Subscribe to commentsPost CommentMouth dissolving film pdfDocument Transcript1. Udhan Ravindra Radhakisan et al. IRJP 2012...
FORMULATION 6-18 Country Patent Title Inventorin the late 1970s asan alternative to conventional dosage Numberforms for pe...
sensitive.GENERAL PROPERTIES AND RELEASE COMPOSITIONOF MOUTH DISSOLVING FILM19MECHANISM A typical compositionof mouth diss...
smaller Metoclopramide Anti-emetic amounts of aqueous solvent usinga high-shear processor Ambroxol hydrochloride Mucolytic...
JP15these synthetic sweeteners carry a disadvantage of after taste(Japanese pharmacopoeia) . AV for JP15 was calculatedeff...
at Failure X 100 / Strip Thickness X width5. Percent ElongationWhenstress is applied, a strip sample stretches and this is...
employed. REFERENCES11. Assay/drug content and contentuniformity 1. Hideaki Okabe, Development of an easily swallowed thin...
7132113B2, November 7,2006. 26. Vasisht Niraj et al,Single dosepharmacokinetic of fentyl buccal soluble11. R. Kupper, M. S...
2011.pdf,Technology catalyst.[Cited 2012 Aug 02] Drug DeliverySystem and Dosage Form. International Journal of Chem. 35.Na...
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  1. 1. Subscribe to commentsPost CommentMouth dissolving film pdfDocument Transcript1. Udhan Ravindra Radhakisan et al. IRJP 2012, 3 (9)INTERNATIONAL RESEARCH JOURNAL OF PHARMACYwww.irjponline.com ISSN 2230 – 8407 Review Article MOUTHDISSOLVING FILM AND THEIR PATENT: AN OVERVIEW UdhanRavindra Radhakisan*, Vijayalaxmi Chavan, Nitin TribhuvanDepartment of Shri Bhagwan College of Pharmacy, Aurangabad,Maharashtra, India Article Received on: 06/07/12 Revised on: 11/08/12Approved for publication:08/09/12*Email:ravi.udhan403@gmail.comABSTRACTNow days theresearchers are focusing on the fast dissolving dosage form(FDDF’s).The fast dissolving dosage forms includes the mouthdissolving tablets,mouth dissolving thin films .The alternative wordsused for these dosage forms are fast disintegrating, orodispersible, fastdissolving. The oral thin filmtechnology (OTF’s) is a dissolvable filmtechnology have evolved from a purely confectionery novelty from adrug delivery platform. The OTH dosage formdissolves in the mothwithout need of water and within 10-15 seconds is the novelty of thisdosage form. On the basis of this novelty many patents areavailable inthe US country. Intraoral delivery is particularly beneficial to patientswith special needs that are unable to tolerate traditional oral(entral/throughGI track) administration due to nausea, vomiting ordysphasia. Many pharmaceutical companies focusing on this Oral thinfilm technology. Today, this filmtechnology is approved by is approvedby FDA.Keywords: Oral Thin Film, Pullulan, FoldingEnduranceINTRODUCTION PATENTS ON MOTH DISSOLVING FILMRELATEDFast-dissolving drug-delivery systems were first developed
  2. 2. FORMULATION 6-18 Country Patent Title Inventorin the late 1970s asan alternative to conventional dosage Numberforms for pediatric andgeriatric patients who experience US 5948430 Water soluble film fororal Zerbe et al.difficulties in swallowing traditional oral solid-dosageadministration with instantforms1. These films are made up of the watersoluble polymer wettability US 6159498 Bioerodable film for deliveryTapolsky et al.which when placed on the tongue instantly dissolves orof pharmaceuticaldisintegrate the medication without need of water.These compounds of mucosalfilms are suitable for the pediatricpatients and avoids nausea, surfacesvomiting or dysphasia caused dueto oral administration of US 6596298B2 Fast dissolving orally Leung etal. consumable filmtraditional dosage forms2.The evolution of thin filmdosage US 6824829B2 Process for manufacturing Berry et al.forms aredescribed in figure:1 form confectionary use to thin film stripcurrentpharmaceutical application3. US 7132113B2 Flavored film Zerbe etsl.TYPES OF MOUTH DISSOLVING FILM US 7182964B2 Dissolvingthin fim xanthone Kupper et al.A. Flash release film. suppliment US7241411B2 Thin film strip Berry et al.B. Flash Dispersible film. US7267718B2 Pullulan film