International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 3, Suppl 2, 2011

ReviewArticle

SUBLINGUALMUCOSAASAROUTEFORSYSTEMICDRUGDELIVERY
NEHANARANG1*,JYOTISHARMA2
ShriBabaMastnathInstituteofPharmaceuticalSciencesandResearch,AsthalBohar,Rohtak124001,InstituteofPharmaceutical Sciences,KurukshetraUniversity,Kurukshetra136119(Haryana),IndiaEmailnarangneha16@gmail.com, narang_neha2006@yahoo.com Received:07Nov2010,RevisedandAccepted:08Dec2010 ABSTRACT Drugdeliveryviatheoralmucousmembraneisconsideredtobeapromisingalternativetotheoralroute.Sublingualrouteisausefulwhenrapid onsetofactionisdesiredwithbetterpatientcompliancethanorallyingestedtablets.Intermsofpermeability,thesublingualareaoftheoralcavity (i.e.thefloorofthemouth)ismorepermeablethanthebuccal(cheek)area,whichinturnismorepermeablethanthepalatal(roofofthemouth) area. The portion of drug absorbed through the sublingual blood vessels bypasses the hepatic firstpass metabolic processes giving acceptable bioavailability. Various techniques can be used to formulate sublingual tablets. New sublingual technologies address many pharmaceutical and patientneeds,rangingfromenhancedlifecyclemanagementtoconvenientdosingforpaediatric,geriatric,andpsychiatricpatientswithdysphagia. This review highlights the different sublingual dosage forms, factors affecting the sublingual absorption, advantages, various in vitro and in vivo evaluationparametersandcommerciallyavailablesublingualdosageforms. Keywords:Sublingualdelivery,Oralcavity,Dysphagia,Improvedbioavailability INTRODUCTION Systemic drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect.Dysphagia(difficultyinswallowing)isacommonproblemof all age groups, especially elderly, children, and patients who are mentally retarted, uncooperative, nauseated or on reduced liquid intake/dietshavedifficultiesinswallowingthesedosageforms1,2. Sublingualadministrationofthedrugmeansplacementofthedrug under the tongue and drug reaches directly in to the blood stream throughtheventralsurfaceofthetongueandfloorofthemouth.The drugsolutesarerapidlyabsorbedintothereticulatedveinwhichlies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drainedintosystemiccirculation. The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane 3. The absorptionofthedrugthroughthesublingualrouteis3to10times greater than oral route and is only surpassed by hypodermic injection. For these formulations, the small volume of saliva is usuallysufficienttoresultintabletdisintegrationintheoralcavity. Sublingualabsorptionismostlyrapidinaction,butalsoshortacting in duration. Nitroglycerine, for example, is an effective antianginal drugbutisextensivelymetabolizedwhentakenorally(>90%).Itis rapidly absorbed through the sublingual mucosa, and its peak plasma level is reached within 12 min. Because of its short biological half life (35 min.), however the blood concentration of nitroglycerine declines rapidly to a level below the therapeutic concentrationwithin1015min. In terms of permeability, the sublingual area of the oral cavity is morepermeablethanthebuccal(cheek)area,whichinturnismore permeablethanthepalatal(roofofthemouth)area. Thedifferences in permeability are generally based on the relative thickness, the blood supply, and degree of keratinization of these membranes. In additiontothedifferencesinthepermeabilityofthevariousmucous membranes, the extent of drug delivery is also affected by the physicochemicalpropertiesofthedrugtobedelivered4. Sublingualproductshavebeendevelopedfornumerousindications ranging from migraines (for which rapid onset of action is important) to mental illness (for which patient compliance is important for treating chronic indications such as depression and schizophrenia)5. Sublingualglands Sublingual glands are also known as thesalivary glands which are present in the floor of mouth underneath the tongue. These glands produce mucin and help to promote the production of saliva. Because of the secretions of the glands, the interior area of the mouth is kept lubricated, which is necessary for chewing and swallowingfood. The lubrication and binding functions of the sublingual glands cannot be underestimated. A secretion from the glands mix with food as it is chewed, making the material slippery and easily swallowed. Because of the saliva content of the masticated food, it can move without difficulty into the throat and on to thedigestive tract. Low levels of saliva production can make the process of swallowing much more difficult and will increase the potential for food to lodge in the throat. Along with providing lubrication, these glandsalsoaidinthepromotionofgoodoralhygiene. Absorptionmeanstransferofdrugfromitssiteofadministrationto the systemic circulation, so it is obvious that absorption is directly proportionaltothemembranelayerthickness.Sublingual>Buccal >Gingival>Palatalhavingmucoseathicknessof100200,200,250, 500600micrometerrespectively.Becauseofthehighpermeability and the rich blood supply, the sublingual route is capable of producing a rapid onset of action which makes it an appropriate route for drugs with short delivery period and in frequent dosing regimen. The drug is released in to saliva and its subsequent spreadingmaycausethedrugtobeabsorbedacrosstheoralcavity6. Sublingualabsorption Sublingual, meaning literally 'under the tongue' refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. There is considerable evidence that most sublingual substances are absorbed by simple diffusion; the sublingual area acting rather likes litmus paper, readily soaking up the substances. However, not all substances are permeableandaccessibletooralmucosa. One of the best known drugs used regularly with great success is Glyceryltrinitrateapotentcoronaryvasodilatorwhichisusedfor the rapid symptomatic relief of angina. It has been found impressively effective when administered sublingually; pharmacologically active after only 1 2 minutes. The administration via an aerosol spray was found to provide rapid relief of symptoms, with firstclass metabolism. The extent of first

