Fast Dissolving Oral Film Of Donepezil HCl By Swapnil Patil

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Fast Dissolving Oral Film Of Donepezil HCl By Swapnil Patil

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Fast Dissolving Oral Film Of Donepezil HCl By Swapnil Patil

  1. 1. 5 sept,2012Sir, You Guided Me When I Was Lost…. You Supported Me When I Was Weak…. You Have Enlightened me all through….. 1 9/05/2012
  2. 2.  Introduction  Literature survey  Objectives  Plan of work  Materials And Methods  Result and Discussions  Conclusion3  References 9/05/2012
  3. 3.  Definition:- Oral film It is relatively a new dosage form in which thin film is prepared using hydrophilic polymers rapidly dissolves on tongue or buccal cavity. Rapid onset of action and improved bioavailability. Useful for geriatric patients.4 9/05/2012
  4. 4. 5 9/05/2012
  5. 5. Fear Water Choking Dysphagia,Travelling Fragile / BrittleGrittiness Stability Microbial Cont. Pain / infection/inflammation Dosing accuracy 6 9/05/2012 Large Dose
  6. 6. Alzheimers Disease Is an irreversible , progressive brain disease that slowly destroys memory & thinking skills and ability to carry out simple task. Cause problems with memory, thinking,& Behavior Symptoms: serious memory loss, Confusion, Behavioral Changes, Difficulty in Speaking/Walking Treatment: Mild to Moderate: Donepezil, Galantamine,rivastigmine Severe: Donepezil , Memantamine7 9/05/2012
  7. 7. Alzheimers Disease Occurs to Geriatric Patients Each and every day Patients has to take Dosage So, Patient compliance is the Key parameter while designing the DDS 8 9/05/2012
  8. 8. Patient Compliance : Problems with Conven D.T Liquids MDT FDF DDS tional (Emulsion Tab/Ca /Susp./Syrup) p Water Needed X X X Swallow/Coughing X X X Choking Fear X X X Dosing Accuracy X X X X Vomisis X X Dysphagia X X X Travelling X X X Mechanical X X X Strength Grittiness X X X X Stability X X X X Microbial X X X X Contamination9 FDF>MDT> Conventional TAB/CAP and Liquids 9/05/2012 X = No problems….DDS
  9. 9. Alzheimers Disease 26.5 millions patients in 2006 Market $ 6 Billions in 2011 in 7 major markets Molecule available for mild to severe Alzheimer So, DONEPEZIl is the undisputed market leader10 9/05/2012
  10. 10. Tab/MDT-Available in India FDF- Not available in IndiaDonepezilHydrochloride 11 9/05/2012
  11. 11. Sr AUTHOR TOPIC STUDY1. Aggarwal J. et A Comparative investigation Polymers: HPMC E15; Gelatin, al1 on different polymers Sodium alginate and polyvinyl alcohol , employed in the formulation pullulan of Higher concentration of polymer oral fast dissolving films and plasticizer resulted in increased disintegration time2 Kunte S et al7 Fast dissolving strips: A oral strips formulated with different novel approach for the concentrations of HPMC E6 and delivery of verapamil maltodextrin found to disintegrate in less than 30 seconds.3 Dinge A. et al5 Formulation and Evaluation  HPMC and xanthan gum of Fast Dissolving Films for successfully taste masked by the use Delivery of Triclosan to the of poloxamer 407 and eugenol Oral Cavity (HPBCD) to improve solubility of TC 12 9/05/2012