composition Scott et al.C. Non-disintegratingmucoadhesive films. US 7347985B2 Breath freshening and oralMaxwell et al.D. Medium disintegrating mucoadhesive films. cleansingproduct withAdvantages4 magnolia bark extracta) No special training isrequired for the administration of US 7579019B2 Pharmaceuticalcarrier Tapolsky et al. device suitable for delivery dosage form. ofpharmaceuticalb) No need of water, drug wet by saliva and instantlycompounds to mucosal dissolves or disintegrates. surfacec) Availabilityof larger surface area for drug absorption. US 1648712B2 Fastdissolving orally Bess et al. consumable film containingd) Destructiveacidic environment effect of stomach can be taste masking agentavoided US 7946296B2 Dissolvable tobacco film Wren et al.e) Sitespecific and rapid onset of action. strip and method of makingf) Drugenters systemic circulation with reduced hepatic the same first passeffect. US 4136145 Medicament carriers in the Fuchs et al. form of filmhaving activeDisadvantage substance incorporated therea) Higherdoses cannot be incorporated. inb) These dosage forms are moisture
  3. 3. sensitive.GENERAL PROPERTIES AND RELEASE COMPOSITIONOF MOUTH DISSOLVING FILM19MECHANISM A typical compositionof mouth dissolving film containThe Quick-DisTM drug delivery systemcomprises a thin, following polymer.printable, low-moisture, non-tackyfilm that is convenient fordosing, suitable for labeling, and flexible foreasy packing, Composition Concentrationhandling and application.These films are 1-10mm in Drug 1-25% Water soluble polymer (filmforming agent) 40-50%thickness and having total surface area about 1-20 cm2.These Plasticizers 0-20%thin films when comes in contact withthe saliva rapidly Fillers, colours, flavours 0-40%hydrates and breaksafter softening release the medicaments.The typical disintegration timewhen comes in contact withthe water is about 1-30 seconds5. Page 392. Udhan Ravindra Radhakisan et al. IRJP 2012, 3 (9)Activepharmaceutical ingredients bezthonium chloride, tweens etc. One ofthe most importantThe API used in formulation of the film is in thepercentage surfactant is polaxamer 407 that is used as solubilizing,ofthe 1-25% with small dose. The micronized API is best wetting anddispersing agent33.suitable candidate for the formulation of the thin filmwhich Colouring agentsimproves dissolution rate and uniformity in thefilm20. For Pigments such as Titanium dioxide or FD & Capprovedpoorly water insoluble drugs the film is prepared by colouringagent are incorporated (not exceedingincreasing solubility bycomplexation with various concentration of 1% w/w) insolution.cyclodextrin. The poloxamer 407 is surfactant used to ORALFILM MANUFACTURING METHODS34increase solubility with thiscomplexes21. Following are some The oral film manufacturing processincludesdrug candidate which are used in mouth dissolving film 1.Solvent Casting Methodformulation22-26. 2. Hot –Melt Extrusion 3.Solid Dispersion Extrusion Drug Molecule Category 4. Rolling MethodRofecoxib NSAID 1. Solvent Casting Method Cetrizine hydrochlorideAnti-histaminic The steps in involved solvent casting method areEtophyline Bronchodilator Montelukast sodium Asthma/Allergic rhinitisØ Water-soluble hydrocolloids (polymer) are dissolved to MeclizineHydrochloride Anti-histaminic form a homogenous viscous solutionFentanyl Analgesic Ø API and other ingredients are dissolved in
  4. 4. smaller Metoclopramide Anti-emetic amounts of aqueous solvent usinga high-shear processor Ambroxol hydrochloride Mucolytic Agent Ø Theentrapped air is removed from the viscous solution by vacuumFilmforming Agents: Ø Coated on a non-treated casting filmFilm formingagents are water soluble polymers which are Ø Sent to aeration-dryingoven and subsequently woundused in formulation of thin film. Theseare HPMC E5, HPMC onto roll stock.E15, HPMC E50, MicrocrystallineCellulose, gelatin Ø As described in Figure2Polyvinyl alcohol, Gelatin,Eudragit, Maltodextrin, Pullulans 2. Hot Melt Extrusion27 . Ø The APIand other ingredients are mixed in a dry statePlasticizers Ø Filled in thehopperThe plasticizers are used in the formulation of mouth ØConveyed, mixed, and melted by the extruderdissolving film to increasethe flexibility by reducing the Ø After being subjected to the heatingprocess and extrudedglass transition temperature of the film. Improperuse of out in a molten state, a die then shapes the melt intheplasticizers may affect the mechanical properties of the film.required film form.The commonly used plasticizers are PEG 400,Glycerol, Ø As described in Figure 3.Propylene Glycol, Acetyl citratecastor oil etc 28. 