AU2020104074A4 - Formulation of Multiple - Unit Tablet of Pantoprazole - Google Patents

Abstract

Formulation of Multiple - Unit Tablet of Pantoprazole The present invention relates to multiple-unit tablet dosage forms, which is composed of several subunits (multiparticulates/pellets). Each small multiparticulates further composed of many layers. Some layer contains drug substance; others are rate controlling polymer.The resulting multiple-unit tablet dosage forms of pantoprazole were satisfactory fabricated. Pelletization technique has some advantages over coated tablet formulation. In coated tablet the coating may be damaged and a pinhole possibly formed that would result in increase release of drug in stomach and may be deactivated in stomach juices. If the coat of some pellets may be damaged that would not affect the release properties of the multiple-unit tablet. Hence they are beneficial in this aspect. The results confirmed the successful preparation of stable and bioequivalent once daily controlled release multiple-unit tablets of pantoprazole. 16

Description

Field of the Invention

The present invention relates to multiple-unit tablet dosage forms, which is composed of several subunits (multiparticulates/pellets). Each small multiparticulates further composed of many layers. Some layer contains drug substance; others are rate controlling polymer.

Background of the Invention

Controlled release multiple-unit tablet or pellet formulations have gained immense popularity owing to their superiority over the conventional dosage form in several respects. Controlled absorption with reduction in peak to trough ratios, targeted release of the drug to specific areas within the gastrointestinal tract, absorption of drug irrespective of the feeding state, minimal potential for dose dumping and facility to produce combination of dosage form. Compaction of coated beads, pellets or spheroids into tablets combines the advantages of oral multiparticulates dosage forms with those of tablets, i.e. cost effectiveness and divisibility. One way to design oral controlled release system is to coat spherical granules (pellets/multiparticulates) with a polymer that regulates their drug release rate .Such reservoir pellets can be filled in hard gelatin capsules or compacted into multiple-unit tablets. These multiple-unit tablets are normally intended to disintegrate into discrete pellets in the gastrointestinal tract and the drug should subsequently be released in a controlled manner from the individual pellets. One challenge in the production of such multiple-unit pelletized tablets is maintaining the desired drug release after compaction as the application of compaction pressure can lead to structural changes of the film coating that consequently, may alter drug release. The compression induced changes in the structure of a film coating may depends upon formulation factors, such as type and amount of coating ,thickness of coating ,structure of pellets and the incorporation of excipients at the time of compaction. When a multiparticulate dosage product is developed in the form of a tablet, it is often enviable to produce compacts that disintegrate into many subunits soon after ingestion, to attain uniform concentrations of active substances in the body. It is imperative to emphasize the fact that the coated subunits in the formulations must withstand the process of compaction without being damaged.After compaction the existence of cracks have been reported in literature with a polymer (ethyl cellulose) coated on pellets. This may lead to undesirable effects on the drug release properties of those subunits. The type and amount of coating on pellets, the size of subunit, the surface properties of pellets, the selection of external and internal additives having a cushioning effect and the rate and magnitude of applied pressure must be carefully considered in the design of such a dosage form. Pelletization technique has some advantages over coated tablet formulation. In coated tablet the coating may be damaged and a pinhole possibly formed that would result in increase release of drug in stomach and may be deactivated in stomach juices. Multiple-unit tablet formulation is composed of several subunits (multiparticulates/pellets). If the coat of some pellets may be damaged that would not affect the release properties of the multiple-unit tablet. Hence they are beneficial in this aspect.Spherical oral dosage forms such as pills have been used in the pharmaceutical industry for a long time, but the full impact of systematically agglomerated spherical units or pellets on controlled release oral dosage form design and performance was not realized till early 1970s.These solid oral dosage form consists of a multiplicity of small discrete particulates i.e. pellet and granules. These systems provide flexibility during formulation development and therapeutic benefits to patients in last two decades. The prime significant advantage of multiparticulates is to attain desired doses without formulation or process changes. Furthermore, controlled-release multiple-unit dosage forms are less susceptible to dose dumping than the reservoir or matrix type single unit tablet since the drug release profile does not depend on the drug release properties of a single unit.Technological advances in dosage form design, the advent of highly specialized equipments and the popularity of controlled-release dosage forms as a means of drug delivery have made multiparticulate a viable and attractive alternative to single dosage forms Multiparticulates (pellets) also have numerous therapeutic advantages over single unit dosage forms. When taken orally, multiparticulates generally disperse freely in the gastrointestinal tract, maximize absorption, minimize side effects, and reduce inter-and intrapatient variability. Multiple-unit dosage form offer several advantages 1. Greater flexibility of dosage form design and development - Multiparticulates can be presented in the form of suspension, filled into capsules or compressed into tablets 2. Ease of design of controlled-release formulations containing more than one drug each having different release characteristics 3. Ease of drug dissolution and analysis of individual drug components. 4. Greater stability of chemically incompatible drugs by formulating them separately. 5. Ease of dose divisibility without compromising release characteristics. 6. Greater safety and efficacy of drugs - Small size of Multiparticulates enables them to disperse freely in the gastrointestinal tract and high local concentrations of inherently irritating or anaesthetic agents can be avoided. Their large surface area promotes complete and uniform absorption, minimize peak plasma fluctuations and thus reduce the potential for systemic side-effects .