  12. 12. Literature survey……….Sr AUTHOR TOPIC STUDY4 Raju S et al 19 Flash release oral films of  HPMC , CMC metoclopramide hydrochloride This case study showed that for pediatric use: formulation hydroxypropyl methyl cellulose was the and in-vitro evaluation most suitable film-forming material for metoclopramide -loaded films, providing fast dissolution films that were not sticky and were easy to handle.5 Saini S et al20 Fast dissolving film of 22 factorial design levocetrizine dihydrochloride prepared by solvent casting method by using Maltodextrin & HPMC E156 Cilurzo F. et Nicotine Fast Dissolving Films  The mint and licorice flavors al4 Made of Maltodextrins and sucralose mixture resulted appropriate to mask DS bitterness TMAs did not significantly affect the film disintegration time and 13 dissolution rate 9/05/2012
  13. 13. Literature survey……….Sr AUTHOR TOPIC STUDY7 Choudhry et al3 Formulation and solvent casting technique evaluation of quick carboxy methyl cellulose, hydroxy dissolving Film of propyl methyl cellulose and hydroxy levocetirizine propyl cellulose dihydrochloride . Neotame masked the bitter taste of levocetirizine dihydrochloride8 Prabhu P. et al26 Formulation and marked increase in the dissolution rate evaluation of fast was exhibited by FDF of levocetirizine dissolving films of dihydrochloride containing HPMC as levocitirizine di a polymer, when compared to hydrochloride conventional tablets.9 Amin A et L 25 Formulation and Pullulan characterization of Solvent casting rapidly dissolving films bitter taste masking was achieved by of cetirizine use of sweeteners- Aspartame, hydrochloride using sucralose pullulan as a film  dissolution media namely 0.1N HCl forming agent and simulated saliva (500ml) 14 9/05/2012
  14. 14. Sr AUTHOR TOPIC STUDY10 Mashru et al24 Development and salbutamol sulphate and polyvinyl Evaluation of Fast alcohol Dissolving Film of 33 factorial design Salbutamol Sulphate Simulated saliva (300 mL) using USP Apparatus 2 (paddles).11 Reinhart Martin et Pivotal On the basis of bioequivalence assessed al9 Bioequivalence study in this pivotal study, therapeutic for Ondansetron equivalence between Ondansetron Rapidfilm® RapidFilm™ and Zofran ODT® could successfully successfully be demonstrated completed 15 9/05/2012
  15. 15.  To formulate and evaluate oral fast dissolving films of Donepezil HCl To study compatibility of Donepezil HCl with excipients To study the effect of different polymers on film forming capacity and plasticizers on the release of Donepezil HCl To prepare the optimized oral fast dissolving film formulation of Donepezil HCl by response surface methodology, Design Expert software 16 9/05/2012
  16. 16. 17 9/05/2012
  17. 17. 18 9/05/2012
  18. 18. Usefulness Useful for geriatric patients Useful for uncooperative and admitted patients In travelling cases, Patients suffering from vomisis, Dysphagia patients : FDF is better than conventional tablets19 9/05/2012
  19. 19.  Literature survey Selection and procurement of drug and excipients Preformulation study including characterization of drugs Identification of the drug  Melting point  UV spectrum  FTIR spectrum  DSC study Calibration curve of Donepezil Hydrochloride in 0.1 N HCl and in Simulated saliva pH 6.8 by UV spectrophotometer20 Drug - excipients compatibility study 9/05/2012
