Hero Rahul Naudiyal2

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OMEPRAZOLE pH SENSITIVEMICROSPHERES PREPARATION ANDEVALUATION

Introduction

Microspheres

Most of our microspheres are polystyrene-based, although someother base polymers are also offered. Plain (non-functionalized)polymer microspheres are ideal for protein adsorption applications,while surface modified microspheres (COOH or NH2) are used forcovalent ligand attachment. Cross-linked polymer microspheresare available for improved solvent, heat, and pressure resistance.Polymer microsphere

Coating MicrospheresPolymer microspheres present a flexible platform for applicationsin diagnostics and bioseparations. They may be coated withrecognitionmolecules such as antibodies, antigens, peptides, or

nucleic acid probes, and can be loaded with hydrophobic dyes andother compounds. Unmodified polymer spheres also find extensiveuse as standards for instrument set-up and calibration.A. Protein AdsorptionPolystyrene microspheres are ideal for protein adsorption andhave been utilized in a range of diagnostic tests and assays.Reference our TechNote 204, Adsorption to Microspheres, forprotein adsorption guidelines, information on the use of blockers,and further references.B. Covalent Ligand AttachmentSurface modified microspheres are available with carboxyl orprimary amine groups for covalent ligand attachment. Referenceour TechNote 205, Covalent Coupling, which provides a basicfoundation for successful attachment of a variety of ligands throughcoupling protocols, buffer recipes, blockers, and references.


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C. Affinity BindingAffinity binding systems offer simple and efficient ligandattachment. Coatings of Fc-binding proteins are able to orientantibodies for optimal activity, and streptavidin offers extremelystable attachment of biotinylated molecules such as proteins,peptides, and oligonucleotides. See TechNote 101, ProActive

Microspheres, for basic attachment protocols.

NEED FOR THE STUDY

The floating drug delivery system or hydrodynamicaly balanced systemare among the several approaches that have been made developed inorder to increase the gastric transit time of drug. The microspheres arecharacteristically free flowing powders consisting of natural or syntheticpolymers and ideally having a particle size less than 200 m.Microspheres incorporating a drug dispersed or dissolved throughoutparticle matrix have the potential for the controlled release of drug 1

Microspheres are one of the multiparticulate delivery system and areprepared to obtain controlled the drug release from the dosage form toimprove bioavailability, reduces the adverse action and prolong the

action of drug, reduce absorption difference in patients, reduce thedosing frequency and adverse effects during prolong treatment. It isneeded to formulate in long acting dosage form, reaching to effectivebiological site rapid. 2,3

Omeprazole is usually administered as conventional tablet form withthe dose 20 mg, Omeprazole is proton pump inhibititor which preventstomach from producing gastric acid. The biological half life of Omeprazole is 1-2 hr.

Microspheres are one of the multiple unit dosage forms. Solventevaporation method is the preparation technique that is widelypreferred for the preparation of controlled release microspheres. Toprepare emulsion by adding the dispersed phase consisting of drug,polymer and appropriate dispersion agent in organic solvent todispersion medium which is immiscible with the dispersed phase


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and minimatrix forms are obtained by removing the solvent used atthe dispersed phase from the droplets which are formed in theemulsion 6.

Advantages of microspheres: -

1. Taste and odor masking of drug

2. Protection of drug against the environment (moisture, light, heatand oxidation)

3. To improve the bioavailability

4. To decrease the side effects

5. To reduce the dose frequency

6. To relative stability7. To increase the patient compliance8. To have better therapeutic efficacy

9. To reduce the fluctuation in plasma drug concentration10. Safe handling of toxic substances

Among the micro particulate systems, microspheres have a specialimportance since it is possible to target drug and provide controlledrelease .8

In this present study is aimed to prepare Floating microspherescontaining Omeprazole to achieve a controlled drug release profile as

well as to increase the gastric transit time.


