A Review on Sublingual Dosage Form

AEGAEUM JOURNAL ISSN NO: 0776-3808

Yadav Dimple Shyamkumar*^, Ms.Jimmy Limbachiya^, Dr.Kinjal Solanki^, Dr.Vikram Pandhya^

^Shankersinh Vaghela Bapu Institute of Pharmacy, Gandhinagar, Gujarat, India.

Abstract

Oral administration is one of the most convenient forms for the intake of drug due to ease of administration, painless, versatility, and paramount patient compliance. The demand of fast disintegrating tablets has been growing, during the last decades especially for geriatric and pediatric patients due to dysphasia. Despite of tremendous innovations in drug delivery, the oral route remains the preferred route for administration of therapeutic agents because of accurate dosage, low cost therapy, self-medication, non-invasive method and ease of administration which ultimately lead to high level of patient compliance. Peroral administration of drug has disadvantages such as Hepatic first pass metabolism and enzymatic degradation within the GI tract that limits oral administration of certain classes of drug like peptides and proteins. So, other absorptive mucosa is considered as potential sites for drug administration. Trans-mucosal routes of drug delivery (i.e. the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity) offer several advantages over peroral administration for systemic delivery.

Keywords: Sublingual Tablets, mechanisms, Properties of Sublingual Tablets, advantages and disadvantages, ingredients used in dosage, Sublingual drug delivery, Improved bioavailability, Techniques, Evaluation. recent trends on Sublingual Tablets and case study.

INTRODUCTION

Drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect. Dysphasia (difficulty in swallowing) is a common problem of all age groups, especially geriatrics, pediatric, and patients who are mentally retarded, uncooperative, nauseated or on reduced liquid intake/diets have difficulties in swallowing these dosage forms. Drugs that are given sublingually reach directly in to the systemic circulation through the ventral surface of the tongue and floor of the mouth. The drug is rapidly absorbed into the reticulated vein that lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drained in to systemic circulation. Considering the oral cavity sublingual area is the most

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permeable part of the buccal cavity. The decreasing order of permeability in the buccal cavity is the sublingual, the buccal area (cheek), then the palatal area. The order is generally based upon the relative thickness and the extent of blood supply to the specific part.

 Sublingual- Under the tongue.  Sublingual dosage form can be define as dosage form that is to be placed beneath the tongue where it will dissolve and the drug will be absorbed directly through the sublingual mucosa.  The dosage form not intended to be swallowed or chewed.  Sublingual administration of the drug means placement of the drug under the tongue and drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth.  The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and brachiocephalic vein and then drained in to systemic circulation.(1,2)

Figure-1 Sublingual Introduction Sublingual Glands Another name of sublingual gland is salivary glands which are present in the floor of the mouth, underneath the tongue. Drugs having short delivery and infrequent dosing regimen could be delivered successfully through sublingual route because of high permeability and rich blood supply, the sublingual route produces a rapid onset of action. A good oral hygiene could be promoted with the help of sublingual glands. Sublingual glands are also known for their binding and lubricating functions, and sublingual gland secretion makes the food slippery and easily swallowable. High content of saliva in the masticated food helps the food to

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move without any difficulty. Saliva secretion plays a major role in shaping the principle physiological environment of oral cavity in terms of pH, fluid volume and composition. Saliva secretion has been promoted by 3 major salivary glands which are parotid, submaxillary, sublingual glands. However minor salivary or buccal glands are also involved in saliva secretions which are situated in or immediately below the mucosa. Saliva regulates oral microbial flora by maintaining the oral pH and enzyme activity. Sublingual glands are known for their viscous saliva with limited enzymatic activity whereas parotid and submaxillary gland produces watery secretion. Saliva helps in lubricating the oral cavity; it facilitates swallowing and prevents demineralization of the teeth. Approximately 0.5-2.0L of saliva has been secreted by salivary gland. However the volume of saliva which is available constantly is around 1.1ml, thus providing a relatively low fluid volume available for drug release from delivery systems compared to GIT. If we compare the GI fluid and saliva, saliva is relatively less viscous. The flow rate of saliva which depends on 3 factors like the time of day, the type of stimulus and the degree of stimulation.(3,4)

Fig. no 2 Sublingual gland. Why sublingual mucosa is more permeable than other region of oral mucosa:  Sublingual mucosa is thinner than other oral region – sublingual epithelial has 8-12 cell region whereas epithelial about 40-50 cell layer thick.  Sublingual region is very rich in blood supply.

