An Overview on: Sublingual Route for Systemic Drug Delivery

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701can create problem in swallowing the food andpotential for food lodge in the throat increases.The absorption is transfer of the drug from its siteof administration into systemic circulation, so itcan be said that absorption is directly proportionallayer thickness. The absorption of the drug followsin this way Sublingual > Buccal > Gingival >Palatal. Due to high permeability and rich bloodsupply, the sublingual route can produce rapidonset of action so the drug with short deliveryperiod can be delivered and dose regimen isfrequent. The drug gets diluted in the saliva andfrom there the drug is adsorbed across the oralcavity.For example: Glyceryl nitrate-a potent coronaryvasodilator which is used for rapid symptomaticrelief of angina. After administration its getspharmacologically active after 1-2 minutes. Oralspray was found to provide rapid relief ofsymptom with first class metabolism. The extent offirst class metabolism when compared to thesublingual spray decreased to 48% with sublingualtablets and 28% with the oral dose. Nitrate whichappears in the plasma concentration can bemaintained for 24 hours when administratedsublingually 9 .The Mechanism of Sublingual AbsorptionThe absorption potential of the buccal mucosa isinfluenced by the lipid solubility and therefore thepermeability of the solution (osmosis), theionization (pH), and the molecular weight of thesubstances. For example, absorption of some drugsvia the buccal mucosa is shown to increase whencarrier pH is lowering (more acidic) and decreasewith a lowering of pH (more alkaline). The cells ofthe oral epithelium and epidermis are also capableof absorbing by endocytosis (the uptake of particlesby a cell as if by hollowly wrapping itself around it.These engulfed particles are usually too large todiffuse through its wall). It is unlikely that thismechanism is used across the entire stratifiedepithelium. It is also unlikely that active transportprocesses operate within the oral mucosa.However, it is believed that acidic stimulation anduptake into the circulatory system.The mouth is lined with a mucous membranewhich is covered with squamous epithelium andcontains mucous glands. The buccal mucosa issimilar to the sublingual mucosal tissue.The salivary glands consist of lobules of cellswhich secrete saliva through the salivary ducts intothe mouth. The three pairs of salivary glands arethe Parotid, the Sub mandibular and the Sublingualwhich lies on the floor of the mouth. The more acidthe taste the greater the stimulation of salivaryoutput, serving also to avoid potential harm to acidsensitive tooth enamel by bathing the mouth incopious neutralizing fluid. With stimulation ofsalivary secretion oxygen is consumed andvasodilator substances are produced, and theglandular blood flow increases, due to increasedglandular metabolism.The sublingual artery travels forward to thesublingual gland, it supplies the gland and branchesto the neighboring muscles and to the mucousmembranes of the mouth, tongue and gums. Twosymmetrical branches travel behind the jaw boneunder the tongue to meet and join at its tip. <strong>An</strong>otherbranches meets and anastomoses with the submental branches of the facial artery. The sublingualartery system stems from the lingual artery – thebody’s main blood supply to the tongue and thefloor of the mouth – which arises from the externalcarotid artery. The proximity with the internalcarotid artery allows fast access to its routesupplying the greater part of the cerebralhemisphereDrugs for sublingual administrationSublingual drug administration is applied in thefield of cardiovascular drugs, steroids, somebarbiturates and enzymes. It has been a developingfield in the administration of many vitamins andminerals which are found to be readily andthoroughly absorbed by this method. Sublinguallyabsorbed nutrition, which avoids exposure to thegastric system and liver, means direct nutritionalbenefits, particularly important for sufferers ofgastro‐intestinal difficulties such as ulcers,hyperactive gut, coeliac disease, those withcompromised digestion, the elderly and invalids –the nutritional benefit is independent ofgastro‐intestinal influences (10,11) . Examples of drugsadministered by this route include antianginal likenitrites and nitrates, anti hypertensive likenifedipine, analgesics like morphine andbronchodilators like fenoterol. Certain steroids likeestradiol and peptides like oxytocin can also beadministered e.g. fentanyl citrate, apomorphine,prochlorperazine dimaleate {PRO}, and hydrazineHCl {HYD}.Sublingual formulationSublingual tabletsThey are to be placed under the tongue and produceimmediate systemic effect by enabling the drugabsorbed directly through mucosal lining of themouth beneath the tongue. The drug absorbed fromstomach goes to mesenteric circulation whichconnects to stomach via portal vein. Thusabsorption through oral cavity avoids first passmetabolism. The tablets are usually small and flat,compressed lightly to keep them soft. The tabletmust dissolve quickly allowing the API to beabsorbed quickly. It is designed to dissolve in smallquantity of saliva. After the tablet is placed in themouth below the tongue, the patient should avoideating, drinking, smoking and possibly talking inVol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 915