  20. 20.  Formulation development of fast dissolving film Formulation design for selection and optimization of film forming polymer concentration Use of Factorial design for the formulation optimization of fast dissolving film of Donepezil Hydrochloride Evaluation of fast dissolving film Analysis of Factorial design results by Design Expert software 21 9/05/2012
  21. 21.  Name: (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy- 2,3-dihydroinden-1-one Molecular weight: 415.95 Melting Point : 231-2320C . HCL Bioavailability: 100 % Solubility: soluble in water MoA: centrally acting reversible acetyl cholinesterase inhibitor Use: in the treatment of Alzheimer’s disease where it is used to increase cortical acetylcholine Dose : 5 -10mg, Maximum dose : 23 mg 22 9/05/2012
  22. 22. 23 9/05/2012
  23. 23. 24 9/05/2012
  24. 24. ConcentrationSr. No Absorbance * Calibration curve of Donepezil (µg/ml) HCl in 0.1 N HCl 1 … … 2 … … 3 … … 4 … … 5 … … 6 … … 7 … … 8 … …Parameter RangeWave Length …….Coefficient of 0.999CorrelationIntercept 0.0336Equation 25 Y= 0.0336x+0.024 9/05/2012 * Represents mean value
  25. 25. ConcentrationSr. No Absorbance* Calibration curve of Donepezil (µg/ml) HCl in Simulated saliva pH 6.8 1 … … 2 … … 3 … … 4 … … 5 … … 6 … … 7 … … 8 … …Parameter RangeWave Length …. nmCoefficient of 0.9989CorrelationIntercept 0.031Equation 26 Y= 0.031x+0.0178 9/05/2012 * Represents mean value
  26. 26. 27 9/05/2012
  27. 27. 28 9/05/2012
  28. 28. Sr. Name of the Ingredient Category Name of Manufacturer CompanyNo.1 Donepezil Hydrochloride Drug ……………2 Pullulan Polymer ……………. …………….3 HPMC E3,E5,E6,E15 Polymer4 Polyvinyl Alcohol Polymer ……………5 Glycerol Plasticizer …………….6 Sucralose Sweetener ……………. 29 9/05/2012
  29. 29. Sr. No. Instrument 1 UV Visible spectrophotometer 2 FTIR spectrophotometer 3 Magnetic Stirrer 4 Dissolution apparatus 5 Micrometer Screw Gauge 6 Stability Chamber30 9/05/2012
  30. 30. Ingredient PercentagSr. no. e amount Examples s (%) 1 Drug 1-23 Antialzheimers etc HPMC,Pullulan, 2 Polymer 40-50 Maltodextinn, Carbopol etc 3 Plasticizer 25-35 PG,PEG , Sorbitol 4 Sweetener 2-10 Sucralose, Aspartame Peppermint , 5 Flavor 2-531 Vanilla,Coffee,Chocalate9/05/2012
  31. 31. Evaluated on theHPMC E3 basis of 11 Polymers Polymers TransparencyHPMC E5 Film FormingHPMC E6 Screening of polymers CapacityHPMC E15PULLULAN Chitosan PVA Pullulan HPMCPOLYOXWSR 1105 ………….. (E3,E5,E6,E15) (.:….) …….PVA PVA X (.:…………….)SODIUM XALGINATE EPVPCHITOSAN HPMC E + PVAGELATIN ……….. ……….. 9/05/2012 32
  32. 32. Plasticizer Glycerol PG …….. …PEG…… …….. ………. Glycerol Final Formulation: HPMC E + PVA + Glycerol33 9/05/2012
  33. 33. Table 1: Effect of the Different polymers on film forming capacity of filmPolymer (2% E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11W/V)HPMC E3 √HPMC E5 √HPMC E6 √HPMC E15 √PULLULAN √POLYOX √WSR 1105PVA √SODIUM √ALGINATEPVP √CHITOSAN √GELATIN √D.W. √ √ √ √ √ √ √ √ √ (0.1N √ 34 HCL) 9/05/2012(…ml)
  34. 34. Table 2: Evaluation of Films prepared by using Explored polymers *Film formingSr No. Polymers Used Appearance capacity1 HPMC E3 +++ Transparent2 HPMC E5 +++ Transparent3 HPMC E6 ++++ Transparent4 HPMC E15 +++ Transparent5 PULLULAN +++++ Very Transparent6 POLYOX WSR 1105 - ----7 PVA +++ Transparent8 SODIUM ALGINATE - ---9 PVP K30 + Semitransparent10 CHITOSAN +++ Transparent11 GELATIN - ----35 9/05/2012