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 Saliva tends to accumulate in sublingual region because two major salivary duct open into this region.  Organised keratins and lipids are absent in sublingual mucosa.  Polar lipids are found in the intercellular space of sublingual mucosa which increased permeation of hydrophilic compound.  Note – Membrane coating granules are the permeability barrier in sublingual mucosa which are present in nonlamellar form.(5) 1.1.2 Disadvantages/ Limitation of Sublingual Tablet:

• Although this site isn't well matched to sustained delivery systems.

• Sublingual medication can't be used once a patient is uncooperative or unconscious.

• Since articulator administration of medicine interferes with ingestion, drinking, and talking, this route is mostly thought-about unsuitable for prolonged administration.

• High dose can not be administered.

• Not appropriate for bitter and aggravating medication.

• Less patient compliance.

• Ingestion and drinking, smoking isn't allowed.

• Extremely ionic drug can not be administered. (6-7)

1.1.3 Special Features of Sublingual Tablet:

 Easily administered.  Available in various size and shapes.  Should not be Obstructive.  It should adhere to the oral cavity easily.  Should processes fast dissolve without water.  Rapid release. (8-9) 1.1.4 The Ideal Characteristics of a Drug To Be Selected:

 No bitter taste.  Dose lowers than 20 mg.  Small to moderate molecular weight.  Good stability in water and saliva.

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 Partially no ionized at the oral cavities pH.  Under going first pass effect.  Many drug properties could potentially affect the performance of sublingual tablets like solubility, crystal morphology, particle size, hygroscopicity, compressibility and bulk density of drug.  Some drugs undergoes extensive first pass metabolism which results in poor bioavailability of its oral dosage forms, that kind of drugs are suitable for sublingual dosage form.  Drugs that are unstable in parenteral preparation are suitable for sublingual dosage form.  Many pharmaceuticals are designed for sublingual administration, including cardiovascular drugs, steroids, barbiturates, enzymes, antiemetics, vitamins, minerals and vaccines. (10-11) 1.1.5 Advantage of Sublingual Tablet:

 Ease of administration to patients who refuse to swallow a tablet, such as paediatric , geriatric patients and psychiatric patients.

 A relatively rapid onset of action can be achieved compared to the oral route, and the formulation can be removed if therapy is required to be discontinued.

 The large contact surface of the oral cavity contributes to rapid and extensive drug absorption.

 Liver is bypassed and also drug is protected from degradation due to pH and digestive enzymes of the middle gastrointestinal tract.

 They also present the advantage of providing fast dissolution or disintegration in the oral cavity, without the need for water or chewing.  Ease of administration to patients who refuse to swallow a tablet, such as paediatric, geriatric patients and psychiatric patients.  Convenience in administration of drug and accurate dosing as compared to liquid formulations.  Water is not required for swallowing the dosage form, which is convenient feature for patients who are traveling and do not have immediate access to water.  Good mouth feels property helps to change the basic view of medication as "bitter pill", particularly for paediatric patients.