7. Reproducibility of plasma profile and therapeutic effect - Multiparticulates reduce variations in gastric emptying rates and transit time thus minimizing intra- and inter subject variability in plasma profiles. Multiparticulates can be formulated into following solid dosage forms 1. Pellets filled into capsules 2. Pellets compressed into tablets called as MUPS (multiple-unit pellet system). Such compressed MUPS tablets are normally intended to disintegrate into discrete pellets in the gastrointestinal tract and release drug from the individual pellets (Santos et al., 2004).

U.S. Patent No. 5,753,265 teaches a multiple unit tableted dosage form, comprising individually enteric-coated layered units, compressed into a tablet. The enteric layers are stated as containing pharmaceutically acceptable plasticizers to obtain the desired mechanical properties.

U.S. Patent Application No. 20040131675 teaches a method of manufacturing a tablet, which comprises compressing coated granules containing a physiologically active substance, at a temperature exceeding room temperature, whereby the tablet can be prevented from rupture of a part of a coating film of the granules at the time of tablet compression.

U.S. Patent No. 7,041,316 teaches an enteric-coated pharmacological dosage form which comprises a core tablet formed by dry mixing, without using an aqueous solution. The use of a plasticizer in the enteric coating is taught. No mention is made of the use of individually enteric- coated multiple units which are compressed into a tablet. U.S. Patent No. ,232,706 teaches an oral pharmaceutical preparation for omeprazole, comprising a nucleus, a first coating, and a second, enteric coating. Multiple unit dosage forms are not taught.

Pantoprazole is available in almost 100 countries. Since its market launch 11 years ago, more than 300 millions patients have been treated with pantoprazole .The high global demand makes pantoprazole currently the most successful patent protected medicine all over the world. Pantoprazole is the third proton pump inhibitor to be marketed in the UK and all over the world. In the United States four million people have active peptic ulcers and approximately 3000 deaths per year were observed. Pantoprazole is mainly used to treat too much acid secretions in the stomach, duodenal ulcer, benign gastric ulcer and gastro-esophageal reflux diseases (GERD) and reflux oesophagitis.Pantoprazole is a proton pump inhibitor that suppress the final step in gastric acid production by forming a covalent bond to two sites of the (H'K+)-ATP-ase enzyme system at the secretary surface of the gastric parietal cell. This effect is dose related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of stimulus. The binding to the (H+' K+)-ATP anti secretary effect that persists longer than 24 hours. Pantoprazole 40 mg is equivalent to pantoprazole sodium sesquihydrate 45.10 mg. Pantoprazole is usually administered in a dose of 20 mg and 40 mg given 1-2 times to maintain effective blood concentration through out the day.It is absorbed after oral administration as controlled release coated tablet with maximum plasma concentrations within 2-3 hours and a bioavailability of 77 %.The pharmacokinetic profile is practically unchanged after multiple dosing, as is expected for a drug with a short half life of about one hour.Pantoprazole is freely soluble in water.The widespread use and benefit of the proton pump inhibiting class of acid suppressing drugs pantoprazole have been valuable tools in the treatment of a range of upper gastrointestinal diseases(Salas M. et al., 2002). Pantoprazole has several advantages compared to its analogues (e.g., omeprazole and lansoprazole) such as specific site of binding, greater stability in neutral pH environment and longer duration of action. Besides, it presents no potential to induce or inhibit the CYP 450 .It is more selective inhibitor of acid secretion than proton pump inhibitor. Pantoprazole has a bioavailability of 77% after the first dose and this does not change after repeated dosing, while that of lansoprazole is 80%, however the bioavailability of omeprazole is 35% after the first dose and it increases to about 60% with repeated doses.This fact indicates that based solely on the pharmacokinetics of these agents, it will take longer to reach the maximum therapeutic effect. Pantoprazole is very effective against Helicobacter pylori infections alone or associated to other drugs, like metronidazole, clarithromycin or amoxicillin .This drug was the first water soluble benzimidazole derivative. Pantoprazole drug also causes irritation to gastric mucosa, which may lead to nausea and vomiting and gets destroyed by gastric enzymes and acid. In the case of oral administration, the enteric /controlled release coating prevents pantoprazole from degradation in the gastric juice (at pH 1-2, pantoprazole degrades in few minutes).Due to the necessity to pass through the stomach for reaching the duodenum for absorption, the pantoprazole is formulated as oral delay release dosage forms. Considering above facts pantoprazole was selected as an ideal drug candidate for controlled release multiple-unit tablet preparation.The model drug used in present invention is pantoprazole.It is an acid labile substance.Pantoprazole has several advantages compared to its analogus (e.g., omeprazole and lansoprazole) such as specific binding site; greater stability in neutral pH environment and longer duration of action. It is more selective inhibitor of acid secretion than other proton pump inhibitors. In case of oral administration pantoprazole drug is destroyed in acid medium (stomach), due to necessity to pass intact through the stomach for reaching the duodenum for absorption, the pantoprazole is formulated as controlled release dosage forms. The rationale of this study was to work out a method of compression of pellets containing pantoprazole in a dose of 40 mg.According to the assumption that the tablet should disintegrate in the intestine into undeformed pellets staying in this environment for 22-24 hour, releasing the drug should be in a controlled way.The better solubility of acrylic polymer coated pantoprazole pellets in alkaline environment of the intestine may results in a larger amount of drug absorbed and its maintained higher concentration in plasma in a controlled release manner