3. Rolling methodSweetening agents In rolling methodsolution or suspension containing drug isThe sweetening agent used informulation of mouth rolled on carrier. The solvent is mainly water andmixture ofdissolving film is used for the purpose of taste masking ofwater and alcohol. The film is dried on rollers (Fig:4)and cutsome bitterdrug and good mouth feel. The commonly used into desired shape andsizes 35.sweetening agents are Fructose, Sucrose, Maltose, Neotame,EVALUATION TEST FOR MOUTH DISSOLVINGAspartame, Mannitol,Sorbitol, Glucose 29. Neotame and FILM36-38Aspartame is sweeterthan sucrose. Acesulfame-K and 1. Uniformity of dosage units of thepreparationsucralose have more than 2000 and 8000 times sweeteningThe uniformity of dosage units of the oral film preparationpower ascompared to sucrose. Rebiana which is an herbal was tested using 20preparations, and the content of drug wassweetener, derived from plantstevia rebaudiana(south determined by analytical method. Theacceptance value (AV)African plant) has more than 200-300 timesweetness but of the preparation is less than 15%, according to the
  5. 5. JP15these synthetic sweeteners carry a disadvantage of after taste(Japanese pharmacopoeia) . AV for JP15 was calculatedeffect whichcan be reduced by mixing or blending the according to the followingEq.natural and synthetic sweeteners. The amalgation ofAV=[M−X]+kssweeteners may lead to synergism and improvement inof the where M is label claim (100%), X is the average (%)offormulation 30. individual contents, k is the acceptability constant(2.2), s isSaliva stimulating agents31-32 the standard deviation. InUSP27, the contents of majorThe purpose of using saliva stimulatingagents is to increase component in the preparation should be within arangethe rate of production of saliva that would aid in the fasterbetween 85% and 115% and the relative standarddeviationdisintegration of the rapid dissolving strip formulations. shouldbe less than or equal to 6.0%.Generally acids which are used in thepreparation of food can 2. Thicknessbe utilized as salivary stimulants.Citric acid, malic acid, The thickness of strip can be measured bymicrometer screwlactic acid, ascorbic acid and tartaric acid are the fewgauge at different strategic locations. This is essential toexamples ofsalivary stimulants, citric acid being the most ascertain uniformity in thethickness of the film as this ispreferred amongst them. These agentsare used alone or in directly related to the accuracy of dose in thestrip.combination between 2 to 6%w/w of weight of the strip. 3. TacktestsSurfactant Tack is the tenacity with which the strip adheres toanSurfactants are used as solublising or wetting or dispersingaccessory (a piece of paper) that has been pressed intoagent so thatthe film is getting dissolved within seconds and contact with the strip.The alternative name for this test isrelease active agent immediately.Some of the commonly dryness test. With help of this test film ischecked for dry toused are sodium lauryl sulfate, benzalkoniumchloride, handle, dry to touch, dry to print, dry to recoat. Page 403. Udhan Ravindra Radhakisan et al. IRJP 2012, 3 (9) 4. Tensilestrength Figure: 1 Evolution of FilmTensile strength is the maximumstress applied to a point atwhich the strip specimen breaks. It iscalculated by theapplied load at rupture divided by the cross-sectionalarea ofthe strip as given in the equation below: Tensile Strength = Load