Narangetal. IntJPharmPharmSci,Vol3,Suppl2,2011,1822 classmetabolismwhencomparedtothesublingualspraydecreased to 48% with sublingual tablets and 28% with the oral dose. Following sublingual administration, nitrate appears in plasma concentrationscanbemaintainedfor24hours7. Sublingual Verapamil (a calcium channel antagonist prescribed for the management of angina, hypertension and certain supraventricular arrhythmias) was effective in controlling the ventricular rate following sublingual administration8. Experiments with some analgesics showed manytimes more rapid absorption from the mouth than the less lipidsoluble morphine. Impressive absorption has been attained with sublingual administration of desoxycortisone acetate, morphine, captopril, nifedipine and 17B Oestradiolinterestingly,ithasalsobeenshownthatthesublingual administrationof17BOestradiolrequiresonly1/4oftheoraldose. Mechanicsofsublingualabsorption The absorption potential of oral mucosa is influenced by the lipid solubility and therefore the permeability of the solution (osmosis); theionization(pH);andthemolecularweightofthesubstances.For example, absorption of some drugs via oral mucosa is shown to increase when carrier pH is lowering (more acidic) and decrease withaloweringofpH(morealkaline) 7,9. The cells of the oral epithelium and epidermis are also capable of absorbing by endocytosis (the uptake of particles by a cell as if by hollowly wrapping itself around it. These engulfed particles are usually too large to diffuse through its wall). It is unlikely that this mechanism is usedacross the entire stratifiedepithelium. Itis also unlikely that active transport processes operate within the oral mucosa. However, it is believed that acidic stimulation of the salivary glands, with the accompanying vasodilation, facilitates absorption and uptake into the circulatory system. The mouth is lined with a mucous membrane which is covered with squamous epithelium and contains mucous glands. The sublingual mucosal tissueissimilartothatofbuccalmucosa12. The salivary glands consist of lobules of cells which secrete saliva throughthesalivaryductsintothemouth.Thethreepairsofsalivary glandsaretheparotid,thesubmandibularandthesublingualwhich lies on the floor of the mouth. The more acid the taste, the greater thestimulationofsalivaryoutput;servingtoavoidpotentialharmto acidsensitive tooth enamel by bathing the mouth in copious neutralizingfluid. The sublingual artery travels forward to the sublingual gland, it suppliestheglandandbranchestotheneighboringmusclesandtothe mucousmembranesofthemouth,tongueandgums.Twosymmetrical branchestravelbehindthejawboneunderthetonguetomeetandjoin atitstip.Anotherbranchmeetsandanastomoseswiththesubmental branches of the facial artery. The sublingual artery stems from the lingual artery the body's main blood supply to the tongue and the floorofthemouthwhicharisesfromtheexternalcarotidartery.The proximity with the internal carotid artery allows fast access to its routesupplyingthegreaterpartofthecerebralhemisphere10,11. Osmosis Inorderforadrugtobeeffectivelyabsorbedsublingually,itneedsto beabletotravelacrossthebuccalmucousmembranes;byaprocessof diffusionknownasosmosiswhichappliestoallformsofabsorptionby the body; governing both intestinal and sublingual absorption. The distribution of water across cell walls depends on the osmotic difference in the blood between the intracellular and extracellular fluid. Small particles that readily dissolve in water, rarely present a probleminpermeationand diffusion, and so are ableto movefreely betweenthetissuesofthebody.Activetransportationintocellsleads to rapid metabolisation of the substances. Molecules such as glucose (fructose) and amino acids are essential for cell metabolism and specialmechanismshaveevolvedtofacilitatetheirrapiddiffusionand permeationacrosscellmembranes11. Drugsforsublingualadministration Medically, sublingual drug administration is applied in the field of cardiovascular drugs, steroids, some barbiturates and enzymes. It has beenadevelopingfieldintheadministrationofmanyvitamins andmineralswhicharefoundtobereadilyandthoroughlyabsorbed by this method. Sublingually absorbed nutrition, which avoids exposure to the gastric system and liver, means direct nutritional benefits, particularly important for sufferers of gastrointestinal difficulties such as ulcers, hyperactive gut, coeliac disease, those with compromised digestion, the elderly and invalids the nutritionalbenefitisindependentofgastrointestinalinfluences12,13. Examples of drugs administered by this route include antianginal likenitritesandnitrates,antihypertensivelikenifedipine,analgesics like morphine and bronchodilators like fenoterol. Certain steroids like estradiol and peptides like oxytocin can also be administered e.g. fentanyl citrate, apomorphine, prochlorperazine dimaleate {PRO},andhydrazineHCl{HYD}, Nobittertaste Doselowersthan20mg,e.g.nifedipine Smalltomoderatemolecularweight Goodstabilityinwaterandsaliva PartiallynonionizedattheoralcavitiespH Undergoingfirstpasseffecte.g.ketotifenfumarate Factorsaffectingthesublingualabsorption14 Lipophilicity of drug: For a drug to be absorbed completely through sublingual route, the drug must have slightly higher lipid solubility than that required for GI absorption is necessary for passivepermeation. Solubility in salivary secretion:Inadditiontohighlipidsolubility, the drug should be soluble in aqueous buccal fluids i.e. biphasic solubilityofdrugisnecessaryforabsorption. pH and pKa of the saliva:AsthemeanpHofthesalivais6.0,this pHfavorstheabsorptionofdrugswhichremainunionized.Also,the absorptionofthedrugsthroughtheoralmucosaoccursifthepKa is greaterthan2foranacidandlessthan10forabase. Binding to oral mucosa:Systemicavailabilityofdrugsthatbindto oralmucosaispoor. Thickness of oral epithelium: As the thickness of sublingual epithelium is 100200 m which is less as compared to buccal thickness. So the absorption of drugs is faster due to thinner epithelium and also the immersion of drug in smaller volume of saliva. Oiltowater partition coefficient: Compounds with favorable oil towaterpartitioncoefficientsarereadilyabsorbedthroughtheoral mucosa. An oilwater partition coefficient range of 402000 is consideredoptimalforthedrugstobeabsorbedsublingually. Advantages Arelativelyrapidonsetofactioncanbeachievedcomparedto theoralroute,andtheformulationcanberemovediftherapyis requiredtobediscontinued. Liverisbypassedandalsodrugisprotectedfromdegradation duetopHanddigestiveenzymesofthemiddlegastrointestinal tract Improved patient compliancedue to the elimination of associated pain with injections; administration of drugs in unconscious or incapacitated patients; convenience of administrationascomparedtoinjectionsororalmedications. Lowdosagegiveshighefficacyashepaticfirstpassmetabolism isavoidedandalsoreducestheriskofsideeffects. Thelargecontactsurfaceoftheoralcavitycontributestorapid andextensivedrugabsorption. Due to rapidity in action these sublingual dosage forms are widelyusedinemergencyconditionse.g.asthma. Rapid absorption and higher blood levels due to high vascularization of the region and therefore particularly useful foradministrationofantianginaldrugs. They also present the advantage of providing fast dissolution ordisintegrationintheoralcavity,withouttheneedforwater orchewing.