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701order to keep the tablet in place. Swallowing ofsaliva should also be avoided since the saliva maycontain dissolved drug. Bland excipients are usedto avoid salivary stimulation. Various techniquescan be used to formulate rapidly disintegrating ordissolving tablets. (12,13) Direct compression is oneof these techniques which require incorporation ofa superdisintegrant into the formulation, or the useof highly water-soluble excipients to achieve fasttablet disintegration. Direct compression does notrequire the use of water or heat during theformulation procedure and is the ideal method formoisture and heat-labile medications.a) Fast disintegrating sublingual tablets (FDT)FDT is defined as a solid dosage form that containsmedicinal substances and disintegrates rapidly(within few seconds) without water when kept onthe tongue. The drug is released, dissolved, ordispersed in the saliva, and then swallowed andabsorbed across the GIT (14) . FDTs also are alsocalled as Orodispersible tablet, mouth-dissolving,quick-dissolving, fast-melt, and freeze-driedwafers. Tablets that disintegrate or dissolve rapidlyin the patient’s mouth are convenient for youngchildren, the elderly and patients with swallowingdifficulties and in situations where potable liquidsare not available. Direct compression is one of thetechniques which require the incorporation of asuperdisintegrant into the formulation, or the use ofhighly water soluble excipients to achieve fasttablet disintegration. Compared to conventionaldosage form the drug dissolution, its absorption aswell as onset of clinical action and itsbioavailability may be significantly greater (15-17) .Though chewable tablets are available in themarket, they are not same as the new FDTs.Patients for whom chewing is difficult or painfulcan use these FDTs. It can be used easily in infantsand in children who have lost their primary teethand who do not have full use of their permanentteeth (18) .Recent market studies indicate that more than halfof the patients prefers FDTs than otherconventional dosage forms (19) and most patientswould ask their doctors for FDTs (70%), purchaseFDTs (70%), or prefer FDTs than regular tablets orliquids (>80%) (20) . The US Food and DrugAdministration Center for Drug Evaluation andResearch (CDER) defines, in the „Orange Book ,an FDT as “a solid dosage form containingmedicinal substances, which disintegrates rapidlyin saliva, usually within a few seconds, whenplaced upon the tongue” (21). The implication ofthese dosage forms is emphasized by the term“Orodispersible Tablet”, by the EuropeanPharmacopoeia which defines it as a tablet that canbe placed in oral cavity where it disperses rapidlybefore swallowing (22) . FDTs has been developedfor numerous indications ranging from migraines(in which quick onset of action is necessary) tomental illness (in which patient compliance isnecessary for treating chronic indications such asmental depression and schizophrenia) (23) .b)Bioadhesive sublingual tabletsThe new sublingual tablet concept presented isbased on interactive mixtures consisting of a watersoluble carrier covered with fine drug particles anda bioadhesive component. With this approach, it ispossible to maintain rapid dissolution incombination with bioadhesive retention of the drugin the oral cavity. Bioadhesion is usually defined asthe bond formed between two biological surfacesor between a biological and a synthetic surface.Problem associated with sublingual tabletformulation is that there is always a risk that thepatient will swallow part of the dose before theactive substance has been released and absorbedlocally into systemic circulation. this could resultsan unwanted prolongation of the pharmacologicaleffect. Addition of a bioadhesive component is awell-known method of increasing the possibility ofa more site-specific release. However, this conceptis normally applied to non-disintegrating tablets ordisc to achieve extended release of the activesubstance and, consequently, such a system will notbe suitable for a fast acting formulation. Therefore,it would be of interest to study a disintegratingtablet which releases the drug quickly, but whichalso has bioadhesive properties which couldprevent the drug from being swallowed.Bioadhesion mechanismsThe mucus layer is often involved in the adhesionof a bioadhesive polymer and is present as either agel layer adhering to the mucosal surface or asolution or suspension of various substances. Themucus layer mainly consists of mucin glycoprotein,Vol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 916