U.S. Patent No. 5,753,265 teaches a multiple unit tableted dosage form, comprising individually enteric-coated layered units, compressed into a tablet.The enteric layers are stated as containing pharmaceutically acceptable plasticizers to obtain the desired mechanical properties.

U.S. Patent Application No. 20040131675 teaches a method of manufacturing a tablet, which comprises compressing coated granules containing a physiologically active substance,

at a temperature exceeding room temperature, whereby the tablet can be prevented from rupture of a part of a coating film of the granules at the time of tablet compression.

U.S. Patent No. 7,041,316 teaches an enteric-coated pharmacological dosage form which comprises a core tablet formed by dry mixing, without using an aqueous solution. The use of a plasticizer in the enteric coating is taught. No mention is made of the use of individually enteric- coated multiple units which are compressed into a tablet. U.S. Patent No. ,232,706 teaches an oral pharmaceutical preparation for omeprazole, comprising a nucleus, a first coating, and a second, enteric coating. Multiple unit dosage forms are not taught.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to multiple-unit tablet dosage forms of pantoprazole as pantoprazole sodium sesquihydrate (freely soluble in water) by employing HPMC seal coating and acrylic polymer as the release-controlling membrane.Various pharmaceutical companies are lucratively developed and marketing sustained release tablet of pantoprazole by applying straight forwardly coating materials on tablet.No recent advance has been done using multiple unit controlled release pellet tablet dosage formulation containing pantoprazole.The resulting multiple-unit tablet dosage forms of pantoprazole were satisfactory fabricated.

Satisfactory tablets having good mechanical strength was produced.The good mechanical strength as evaluated on the basis on hardness and friability values.Disintegration of all the formulations was fast, thereby releasing coated pantoprazole pellets in the dissolution fluids.All formulations complied for weight variation test.Friability results indicated that the percentage loss was not more than 1 %. The all results revealed that multiple-unit formulation possessed good physical properties in accordance to specified ranges.All the six tablet formulations after compaction showed an initial burst effect and later on diffusion effects, which is characteristic of such multiple-unit systems, followed by completely unswerving drug release pattern. Drug release from multiple-unit tablet formulation also showed excellent results as 80 % of aceclofenac drug release after 18 hours.The pharmacological screening (anti ulcer and pharmacokinetic studies) were carried out in rats and rabbits. The results revealed that the controlled release multiple-unit pantoprazole tablets showed significant anti-ulcer activity, when compared to standard which is evident by decrease in ulcer index. The bioavailability studies were carried out in rabbits. In the present invention HPLC method was developed for estimation of pantoprazole drug in rabbit plasma. The observations were carried out upto lh to 30 hours.The results confirmed the successful preparation of stable and bioequivalent once daily controlled release multiple-unit tablets of pantoprazole. The invention can be claimed in following manner: 1. A pharmaceutical composition of multiple-unit tablet dosage forms of pantoprazole comprises Nonpareil Seeds (80.9mg/tablet), pantoprazole B.P. (45.10.0 mg/tablet), PVPK-30 (10.0mg/tablet), Purified talc (15.0mg/tablet), purified water (0.38mg/tablet). 2. A method of preparation of pharmaceutical composition of multiple-unit tablet dosage forms of pantoprazole comprising the steps of : weighing the binder solution and dissolved in methylene chloride ;shifting pantoprazole through 200 mesh sieves and is dissolved in methanol with constant slowly stirring; adding the binder solution with constant stirring for fifteen minutes and the solution was filtered through 100 mesh sieves; rolling nonpareil seeds of size 800-1000 micrometer in roto granulator at the rate of 8.4 disc frequencies; spraying the solution on the starter seeds using a pneumatic pump and spray gun with a 1.0 mm nozzle at the rate enough to prevent over wetting and agglomeration of pellets. 3. The method as claimed in claim 2, wherein pantoprazole is loaded on Nonpareil Seeds using Solution layering Technology. 4. The method as claimed in claim 2, wherein said pellets are coated with flexible acrylic polymer dispersions blends of (Eudragit NE 30D) and plasticized (Eudragit L 30D-55). 5. The method as claimed in claim 4, wherein Eudragit NE 30 D and eudragit L 30D-55 are used as an aqueous polymeric dispersion in ratios of (50:50) for coating of aceclofenac pellets to impart the controlled release property.