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 Fast dissolution of medicament and absorption which will leads to rapid, onset of action.  Some drugs are absorbed from the mouth pharynx and oesophagus as the saliva passes down into the stomach, in such cases bioavailability of drugs is increased.  It provides advantages of liquid formulations in the form of solid dosage form.  Pregastric absorption can result in improved bioavailability and as a result of reduced dosage, improved clinical performance through a reduction of unwanted effects.(12)  The Mechanism of sublingual absorption: The absorption potential of the buccal mucosa is influenced by the lipid solubility and therefore the permeability of the solution (osmosis), the ionization (pH), and the molecular weight of the substances. For example, absorption of some drugs via the buccal mucosa is shown to increase when carrier pH is lowering (more acidic) and decrease with a lowering of pH (more alkaline).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 used across the entire stratified epithelium. It is also unlikely that active transport processes operate within the oral mucosa. However, it is believed that acidic stimulation 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 salivary glands consist of lobules of cells which secrete saliva through the salivary ducts into the mouth. The three pairs of salivary glands are the Parotid, the Sub mandibular and the Sublingual which lies on the floor of the mouth. The more acid the taste the greater the stimulation of salivary output, serving also to avoid potential harm to acid sensitive tooth enamel by bathing the mouth in copious neutralizing fluid. With stimulation of salivary secretion oxygen is consumed and vasodilator substances are produced, and the glandular blood flow increases, due to increased glandular metabolism. The sublingual artery travels forward to the sublingual gland, it supplies the gland and branches to the neighbouring muscles and to the mucous membranes of the mouth, tongue and gums. Two symmetrical branches travel behind the jaw bone under the tongue to meet and join at its tip. Another branches meets and anastomoses with the sub mental branches of the facial artery. The sublingual artery system stems from the sublingual artery the body’s main blood supply to the tongue and the floor of

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the mouth which arises from the external carotid artery. The proximity with the internal carotid artery allows fast access to its route supplying the greater part of the cerebral hemisphere. (13-14)

Figure 3: Mechanism of sublingual drug absorption  Historical Development of Sublingual Dosage Form:  Difficulty in swallowing (Dysphagia) is a common problem in all age groups, especially the elderly and paediatrics, because of physiological changes associated with these age groups. It is common to see those afflicted carrying a small device with them, which is used for crushing tablets, enabling easy ingestion. Other categories that experience problems using conventional oral dosage forms include are the mentally ill, uncooperative and nauseated patients, those with conditions of motion sickness, sudden episodes of allergic attack and coughing. Sometimes, it may be difficult to swallow conventional products due to unavailability of water. These problems led to the development of a novel type of solid oral dosage form called mouth-dissolving tablets, which disintegrate and dissolve rapidly in saliva without the need of the water. They are also known as fast dissolving tablets, melt-in-mouth tablets, rapimelts, porous tablets, oro-dispersible, quick dissolving or rapidly disintegrating tablets. indicates the contribution of various researchers in the field of sublingual tablets and the indicates the patented technology in the field of sublingual technology.(15-16) S.No. Year Contribution 1 1986 Freeze drying process converts the mixture of active water dispersible carrier materials into open matrix network that disintegrates rapidly. 2 2001 Formulation and optimization of captopril sublingual tablet using d- optimal design.

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3 2003 In vitro and in vivo evaluation of a new sublingual tablet system for rapid Oromucosal absorption using fentanyl citrate as the active 4 2006 Formulation and optimization of sublingual tablets of rabeprazole sodium. 5 2009 Development and optimization of a sublingual Tablet formulation for physostigmine salicylate. 6 2011 Sublingual route for the systemic delivery of ondansetron 7 2012 Formulation and in-vitro evaluation of fast disintegrating Rosiglitazone sublingual tablets. 8 2012 formulation and evaluation of sublingual tablets of losartan potassium. 9 2012 Development and characterization of sublingual tablet of lisinopril. 10 2013 formulation and evaluation of immediate release tablets of linezolid.