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Omeprazole /w EPDw UJNzEw

Omeprazole is a an oral antiulcer agent. Omeprazole ischaracterized as a gastric acid pump inhibitor because it blocks the

final step of gastric acid production. It has a long duration of action

and is very potent, allowing for once-daily administration. Despite

its potency, it must be used in combination with antibiotics to be

effective against Helicobacter pylori. Due to concern regarding

long-term use, it was originally approved by the FDA in September

1989 for acute treatment only. In December 1994, an FDA advisory

committee recommended it be approved for maintenance therapy of

healed erosive esophagitis. In April 1996, it was approved for the

treatment of H. pylori-associated duodenal ulcer. Belongs to a new

class of antisecretory agents, the substituted benzimidazoles, whichsuppress gastric acid secretion by inhibiting the H+/K+ ATPase

enzyme system of parietal cells. it, following activation in an acidic

pH, binds irreversibly to the H+/K+ ATPase pump on the secretory

surface of the parietal cell membrane. Subsequently, the secretion

of hydrogen ions into the gastric lumen is inhibited. it inhibits both

basal and stimulus-induced acid secretion.


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Litrature survey

Review of Literature :

An explicit literature review was done by exploringthrough various national & international journals, officialstandard reference books and by surfing through variouswebsites on the internet.

Varaporn et.at. studied the floating property and releasecharacteristic of hallow microsphere of Acyclovir.themicrospheres were prepared by solvent evaporation technique.The present study shows that the hallow microspheres improve

the bioavailability and patients compliance by prolonging theresidence time in gastrointestinal track. E.Dini et.at, synthesis and characterization of cross linked

chitosan microspheres containing an hydrophilic drug,Hydroquinone. The microspheres were prepared bysuspension cross linking method using glutaraldehyde. It wasfound that slower drug release rate was obtained frommicrospheres prepared by using a high concentration of

chitosan Anandkumar Shrivastava et.at. preparation of characterization

of floating microsphere of cemitidine. The cemitidinemicrosphere were prepared by solvent evaporationmethod,thus this study shows that floating microspheres willincrease the gastric residence time

T. Comoglue et.at. in this work prepared the microspheres of pantaprazole by solvent evaporation method andcharacterize.the pantaprazole is the proton pump inhibitor. Usein treatment of gastric ulcer and gastroesophagal disease. sopurpose of this study was to developed the microspheres thatabsorb through gastrointestinal track


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Hui Yun Zhou et.at. prepared the Cellulose acetate (CA) /Chitosan multimicrospheres of Ranitidine. He microsphereprepared by w/o/w emulsion technique. The concentration of CA and the ratio of CA:chitosan influence the drug release. Itprolong the release of Ranitidine

[1] K Takeuchi, K Akira, Journal of Gastroenterology and Hepatology., 1999 , 142, 251.[2] JD Korwin, P Ducrotte, T Vallot, Presse Med ., 2004 , 33, 11, 746.[3] J Bateman, B Teusher, R Telford, Pharmaceutics I (PSCI) , 2002 ,423.[4] A Farinha, A Bica, Eur J Pharm Sci ., 1999 , 7, 4, 311.

[5] S Bozdang, S Calis, M Sumnu, Farm Vestn ., 1997 , 48, 119.[6] A Pilbrant, C Cederberg, Scand J Gastroenterol ., 1995 , 20, 336.[7] C Cederberg, T Anderson, I Skanberg, Scand J Enterol ., 1989 , 166,33.[8] ML Buck, Pediatric Pharmacotherapy ., 1999 , 5: 4A.[9] VP Pandey, A Phanindrudu, Boll Chim Farm ., 2002 , 141, 6, 419.[10]M Turkoglu, H Varol, M Celikok, Eur J Pharm Biopharm ., 2004 ,57, 2, 279.

[11]MA Navarro, N Raei, Gastroenterol Hepatol ., 1998 , 21, 2, 63.[12] AR Kulkarni, KS Soppimath, TM Aminabhavi, J Controlled Release. , 2001 , 75, 331.[13] RC. Ganorkar, F Liu, M Baudys, SW Kim, J Controlled Release .,1999 , 59, 287.[14] AR Kulkarni, KS Soppimath, WE Rudzinski, TM Aminbhavi, Drug

Met Rev ., 2000 , 33,149.