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Narangetal. IntJPharmPharmSci,Vol3,Suppl2,2011,1822 Disadvantages Sincesublingualadministrationofdrugsinterfereswitheating, drinking, and talking, this route is generally considered unsuitableforprolongedadministration. Although this site is not well suited to sustaineddelivery systems. Sublingual medication can not be used when a patient is uncooperativeorunconscious. The patient should not smoke while taking sublingual medication, because smoking causes vasoconstriction of the blood vessels. This will decrease the absorption of the medication. per I.P. Sublingual films were also evaluated for thickness using micrometer screw gauge18, tensile strength18, folding endurance19, surfacepH20,andswellingindex21. Disintegrationtime(DT) Arelativelysimplemethodwithrigorousconditionswasdeveloped to evaluate the DT of sublingual tablets. Each individual tablet was dropped into 10mL glass test tube (1.5cm diameter)containing 2 mL distilled water, and the time required for complete tablet disintegration was observed visually and recorded using a stopwatch. The visual inspection was enhanced by gently rotating thetesttubeata45oangle,withoutagitation,todistributeanytablet particlesthatmightmaskanyremainingundisintegratedportionof thetablets.IntheUSPdisintegrationtestforsublingualtablets,the disintegration apparatus for oral tablets is used without the coveringplasticdisks,22 and2minutesisspecifiedastheacceptable timelimitfortabletdisintegration23. Wettingtime(WT) Although a wetting test is not a USP standard test, it is useful for quality control and provides supportive evaluation of these sublingual tablets. Unlike the disintegration test, the wetting test uses minimal water, which may be more representative of the quantityofmoistureavailablesublingually.Usingthistest,thetime required for moisture to penetrate the tablet completely is measuredandpossiblyrepresentsthetimerequiredtoreleasedrug in the presence of minute volumes of saliva. Tablet WT was measuredbyaproceduremodifiedfromthatreportedbyBietal.24 The tablet was placed at the center of 2 layers of absorbent paper fitted into a rectangular plastic dish (11 cm 7.5 cm). After the paperwasthoroughlywettedwithdistilledwater,excesswaterwas completelydrainedoutofthedish.Thetimerequiredforthewater to diffuse from the wetted absorbent paper throughout the entire tabletwasthenrecordedusingastopwatch. Invivoevaluation Pharmacokineticdataanalysisandbioavailabilityevaluation Rabbits have been described as one of the few laboratory animals thatdonothavekeratinizedmucosa,thuscloselyresemblinghuman sublingualmucosaltissue25. The maximal plasma concentration (Cmax) and the time to reach maximum plasma concentration (Tmax) can be directly obtained from the plasma data. The area under the plasma concentration curve(AUC)canalsocalculatedusingthetrapezoidalruleand then thebioavailability. Permeationstudies Ex vivo permeation studies through porcine oral mucosa is carried outusingthemodifiedFranzdiffusioncellofinternaldiameterof2.5 cm. The buccal mucosa was excised and trimmed evenly from the sides and then washed in isotonic phosphate buffer of pH 6.6 and usedimmediately.Themembranewasstabilizedbeforemountingto removethesolublecomponents.Themucosawasmountedbetween the donor and receptor compartments. The receptor compartment wasfilledwith200mlofisotonicphosphatebufferofpH7.4which wasmaintainedat370.2oCandhydrodynamicsweremaintainedby stirringwithamagneticbeadat50rpm.Onefilmofdimension2cm X 2 cm and previously moistened with a few drops of simulated saliva. The donor compartment was filled with 1ml of simulated saliva of pH 6.8. Samples were withdrawn at suitable interval replacingthesameamountwithfreshmedium26, 27.Thepercentage ofdrugpermeatedwasdeterminedbymeasuringtheabsorbancein aUVVisiblespectrophotometer. Recentdevelopments Nitroglycerinedelivering sublingual aerosol formulation (nitroglycerine in propellants) in a metereddose spraying pump, Nitrolingual spray, was developed. It delivers nitroglycerine by spraying onto or under the tongue in the form of spray droplets, which ultimately increase the absorption and hence the bioavailabilityofnitroglycerine.Therapidonsetofactionisalways requiredincaseofhypertension. 20