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701inorganic salts, proteins, lipids and water with thecomposition varying depending on its source. Theelectronic theory involves an electronic transferbetween the two materials causing a double layerof electric charge, which results in attraction forces.The adsorption theory involves adhesion betweenthe mucosa and the adhesive material by van derwaals interaction, hydrogen bonds and relatedforces. The wetting theory involves interfacialtensions between the two materials. Penetration ofthe polymer chains into the mucus network andvice versa, causing a mechanical bond, is referredto as the diffusion theory. The importance of watercontent and movement of water into the adhesivematerial from the mucosa, i.e. dehydration of themucosa, has also been suggested as a mechanicalfor adhesion.Measurement of bio-adhesive strengthBio-adhesion strength of the tablets was measuredon a modified physical balance. The method usedbovine cheek pouch as the method mucosal andIPB ph 6.6 as the moistening fluid. The surface ofthe mucosal membrane was first blotted with afilter paper and then moistened with 25/L 1 of IPBpH 6.6. the weight in grams is required to detachthe tablets from the mucosal surface gave themeasure of bio-adhesive strength.c) Lipid matrix sublingual tabletsSuch tablets are formulated using advances insublingual and liposomal technology to create adosage form that offers a faster and more completeabsorption than traditional oral routes ofadministration. The lipid matrix sublingual tablet isa bioavailable, quick, convenient and consistentdosage form for many neutraceuticals that are oftentaken orally.For e.g., Glutathione MB12(methylcobalamin)melatonin.d) Sublingual vitamin tabletVitamin D i.e. cholecalciferol is a natural precursorof calcium regulating hormone calcitriol. VitaminD is thus used in hypocalcaemia/hyperparathyroidism. Because of its incompleteabsorption from GI tract, local intestinaldegradation and hepatic metabolism, it is givensublingually.2)Thin film drug deliveryThin film drug delivery is a process of deliveringdrugs of the systemic circulation via thin film thatdissolves when in contact with liquid, oftenreferred to a dissolving films or strips and dissolvewithin 1 min when placed in the mouth withoutdrinking or chewing.Such dissolving film or strip are typically designedfor oral administration, with the user placing thestrip on or under the tongue or along the inside ofthe cheek. Thin film’s ability to dissolve rapidlywithout the need for water provides an alternativeto patients with swallowing disorders and topatients suffering from nausea, such as thosepatients receiving chemotherapy.The first developed fast-dissolving dosage formconsisted in tablet form, and the rapiddisintegrating properties were obtained through aspecial process or formulation modifications 24 .More recently, fast-dissolving films are gaininginterest as an alternative to fast-dissolving tablets todefinitely eliminate patients’ fear of chocking andovercome patent impediments. Fast-dissolvingfilms are generally constituted of plasticizedhydrocolloids. Problems are caused by foamingduring the film formation due to the heating of thematerial or solvent evaporation, the flaking duringthe slitting and the cracking in the cutting phase.The films should be stable to moisture, facilitatethe handling, have to be flexible and exhibit asuitable tensile stress and do not stick to thepackaging materials and fingers.Film can be prepared by five method: 1) Solventcasting. 2)Semisolid casting. 3)Hot melt extrusion.4)Solid dispersion extrusion. 5) Rolling.1) Solvent casting methodFilm is formulated using the solvent castingmethod, whereby the water-soluble ingredients aredissolved to form a clear viscous solution. The APIand other agents are dissolved in smaller amountsof the solution and combined with the bulk. Thismixture is then added to the aqueous viscoussolution. The entrapped air is removed by vacuum.The resulting solution is cast as a film and allowedto dry, which is then cut into pieces of the desiredsize. 252)Semisolid castingSolution of water soluble film forming polymer ismixed with solution of acid insoluble polymerwhich forms homogenous viscous solution. Theratio should be 1:4. For e.g. cellulose acetatephthalate, cellulose acetate butyrate. It is thensonicated which is coated on non-treated castingfilm.3)Hot Melt ExtrusionIn present method the mass is prepared first underthe control of temperature and steering speed.Afterwards, the film is coated and dried in a dryingtunnel, once again the temperature, air circulationand line speed are controlled. Then follows aslitting and in the last step the films are punched,pouched and sealed. 264)Solid Dispersion ExtrusionSolid dispersions are prepared by immisciblecomponents and drug. Finally the solid dispersionsare shaped in to films by means of dies.5)RollingSolution or suspension drug is rolled on the carrier.The solvent is mainly water and mixture of waterVol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 917

