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Vildagliptin SR tablets are used for type-II diabetes. it is used along with metformin by Doctors prescription.

Vildagliptin SR tablets are used for type-II diabetes. it is used along with metformin by Doctors prescription.

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  • FORMULATION AND EVALUATION OF SUSTAINED RELEASE TABLETS OF VLIDAGLIPTIN
  • INTRODUCTION
  • CLASIFICATION OF ANTI-DIABETIC DRUGS
  • LITERATURE REVIEW
  • AIM
  • List of materials used
  • Drug profile
  • List of equipments used
  • PRE FORMULATION STUDIES
  • Drug-Excipients compatibility studies by FT-IR
  • PRE COMPRESSION PARAMETERS
  • Pre compression properties
  • Compression parameters
  • The λmax of vildagliptin was 245 nm.
  • Calibration curve
  • n=3 , ±=S.D
  • Graphs of Cumulative percentage drug release of all formulations
  • First order
  • Hixon-crowell diffusion kinetics
  • SUMMARY
  • CONCLUSION
  • BIBILOGRAPHY

Transcript

  • 1. FORMULATION AND EVALUATION OF SUSTAINED RELEASETABLETSOF VILDAGLIPTINUnder the Guidance ofMr. P.VISHNU M.Pharm.Assistant ProfessorPresented ByCHAITANYA.B B.Pharm.Department of PharmaceuticsCMR COLLEGE OF PHARMACY(Approved by AICTE & PCI and affiliated to JNTU Hyderabad)6/12/2012
  • 2. SRF’s describes the slow release of a drug substance from a dosage form tomaintain therapeutic response for extended period of time. Time depends on thedosage form. In oral form it is in hours, and in parenteral’s it is in days andmonths. Ex: Aspirin SR, Dextrim SR.INTRODUCTIONADVANTAGES:Decreased local and systemic side effectsBetter drug utilizationImproved efficiency in treatmentDISADVANTAGES:Decreased systemic availability in comparison to immediate-release conventionaldosage formsRetrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.Reduced potential for dosage adjustment of drugs normally administered in varyingstrengths.6/12/2012
  • 3. Drug Selection For Oral Sustained Release Drug Delivery Systems:Parameter CommentElimination half life Preferably between 0.5- 8 hElimination rate constant Required for designAbsolute bioavailability Should be 75% or moreIntrinsic absorption rate Must be greater than release rateBiopharmaceutical parameters for drug selection6/12/2012Parameter Preferred valueMolecular weight/ size < 1000Solubility > 0.1 mg/ml for pH 1 to pH 7.8Apparent partitioncoefficientHighAbsorption mechanism DiffusionGeneral absorbability From all GI segmentsRelease Should not be influenced by pH andenzymesPharmacokinetic parameters for drug selection
  • 4. MATRIX TABLETS:These are the type of controlled drug delivery systems, which release the drug incontinuous manner by both dissolution as well as diffusion controlled mechanisms. Tocontrol the release of the drugs, which are having different solubility properties, the drugis dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellablehydrophobic materials or plastic materials.Advantages of matrix systems•Very easy to fabricate in a wide range of sizes and shapes.•Suitable for both non-degradable and degradable system.•No danger of dose dumping in the case of rupture.Disadvantages of matrix systems•Not all the drugs can be blended with a given polymeric matrix.•Water soluble drugs have a tendency to burst from the system.6/12/2012