6. The method as claimed in claim 2, wherein pantoprazole pellets are prepared by extrusion/spheronization method. 7. The method as claimed in claim 2, wherein pantoprazole pellets are prepared by Rotogranulator solution layering techniques.

Detailed Description of the Invention

The aim of invention involves fabricate and evaluate multiple-unit controlled release tablet formulation of pantoprazole as pantoprazole sodium sesquihydrate (freely soluble in water) by employing HPMC seal coating and acrylic polymer as the release-controlling membrane.Various pharmaceutical companies are lucratively developed and marketing sustained release tablet of pantoprazole by applying straight forwardly coating materials on tablet.No recent advance has been done using multiple-unit controlled release pellet tablet dosage formulation containing pantoprazole. The model drug used in present research work is pantoprazole.It is an acid labile substance.Pantoprazole has several advantages compared to its analogus (e.g., omeprazole and lansoprazole) such as specific binding site; greater stability in neutral pH environment and longer duration of action.It is more selective inhibitor of acid secretion than other proton pump inhibitors. In case of oral administration pantoprazole drug is destroyed in acid medium (stomach), due to necessity to pass intact through the stomach for reaching the duodenum for absorption, the pantoprazole is formulated as controlled release dosage forms. The rationale of this study was to work out a method of compression of pellets containing pantoprazole in a dose of 40 mg.According to the assumption that the tablet should disintegrate in the intestine into undeformed pellets staying in this environment for 22-24 hour, releasing the drug should be in a controlled way.The better solubility of acrylic polymer coated pantoprazole pellets in alkaline environment of the intestine may results in a larger amount of drug absorbed and maintained its higher concentration in plasma in a controlled release manner. Materials Pantoprazole (Pantoprazole sodium sesquihydrate) was procured from Mcneil Pharma S.T.,Kangra,(H.P.) as gift sample. Non pareil seeds, PVPK-30, Purified talc, Eudragit L-100, Eudragit S-100, PEG-6000, Aerosil-200, MCC PH 101, lactose, Starch, Magnesium stearate, Methanol, Methylene chloride, Isopropyl alcohol and deionized water etc were used in present research work. All these excipients were of pharmacopoeial grade and were procured from Excellent pharma New-Delhi, Kanwarlal group of companies, Chennai, Sanmour pharma ltd., Mumbai, Jaipur pharmaceutical works, Jaipur (Rajasthan),Mcneil pharma S.T.,Kangra, Himachal Pradesh and Sancure laboratory S.G.N.R, (Rajasthan). Equipment Extruder/spheronizer (Umang pharmatech, Mumbai), Roto granulator (Remi ltd., Mumbai), Homogenizer (Remi ltd., Mumbai) and Mechanical stirrer (Remi ltd., Mumbai) etc. 1.Preparation of Pantoprazole Pellets by Using Extrusion / Spheronization Techniques Pantoprazole is acid labile and having freely water solubility. So it is very necessary to protect the drug from acid environment (stomach) to retain its pharmacological profile. The aim of the present investigation was to design controlled release multiple-unit tablets of pantoprazole that rapidly disintegrate into controlled-release pellets keeping the integrity of the seal coat and controlled release core preserved.The core pantoprazole pellets were prepared by extrusion/ spheronization technique and solution layering roto granulator technology Procedure for Preparation of Pantoprazole Pellets Approximately 100 gm batch of pantoprazole and microcrystalline cellulose PH 101 in different concentrations were passed through sieve no.100 and then mixed in a mortar for 15 minutes. All the powders were blended by geometric dilution methods using pestle and mortar. Binder solution PVPK-30 (4 %) was added to powder blends. Purified water 50 ml was added to powder blends gradually and blend kneaded to get suitable wet mass. The moist wet mass was transferred into the extruder to obtain the extrudates.The extrudates were immediately transferred to a spheronizer.Wet pellets were dried in fluidized-bed dryer at 500 C for 12 hours.