Table-1 The Patented Technology in the field of Sublingual Technology

Anatomy of oral mucosa The surface area of the oral mucosa is about 100 cm2. Three different types of oral mucosa are recognized:  the masticatory mucosa- 25% is covered, having 100-200μm thick and also coveres gingiva and hard palate.  the lining mucosa – 60% in covered, with 500-800μm thick and covers lips, cheeks, soft palate and lower surface of toungue and floor of oral cavity.  the specialized mucosa.- 15% covered in dorsum of the toungue and involved in taste. (17)

Figure no 4: oral cavity (layers found in keratinized oral mucosa that include a deeper lamina propria and basement membrane in-between and superficial layers of strafied squamous epithelium that include from deepest to most superficial(19)

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Oral mucosa consists of two layers, the surface stratified squamous epithelium and the deeper lamina propria. In keratinized oral mucosa, the epithelium consists of four layers:[ 19]

 Stratum basale (basal layer)  Stratum spinosum (prickle layer)  Stratum granulosum (granular layer)  Stratum lucidum (clear layer)

 Stratum corneum (keratinized layer)

Buccal Epithelium: The buccal epithelium is a non-keratinized stratified squamous composed of multiple layers of cells that show different patterns of maturation between the deepest cells and the surface. The basal cells of the buccal epithelium are capable of division and maintain a constant epithelial population as cells move toward the surface as epithelium rests on the basal membrane, an irregular continuous interface between the epithelium and the connective tissue so improves the barrier function of the epithelium and preventing large molecules from passing through the oral mucosa. Although buccal absorption is not the specific goal of oral fast dissolving tablets, this can occur when the drug is released in the oral cavity in contact with buccal mucosa. The accepted range of normal mechanism through the buccal mucosa involves two major routes transcellular (intracellular) and paracellular (intercellular) . The transcellular route involves passage through the cellular membranes with a polar and a lipid domain, while the paracellular route essentially consists of passive diffusion through the drug permeation and extracellular lipid domain. It is generally recognized that the lipid delivery systems matrix of the extracellular space plays an important role in the barrier function of the paracellular pathway, especially with compounds that are hydrophilic and have a high molecular weight, such as peptides. Vascularization of the Oral mucosa Arterial, venous and lymphatic capillaries penetrate the multi layered epithelium, infiltrating the connective tissue. mucosa is primarily supplied by the external carotid artery, serves the large buccal blood vessels. The floor of the mouth areas , the root of tongue and cheek areas are mostly vascularized. Vascular drainage from the oral mucosa is primarily via the lingual, facial and retromandibular veins flow together into the internal jugular vein. This is the mechanism responsible for bypassing first-pass hepatic metabolism.

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Salivary Flow Saliva is the source for disintegration or dissolution of drug , the characteristics of saliva are important to oral fast dissolving tablet . The saliva is mainly secreted in the oral cavity through parotid, submandibular (submaxillary) and sublingual glands, and also by many minor glands. The main constituent of saliva is water (99.5% w/v). The remaining 0.5% w/v consists of dissolved compounds. Saliva were mainly hyponotic solution. The principle component of saliva are: inorganic electrolytes including sodium, potassium, calcium, magnesium, bicarbonate and phosphatase, gases[like carbondioxide, nitrogen, oxygen], lipase, maltase, mucine , protein, serum albumin and immunoglobuline, alpha amylase. Saliva has weak buffering capacity and its normal ph is slightly acidic (ph 6-7) but the salivary flow can have ph 5 (low flow) and 7.4(high flow). (17) Advantages of oral cavity 1. Accessible 2. Self administrable 3. Oral mucosa repairs rapidly 4. Different areas of the oral cavity have different permeability characteristics 5. Highly hydrated environment to dissolve drug 6. Sustained delivery possible 7. Potential reduction of systemic side effects 8. Avoid the hepatic first-pass effect 9. High blood supply(18) Disadvantages of oral cavity 1. Permeability barrier of the oral mucosa 2. Saliva washes away drug 3. Mastication and speech may dislodge 4. Delivery device 5. Requires formulation for agreeable taste 6. Highly enzymatic environment 7. Relatively small surface area. (18)