  • 5. Drug Release Mechanism from Matrix Systems:Drug Release from Hydrophilic Colloid Matrices:The classic description of the events following immersion of a matrix in aqueous mediais as follows:Surface area (if water soluble) dissolves and gives a ‘burst effect’.The hydrophilic polymer hydrates and an outer gel layer is formed.The gel layer becomes a barrier to the uptake of further water and to the transfer of drug(if soluble) release occurs by diffusion through the gel layer, insoluble drug is releasedby erosion followed by dissolution.Following erosion the new surface becomes hydrated and forms a new gel layer.Drug Release from Fat Matrices:The drug embedded into a melt of fats and waxes is released by leaching andor hydrolysis as well as dissolution of fats under the influence of enzymes and pH chan-ges in the gastro intestinal tract. Fatty acids are more soluble in an alkaline rather thanacidic medium. Fatty esters are more susceptible to alkali catalyzed hydrolysis than to acidcatalyzed hydrolysis. Polyethylene, ethyl cellulose and glycerine esters of hydrogenatedresins have been added to modify release pattern.6/12/2012
  • 6. Drug Release from Inert Matrices:The release of drugs from insoluble matrices has been investigated and fourtypes of drug matrix systems can be considered:•Drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusionmechanism.•Drug dispersed in the matrix and then, after dissolution of the drug, diffusion occurs viaa solution- diffusion mechanism.•Drug dissolved in the matrix and diffusion occurs through water- filled pores in the matrix.•Drug dispersed in the matrix and then, after dissolution, diffusion occurs through waterfilled pores6/12/2012
  • 7. DIABETES MELLITUSDiabetes mellitus is a metabolic disorder in which the body does not produce orproperly use insulin. It causes disturbances in carbohydrate, protein, lipid metabolismand complications such as retinopathy, microangiopathy and nephropathy.It is a group of metabolic disorders characterized by hyperglycemia. These metabolicdisorders include alterations in the carbohydrate, protein and fat metabolismsassociated with absolute or relative deficiencies in insulin secretion or insulin action.The characteristics symptoms of diabetes are polyurea , polydypsia , polyphagia,pruritis, unexpected weight loss..etc.Classification of Diabetes Mellitus:1. Insulin dependent diabetes mellitus (IDDM)2. Non Insulin dependent diabetes mellitus (NIDDM)3. Maturity onset diabetes of youth (MODY)4. Gestational Diabetes6/12/2012
  • 8. CLASIFICATION OF ANTI-DIABETIC DRUGS Insulin SecretagoguesSulfonyl ureas E.g : Tolbutamide (Orinase), Glipizide (Glucotrol)..Meglitanides E.g. : Repaglinide ( Prandin).. SensitizersBiguanides E.g. : Metformin (Glucophage)…Thiazolidinediones E.g. : Rosiglitazone ( Avavdia).. Alpha Glucosidase inhibitor E.g. : Acarbose ( Glucobay).. Peptide analoguesI. Incretin mimeticsGlucagon like peptides (GLP) analogs and agonist E.g. Exenatide..Gastric inhibitory peptide (GIP)analogsII. DPP-4inhibitots E.g. : Vildagliptin ( Galvus)III. Amylin analogs E.g. : Pramlinitide6/12/2012
