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Fast Dissolving Oral Film Of Donepezil HCl By Swapnil Patil
Citation preview
You Guided Me When I Was Lost….You Supported Me When I Was Weak….You Have Enlightened me all through…..
Sir,
9/05/20121
5 sept,2012
Introduction
Literature survey
Objectives
Plan of work
Materials And Methods Result and Discussions
Conclusion
References9/05/20123
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.
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Grittiness
Fragile / Brittle
Fear Choking
Pain / infection/inflammation
Large Dose Dosing accuracy
Stability
Microbial Cont.
WaterDysphagia,Travelling
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Alzheimers DiseaseIs an irreversible , progressive brain disease that slowly destroys memory & thinking skills and ability to carry out simple task.
Symptoms: serious memory loss, Confusion, Behavioral Changes, Difficulty in Speaking/Walking
Treatment: Mild to Moderate: Donepezil, Galantamine,rivastigmineSevere: Donepezil , Memantamine
Cause problems with memory, thinking,& Behavior
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Alzheimers Disease
Occurs to Geriatric
Patients
So,
Patient compliance is the Key
parameter while designing the DDS
Each and every day Patients has to take Dosage
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Problems with DDS
Conventiona
l Tab/Ca
p
D.T Liquids (Emulsion /Susp./Syrup
)
MDT FDF
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 Strength
X X X
Grittiness X X X X
Stability X X X X
Microbial Contamination
X X X X
Patient Compliance :
FDF>MDT> Conventional TAB/CAP and LiquidsX = No problems….DDS
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Alzheimer's 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 leader
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Donepezil Hydrochloride
Tab/MDT-Available in India
FDF- Not available in India
11
Sr AUTHOR TOPIC STUDY
1. Aggarwal J. et al1
A Comparative investigation on different polymers employed in the formulation oforal fast dissolving films
Polymers: HPMC E15; Gelatin, Sodium alginate and polyvinyl alcohol , pullulanHigher concentration of polymer and plasticizer resulted in increased disintegration time
2 Kunte S et al7 Fast dissolving strips: A novel approach for the delivery of verapamil
oral strips formulated with different concentrations of HPMC E6 and maltodextrin found to disintegrate in less than 30 seconds.
3 Dinge A. et al5 Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity
HPMC and xanthan gumsuccessfully taste masked by the use of poloxamer 407 and eugenol(HPBCD) to improve solubility of TC
9/05/201212
Sr AUTHOR TOPIC STUDY4 Raju S et al 19 Flash release oral films of
metoclopramide hydrochloride for pediatric use: formulation and in-vitro evaluation
HPMC , CMCThis case study showed that hydroxypropyl methyl cellulose was the 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 levocetrizine dihydrochloride
22 factorial designprepared by solvent casting method by using Maltodextrin & HPMC E15
6 Cilurzo F. et al4
Nicotine Fast Dissolving Films Made of Maltodextrins
The 'mint' and 'licorice' flavors and sucralose mixture resulted appropriate to mask DS bitternessTMAs did not significantly affect the film disintegration time and dissolution rate
Literature survey……….
9/05/201213
Sr AUTHOR TOPIC STUDY7 Choudhry et
al3Formulation and evaluation of quick dissolving Film of levocetirizine dihydrochloride
solvent casting technique carboxy methyl cellulose, hydroxy propyl methyl cellulose and hydroxy propyl cellulose. Neotame masked the bitter taste of levocetirizine dihydrochloride
8 Prabhu P. et al26 Formulation and evaluation of fast dissolving films of levocitirizine di hydrochloride
marked increase in the dissolution rate was exhibited by FDF of levocetirizine dihydrochloride containing HPMC as a polymer, when compared to conventional tablets.
9 Amin A et L 25 Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pullulan as a film forming agent
PullulanSolvent castingbitter taste masking was achieved by use of sweeteners- Aspartame, sucralose dissolution media namely 0.1N HCl and simulated saliva (500ml)
Literature survey……….