METHOD SELECTED

OBJECT:- To prepare pH sensitive microspheres

ABSTRACTOmeprazole, a proton-pump inhibitor used in peptic ulcers, gastro-esophageal-reflux disorder,


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Zollinger-Ellison syndrome and in H. pylori infections. The omeprazoleis unstable at acidic pH,undergoes degradation in stomach. To prevent the degradation instomach, dosage forms aresupplied as enteric-coated tablets or granules encapsulated in gelatincapsules. The efficiency of such dosage forms depends upon the - extent of coating, solubility of coating material; type of dosage form etc. Recently, pH-sensitive polymer are utilized to deliver drug to intestine. The

polymer swells only in alkaline pH and releases the drug as it enters theintestine. In this

research, pH-sensitive formulations were developed to deliver theomeprazole effectively. Usingthe stimuli-responsive polyacrylamide-g-sodium alginate polymer,microspheres were prepared by coaservation followed by cross-linking with gluteraldehyde.Omeprazole drug were loaded inmicrospheres. All microspheres were evaluated for size distribution,content uniformity, in vitrodissolution and pulsatile swelling study. Pharmacological screeningswere done for antacid and antiulcer activities of different omeprazole containing formulations.

Results indicated that the pH, free acidity, total acidity, and ulcer-index in both non-lighted and ligated ulcer models werecomparatively reduced in rats treated with the omeprazole containing

pH-sensitive microspheresthan enteric-coated granules than neat omeprazole. Thus, developed

formulation release wassuperior in intestine and thus produced superior action.

INTRODUCTIONOmeprazole, a proton-pump inhibitor is widely prescribed for thetreatment of peptic ulcer,


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Zollinger-Ellison syndrome, Gastro-esophageal reflux disease (GERD),H.Pylori infection andNSAID associated ulcers. Its oral bioavailability (40-50%) in humans ispoor due to acidsensitivity and first pass metabolism. Attempts were made earlier toimprove the bioavailabilityby formulating it as enteric-coated granules encapsulated in gelatin shelland enteric-coated tablets. The efficiency of such dosage forms dependsupon the number of parameters such asextent of coating, solubility of coating material and type of dosage formetc.In the present study, omeprazole was encapsulated in acrylamide and

that was crosslinked withgluteraldehyde. These microspheres are sensitive to pH changes andrelease the drug in analkaline pH undergoing swelling. Microspheres were prepared bycoaservation followed bycrosslinking with gluteraldehyde. They were then evaluated for contentuniformity, size analysis,in-vitro dissolution and pulsatile swelling. Absence of interactionbetween omeprazole andpolymer was determined using IR spectral data. Pharmacologicalscreening was carried out forantacid and antiulcer activities using pylorus ligation and non-ligationmethods in rats. Theparameters used to evaluate where change in pH, total acidity and ulcerindex. The results werecompared against data generated for neat omeprazole, and two marketedformulation viz.OMEZ, OCID.

DRUG PROFILE- omeprazole


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Chemical formula:-C 17H19N3O3S Molecular weight:- 345.416 Categories:-

Anti-Ulcer Agents Enzyme Inhibitors Proton-pump Inhibitors

Mechanism of action:-

Omeprazole is a proton pump inhibitor that suppresses gastric acidsecretion by specific inhibition of the H + /K +-ATPase in the gastricparietal cell. By acting specifically on the proton pump, omeprazoleblocks the final step in acid production, thus reducing gastric acidity.

DRUG INTRACTION:-

Drug InteractionAlprazolam Omeprazole may increase the effect of thebenzodiazepine, alprazolam.

Atazanavir This gastric pH modifier decreases the levels/effectsof atazanavir

Chlordiazepoxide Omeprazole may increase the effect of the
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benzodiazepine, chlordiazepoxide.Cilostazol Omeprazole increases the effect of cilostazol

Clonazepam Omeprazole may increase the effect of the

benzodiazepine, clonazepam.Clorazepate Omeprazole may increase the effect of thebenzodiazepine, clorazepate.

Cyclosporine Omeprazole increases the effect and toxicity of cyclosporine

Diazepam Omeprazole may increase the effect of thebenzodiazepine, diazepam.

Estazolam Omeprazole may increase the effect of the

benzodiazepine, estazolam.