  • 9. LITERATURE REVIEWHindustan Abdul Ahad et al., (2012) reported to prepare the Formulation of Glimepiride SRMatrix Tablets Using Hibiscus Rosa-Sinensis Leaves Mucilage and Povidone. Variousformulations of Glimepiride tablets were prepared. The tablets were evaluated and theoptimized formulation was tested for accelerated stability studies. The in vitro dissolutiondata was fitting to zero order and the release of drug followed Higuchis release. The stabilitystudies revealed that the tablets retain their characteristics even after stressed storageconditions. it was concluded that the dried Hibiscus mucilage and Povidone combination canbe used as an effective matrix forming material for making SR matrix tablets of Glimepiride.Mohd Azharuddin et al.,(2011) reported to prepare Formulation And Evaluation of CR MatrixTablets of Antihypertensive Drug Using Natural And Synthetic Hydrophilic Polymers. Tabletswere prepared by direct compression method using different drug: polymer concentration.FT-IR and DSC study revealed no chemical interaction between drug and polymers. Pre andpost compression parameters complied with pharmacopoeial limit for the tablets. In-vitrorelease studies was performed and the results indicates that matrix tablet (F9) containing50% w/w blend of natural and synthetic polymer has better CR for a period of 24 hr.6/12/2012
  • 10. DRK.L.Senthilkumar et al.,(2011) reported to prepare the Metformin Hcl tablets by using differentpolymers like HPMC K 100M,HPMC K15 with different ratios. Tablets were prepared by wetgranulation technique. Finally It is concluded that formulation of sustained release tablet ofMetformin containing 13 % HPMC K100 with binder PVP K30 as an optimized formulation ofsustained release tablets for 10 hour release as it fulfils all the requirements for sustained releasetablets.Harsha V. Patel et al., (2009) reported to prepare the sustained release matrix tablets ofMetformin Hcl. The tablets were prepared by the non-aqueous wet granulation method. Isopropyalcohol solution of polyvinylpyrrolidone (PVPK30) was used as granulating agents along withhydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC-K15) and locust beangum (LBG). The results of dissolution studies indicated that formulation of (HPMC: LBG, 200:30 mgcould extend the drug release up to 8 hours. The successful formulation of the study, exhibitedsatisfactory drug release was compared with the marketed formulation (Obimet SR™) and showedvery close to release profile which suggests sustained release profile.6/12/2012
  • 11. AIMTo prepare and evaluate the Sustained release matrix tablets of an anti diabeticdrug of Vildagliptin(50mg)OBJECTIVES•To study the preformulation factors such as melting point, compatibility studies,etc.•To formulate a sustained release composition which releases drug over a timeperiod of about 24 hours.•To develop a physicochemical stable dosage form.•To develop a in vitro dissolution profile of all formulations.•To evaluate the optimized formulation by establishing drug release kinetics usingvarious dissolution models.6/12/2012
  • 12. PLAN OF WORKSelection of thedrugSelection of excipientsDrug- excipient compatibility by FT-IRPre-compression evaluationcompressionAngle of reposeBulk densityTapped densityHausner’ ratioCarr’s indexPost compressionevaluationThickness of TabletHardnessWeight VariationFriabilityDrug ContentDissolution time6/12/2012