9/05/201214
Sr AUTHOR TOPIC STUDY10 Mashru et al24 Development and
Evaluation of Fast Dissolving Film of Salbutamol Sulphate
salbutamol sulphate and polyvinyl alcohol 33 factorial design Simulated saliva (300 mL) using USP Apparatus 2 (paddles).
11 Reinhart Martin et al9
Pivotal Bioequivalence study for Ondansetron Rapidfilm® successfully completed
On the basis of bioequivalence assessed in this pivotal study, therapeutic equivalence between Ondansetron RapidFilm™ and Zofran ODT® could successfully be demonstrated
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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
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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 tablets
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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
Drug - excipients compatibility study9/05/201220
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 9/05/201221
Name: (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one
Molecular weight: 415.95 Melting Point : 231-2320C 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
. HCL
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Sr. NoConcentration
(g/ml)Absorbance *
1 … …
2 … …
3 … …
4 … …
5 … …
6 … …
7 … …
8 … …
Calibration curve of Donepezil HCl in 0.1 N HCl
Parameter Range
Wave Length …….
Coefficient of Correlation
0.999
Intercept 0.0336
Equation Y= 0.0336x+0.024
9/05/2012* Represents mean value
25
Sr. NoConcentration
(g/ml)Absorbance*
1 … …
2 … …
3 … …
4 … …
5 … …
6 … …
7 … …
8 … …
Calibration curve of Donepezil HCl in Simulated saliva pH 6.8
Parameter Range
Wave Length …. nm
Coefficient of Correlation
0.9989
Intercept 0.031
Equation Y= 0.031x+0.0178
9/05/2012* Represents mean value
26
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Sr.
No.Name of the Ingredient Category Name of Manufacturer Company
1 Donepezil Hydrochloride Drug ……………
2 Pullulan Polymer …………….
3 HPMC E3,E5,E6,E15 Polymer…………….
4 Polyvinyl Alcohol Polymer ……………
5 Glycerol Plasticizer …………….
6 Sucralose Sweetener …………….29
Sr. No. Instrument
1 UV Visible spectrophotometer
2 FTIR spectrophotometer
3 Magnetic Stirrer
4 Dissolution apparatus
5 Micrometer Screw Gauge
6 Stability Chamber
9/05/201230
Sr. no. IngredientsPercentage amount (%) Examples
1 DrugDrug 1-231-23 Antialzheimers etcAntialzheimers etc
2 PolymerPolymer 40-5040-50HPMC,Pullulan, HPMC,Pullulan, Maltodextinn, Carbopol etcMaltodextinn, Carbopol etc
3 PlasticizerPlasticizer 25-3525-35 PG,PEG , SorbitolPG,PEG , Sorbitol
4 SweetenerSweetener 2-102-10 Sucralose, AspartameSucralose, Aspartame
5 FlavorFlavor 2-52-5Peppermint ,Peppermint , Vanilla,Coffee,Chocalate9/05/201231
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11 Polymers
Screening of polymers
ChitosanPullulan HPMC
(E3,E5,E6,E15)
PVA
…………..
X
…….
X (.:…………….)
E
(.:….)
PVA
Evaluated on the basis of
TransparencyFilm Forming
Capacity
HPMC E + PVA
……….. ………..
HPMC E3
HPMC E5
HPMC E6
HPMC E15
PULLULAN
POLYOX
WSR 1105
PVA
SODIUM
ALGINATE
PVP
CHITOSAN
GELATIN32
Polymers
9/05/2012
Plasticizer
Glycerol
…PEG……
PG
……..
……….
……..
Glycerol
Final Formulation: HPMC E + PVA + Glycerol33
9/05/2012
Polymer (2%
W/V)
E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11
HPMC E3 √
HPMC E5 √
HPMC E6 √
HPMC E15 √
PULLULAN √
POLYOX
WSR 1105
√
PVA √
SODIUM
ALGINATE
√
PVP √
CHITOSAN √
GELATIN √
D.W.