Table -Composition of core pantoprazole pellets

S.No. Batch Pantoprazole (gm) MCC PH 101 (gm) PVPK-30 (gm) 1. P-1 20 80 4 2. P-2 25 75 4 3. P-3 30 70 4 4. P-4 40 60 4 5. P-5 50 50 4 6. P-6 60 40 4

During preparation of pellets by extrusion-spheronization following process parameters were kept constant. Constant Parameters for Extrusion a. Die-roller size (pore diameter) 1mm b. Speed of Die -roller 15rpm Constant Parameters for Spheronization a. Friction plate type crosshatch pattern b. Groove size 1mm c. Spheronization rate :1000 rpm d. Spheronization time :10 minutes e. Feed size :100 gm Spherical pellets were formed from the base formula as feed size of 100 gm,spheronization speed of 1000 rpm and spheronization time 10 minutes. The values of these process parameters were taken for the formulation of pantoprazole pellets for further study.

2. Preparation of Pantoprazole Pellets Using Solution layering Modified Roto Granulator Technique The method utilized to produce pellets in a roto granulator involves surface layering of drug onto an inert substrate (nonpareil seeds).Normally surface layering of a drug in a roto granulator is done on spherical shaped nonpareil seeds/ beads such as microcrystalline cellulose. Spherical shape of the pellets / starter seeds provides excellent rolling in the roto granulator and minimizes agglomerates and / or aggregation during processing. In addition, economic availability of such nonpareils has increased the popularity of processing pellets in a roto granulator, especially of low dose drug. Processing of pellets The controlled release multiparticulates pellet formulation (PR-1) each containing 40 mg of pantoprazole in controlled release form were designed for once daily dosing.The formulations were, so designed that the preparations release not less than 80 % of drug in 18 hours. The drug dose (40 mg of pantoprazole) was contained in about 240-250 mg offinal pellet formulation. Formulation details are indicated below. Pantoprazole Drug loading on Nonpareil Seeds by Using Solution layering Roto Granulator Technology Drug pellets of known amount batch size containing 40 mg of pantoprazole (pantoprazole sodium sesquihydrate) were prepared. PVPK-30 (25 gm) was weighed accurately and dissolved in purified water with constant stirring.The drug pantoprazole was dissolved in water with constant stirring and added to the above solution with constant slow stirring.Purified talc (shifted through 200 mesh sieves) was added to the above solution with constant stirring for fifteen minutes and the solution was filtered through 100 mesh sieves. The solutions were continuously sprayed on the starter seeds using a pneumatic pump and spray gun with a 1.0 mm nozzle at the rate enough to prevent over wetting and agglomeration of pellets. After the completion of the process, the pellets were rolled for additional 30 minutes, before subjecting to tray drying.After the completion of drug loading process, the drug pellets were dried in a tray dryer at 55-60 0 C temperature for 20-24 hours.The dried pellets were shifted to collect 12 mesh fraction, 12 mesh over size (agglomerates) and 20 mesh undersize (Fines).

Table - Composition of pantoprazole drug pellets S.No. Ingredients Qty (mg) / tablet Qty (gm) / batch

1 N.P.seed (800-1000 p) 80.9 202.25

2. Pantoprazole 40 mg equivalent 45.10 112.75 to pantoprazole sodium sesquihydrate 45.10 mg PVPK-30 10.0 25 3.

4. Purified talc 15.0 37.5

Purified water (RC 20 %) 0.38 950 5.