  35. 35. Table 3: Preparation of Trial batches with Pullulan Table 4: Preparation of Trial batches with ChitosanSr.No. Components P1 P2 P3 P4 Sr.No. Components C1 C2 C3 C41 Donepezil HCl (mg) … … … … 1 Donepezil HCl (mg)2 Pullulan (mg) … … … … 2 Chitosan (mg)3 Glycerol (ml) … … … … 3 Glycerol (ml)4 PEG 400 (ml) … … … … 4 PEG 400 (ml)5 PG (ml) … … … … 5 PG (ml)6 D.W. (ml) … … … … 6 0.1N HCl (ml) Table 6: Preparation of Trial Batches with HPMC E Table 5: Preparation of Trial batches with PVA series polymerSr.No Components V1 V2 V3 V4 Sr.No. Components E1 E2 E3 E41 Donepezil HCl (mg) … … … … Donepezil HCl 1 (mg) … … … …2 PVA (mg) … … … … 2 HPMC E3(mg) … … … …3 Glycerol (ml) … … … … 3 HPMC E5(mg) … … … …4 PEG 400 (ml) … … … … 4 HPMC E6(mg) … … … …5 PG (ml) … … … … 5 HPMC E15(mg) … … … …6 D.W. (ml) … … … … 6 D.W.(ml) … … … … 36 9/05/2012
  36. 36. Table 7: Evaluation of Trial Batches of Pullulan/Chitosan/PVA/HPMC E Series Films *All values are mean ± SD, (n=3)Sr Formulatio Film Appearance Disintegra RemarkNo. ns forming tion Time Sr Film Disintegrat Formulati capacit *(sec) No forming Appearance ion Time Remark ons y . capacity (sec)*1 P1 Best Transparent … … 1 C1 Average ++2 P2 Best Transparent … … 2 C2 Average ++3 P3 Best Transparent … … 3 C3 Average ++4 P4 Good Transparent … … 4 C4 Average ++ Disinteg Sr Formula HP Film Appear Disinte Film N tions MC formi ance gration Sr Formul ration forming Appearance No. ations capacity Time o. grad ng Time (sec)* es capac (sec)* 1 V1 Good … … used ity 2 V2 Good … … 1 E1 E3 2 E2 E5 3 V3 Average … … 3 E3 E6 4 37 V4 Average … … 4 E4 E15 9/05/2012
  37. 37. Table 8: Preparation of Trial Films using combinations of HPMC E and PVA Sr.No. Components M1 M2 M3 M4 M5 1 Donepezil HCl (mg) … … … … … 2 HPMC E(mg) … … … … … 3 PVA(mg) … … … … … 4 D.W.(ml) … … … … … Figure 1: The comparative study of M1 to M5 Figure 2: Dissolution profiles of formulations formulation containing HPMC E and PVA 38 Formulations 9/05/2012
  38. 38. Table 10: Preparation of trial films using combinations of HPMC E and PVA with different plasticizerSr.No. Components R1 R2 R3 R4 R5 R6 R7 R81 Donepezil HCl(mg) … … … … … … … …2 HPMC E…(mg) … … … … … … … …3 PVA(mg) … … … … … … … …4 Glycerol (ml) … … … … … … … …5 PEG 400 (ml) … … … … … … … …6 PG (ml) … … … … … … … …7 D.W.(ml) … … … … … … … … Table 11: Evaluation of Trial Films of HPMC E and PVA with different plasticizerSr Formulation Appearance Disintegration Thickness FoldingNo. s time (sec)* (mm)* endurance*1 R1 Transparent … … …2 R2 Transparent … … …3 R3 Transparent … … …4 R4 Difficult to remove … … …5 R5 Transparent … … …6 R6 Transparent … … …7 R7 Transparent … … … 39 9/05/20128 R8 Difficult to remove … … …
  39. 39. Formulations Figure 3: Effect of Plasticizer on Folding Endurance Formulations40 Figure 4: Effect of Plasticizer on DT 9/05/2012
  40. 40. Plasticizers Figure 6: Films of Different batches41 9/05/2012
  41. 41. 42 9/05/2012
  42. 42. Components S1 S2 S3 S4 S5 S6 S7 S8 S9Donepezil HCl … … … … … … … … …(mg)HPMC (mg) … … … … … … … … …PVA(mg) … … … … … … … … …Glycerol (ml) … … … … … … … … …Sucralose (mg) … … … … … … … … …D.W.(ml) … … … … … … … … …** Area of the Final film- 2cm X 2cm***43 Dose of drug per film- 5 mg 9/05/2012