Various types of sublingual dosage forms are available but tablets, films and sprays are in trends these days. For the preparation of these dosage forms different methods are described depends upon thefeasibilityandadvantagesovertheothers. Methodofpreparationofsublingualformulations Sublingualtablets Various techniques can be used to formulate sublingual tablets. Direct compression is one of the techniques which require the incorporationofasuperdisintegrantintotheformulation,ortheuse of highly watersoluble excipients to achieve fast tablet disintegration.Directcompressiondoesnotrequiretheuseofwater orheatduringtheformulationprocedureandistheidealmethodfor moisture and heatlabile medications. Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of tablet can easily exceed that of other production methods. Directly compressible tablet's disintegration and solubilization depends on single or combined action of disintegrats, water soluble excipients and effervescent agent. Disintegration efficacy is strongly affected by tablet size and hardness.Largeandhardtabletshavedisintegrationtimemorethan that usually required. As consequences, products with optimal disintegration properties often have medium to small size and /or highfriabilityandlowhardness15,16. Films Solventcastingisaprocesswhichcomprisesofcastingadopefrom a casting die onto a casting support, drying the cast dope on the casting support form film, stripping off the film from the casting support, and further drying the film while conveying the film with carrying it at both side edges of the film by a pin tenter, wherein residual volatile component content of both side edges of the film beingcarriedbythepintenterisfrom30mass%to320mass%of solid matter at the beginning of being cared by the pin tenter 17. Solvent Evaporation technique can also be used instead of solvent castingforthepreparationofsublingualfilms. Sublingualspraysarealsointrendwhichimprovesthetimetoreach maximum plasma concentration as compared to other types of sublingualdosageforms.E.g.incaseofoxycodone,maximumplasma concentrationsisreachedwithin20minuteswhencomparedwith immediate release oral tablets (1.3 hours), intramuscular (1 hour), andintranasaloxycodone(0.42hour)inhealthyvolunteers 8. InVitroandInVivoEvaluation Physicalevaluation All batches of sublingual formulations like tablets and films were evaluated for weight variation and drug content. But hardness and friability were calculated for tablets. As the hardness of sublingual tabletisimportantfactor,becauseifthesublingualtabletistoohard, the solvent borne drug attenuation may not be absorbed into an interior portion of the tablet and therefore remains on a surface portionofthetablet,wherethedrugattenuationmaynotadhereto the sublingual tablet. If the sublingual tablet is too soft, the sublingual tablet may be disintegrated by the solvent of the drug attenuation. Preferably, the solvent borne drug attenuation should be absorbed into the interior of the sublingual tablet. Weight variation test was conducted by selecting 20 tablets at random as