Flurazepam Omeprazole may increase the effect of thebenzodiazepine, flurazepam.Fosphenytoin Omeprazole increases the effect of hydantoinIndinavir Omeprazole decreases the absorption of indinavir

Itraconazole The proton pump inhibitor, omeprazole, maydecrease the absorption of itraconazole.

Ketoconazole The proton pump inhibitor, omeprazole, maydecrease the absorption of ketoconazole.

Midazolam Omeprazole may increase the effect of thebenzodiazepine, midazolam.Methotrexate Omeprazole increases the levels of methotrexate

Halazepam Omeprazole may increase the effect of thebenzodiazepine, halazepam.

KetazolamOmeprazole may increase the effect of the

benzodiazepine, ketazolam.Prazepam Omeprazole may increase the effect of thebenzodiazepine, prazepam.

Quazepam Omeprazole may increase the effect of thebenzodiazepine, quazepam.
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Triazolam Omeprazole may increase the effect of thebenzodiazepine, triazolam.Mephenytoin Omeprazole increases the effect of hydantoin

Phenytoin

Omeprazole increases the effect of hydantoinEthotoin Omeprazole increases the effect of hydantoin

Voriconazole Voriconazole increases the effect and toxicity of omeprazole

St. John's Wort St. John's Wort decreases the levels/effects of omeprazole

Dasatinib Omeprazole may decrease the serum level of dasatinib.

Enoxacin Omeprazole may decrease the absorption of enoxacin.Disopyramide The beta-blocker increases toxicity of disopyramide

Tacrolimus

Omeprazole may increase the blood concentration of Tacrolimus. Monitor for changes in thetherapeutic/toxic effects of Tacrolimus if Omeprazole therapy is initiated, discontinued oraltered.

Tipranavir

Tipranavir, co-administered with Ritonavir, maydecrease the plasma concentration of Omeprazole.Consider alternate therapy or increase the dose of Omeprazole based on the therapeutic response.

Trimipramine

The strong CYP2C19 inhibitor, Omeprazole, maydecrease the metabolism and clearance of Trimipramine, a CYP2C19 substrate. Consideralternate therapy or monitor for changes intherapeutic and adverse effects of Trimipramine if Omeprazole is initiated, discontinued or dosechanged.

CefditorenProton pump inhibitors such as omeprazole maydecrease the serum concentration of cefditoren. If
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possible, avoid use of cefditoren with proton pumpinhibitors (PPIs). Consider alternative methods tominimize/control acid reflux (eg, diet modification)or alternative antimicrobial therapy if use of PPIs cannot be avoided.

Clopidogrel

Omeprazole may decrease serum concentrations of the active metabolite(s) of clopidogrel. Clopidogrelprescribing information recommends avoidingconcurrent use with omeprazole, due to thepossibility that combined use may result in decreasedclopidogrel effectiveness

CLINICAL PHARMACOLOGY:-

Pharmacodynamics:

Omeprazole is a compound that inhibits gastric acid secretion and isindicated in the treatment of gastroesophageal reflux disease (GERD),the healing of erosive esophagitis, and H. pylori eradication to reduce

the risk of duodenal ulcer recurrence. Omeprazole belongs to a newclass of antisecretory compounds, the substituted benzimidazoles, thatdo not exhibit anticholinergic or H2 histamine antagonistic properties,but that suppress gastric acid secretion by specific inhibition of theH+ /K + ATPase at the secretory surface of the gastric parietal cell. As aresult, it inhibits acid secretion into the gastric lumen. This effect isdose-related and leads to inhibition of both basal and stimulated acidsecretion irrespective of the stimulus.

Mechanism of action:- The inhibitory effect of omeprazole on gastric acid secretion invivo and in vitro is presented. In the gastric fistula dog omeprazolewas found to be about 10 times more potent than cimetidine. When
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omeprazole was administered in vivo , the inhibition of acidsecretory rates was found to correlate with the degree of inhibitionof the gastric H +K+ATPase purified from the omeprazole treated

animals. The inhibitory action of omeprazole was found to dependon acid induced transformation of omeprazole into an activeinhibitor of the gastric H +K+ATPase, as no inhibition was obtainedwhen omeprazole was incubated under neutral conditions witheither the isolated gastric mucosal or the H +K+ATPasepreparations. A model is proposed in which the inhibition of acidformation is mediated by an inhibitory compound generated fromomeprazole within the acid compartment of the parietal cell.