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701and alcohol. The film is dried on the rollers andgives desired shape and size 27 .EvaluationHardness and thicknessThe test is done as per the standard methods. Thehardness of three randomly selected tablets fromeach formulation is determined by placing eachtablet diagonally between the two plungers of tablethardness tester (with the nozzle) and applyingpressure until the tablet broke down into two partscompletely and the reading on the scale is noteddown (28) .The thickness of three randomly selectedtablets from each formulation is determined in mmusing a vernier caliper (Pico India). The averagevalues is calculated 28 .Drug ContentRandomly ten tablets are selected fromformulation, finely powdered and powderequivalent mg of drug is accurately weighed andtransferred to 100 ml volumetric flasks containingsolution of desired pH. The flask is shaken to mixthe contents thoroughly. The volume is made up tothe mark with solution and filtered. One ml of thefiltrate is suitably diluted and drug content isestimated using a double beam UV-visiblespectrophotometer. This procedure is repeatedthrice and the average value is calculated.Wetting time (WT)It is useful for quality control and providessupportive evaluation of these sublingual tablets.Unlike the disintegration test, the wetting test usesminimal water, which may be more representativeof the quantity of moisture available sublingually.Using this test, the time required for moisture topenetrate the tablet completely is measured andpossibly represents the time required to releasedrug in the presence of minute volumes of salivaThe tablet was placed above absorbent paper fittedinto a petri dish. After the paper is thoroughlywetted with distilled water, excess water iscompletely drained out of the dish. The timerequired for the water to diffuse from the wettedabsorbent paper throughout the entire tablet is thenrecorded using a stopwatch 28Disintegration testA relatively simple method with rigorousconditions is developed. Each individual tablet isdropped into 10‐ml glass test tube (1.5‐cmdiameter) containing 2ml distilled water, and thetime required for complete tablet disintegration isobserved visually and recorded using a stopwatch.The visual inspection is enhanced by gentlyrotating the test tube at a 45 0 angle, withoutagitation, to distribute any tablet particles thatmight mask any remaining undisintegrated portionof the tablets. In the USP disintegration test forsublingual tablets, the disintegration apparatus fororal tablets is used without the covering plasticdisks, 29 and 2 minutes is specified as the acceptabletime limit for tablet disintegration [29]. .Water absorption ratioA piece of tissue paper folded twice is placed in asmall Petri dish Containing 6 ml of water. A tabletis put on the tissue paper and allowed to completelywet. The wetted tablet is then weighted. Waterabsorption ratio, R was determined using followingequation 28 .R = 100 × Wa –Wb/Wawhere, Wa = Weight of tablet after waterabsorptionWb = Weight of tablet before water absorption.In vitro disintegrating testDisintegration times for sublingual tablets isdetermined using USP tablet disintegrationapparatus with desired medium. The volume ofmedium was 900 ml and temp was 37± 2 °C. Thetime in seconds taken for complete disintegrationof the tablets with no palatable mass remaining inthe apparatus is measured 28 .In vitro dissolution testIn-vitro release rate of sublingual tablets will becarried out using United State Pharmacopoeia(USP) XXIV dissolution testing apparatus (Paddlemethod). A aliquot sample of the solution iswithdrawn from the dissolution apparatus. Thesamples are replaced with fresh dissolutionmedium of same quantity. The samples are filteredthrough Whatman filter paper No 40 and analyzedin UV spectrophotometer. The percentage drugrelease is calculated using an equation obtainedfrom the calibration curve 30 .Test for filmTensile StrengthTensile strength is the maximum stress applied to apoint at which the film specimen breaks 31 . It iscalculated by the applied load at rupture divided bythe cross-sectional area of the film as given below:Tensile strength = Load at failure × 100Film thickness × film widthPercent ElongationA film sample stretches when stress is applied andit is referred to as strain. Strain is basically thedeformation of film divided by original dimensionof the sample. Elongation of film increases as theplasticizer content increases.Vol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 918