Narangetal. IntJPharmPharmSci,Vol3,Suppl2,2011,1822 CONCLUSION Recently many drugs have been formulated for sublingual drug delivery with an objective of rapid drug release and restricting the region of drug release to mouth. Compared to commonly used tablets,capsulesandotheroraldosageforms,sublingualabsorption is generally much faster and more efficient. Sublingual dosages are convenient for young children, the elderly and patients with

swallowing difficulties, and in situations where potable liquids are not available. Peak blood levels of most products administered sublingually are achieved within 1015 minutes, which is generally much faster than when those same drugs are ingested orally. Sublingualabsorptionisefficient.Thepercentofeachdoseabsorbed is generally higher than that achieved by means of oral ingestion. Varioustypesofsublingualdosageformsareavailableinmarketlike tablets,filmsandsprays.

Table1:Drugsusedintheformulationofsublingualdosageforms Drug Physostigminesalicylate Scopolamine Captopril Furosemide Nifedipine Nitroglycerine Vinpocetine Terbutalinesulphate Amlodipinebesylate OndansetronHydrochloride Salbutamolsulphate Category AntiAlzheimers Opioidanalgesic AntihypertensiveAgent Diuretic Antianginal Antianginal NeutropicAgent Bronchodilator Antihypertensive Antiemetic Antiasthmaticagent

Dosageform Tablet Spray Tablet Tablet Tablet Tablet Tablet Tablet Tablet Film Film