Side effect:-

Diarrhea; gas; headache; nausea; stomach pain; vomiting.Severe allergicreactions (rash; hives; itching; difficulty breathing; tightness in the chest;swelling of the mouth, face, lips, or tongue; unusual hoarseness); bone

pain; chest pain; dark urine; fast, slow, or irregular heartbeat; fever,chills, or sore throat; red, swollen, blistered, or peeling skin; severediarrhea; severe stomach pain or cramps; swelling of the hands, ankles,or feet; unusual bruising or bleeding; unusual tiredness; vision changes;yellowing of the eyes or skin.

Storage:- Store below 25C

Uses:-

Omeprazole is used to treat a number of problems.

It is a member of a class of drugs called proton pump inhibitors,sometimes known as PPIs.
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In general, this drug is used to treat gastro-oesophageal reflux disease(GORD ), or gastric or duodenal (upper intestinal) ulcers.

Benefits of being on this drug include the prevention of excess acid

production by the stomach which can lead to the relief of GORDsymptoms and may allow healing of ulcers or erosions.

Listed below are the typical uses of omeprazole:

Treatment of gastro-oesophageal reflux disease (sometimes calledGORD, dyspepsia or heartburn ) and relief of associated symptomssuch as dyspepsia (indigestion , including pain , bloating or nausea ),heartburn and epigastric pain (pain in the chest behind the breastbone)

Treatment of duodenal (upper intestinal) and gastric (stomach)ulcers and erosions, including ulcers associated with non-steroidalanti-inflammatory (NSAID) drug use

Eradication of a bacteria (Helicobacter pylori) which is often foundin the gut and is the cause of stomach ulcers in many patients(omeprazole is used in combination with antibiotics for thispurpose).

Prevention of stomach acid aspiration (inhalation of stomach acidinto the airways), which may happen during a surgical operation

Controlling symptoms of Zollinger Ellison syndrome (a disorderin which excess stomach acid is produced). a high dose givenintravenously following surgical treatment of severe peptic(stomach) ulcer bleeding treatment may prevent a recurrent of ulcer bleeding.

Warnings:- Omeprazole should be used with caution in: those withliver disease.

It should not be used in: patients with dyspepsia (indigestion) or asuspected stomach ulcer if there are 'alarm' symptoms of stomach cancer (bleeding in stools, difficulty in swallowing, recurrent vomiting orweight loss ) as this means there is a possibility of cancer which needs to
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be excluded before treatment with omeprazole is started, as omeprazoletreatment may temporarily relieve some cancer symptoms and so delaycancer diagnosis.

Half Life:- 0.5-1 hourAbsorption:- Absorption is rapid, absolute bioavailability (compared tointravenous administration) is about 30-40% at doses of 20-40 mg

Exepient Data:-

Acrylamide

Structure

Chemical formula:- C17 H14 N4 OMolecular weight:- Average: 290.3193
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Sodium alginate

Structure

Chemical formula:- (C 6 H7 NaO 6 ) nMolecular weight:- 222 (actual average)Solubility:- Dissolves slowly in water, forming a viscoussolution; insoluble in ethanol and etherUsed as:- Stabilizer, thickener, gelling agent, emulsifier

Material and Method:-

Materials:-

1) Drug: Omeprazole2) Polymers: HPMC,PEG6000,Acryl amide,

Sodium Alginate,Poloxomer etc

Method:-

Preparation of microspheres by solvent evaporation method

Development of formulation and evaluation


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Grafted polymer synthesisSodium alginate (Na-alg) was hydrated for 24 hr with constant stirring.Acrylamide (AAm)solution was then added followed by (0.005mol) of ceric ammoniumnitrate (CAN). The mixture

hours. The grafted polymerwas precipitated by acetone and washed with methanol. It was then driedovernight under