  6. 6. at Failure X 100 / Strip Thickness X width5. Percent ElongationWhenstress is applied, a strip sample stretches and this isreferred to asstrain. Strain is basically the deformation ofstrip divided by originaldimension of the sample. Generallyelongation of strip increases as theplasticizer contentincreases. %Elongation = Increase in length of strip x100 / Initial length of strip6. Tear resistanceTear resistance of plasticfilm or sheeting is a complex Figure: 2 Solvent Casting FilmSystemsfunction of its ultimate resistance to rupture. Basically verylowrate of loading 51mm (2 in.)/min is employed and isdesigned tomeasure the force to initiate tearing. Themaximum stress or force (thatis generally found near theonset of tearing) required to tear thespecimen is recorded asthe tear resistance value in Newton’s (orpounds-force).7. Young’s modulusYoungs modulus or elastic modulusis the measure ofstiffness of strip. It is represented as the ratio ofapplied stress Image Source: Particle Scienceover strain in the regionof elastic deformation as follows: Young modulus = Slope x 100 / stripthickness x cross- Figure: 3 Film Extrusion System head speedard andbrittle strips demonstrate a high tensile strength andYoungs moduluswith small elongation.8. Folding EnduranceFolding endurance isdetermined by repeated folding of thestrip at the same place till thestrip breaks. The number oftimes the film is folded without breaking iscomputed as thefolding endurance value. Image Source: ParticleScience9. Disintegration TimeThe disintegration time limit of 30 s orless for orally Figure: 4 Rolling Methoddisintegrating tablets describedin CDER guidance can beapplied to fast dissolving oral strips.Although, no officialguidance is available for oral fast disintegratingfilms/strips,this may be used as a qualitative guideline for qualitycontroltest or at development stage. Pharmacopoeial disintegratingtestapparatus may be used for this study. Typicaldisintegration time forstrips is 5–30 s.10. Dissolution TestDissolution testing can beperformed using the standardbasket or paddle apparatus described inany of thepharmacopoeia. The dissolution medium will essentiallybeselected as per the sink conditions and highest dose of theAPI.Many times the dissolution test can be difficult due totendency of thestrip to float onto the dissolution mediumwhen the paddle apparatus is
  7. 7. employed. REFERENCES11. Assay/drug content and contentuniformity 1. Hideaki Okabe, Development of an easily swallowed thinfilmThis is determined by any standard assay method describedformulation. International Journal of Pharmaceutics2008, (355):62–66.for the particular API in any of the standard pharmacopoeia. 2.Francesco C, Paola M, Andrea C Luisa M, Maltodextrin fast dissolvingfilm a feasibility study, [cited on 2012 June 08] Available from:Contentuniformity is determined by estimating the API www.tecnova-srl.it.content in individual strip. Limit of content uniformity is 85– 3.Sajay G, Advances in development, scale-up and manufacturingof115%. microbicide gels, films, and tablets. Antiviral research2010:19-29. 4. Nehal Siddiqui MD, Garg G, Sharma PK, A ShortReview on A Novel Approach in Oral Fast Dissolving Drug DeliverySystem and Their Patents. Advances in Biological Research2011; (5suppl 6): 291-303. 5. Quick dissolving films: A novel approach to drugdelivery, Development Technologies, 2003 ;( 3Suppl 3):1-7. [Cited on2012 Jan 17] Available from: http://www. drugdeliverytech.Com. Page414. Udhan Ravindra Radhakisan et al. IRJP 2012, 3 (9)6. H.Zerbe,J.Guo, Water soluble film for oral administration with instant 23. MishraR, Amin A, Formulation and Characterization of Rapidly wettability, USpatent 5948430, September 7, 1999. Dissolving Films of Cetirizinehydrochloride using Pullulan as a Film7. G.Tapolsky, D.Osborne,Bioerodable film for delivery of Forming. Ind J Pharm Edu Res 2011(45 Suppl 1):71-77. pharmaceutical compounds of mucosal surfaces,US patent number 24. Sapkal Nidhi et al, Development of fastdissolving oral thin films of 6159498, December 12,2000. ambroxolhydrochloride: Effect of formulation variables. Journal of8. S. Leung, R.Leone, L. Kumar, Fast dissolving orally consumable film, AdvancedPharmaceutical Research. 2011 (2 Suppl 2):102-109. US patent6596298B2, July 22,2003. 25. Raju S et al, Flash release oral films ofmetoclopramide hydrochloride9. C. Berry, W. Clauser, Process formanufacturing thin film strip, US for pediatric use: Formulation and in-vitro evaluation. J. Chem. Pharm. patent 6824829B2,Nov 23,2004.Res. 2011 (3Suppl 4):636-646.10. H. Zerbe, Flavored film ,US patent