Table - Process parameter of roto granulator during drug layering S.No. Parameters PR-I

1. Inlet air temperature (°C) 45-50

2. Process bed temperature (°C) 32-33

3. Exhaust air temperature (0 C) 36-38

4. Atomization pressure (bar) 1.2

5. Pneumatic pump speed (rpm) 10

6. Spray rate (gm/min.) 7.5

7. Disc frequency 8.4

8. Damper Inlet (%) 50

9. Exhaust /Outlet (%) 60

10. Room humidity (% RH) 50-55

11. Processing time (hrs) 2.5

Coating Process A.Seal Coating on Pantoprazole Pellets Approximately 500 gm pellets of optimized batch's P-1 and PR-i were divided into two parts of 250 gm each and transferred into a roto granulator (fluidized-bottom side spray system) and then coated with seal coating solution HPMC E-15 and HPMC E-5 respectively. Formula for seal coating details is indicated as below. During the coating operations the coating solution was continuously stirred in order to prevent sedimentation of the insoluble materials. The operation conditions during the coating process were as follows: inlet and outlet temperatures of drying air were 55-60C and 35-40C respectively.Pneumatic spraying pressure and spraying rate were set correspondingly at 1.5 bars and 7.5 gm/min. After coating, the resulted coated pellets were dried at 50-60 °C for 24 hours. The processing conditions employed for seal coating on pantoprazole drug pellets are depicted as following.

Table - Formula for seal coating S.No Ingredients P-7 P-8 PR-2 PR-3 1. HPMC E-15 (gm) 25 50 2. HPMC E-5 25 50 ( gm) 3. Poly ethylene 10 10 10 10 glycol -6000(gm) 4. Purified talc(gm) 10 10 10 10 5. Iso propyl alcohol 750 750 750 750 (gm)

6. Methylene chloride 750 750 750 750 (gm)

Table - Process constraint of roto granulator during seal coating on pantoprazole pellets S.No. Parameters P-7 P-8 PR-2 PR-3

1 Inlet air temperature 58 55 55-60 55-60 (0 C) 2. Process bed 38 36 35-40 35-40 temperature ( C) 3. Exhaust air temperature 42 42 45 45 (0 C) 4. Atomization 1.5 1.5 1.5 1.5 pressure (bar) 5. Pneumatic pump 08 08 08 08 speed (rpm) 6. Spray rate 7.5 7.5 7.5 7.5 (gm/min.) 7. Disc frequency 8.1 8.1 8.1 8.1

8. Damper Inlet(%) 65 65 65 65

9. Exhaust /Outlet 80 80 80 80 (%) 10. Room humidity 65-70 65-70 65-70 65-70 (%) 11. Processing time 2 2.1 2.5 2.5 (hrs)

B.Coating Formula for Controlled Release Controlled / Enteric coated dosage forms are designed to resist irritation in stomach and destructive action by gastric fluids. Solution of acrylic polymers in organic solvents were utilizes as the controlled release / enteric coating in the present research formulation.Eudragit L-100 and eudragit S-100 were used to coat pantoprazole pellets. The polymeric coating of pellets must remain intact during compression in order to retain its controlled release properties. Preparation of Eudragit L-100 and Eudragit S-100 Dispersion The weighed quantities of eudragit L-100 and eudragit S-100 were dissolved in mixture of IPA and methylene chloride .Poly ethylene glycol-6000 were dissolved in mixture of IPA and methylene chloride and transferred to eudragit L-100 and eudragit S-100 solution separately under slowly stirring conditions. Purified talc was dispersed in the above solution and stirred continued for about 30 minutes until uniform solution is obtained.

Controlled Release Coating Process The seal coating pellets of different batches P-7, P-8, PR-2 and PR-3 were transferred into a roto granulator and coated with different controlled release coating solution. The formula was shown as below.During the coating operations; the coating solution was continuously stirred in order to prevent sedimentation of the insoluble material. The operating conditions during the coating process were as follows: inlet and outlet temperatures of drying air were 56-58 'C and -32 0 C respectively. Pneumatic spraying pressure and spraying rate were set correspondingly at 1.5 bars and 7.5 gm/min. After coating, the resulted coated pellets were dried at 60-65 °C for 24 hours. Process constraint of roto granulator during controlled release coating on pantoprazole drug and seal loaded pellets are shown in following table.

