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

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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

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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……….

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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……….

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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

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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

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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

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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

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Plasticizer

Glycerol

…PEG……

PG

……..

……….

……..

Glycerol

Final Formulation: HPMC E + PVA + Glycerol33

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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

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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

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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

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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

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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

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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

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Formulations

Formulations

Figure 3: Effect of Plasticizer on Folding Endurance

Figure 4: Effect of Plasticizer on DT

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Figure 6: Films of Different batches

41

Plasticizers

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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

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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

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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.

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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 … … … … … … … … …

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Figure 6: Dissolution profiles of formulations S1 TO S9

48

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% D R at 5 min = +92.38 -… * X1 – …* X2– …. X1*

X2 –0….. *X12+ 0…..* X2

2

(R2 = 0.9659)51

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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 ....

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