(…ml)
√ √ √ √ √ √ √ √ √ (0.1N HCL)
√
Table 1: Effect of the Different polymers on film forming capacity of film
34
9/05/2012
Sr No. Polymers Used*Film forming capacity
Appearance
1 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 - ----
Table 2: Evaluation of Films prepared by using Explored polymers
35
9/05/2012
Sr.No. Components P1 P2 P3 P4
1 Donepezil HCl (mg) … … … …
2 Pullulan (mg) … … … …
3 Glycerol (ml) … … … …
4 PEG 400 (ml) … … … …
5 PG (ml) … … … …
6 D.W. (ml) … … … …
Table 3: Preparation of Trial batches with Pullulan Table 4: Preparation of Trial batches with Chitosan
Sr.No. Components C1 C2 C3 C4
1 Donepezil HCl (mg)
2 Chitosan (mg)
3 Glycerol (ml)
4 PEG 400 (ml)
5 PG (ml)
6 0.1N HCl (ml)
Table 5: Preparation of Trial batches with PVA
Sr.No Components V1 V2 V3 V4
1 Donepezil HCl (mg) … … … …
2 PVA (mg) … … … …
3 Glycerol (ml) … … … …
4 PEG 400 (ml) … … … …
5 PG (ml) … … … …
6 D.W. (ml) … … … …
Table 6: Preparation of Trial Batches with HPMC E series polymer
Sr.No. Components E1 E2 E3 E4
1Donepezil HCl
(mg)… … … …
2 HPMC E3(mg) … … … …
3 HPMC E5(mg) … … … …
4 HPMC E6(mg) … … … …
5 HPMC E15(mg) … … … …
6 D.W.(ml) … … … …36
9/05/2012
Sr No.
Formulations
Film forming capacity
Appearance Disintegration Time *(sec)
Remark
1 P1 Best Transparent++
… …
2 P2 Best Transparent++
… …
3 P3 Best Transparent++
… …
4 P4 Good Transparent++
… …
Table 7: Evaluation of Trial Batches of Pullulan/Chitosan/PVA/HPMC E Series Films*All values are mean ± SD, (n=3)
Sr No.
Formulations
Film forming capacity
AppearanceDisintegration Time
(sec)*Remark
1 C1 Average
2 C2 Average
3 C3 Average
4 C4 Average
Sr No.
Formulations
Film forming capacity
Appearance
Disintegration Time (sec)*
1 V1 Good … …
2 V2 Good … …
3 V3 Average … …
4 V4 Average … …
Sr No.
Formulations
HPMC grades used
Film formi
ng capac
ity
Appearance
Disintegration Time (sec)*
1 E1 E3
2 E2 E5
3 E3 E6
4 E4 E1537
9/05/2012
Figure 1: The comparative study of M1 to M5 formulation
Figure 2: Dissolution profiles of formulations containing HPMC E and PVA
38 Formulations
Sr.No. Components M1 M2 M3 M4 M5
1 Donepezil HCl (mg) … … … … …
2 HPMC E(mg) … … … … …
3 PVA(mg) … … … … …
4 D.W.(ml) … … … … …
Table 8: Preparation of Trial Films using combinations of HPMC E and PVA
9/05/2012
Sr.No. Components R1 R2 R3 R4 R5 R6 R7 R8
1 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 10: Preparation of trial films using combinations of HPMC E and PVA with different plasticizer
39
Sr No.
