10% > 90%

DOMPERIDONE PART:
Dissolution Parameters
Apparatus Paddle (with sinker)
Medium 900 ml 0.1 N HCl
Speed 100 rpm
Time Points 1,4,8,10,12 hrs
Temperature 37±0.50C

DISSOLUTION PROFILE FOR DOMPERIDONE SUSTAINED RELEASE:
Time Period (hr) 1hrs 4 hrs 8 hrs 10 hrs 12 hrs
Dissolution( % released) 18 61 80 86 94

SEPARATION OF EACH COMPONENT:
Component SR layer EC tablet
Time LT 2 min NMT 3 min