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Sublingual formulations Bioadhesive sublingual tablet: The new sublingual tablet concept presented is based on interactive mixtures consisting of a water-soluble carrier covered with fine drug particles and a Bioadhesive component. With this approach, it is possible to obtain rapid dissolution in combination with Bioadhesive retention of the drug in the oral cavity.(21) Fast-disintegrating sublingual tablets: The Tablets that disintegrate or dissolve rapidly in the patient’s mouth are convenient for young children, the elderly and patients with swallowing difficulties, and in situations where potable liquids are not available. Only the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. Medication can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa. (22) Thin film drug delivery: Delivering drugs to the systemic circulation via a thin film that dissolves when in contact with liquid referred to as a dissolving film or strip. Thin film are made using different grade of biopolymers. The advantage of this type of formulation is it have potential to improve the onset of action in lower dose. (23) Lipid matrix sublingual tablet: Lipid Matrix Sublingual Tablet is formulation which uses advances in sublingual and liposomal technology to formulate a dosage form that offers a faster and more complete absorption than traditional oral routes of administration. The Lipid Matrix Sublingual Tablet is a bioavailable, quick, convenient, and consistent dosage form for many specialty neutraceuticals that are often taken orally. Examples: Glutathione MB12 (Methylcobalamin). (24) Sublingual immunotherapy: SLIT, is a form of immunotherapy that involves putting drops of allergen extracts under the tongue. SLIT is usually delivered one of two ways: drops (or tablets) of allergen extract are placed under the tongue, then either swallowed or spat out. Swallowing the extract seems to work better. Immunotherapy by the oral route (swallowed and not kept under the tongue for any period of time), causes too many gastrointestinal side effects (nausea, vomiting, diarrhoea), and therefore is not used.it is mostly recommended for Paediatric patients with allergic rhinitis and/or asthma due to grass pollen. (25) Sublingual vitamin tablet: Vitamin B12 (Cyanocobalamin) is the only vitamin which can be taken sublingually. Recommended dose to be taken is once a day. (26)

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Table 2 : Drugs used in sublingual tablets. Drug Category Dosage form Captopril Antihypertensive agent Tablet Furesamide Diuretic Tablet Scopolamine Opioid analgesic Spray Ondansatron Hcl Antiemetic agent Film Salbutamol Sulphate Antiasthmatic agent Film

Table 3: Excipients used in sublingual tablets.

Excipients Uses HPMC Tablet binder, Stabilizing agent. Lactose Monohydrate Diluent, Tablet binder Crosspovidone Superdisintegrant Cross carmellose sodium Superdisintegrant Sodium starch glycolate Superdisintegrant

Novel Technologies used in Sublingual Dosage Form:  Non-Patented Technology  Lyophilization or Freeze drying (20) A process, in which water is removed or sublimed from a product, after it is frozen, is lyophilization or freeze drying. The tablets obtained by this technique can dissolve or disintegrate more rapidly than any other solid dosage forms because it will form an amorphous porous structure. Drugs which are water-insoluble with fine particle size, drugs with low aqueous solubility and drugs having low stability in suspension forms are best ideal candidates for this technique. Advantages: 1. Lyophilization is useful for heat sensitive drugs. 2. Tablets obtained by this technique dissolve more rapidly than any other solid dosage forms because it will form an amorphous porous structure. 3. As it melts fast, provides good mouth feel. 4. Improved absorption and increased bioavailability.

Figure no 5 :Lyophilization

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 Moulding method(20) Tablets are designed using hydrophilic ingredients, with the aim to get maximum drug dissolution. Powder mass is wetted with hydroalcoholic solvent and compressed into a dosage form. The solvent system is then allowed to evaporate. Taste of drug particles is developed by spray congealing the molten mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethene glycol with an active ingredient into lactose based tablet triturate. Characteristics of moulding method are, very porous as solvents are removed by drying leaving porous mass which promotes rapid dissolution. Moulded tablets are generally prepared by mixing the active drug with lactose, dextrose, sucrose, mannitol, or some other appropriate diluent that can serve as the base. This base must be readily water soluble and should not degrade during the tablet's preparation. Lactose is the preferred base but mannitol adds a pleasant, cooling sensation and additional sweetness in the mouth. (21)