  • 13. S. No. NameCategory Suppliers ofMaterial1Vildagliptin Hypoglycaemic agent Affine ChemicalsLtd.2MCC IP(Avicel PH101)DiluentRan Q Remedies3HPMC K 100LV Drug release retardingpolymer Dow Chemicals4HPMC K 15M Drug release retardingpolymer Dow Chemicals5HPMC K 100 M Drug release retardingpolymer Dow Chemicals6HPMC K4M Drug release retardingpolymer Dow Chemicals7 Povidone K 30 Binding agent Basf8 MCC IP(PH 102) Diluent Ran Q Remedies9 Talc Glidant Aravelli pvt.Ltd.10MagnesiumStearateLubricant Amshi Drug andChemicals11 Water VehicleList of materials used6/12/2012
  • 14. DRUG PROFILEChemical name: (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine- 2-carbonitrileMolecular Formula : C17H25N3O2Molecular Weight : 303.399Chemical structure :6/12/2012
  • 15. Description : A white or slightly yellow colour powder.Melting Point : 150oC.Solubility : freely soluble in water and organic solvents.Therapeutic Category : dipeptidyl peptidase-4(DPP-4),anti diabetic agent.Mechanism of Action : Vildagliptin inhibits dipeptidyl peptidase-4 (DPP-4). This inturn inhibits the inactivation of GLP-1 by DPP-4, allowing GLP-1 to potentiate thesecretion of insulin in the beta cells.It inhibits the inactivation of GLP-1 and GIP by DPP-4,allowing GLP-1 andGIP to potentiate the secretion of insulin in the beta cells and suppress glucagonrelease by the alpha cells of the islets of Langerhans in the pancreas.GIP - glucose dependent insulinotropic polypeptideGLP-1 -glucagon like peptide16/12/2012
  • 16. Absorption:The absolute bioavailability is 85%.Distribution :The plasma protein binding of vildagliptin is low (9.3%).Metabolism:The major metabolite (LAY 151) is pharmacologically inactive and is thehydrolysis product of the cyano moiety, accounting for 57% of the dose,followed by the amide hydrolysis product (4% of dose).Elimination :The half-life after i.v administration is - 2 hours.The half-life after oral administration is -3hours.Dose: 50-100 mg daily once6/12/2012
  • 17. LIST OF EQUIPMENTS USEDCompression Machine CadmachElectronic BalanceSartoriusFluidized Bed Dryer BetochemMulti Mill BetochemVernier Caliper Mitutoyo CorpsTablet Friability TesterLabindia-Ft1020Tablet Hardness TesterMonsanto typeKarl Fischer Apparatus LabindiaDissolution Test Apparatus Labindia-Ds 8000Uv-Visible Spectrophotometer Labindia-Uv 3200 DoubleBeam Spectrophotometer6/12/2012
  • 18. S.No Properties Description1. Color White to slightly yellowish crystalline powder2. Odor Characteristic3. Taste MetallicOrganoleptic characteristics4. Melting point 150⁰CPRE FORMULATION STUDIES6/12/2012
  • 19. Drug- excipient compatibility studies by FT-IR:2mg drug+ 200mg KBrMix wellPellet preparationSample cellspectra were recorded over the wave number of 4000 to 400cm-1.6/12/2012
  • 20. Drug-Excipient compatibility studies by FT-IRDrug-Excipient compatibility studies by FT-IR6/12/2012
  • 21. MANUFACTURING PROCEDURE:Weigh accurate amounts of Vildagliptin+pH101+polymers HPMC(K15M,K100M,K4M& K100LV)mix for 5 min and sieved through 40 meshpreparation of binding solution(PVP K-30+water)preparation of wet mass(binding solution +mixed ingredients)sieved through 16 meshDry the wet granules at 60⁰C until LOD is 1-3 % w/wadd pH102 to the granulesdried granules were mixed with talc, magnesium stearate (sieved through 60 mesh)finally compress the tablet.6/12/2012