  43. 43. Table 12: Evaluation Parameter of Factorial Batches of Fast Dissolving Oral Films Formulation Thickness Folding Weight of the Surface Appearance Endurance Code film (mg)* (mm)# pH* * S1 … … … … … S2 … … … … … S3 … … … … … S4 … … … … … S5 … … … … … S6 … … … … … S7 … … … … … S8 … … … … … S9 … … … … … 44 9/05/2012
  44. 44. Table 13 : Evaluation of Factorial Batches of Fast Dissolving Oral Films Formulation Tensile strength Disintegration Drug content per film (2 x Code (N/mm 2) Time (sec) 2cm) (mg) S1 … … … S2 … … … S3 … … … S4 … … … S5 … … … S6 … … … S7 … … … S8 … … … S945 … … … 9/05/2012
  45. 45. Time (min) Cumulative % drug release* 0.1 N HCl Simulated saliva (pH6.8) 1 … … 2 … … 3 … … 4 … … 5 … … 46 9/05/2012Figure 5: Dissolution profiles of S4 formulations in 0.1 N HCl and in simulated saliva.
  46. 46. Table 14: Dissolution data of factorial batches of fast dissolving oral films Cumulative % Drug ReleaseTIME S4(Min) S1 S2 S3 S5 S6 S7 S8 S9 1 … … … … … … … … … 2 … … … … … … … … … 3 … … … … … … … … … 4 … … … … … … … … … 5 … … … … … … … … … 7 … … … … … … … … … 10 … … … … … … … … … 15 … … … … … … … … … 47 9/05/2012
  47. 47. Figure 6: Dissolution profiles of formulations S1 TO S9 48 9/05/2012
  48. 48. 49 9/05/2012
  49. 49. 50 9/05/2012
  50. 50. % D R at 5 min= +92.38 -… * X1 – …* X2– …. X1* X2 –0….. *X12+ 0…..* X22 (R2 = 0.9659) 51 9/05/2012
  51. 51. 52 9/05/2012
  52. 52. 53 9/05/2012
  53. 53.  The FTIR and DSC study revealed that, polymers and excipients used were compatible with drug. The Fast dissolving films were formulated using solvent casting technique. Amongst all the formulations, formulation containing HPMC E combine with PVA as film forming polymer has shown excellent in vitro disintegration time and in vitro cumulative percent drug release , compared to other formulations. Formulation………………………………………………………………… …………………….was considered as the best formulation. From above discussion, it can be concluded that the successful formation and optimization of fast dissolving films of Donepezil HCl using HPMC E and PVA. Hence Donepezil Hydrochloride can be conveniently administered orally in the form of films54 9/05/2012
  54. 54. 1. Aggarwal J, Singh G, Saini S., Fast dissolving films: A novel approach to oral drug delivery. Int Res J of Pharm, 2011; 2(12): 69-74.2. Arya A, Chandra A, Sharma V, Pathak K, Fast Dissolving Oral Films: An Innovative DrugDelivery System and Dosage Form, Int J of ChemTech Research, 2010; 2(1):576-583.3. Choudhary D.R., Patel V.A. , Kundawala A.J., Formulation and evaluation of quick dissolving Film of levocetirizine dihydrochloride , Int J Pharma Tech ,2011;3 (1) :1740-17494. Cilurzo F., Minghetti P., Buratti S., Selmin F., Chiara G.. Gennari ,  Montanari L., Nicotine Fast Dissolving Films Made of Maltodextrins: A Feasibility Study, AAPS PharmSciTech,2010.5. Dinge A and Nagarsenker M., Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity, Ame. Asso. of Pharma Scientists PharmSciTech. ,2008; 9(2): 349–356.6. Dixit R.P.,Puthli S.P., Oral strip technology: Overview and future potential , J of Cont Release, 2009 ;139: 94–1077. Kunte S., Tandale P., Fast dissolving strips: A novel approach for the delivery of verapamil , J Pharm Bioallied Sci. , 2010; 2(4): 325–3288. Margareth R. C. , Raimar L., May A., Simulated biological fluids with possible application in dissolution testing, Dissolution Technologies 18(3):15–289. Reinhart M. , Pivotal Bioequivalence study for Drug Rapidfilm® successfully completed ,55 Labtec_Press Release_Dummy.rtf dated on 01/14/08 9/05/2012