References 28 29 30 31 32 33 34 35 36 19 37

Table2:Somemarketedsublingualtablets BrandName Abstral Subutex Avitan Edular Isordil NicoretteMicrotab Lemon Suboxone Saphris ProhealthMelatonin Nitrostat Temgesic REFERENCES 1. Ishikawa T, Koizumi N, Mukai B. Pharmacokinetics of acetaminophen from rapidly disintegrating compressed tablet prepared using microcrystalline cellulose (PHM06) and spherical sugargranules. Chem PharmBull(Tokyo)2001; 49: 23032. PriceTM,BlauerKL,HansenM,StanczykF,LoboR,BatesGW. Singledose pharmacokinetics of sublingual versus oral administrationofmicronized17betaestradiol.ObstetGynecol 1997;89:34045. R.P Walton Absorption of drugs through the oral mucosa. III Fatwater solubility coefficient of alkaloids. Proc Soc Exp Bio Med1935;32:1488. KurosakiY,TakatoriT,NishimuraH,NakayamaT,KimuraT. Regional variation in oral mucosal drug absorption permeability and degree of keratinization in hamster oral cavity.PharmRes1991;8:12971301. Ghosh TK, Chatterjee DJ, Pfister WR. Quick dissolving oral dosage forms: Scientific and regulatory considerations from a clinical pharmacology and biopharmaceutical perspective. In: GhoshTKandPfisterWR(Eds).DrugDeliverytotheOralCavity MoleculestoMarket.NY,USA:CRCPress,2005:337356. Shojaie AH. Buccal mucosa as a route for systemic drug delivery:Areview.JPharmPharmSci1998;1(1):1530. RichmanMD,FoxD,ShangrawRF.Preparationandstabilityof glyceryl trinitrate sublingual tablets prepared by direct compression.JPharmSci1965;54(3):447451. JohnDN,FortS,LewisMJ,LuscombeDK.Pharmacokineticsand pharmacodynamicsofVerapamilfollowingsublingualandoral 9. 10. 11. 12. 13. 14. 15. 16. administrationtohealthyvolunteers.BrJClinPham1992;33: 623627. McElnayJC,AlFuraihTA,HughesCM,ScottMG,ElbornJS,Nicholls DP.TheeffectofpHonthebuccalandsublingualabsorptionof captopril.EurJClinPharmacol1995;48(5):373379. Mary Elizabeth RN, Martelli BS. Sublingual and buccal medicationadministration.EncyclopediaofNursingandAllied Health,20050229 LeaL.SublingualAdministration.ColonHealth1996;13 Boer D et al. Drug absorption by sublingual and rectal routes. BritishJAnaesthesia1984;56:6982. AlGhananeem AM, Malkawi AH, Crooks PA. Effect of pH on Sublingual Absorption of Oxycodone Hydrochloride.AAPS PharmSciTech2006;7(1):Article23. Katz M, Barr M. A study of sublingual absorption I. Several factors influencing the rate of adsorption. J Am Pharm Assoc AmPharmAssoc(Baltim)1955;44(7):419423. Allen LV. Rapiddissolve technology: an interview Int J Pharm Technol2003;7:449450. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste making and clinical studies. Crit Rev Ther Drug Carrier Syst 2004;21:433476. Weinberger M. Pharmacological management of Asthma. J AdolescentHealthCare1987;8(1):7483. Nafee NA, Boraie NA, Ismail FA, Mortada IM. Design and characterization of mucoadhesive buccal patches containing cetylpyridiniumchloride.ActaPharm2003;53:199212. KolandM,SandeepVP,CharyuluNR.Fastdissolvingsublingual films of ondansetron hydrochloride: effect of additives on in 21 Drug FentanylCitrate Buprenorphine Lorazepam Zolpidemtartrate Isosorbidedinitate Nicotinebitartrate Buprenorphinehydrochloride+ naloxone Asenapine Melatonin Nitroglycerine Buprenorphine Category OpioidAnalgesic OpioidAnalgesic Antianxiety Sedatives/ Hypnotics Vasodilators Narcotic+ Opioidantagonist Antipsychoticagent Hormone Antianginal OpioidAnalgesic Strength 50, 100,200,300,400,600,800g 2and8mg 1,2mg 5,10mg 2.5,510mg 2m 2/0.5,8/2mg 5,10mg 2mg 0.3mg(1/200grain),0.4mg(1/150grain),or0.6mg (1/100grain) 200g

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