  • 22. INGREDIENTS(mg/tab)F1 F2 F3 F4 F5 F6 F7 F8Vildagliptin 50 50 50 50 50 50 50 50MCCpH101 130 130 130 130 130 130 130 ―HPMC K 100LV ― ― ― 120 ― ― 50 148HPMC K 15M ― 120 ― ― 50 ― ― 100HPMC K 100 M ― ― 120 ― ― 50 ― ―HPMC K4M 120 ― ― ― 90 90 90 32Povidone K 30 12 12 12 12 12 12 12 12MCCpH 102 20 20 20 20 20 20 20 20Talc 4 4 4 4 4 4 4 4MagnesiumStearate4 4 4 4 4 4 4 4Water q.s q.s q.s q.s q.s q.s q.s q.s340 340 340 340 360 360 360 370Formulations of Vildagliptin matrix tablets (50mg tablet)Total wt (mg)6/12/2012
  • 23. 6/12/2012PRE COMPRESSION PARAMETERSAngle of reposeBulk densityTapped densityCompressibility indexHausner’s ratio
  • 24. S.NoFormulation codeBulkDensity(g/ml)TappedDensity(g/ml)Compressibility Index(%)Hausner’sRatioAngle ofrepose(⁰)1 F-1 0.48±0.02 0.625±0.1 21.23±0.21 1.32±0.14 38.5±0.232 F-2 0.583±0.15 0.745±0.21 23.60±0.16 1.27±0.05 38.5±0.153 F-3 0.490±0.12 0.635±0.31 22.45±0.31 1.33±0.08 37.2±0.264 F-4 0.581±0.01 0.714±0.14 16.67±0.25 1.2±0.16 36.5±0.095 F-5 0.654±0.21 0.802±0.26 15.07±0.31 1.19±0.21 35.4 ±0.216 F-6 0.694±0.09 0.834±0.09 16.09±0.16 1.21±0.18 34.5±0.197 F-7 0.510±0.06 0.641±0.28 17.74±0.17 1.22±0.22 35±0.178 F-8 0.582±0.01 0.714±0.13 12.45±0.13 1.15±0.24 32.5±0.14Pre compression parameters6/12/2012
  • 25. 6/12/2012Compression parametersDescription White, Round biconvex tabletsdebossed with R on one sideand F8 on other sideTooling 13.10*6.50 mm,Round shapebiconcave punchesWeight of 10 tablets (g) 3.7Weight of individual tablet (mg) 370.000 5% (340.00-370.000)Hardness(k p) NLT 3 (6-7)Thickness (mm) 5.50 0.2 (5.48-5.52)Friability % NMT 1%
  • 26. 6/12/2012Post compression parameters: Thickness of Tablet Weight variation test Hardness Friability Water content Assay Dissolution studies
  • 27. BatchcodeWeightVariation(mg)n=20Thickness(mm)n=10Hardness(Kg/cm²)n=5Friability(%w/w)n=10Assay(%)n=5Watercontent(%)F1 340±3.01 5.52±0.2 6.5±0.02 0.15±0.01 96.5±0.9 6.39±0.01F2 340±2.89 5.48±0.2 7.0±0.2 0.18±0.01 96.0±1.86.35±0.21F3 340±3.05 5.5±0.2 6.5±0.2 0.21±0.01 95.5±1.56.45±0.15F4 340±2.98 5.52±0.2 6.8±0.2 0.19±0.01 105±2.16.58±0.21F5 360±3.00 5.48±0.2 6.9±0.02 0.34±0.01 97.5±1.46.15±0.18F6 360±2.95 5.52±0.2 6.9±0.2 0.19±0.02 96±0.9 6.38±0.24F7 360±2.99 5.48±0.2 7.0±0.01 0.22±0.01 98±0.51 6.55±0.09F8 370±2.97 5.52±0.2 7.1±0.2 0.21±0.01 99.8±0.84 6.13±0.16Physical properties of sustained release matrix tablets of vildagliptin6/12/2012
  • 28. The λmax of vildagliptin was 245 nm.6/12/2012
  • 29. Calibration curve with pH 6.8 phosphate bufferS.No Concentration(μg/ml)Absorbance1. 0 02. 2 0.1893. 4 0.3754. 6 0.5395. 8 0.7566. 10 0.923Results of calibration curveR² = 0.99900.10.20.30.40.50.60.70.80.910 5 10 15absorbanceconcentration(μg/ml)6/12/2012
  • 30. Apparatus USP type II (Paddle)Type of medium Phosphate buffer pH 6.8Samplingtime intervals(hr)1, 4, 8, 12, 16, 20 & 24λmax 245nmIn-vitro Dissolution studies:Bowl Temperature - 37 CBath Temperature - 40 CStir speed - 50 rpm6/12/2012
  • 31. S.No Time(hr)F1 F2 F3 F4 F5 F6 F7 F81. 1 5.6±0.5 6.7±0.4 3.5±0.3 30.5±1 5.8±0.4 4.9±0.4 5.5±0.5 6.9±0.52. 4 32.2±1.3 28±1.1 19.9±0.8 65.1±1.2 30.1±1.4 23.9±1.1 30.7±1.4 28.4±1.13. 8 46.3±1.6 36.6±1.5 35.2±1.8 86.9±1.9 38.4±1.1 31.5±0.7 52.5±1.2 44.6±1.54. 12 55.2±0.8 49.6±1.9 42.4±1.3 95.4±0.6 49.3±1.1 38.9±1.2 69.1±1.8 58.9±1.15. 16 72.4±0.5 58±0.7 46.7±1.5 99±1.1 57±1 43.6±1.5 81.5±0.8 72.9±0.96. 20 80.8±2 67.2±0.8 50.1±1 - 66.7±1.9 57.5±0.8 99.4±0.8 87.5±0.67. 24 85.3±1.3 73.2±2.3 55.6±1.3 - 71.1±0.4 62.2±1.3 - 98.6±1Cumulative percentage drug release profile of all formulations6/12/2012n=3 , ±=S.D