Table - Formula of controlled release coating materials S.No. Ingredients(gm) P-7 P-8 PR-2 PR-3

1. Eudragit L-100 50 - 20

2. Eudragit S-100 - 50 20

3. Poly ethylene 20 20 20 20 glycol -6000

4. Purified talc ( gm) 20 20 20 20

5. IsoPropyl 1500 1500 1500 1500 Alcohol (gin) 6. Methylene 1500 1500 1500 1500 chloride (gin)

Table - Process constraint of roto granulator during controlled release coating on pantoprazole drug and seal loaded pellets S.No. Parameters P-7 P-8 PR-2 PR-3 1. Inlet air temperature (° C) 56-58 56-58 56-58 56-58 2. Process bed temperature (° C) 30-32 30-32 30-32 30-32 3. Exhaust air temperature (0 C) 40-42 40-42 40-42 40-42 4. Atomization pressure (bar) 1.5 1.5 1.5 1.5 5. Pneumatic pump speed (rpm) 08 08 08 08 6. Spray rate (gm/min.) 7.5 7.5 7.5 7.5

7. Disc frequency 8.1 8.1 8.1 8.1 8. Damper Inlet (%) 65 65 65 65 9. Exhaust /Outlet(%) 70 70 70 70 10. Room humidity(%) 60-70 60-70 60-70 60-70 11. Processing time 2.5 2.5 2.5 2.5 (hrs)

Compaction of Pantoprazole Controlled Release Pellets into Tablets Depending upon the additives used to provide cushioning effects, six multiple-unit tablet formulations of each method were premeditated. All the six formulations are contained pantoprazole pellets in seal and controlled release form. Procedure Drug pellet of known amount of approximately 286 gm of batches P-19 and 281 mg of batches PR-2 contains 40 mg of pantoprazole equivalent to pantoprazole sodium sesquihydrate 45.10 mg were obtained after seal and controlled release coating. Direct compression technique was adopted for preparing the pantoprazole controlled release multiple unit-tablet .Batch size of the each formulation was 500 tablets. The formula are shown following table.Each batch was divided into three parts .The procedure involved 1. Sifting the directly compressible excipients i.e. spray-dried microcrystalline cellulose and spray dried lactose through 40 mesh size sieve. 2. The formulation P-9 and PR-5 contained pantoprazole controlled release pellets, spray dried microcrystalline cellulose PH 101 and spray dried lactose in quantities of 10 mg, 20 mg and 50 mg each as the cushioning agents. 3. The formulation P-10 and PR-6 contained pantoprazole controlled release pellets, MCC and non pareil seeds (composed of MCC) as the cushioning beads in quantities of 10 mg and 20 mg and 50 mg each as the cushioning beads. 4. The formulation P-11 and PR-4 contained pantoprazole controlled release pellets and spray dried microcrystalline cellulose as cushioning excipients.These cushioning excipients required to fill efficiently the void space between the pellets. The quantity of MCC used in this formulation is 30 mg and 100 mg in each tablet for the present study, while designing the tablet formulation. 5. Blending the mixture of step-2, 3 and 4 with starch, purified talc, magnesium stearate and aerosil respectively. 6 .Compaction the blends of step no-5 into multiple-unit tablet using cadmach eight station tablet compression machine. 7. The compaction force applied for compaction is 5 kN. 8. Drying the tablets in a tray dryer at 45- 500 C for 12 hours.

9. Film coating of tablets in rota granulator with HPMC as the coating polymer, as the same conditions described in coating of pantoprazole drug pellets. Film coating of multiple-unit tablets in rota granulator was made with HPMC as the coating polymer. HPMC was first dissolved in purified water under stirred condition. Polyethylene glycol-6000 was dissolved in slightly hot water and then incorporated in the polymer solution with slowly stirring. Purified talc was firstly sifted through 200 mesh screen and then incorporated into the solution of polymer under slowly stirred conditions. The polymeric solution was further stirred for 20 minutes to obtained smooth and homogenous coating solution. This coating solution was passed through 100 mesh nylon cloth. The processing conditions employed for coating of multiple-unit aceclofenac tablet formulations are depicted in following table.

Table - Formula for pantoprazole tablet (mg / tablet) S.No. Ingredients(mg) P-9 P-10 P-11 PR-4 PR-5 PR-6

Pantoprazole 1. controlled release 286 286 286 281 281 281 pellets 2. MCC PHIO 10 10 30 100 50 50

3. Lactose 20 - - - 50 Cushioning 4. excipients (NP - 20 - - - 50 seeds 16/20 mesh) 5. Starch 10 10 10 10 10 10

6 Purified talc 5 5 5 2 2 2

7. Magnesium 2 2 2 2 2 2 stearate 8. Aerosil 1 1 1 1 1 1 HPMC 5cps(Film 9. coatings on 4 4 4 4 4 4 tablets) 10. PEG-6000 1 1 1 1 1 1 11. Purified talc 1 1 1 2 2 2 12. Water 80 80 80 80 80 80 13 Totaltweight of 340 340 340 403 403 403 tablet____________ __

Table - Process constraint of roto granulator (coating of pantoprazole multiple-unit tablets) S.No. Parameters P-9 P-10 P-11 PR-5 PR-6 PR-7