Formulations
Appearance Disintegration time (sec)*
Thickness (mm)*
Folding endurance*
1 R1 Transparent … … …2 R2 Transparent … … …3 R3 Transparent … … …4 R4 Difficult to remove … … …
5 R5 Transparent … … …6 R6 Transparent … … …7 R7 Transparent … … …8 R8 Difficult to remove … … …
Table 11: Evaluation of Trial Films of HPMC E and PVA with different plasticizer
9/05/201240
Formulations
Formulations
Figure 3: Effect of Plasticizer on Folding Endurance
Figure 4: Effect of Plasticizer on DT
9/05/2012
Figure 6: Films of Different batches
41
Plasticizers
9/05/201242
Components S1 S2 S3 S4 S5 S6 S7 S8 S9
Donepezil HCl
(mg)… … … … … … … … …
HPMC (mg) … … … … … … … … …
PVA(mg) … … … … … … … … …
Glycerol (ml) … … … … … … … … …
Sucralose (mg) … … … … … … … … …
D.W.(ml) … … … … … … … … …
** Area of the Final film- 2cm X 2cm *** Dose of drug per film- 5 mg 9/05/201243
9/05/2012
Table 12: Evaluation Parameter of Factorial Batches of Fast Dissolving Oral Films
Formulation
CodeAppearance
Weight of the film (mg)*
Thickness
(mm)#
Surface pH*
Folding Endurance
*
S1 … … … … …
S2 … … … … …
S3 … … … … …
S4 … … … … …
S5 … … … … …
S6 … … … … …
S7 … … … … …
S8 … … … … …
S9 … … … … …44
9/05/2012
Formulation
Code
Tensile strength
(N/mm 2)
Disintegration
Time (sec)
Drug content per film (2 x
2cm)
(mg)
S1 … … …
S2 … … …
S3 … … …
S4 … … …
S5 … … …
S6 … … …
S7 … … …
S8 … … …
S9 … … …
Table 13 : Evaluation of Factorial Batches of Fast Dissolving Oral Films
45
Time (min) Cumulative % drug release*
0.1 N HCl Simulated saliva (pH6.8)
1 … …
2 … …
3 … …
4 … …
5 … …
9/05/2012Figure 5: Dissolution profiles of S4 formulations in 0.1 N HCl and in simulated saliva.
46
9/05/2012
Table 14: Dissolution data of factorial batches of fast dissolving oral films
TIME
(Min)
Cumulative % Drug Release
S1 S2 S3S4
S5 S6 S7 S8 S9
1 … … … … … … … … …
2 … … … … … … … … …
3 … … … … … … … … …
4 … … … … … … … … …
5 … … … … … … … … …
7 … … … … … … … … …
10 … … … … … … … … …
15 … … … … … … … … …
47
9/05/2012
Figure 6: Dissolution profiles of formulations S1 TO S9
48
9/05/201249
9/05/201250
9/05/2012
% D R at 5 min = +92.38 -… * X1 – …* X2– …. X1*
X2 –0….. *X12+ 0…..* X2
2
(R2 = 0.9659)51
9/05/201252
9/05/201253
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 films
9/05/201254
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) :1740-1749
4. 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: 94–107
7. Kunte S., Tandale P., Fast dissolving strips: A novel approach for the delivery of verapamil , J Pharm Bioallied Sci. , 2010; 2(4): 325–328
8. Margareth R. C. , Raimar L., May A., Simulated biological fluids with possible application in dissolution testing, Dissolution Technologies 18(3):15–28
9. Reinhart M. , Pivotal Bioequivalence study for Drug Rapidfilm® successfully completed , Labtec_Press Release_Dummy.rtf dated on 01/14/08
9/05/201255
10. Tripathi K.D. , Essentials of medical pharmacology, 5th ed., Jaypee Brothers Medical Publishers ,2009:84,337-340
11. www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?PrintAll=1
12. www.aricept.com/13. www.drugbank.ca/drugs/DB0084314. www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/
donepezilhydrochloride.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, 5th
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.
9/05/201256
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):636-646
20. 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):1322-1325
21. 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): 102-109
23. 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) : 25–34
25. 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 levocitirizine
9/05/201257
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 :1,3
3.……………………………………………………………………………………communicated to AAPS PharmSciTech.
9/05/201258
9/05/2012
Now…..May be Donepezil is available in FD Films
Thank You ....
59