  • 32. Graphs of Cumulative percentage drug releaseof all formulations6/12/201201020304050607080900 5 10 15 20 25 30%CDRTime(hrs)Cumulativedrug releaseof F1,F2,F3F1F2F3
  • 33. Order of drug release:Zero orderFirst orderR² = 0.9850204060801001200 10 20 30%OFDRUGRELEASETIME(Hr)R² = 0.81500.511.522.50 10 20 30Log%DRUGREMAINTIME(Hr)6/12/2012
  • 34. Mechanism of drug release:Higuchi Plot of Diffusion Kinetics :R² = 0.9940204060801001200 2 4 6DRUGRELEASE%SQUARE ROOT OF TIME(Hr)R² = 0.99000.511.522.50 0.5 1 1.5LOG%CDRLOG TIME (Hr)R² = 0.87301234560 10 20 30CUBEROOTOF%DRUGRELEASETIME(Hr)Korsemeyer peppas Diffusion kineticsHixon-crowell Diffusion kinetics6/12/2012
  • 35. SUMMARY•Eight formulations were developed by different grades of HPMC (K100 LV, K15M,K4Mand K100M) by wet granulation technique.•The preformulation studies like organoleptic properties, melting point were carried out.•The drug-excipients compatibility studies were conducted by using FTIR, there was nointeraction between drug and excipients.•The calibration curve was prepared in pH 6.8 phosphate buffer, the λmax was found tobe 245nm.•The developed formulations were evaluated for various pre-compression and post-compression parameters.•The invitro dissolution profile was conducted to all formulations.•Among all formulations,F8 was found to be the most suitable sustained releaseformulation.•The best linearity was found in zero order release and mechanism of release wasfitted to Higuchi diffusion.6/12/2012
  • 36. CONCLUSIONVildagliptin is used for the treatment and relief of diabetes mellitus-type II.Drug release from the matrix was found to depend on the combination ofpolymer concentration, where as the polymer concentration was employed from20-50%w/w of the average tablet weight.HPMC K100LV, HPMC K15M, HPMC K4M required to channelize the drug releasewas optimized to 95 to 99%.In conclusion, a stable sustained release matrix tablet formulation ofVildagliptin was successfully developed and in vitro drug release patternup to 24 hours.6/12/2012
  • 37. 1. Lee VHL, Controlled Drug Delivery Fundamentals and Applications: Introduction, MarcelDekker, (2nded) INC, and New York. 1987:29.2. Banker GS and Anderson NR. The Theory and Practice of Industrial Pharmacy: Tablet,Lachman, (3rded) Varghese Publishing House, Bombay, 1990, 293-303.3. John C and Morten C. The Science ofDosage Form Design, Aulton: Modified releaseperoral dosage forms, (2nded) Churchill Livingstone. 2002:290-300.4. Brahmankar DM and Jaywalk SB.Biopharmaceutics and Pharmacokinetics:Pharmacokinetics, (2nd ed) Vallabh Prakashan, Delhi, 2009, 399-401.5. Lee VHL. Controlled Drug Delivery Fundamentals and Applications: Influence of drugProperties on design, (2nded) Marcel Dekker, INC, New York. 1987:16-25.6. Ho WH and Lee HLV. Controlled Drug Delivery Fundamentals and Applications: Designand fabrication of oral controlled release drug delivery system, (2nded) MarcelDekker,INC, New York. 1987:373-420.BIBILOGRAPHY6/12/2012
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  • 39. 6/12/2012THANK YOU