1. Inlet air temperature 57 58 57 57.5 60 58.5 (°C) 2. Process bed 0 36 36 37 34 36 37 temperature ( C)

3. Exhaust air 0 40 41 44 44 43 43 temperature ( C)

4. Atomization pressure 1.5 1.5 1.5 1.5 1.5 1.5 (bar) 5. Pneumatic pump 08 08 08 08 08 08 speed (rpm) 6. Spray rate (gm/min.) 7.5 7.5 7.5 7.5 7.5 7.5

7. Disc frequency 8.1 8.1 8.1 8.1 8.1 8.1

8. Damper inlet (%) 65 65 65 65 65 65

9. Exhaust /outlet (%) 80 80 80 80 80 80

10. Room humidity 65-70 65-70 65-70 65-70 65-70 65-70

11. Processing time 4.3 4.3 4.3 4.3 4.3 4.3 ( hrs)

The compressed multiple-unit tablets were evaluated for various physical parameters such as hardness, friability, disintegration time, uniformity of weight, Release profile, Pharmacological activities, In vitro and in vivo studies. Multiple-unit tablet formulation (pellets prepared by extrusion) and (pellets prepared by roto granulator techniques) had shown very good mechanical strength as evaluated on the basis of hardness and friability. As expected, tablets of both formulations were relatively less friable owing to good bonding between the drug pellets and the excipients. The formulations P-i1 and PR-5 under present research work indicating that the preparations are suitable for once daily dosage form.In yet another embodiment of the invention, microcrystalline cellulose PHIO used for cushioning purpose considered to be the most important excipients for compaction of multiple unit pellets. The size of these indentations correlated with the size of the excipients pellets of lower porosity caused deeper indentations.Changes in the dimensions of the pellets under investigation were less dependent on the porosity of the excipients pellets, while the use of excipients powder particles had a greater influence on the pellet dimensions than the use of excipients pellets.The powder particles, however did not indent the drug pellets, thereby resulting in pellets of more regular shape after compaction. This maintained the controlled release drug release profile even after pellets compaction. The use of HPMC E-15 as seal coating and acrylic polymer eudragit L-100 as controlled release coating did not alter in the compression performance of the drug pellets and this coating was proficient to acclimatize to the changes in amount and form that the pellets undergo during compaction without damage being incurred.The release kinetic studies showed excellent results as release of 80 % of pantoprazole drug release with in 18 hours from both multiple unit dosage forms.The pharmacological screening (anti-ulcer and pharmacokinetic studies) were carried out in rats and rabbits.The results revealed that the controlled release multiple-unit pantoprazole tablets showed significant anti-ulcer activity, when compared to standard which is evident by decrease in ulcer index.The pharmacokinetic studies also showed excellent results for both formulations.

Claims (7)

1. We Claim: 1. A pharmaceutical composition of multiple-unit tablet dosage forms of pantoprazole comprises Nonpareil Seeds (80.9mg/tablet), pantoprazole B.P. (45.10.0 mg/tablet), PVPK-30 (10.0mg/tablet), Purified talc (15.0mg/tablet), purified water (0.38mg/tablet).
2. 2. A method of preparation of pharmaceutical composition of multiple-unit tablet dosage forms of pantoprazole comprising the steps of : weighing the binder solution and dissolved in methylene chloride ;shifting pantoprazole through 200 mesh sieves and is dissolved in methanol with constant slowly stirring; adding the binder solution with constant stirring for fifteen minutes and the solution was filtered through 100 mesh sieves; rolling nonpareil seeds of size 800-1000 micrometer in roto granulator at the rate of 8.4 disc frequencies; spraying the solution on the starter seeds using a pneumatic pump and spray gun with a 1.0 mm nozzle at the rate enough to prevent over wetting and agglomeration of pellets.
3. 3. The method as claimed in claim 2, wherein pantoprazole is loaded on Nonpareil Seeds using Solution layering Technology.
4. 4. The method as claimed in claim 2, wherein said pellets are coated with flexible acrylic polymer dispersions blends of (Eudragit NE 30D) and plasticized (Eudragit L 30D-55).
5. 5. The method as claimed in claim 4, wherein Eudragit NE 30 D and eudragit L 30D-55 are used as an aqueous polymeric dispersion in ratios of (50:50) for coating of aceclofenac pellets to impart the controlled release property.
6. 6. The method as claimed in claim 2, wherein pantoprazole pellets are prepared by extrusion/spheronization method.
7. 7. The method as claimed in claim 2, wherein pantoprazole pellets are prepared by Rotogranulator solution layering techniques.