Production of pH-sensitive microspheresThe grafted polymer solution was added drop wise into a solution of

gluteraldehyde in a mixtureof ethanol and HCl to obtain microspheres. These were then stirred for 1h, decanted and washedwith water. They were made pH-sensitive by stirring in 1 M NaOH for 4

Drug was loaded into the microspheres by stirring them in drug solutionfor 4 h, decanting them,

Preformulation studies:-

HPLC analysis methodOmeprazole samples were analyzed using a modified reversedphasehigh performance liquid chromatography (HPLC) method [9]employing a water instrument with a Shimadzu UV detector set at 302nm and a water US-60 injector. The samples were eluted at a flow

rate of 1.0 mL/min at room temperature, under isocratic conditions.Separation was achieved using octadecylsilane column -Bondapak C18 column (Waters Assoc.; 10 m, 150 mm 3.9 mm id). The mobilephase consisted of acetonitrile: phosphate buffer pH 7.5 (25:75%v/v). Standard calibration curves, based on the average of the peak height of different concentrations using a known amount of drug in


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the concentration range of 0.5- 5.0 g/mL, were used to determine the intra- and inter-day precision of the method. Standard solutions wereprepared daily by dissolving the appropriate amount of drug in ethanolto yield the final solution (10 g/mL), and the calibration curves were constructed before each sample set was analyzed to ensurereproducibilityof the analysis.

Kinetic studyDegradation of omeprazole in aqueous solutions

(effect of pH)The effect of pH (6.0, 7.5, 9 and 10) of the medium on the stabilityof omeprazole was carried out at constant temperature of 25C.Solutionsof omeprazole were prepared in the selected buffer at differentpH values. The solutions were placed in brown glass vials coveredwith Teflon lined screw caps and stored at 25C in a thermostaticallycontrolled oven (Heraeus thermostatic oven, Karl Kolb Scientifictechnical supplies, Buchschlag-Frankfurt, Germany). At differenttime intervals, 0, 24, 48, 72, 96, 120, 168 h, samples were taken outof the oven, frozen immediately and kept in a freezer (- 20C) untilthey were analyzed.

EVALUATION PARAMETERS FOR pH SENSITIVEMICROSPHERES

The evaluation of microspheres shall be carried out by using followinginstruments.

o Compatibility study: - Compatibility of drug with variouspolymers will be investigated using UV/IR.

o Surface Morphology: SEM/ Optical microscope. o Particle size determination: Sieve analysis/SEM/Optical

microscope.


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o Estimation of drug content by using UV-Spectroscopicmethod

o In vitro dissolution study: USP Dissolution Apparatus(DISSO 2000, LAB INDIA)

EVALUATION

Identification of omeprazole was by comparison with that of anauthentic sample and by verification of the presence of functional groupsin its infra-red (IR) spectra. Also, various concentrations of the drug in0.1M HCl were evaluated by ultraviolet (UV) spectroscopy (Shimadzu

1700) to determine if it would obey Beers law.

Particle size determinationThe particle size of the microspheres was determined with an opticalmicroscope under regular polarised light, and mean particle size wascalculated by measuring 100 microspheres (n = 3) with the help of acalibrated oculometer.

Tapped densityTapping method was used to calculate tapped density. The volume of aweighed quantity of the microspheres was determined, after 100 taps,using a tapped density apparatus (Pharma Chem Machineries, model C-BD 100),DT = MT/VT ... (1) where DT = tapped density, MT is mass of microspheres and VT =volume of microspheres after tapping

Carrs (Compressibility) index This parameter was calculated from bulk density (the ratio of weighedquantity of microspheres to its volume), DP, and tapped density as in Eq2 [9]Compressibility index = (DT DP)/DTx100 ... (2)


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Angle of reposeThe angle of repose, q, of the microspheres, which measures resistanceto particle flow, was determined by the fixed funnel method [10] andcalculated as in Eq 3.Tan q = S/D .... (3) where S = surface area of the free standing height of the microspheresheap and D = diameter of the heap.

Scanning electron microscopyScanning electron microscopy (SEM) studies were performed todetermine the porous/hollow nature of the microspheres. Surface

morphology of microspheres was also noted.