  55. 55. 10. Tripathi K.D. , Essentials of medical pharmacology, 5th ed., Jaypee Brothers Medical Publishers ,2009:84,337-34011. www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cf m?PrintAll=112. www.aricept.com/13. www.drugbank.ca/drugs/DB0084314. www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/donepezilhydrochlorid e.pdf15. www.mims.com/USA/drug/info/Donepezil%20Hydrochloride/Donepezil %20Hydrochloride%20Tablet,%20Film%20Coated?type=full16. Sau-hung S., Robert D., Lori, Fast dissolving orally consumable films, U.S. Patent 6,596,298, July 22, 2003.17. Rowe R., Sheskey P., Owen S., Handbook of Pharmaceutical Excipients, 5 th ed. The Pharmaceutical Press, Grayslake, American Pharmacists Association, Washington 2006, 5th ed, 301-303 ,346-349, 592-593, 742-743.18. Ozaki Y ,Nomoura T., Pullulan binder and its uses., U.S. Patent 5411945, May2, 1995.56 9/05/2012
  56. 56. 19. Raju S., Reddy P., Kumar V., Flash release oral films of metoclopramide hydrochloride for pediatric use: formulation and in-vitro evaluation, j. Chem. Pharm. Res., 2011;3(4):636-64620. Saini S., Nanda A., Dhari J., Formulation, development & evaluation of oral fast dissolving anti- allergic film of levocetrizine dihydrochloride , J. Pharm. Sci. & Res., 2011;3(7):1322-132521. Samita G., Kumar G., Fast dissolving drug delivery and its technologies. The Pharma Innovation ,2012; 1(2): 34-39.22. Sapkal N., Kilor V., Daud A., Development of fast dissolving oral thin films of ambroxol hydrochloride: Effect of formulation variables., J of Adv Pharma Res, 2011; 2(2): 102-10923. Gupta M, Patel M. Enhancement of Dissolution Rate of Rapidly Dissolving Film of Meclizine hydrochloride By Complexation of Meclizine Hydrochloride with beta Cyclodextrine.J of Applied Pharma Sci,2011;1(9):150-153.24. Mashru R.C., Sutariya V.B., Sankalia M.G., Parikh P.P,. Development and evaluation of fast dissolving film of salbutamol sulphate, Drug Dev Ind Pharm 2005 ; 31 (1) : 25–3425. Mishra R, Amin A. Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pullulan as a film forming agent, Ind J Pharm Edu Res ,2011; 45(1): 71-77.26. Prabhu P., Malli R., Koland M., Formulation and evaluation of fast dissolving films of levocitirizine57 9/05/2012
  57. 57. 1. Patil S. L*., Mahaparale P. R. , Fast Dissolving Oral Films: An Innovative Drug Delivery System, published in International Journal of drug discovery and medical research, 2012; 1 (1): 39-43.2 Patil S.L*., . Mahaparale P.R., Screening of the polymers for formulation of oral fast dissolving film, published in Inventi Rapid Pharm Tech, 2012 ; 1 :1,33. ……………………………………………………………………………… ……communicated to AAPS PharmSciTech.58 9/05/2012
  58. 58. Now…..May be Donepezil is available in FD Films59 Thank You ... . 9/05/2012

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