  8. 8. 7132113B2, November 7,2006. 26. Vasisht Niraj et al,Single dosepharmacokinetic of fentyl buccal soluble11. R. Kupper, M. Smothers,Dissolving thin film xanthone supplement, US film. Pain Medicine 2010;11: 1017–1023. patent 7182964B2, February 27, 2007. 27. KulkarniAS, Deokule HA, Ghade DM, Exploration of different12. C. Berry, W.Clauser, Thin film strip, US patent 7241411B2,July 10, polymers foruse in the formulation of oral fast dissolving strips. Journal 2007. ofCurrent Pharmaceutical Research 2010 (2 Suppl 1): 33-35.13. R. Scott,D. Cade, X. He, Pullulan film composition, US patent 28. Gavaskar B,Overview On Fast Dissolving Films.Int J Pharmacy and 7267718B2,September 11,2007. Pharma Sci (2Suppl 3):152-165.14. J. Maxwell, M.Greenberg, Breath freshening and oral cleansing product 29. MahajanA, Chabra N, Aggarwal G, Formulation and Characterization withmagnolia bark extract, US patent 7347985B2, March 25, 2008. of FastDissolving Buccal Films: A Review. Scholars Research Library15.G.Tapolsky, D.Osborne, Pharmaceutical carrier device suitable for DerPharmacia Letter, 2011,( 3Suppl 1): 152-165. delivery ofpharmaceutical compounds to mucosal surface US patent 30. Rathi V,Senthil V, Kammili L, A Brief Review on oral film technology. number,US patent 7579019B2, August 25, 2009. IJRAP 2011 2(4):1138-1147.16. W. Bess, N. Kulkarni, S.Ambike ,M.Ramsay, Fast dissolvingorally 31. S. Sau-Hung, S Robert,Fast dissolving orally consumablefilms, US consumable film containing taste masking agent, US patentPatent 6,596,298 July 22, 2003. 71648712B2, January 19,2010. 32.Patel AR, Prajapati DS, Raval JA, Dissolving Films As A Newer17. S.Wrenn, M. Marun, Dissolvable tobacco film strip and method of VentureIn Fast Dissolving Dosage. J Drug Dev. & Res., April-June making thesame, US patent number,7946296B2,May 24,2011. 2010, 2(2):232-246.18. P.Fuchs, J.Hillmann Medicament carriers in the form of filmhaving 33. Saini S, Nanda A, Hooda M,Fast Dissolving Films (Fdf):Innovative active substance incorporated there in, US patent numberDrug Delivery System. Pharmacology online 2011 (2):919-928.4136145,Jannuary 13,1979. 34.http://www.pharmatek.com/pdf/PTEKU/PTEK-U_Jul14-19. Arun A,Amrish CV, Pathak SK, Dissolving Oral Films: An Innovative
  9. 9. 2011.pdf,Technology catalyst.[Cited 2012 Aug 02] Drug DeliverySystem and Dosage Form. International Journal of Chem. 35.Narasimha R, formulation and evaluation of rapidly dissolving buccalTech Research 2010; (2 Suppl1) 576-583. patches. InternationalJournal of Pharmacy and Biological Sciences20. Bhura N, Sanghvi K,Patel U,Parmar B, A Review On Fast Dissolving 2011 (1 Suppl 3):145-159. Film. IJRBS 2012 3:66-69. 36. Minako Nishigaki , Development ofFast Dissolving Film Containing21. Dinge A, Nagarsenker M,Formulation and Evaluation of Fast Dexamethasone as as AntiemeticMedication: Clinical Usefulness. Int J Dissolving Films for Delivery ofTriclosan to the Oral Cavity. AAPS of Pharmaceutics2012 421:12-17.PharmSciTech 2008 (9Suppl2):349-356. 37. Dixit RP, Puthil SP, OralStrip Technology: Overview and Future22. Kulkarni PK et al,Formulation and Evaluation of Mouth Dissolving Potential. Journal ofControlled Release 2009 139:94-107. Film Containing Rofecoxib. IRJP2011 (2 Suppl 3):273-278. 38. Prabhakara P, Formulation andEvaluation of Fast dissolving film of levocetirizine di hydrochloride.International Journal of Pharmaceutical Investigation 2011 (2 Suppl1):99-104. Source of support: Nil, Conflict of interest: NoneDeclaredIRJP is an official publication of Moksha Publishing House.Website: www.mokshaph.com. All rights reserved. Page 42

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