Drug loadingThe drug content of the floating microspheres was carried out bydissolving the microspheres in a small amount of dichloromethane in aseparating funnel and extracting the drugs into 0.1N HCl by evaporatingthe dichloromethane. Determination of drug loading (n = 3) was carriedout at 288 nm spectrophoto-metrically

In vitro floatability In vitro floatability studies on floating microspheres were carried outusing USP XXIV dissolution apparatus II [11]. The microspheres wereplaced in 0.1M hydrochloric acid containing 0.02 %v/v Tween 80 withthe paddle rotating at 100 rpm for 12 h. Tween 80 served to mimic theeffect of natural surfactants in the stomach. The floating and the settledportions of the microspheres were recovered separately, dried andweighed. Buoyancy (floatability) was calculated as in Eq 4.Buoyancy (%) = Qf / (Qf + Qs) x 100 .. (4) where Qf and Qs are the weights of the floating and the settledmicrospheres, respectively.


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In vitro drug release studiesDrug release studies were carried out in a six-basket USP XXIVdissolution apparatus type I rotating at 100 rpm in 0.1Mhydrochloric acid as dissolution medium (900ml) maintained at 37 0.5C. At specific time intervals, up to 12 h, aliquots were withdrawnand analysed at 288 nm spectrophotometrically (Shimadzu 1700) aftersuitable dilution. The withdrawn volume was replaced with an equalvolume of fresh 0.1M hydrochloric acid to maintain sink conditions.All experiments were performed in triplicate. The drug release data werefitted to Zero order (cumulative % drug release versus time), First order(log cumulative % drug retained versus time) and Higuchi models(cumulative % drug released versus square root of time) to assess the

kinetics of drug release and determine the release mechanism of the drugfrom the floating microspheres.

RESULTS AND DISCUSSIONDevelopment of formulation and evaluationGrafted polymer synthesis and production of pH-sensitivemicrospheresThe grafted polymer obtained with different ratio of Na-alg and AAmare shown in (Table 1).FTIR studiesThe FTIR spectra of omeprazole, Na-alg, Na-alg-g-pAAm, microspherescontaining omeprazoleare displayed in (Figures 1 - 4). The peak at 1616 cm-1 shows the CNimine group present in themicrospheres by the crosslinking between the gluteraldehyde and CANand polymers. Themicrospheres containing omeprazole shown peak at 1700 cm-1 indicatedthe presence of pendentgluteraldehyde in the microspheres. The spectra results that there is nointeraction betweenomeprazole and polymer. And it shows the presence of all peaks, whichwere present in thecross-linked polymer and pure omeprazole.


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Swelling studiesThe % water uptake Q was 108 at acidic pH and 1552 at alkaline pH andshown in (Table 2).This indicates that pH sensitive microspheres were highly swellable atalkaline medium, hencefacilitates the drug release in intestine. The swelling was displayed in(fig 5).Drug release studiesIn-vitro drug release studies were carried out in simulated gastricsolution for 12 h and therelease of drug in acidic pH was very low where as it increases inintestinal pH and shown in (fig

6). The release data were fitted with Peppas equation, and the values of k, n, t calculated and isdisplayed in (Table 3). The calculated values of n were found to be 0.4to 0.6 and the values of k ranges from -1 to 5 min 10 -2 .Antiulcer studiesAntiulcer and anatacid properties were estimated for neat omeprazole,OMEZ,OCID andmicrospheres containing omeprazole. The pyloric ligation and non-ligation methods results weretabulated in (Table 4 - 7) for 30 min and 4 h after the drug pyloricligation and non-ligationrespectively. The ulcer protection of pH-sensitive microspheres wassuperior to neat omeprazoleand marketed formulation.


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FTIR SPECTRUM of OMEPRAZOLE

FTIR spectrum of SODIUM ALGINATE


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% grafting, drug content, and microspheres size

S.No Polymer(Na-alg-g-pAAm)

% of Grafting Drug content microspheressize (in m)

1.2.3.

55-4545-5535-65

253545

18.320.823.7

780.5

Hero Rahul Naudiyal2

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