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701Percent Elongation-L * 100Lowhere,L = Increase in length of filmLo = Initial length of film.Young's ModulusYoung's modulus or elastic modulus is the measureof stiffness of film. It is represented as the ratio ofapplied stress over strain in the region of elasticdeformation as follows:Young's Modulus = Slope * 100Film thickness *Cross-head speedFolding EnduranceFolding endurance is determined by drying processrepeated folding of the film at the same place tillthe breaks. The number of times the film is foldedwithout dry breaking is computed as the foldingendurance value 32 .ThicknessThe thickness of the polymer films was measuredby using screw gauge. The thickness of each stripat six different areas was determined and standarddeviation was calculated 33In vitro disintegration timeIn vitro disintegration time is determined visuallyin a glass dish of 25ml distilled water with swirlingevery 10 sec. The disintegration time is the timewhen the film starts to break or disintegrates. Thedisintegration time of prepared films was measuredin triplicate 34 .Uniformity of drug contentThe film of area 1x1 cm2 was cut and dissolved in6.8 phosphate buffer solution and made up to 100mL in a volumetric flask. Then 1 mL waswithdrawn from the solution and diluted to 10mL.The absorbance of the solution was taken at 276nm and concentration was calculated. By correctingdilution factor, the drug content was calculated.The test was performed in triplicate 35 .In-vitro dissolution studiesDissolution study was carried out in USP paddletype apparatus using 300 mL of stimulated salivaryfluid (pH 6.8) as a dissolution medium at 50 rpm.Temperature of the dissolution medium wasmaintained at 37±0.5ºC. Samples of 5ml werewithdrawn at every 4 minute interval, filtered(through 0.45µ) and replaced with 5ml of freshdissolution medium. The samples were suitablydiluted and estimated spectrophotometrically at 276nm by using ELICO-164 double beam UV-Visiblespectrophotometer. The dissolution experimentswere conducted in triplicate. Dissolution rate wasstudied for all designed formulations anddissolution parameters were calculated.CONCLUSIONSublingual drug delivery have been used forformulation of many drugs with view point of rapiddrug release and quick onset of action. Sublingualproducts were developed to overcome the difficultyin swallowing conventional tablet, among pediatric,geriatric and psychiatric patients with dysphagia.The target population has expanded to those whowant convenient dosing without water anywhere,anytime. The potential for such dosage forms ispromising because strong market acceptance andpatient demand. Peak blood levels of most productsadministered sublingually are achieved within10‐15 minutes, which is generally much faster thanwhen those same drugs are ingested orally.Sublingual absorption is efficient. The percent ofeach dose absorbed is generally higher than thatachieved by means of oral ingestion. Various typesof sublingual dosage forms are available in marketlike tablets, films and sprays.Vol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 919

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701Table 1:Superdisintegrant Commercially available Mechanism0f actionCross linkedCelluloseCrosscarmellose®Ac-Di-Sol®,Nymce ZSX®Primellose®,Solutab®,Vivasol®, L-HPCCross linked PVP Crosspovidone M®Kollidon®Polyplasdone®Crosslinked starchCrosslinked alginicAcidExplotab®Primogel®Alginic acid NFSwells 4-8 foldsin < 10seconds.Swelling andwicking bothSwells very littleand returnsto original sizeaftercompression butact bycapillary actionSwells 7-12 foldsin < 30seconds.Rapid swelling inaqueousmedium orwicking actionSpecial commentSwells in twodimensions.Directcompressionor GranulationStarchfree.Waterinsoluble andspongy innature so getporous tabletSwells in threedimensionsand highlevel serve assustain releasematrixPromotedisintegrationin both dryor wetgranulation.Table 2: Marketed Products of Sublingual TabletBrand Name Catergory SrengthAbstral Fentanyl Citrate Opioid <strong>An</strong>algesic50, 100, 200, 300, 400, 600,800 µgSubutex Buprenorphine Opioid <strong>An</strong>algesic 2 and 8mgAvitan Lorazepam <strong>An</strong>tianxiety 1, 2 mgEdular Zolpidem tartrate Sedatives/ Hypnotics 5, 10 mgIsordil Isosorbide dinitrate Vasodilators 2.5, 5 10mgSuboxone BuprenorphinehydrochlorideNarcotic + Opioid antagonist 2/0.5, 8/2 mgNitrostat Nitroglycerine <strong>An</strong>tianginal 0.3 mg , 0.4 mg , or 0.6 mgFig. 1:Vol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 920

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701Fig. 2: Diagram of sublingualgland and sublingual arteryFig. 3: Thin Film Drug DeliveryREFERENCES1. Zhang H, Zhang J, Streisand JB. OralMucosal Drug Delivery: ClinicalPharmacokinetics and TherapeuticApplications. Clin Pharmaco 2002:41(20):661-680.2. A Short Review on “A Novel Approach inOral Fast Dissolving Drug DeliveryVol. 3 (2) Apr – Jun2012 www.ijrpbsonline.com 921

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