 Spray Drying It consists of bulking agent mannitol and sodium starch glycolate or croscarmellose sodium as a disintegrating agent. Addition of effervescent agent’s citric acid and sodium bicarbonate results in improved dissolution and disintegration. Sublingual tablets obtained by this method disintegrates less than 20 seconds in an aqueous medium. In this method, aqueous solution containing matrix (Gelatin either hydrolyzed or unhydrolyzed) and other components are sprayed in spray dryer resulting in the formation of a free flowing support matrix. (24) This free flowing support matrix then mixed with the active ingredient and finally compressed to form fast dissolving tablet which is schematically given in figure

Figure no 6: Spray Dry Process

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 Sublimation Method This technique is used to produce Sublingual tablets with high porosity. To form a porous matrix, volatile ingredients are added along with other excipients and compressed to form tablet and then compressed tablets are subjected to sublimation process. A schematic flow of the procedure involved in the preparation Sublingual tablet using sublimation technique given in figure 7. By utilizing a mixture of camphor and mannitol.

Figure no 7: Sublimation Process

 Mass Extrusion Taste masking of bitter drug granules using mass extrusion technique is main step of this process and then tablets are compressed using taste masked granules and excipients including superdisintegrant. Procedure for preparation of Sublingual tablets by this technique is given in figure 8. For taste masking, softening of active blend is done by utilizing mixture of polyethylene glycol and methanol.

Figure no 8: Mass Extrusion.

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 Direct Compression Direct compression is the easiest method with advantage of low manufacturing cost, conventional equipment, commonly available excipients and less number of processing steps. By direct compression method, it can accommodate high dose and also possible to exceed the final weight of the tablet as compared with another method. Super disintegrants, water-soluble excipients and effervescent agents are used in tablet formulations which determine the disintegration property of tablet.

Evaluation of Sublingual Dosage Form:(27-30) There are two types:1. Pre – compression 2. Post- compression 1. Pre-compression a) Angle of repose : Determined by funnel method. Weigh the blend accurately and take in a funnel. Adjust the height of the funnel in such a way that funnel tip(that should be 2cm above the surface) touches the apex of the heap of the blend. The blend of drug and excipients was allowed to flow through the funnel freely on to the surface and measure the diameter of the powder cone formed. Angle of repose calculated using the equation: tan θ = h/r Where, h is the height of the powder cone r is the radius of the powder cone.

Flowability Angle of Repose Excellent <25 Good 25-30 Moderate flow 30-40 Poor flow >40

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b) Bulk density: A weighed quantity of blend was poured into a graduated measuring cylinder and volume and weight are measured. BD =Weight of the powder/Volume of the packing. c) Tapped Density: Take a graduated measuring cylinder and place a known mass of drug- excipients blend. At a height of 10 cm and interval of 2 seconds, the cylinder was allowed to fall under its own weight onto a hard surface and tapping was continues till further no change in volume noticed. Tapped density(TD) :

d) Compressibility index: Carr’s compressibility index is used to determine the Compressibility Index of the blends. Carr’s compressibility(CI%):

[ ]

 POST-COMPRESSION e) Weight Variation: According to I.P. procedure for uniformity of weight, twenty tablets are taken and their weight is determined individually and collectively on an electronic weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of determining the drug content uniformity. Average weight Maximum % of Tablets (mg) deviation 80 mg or less ±10 More than 80 ±7.5 mg but less than 250 mg

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250 mg or more ±5

f) Thickness: Thickness of tablets is determined using Vernier caliper. An average value is calculated by using tablets in triplicate and then the mean ± standard deviation values of thickness are notified. g) Tablet Hardness: Hardness of tablet is defined as the force applied across the diameter of the tablet in the order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage. transformation and handling before usage depends on its hardness. Hardness in case of MDTs is kept low to allow rapid disintegration in mouth. It is done by using hardness tester like Pfizer hardness tester or Monsanto tablet hardness tester. h) Friability: Friability is measured of mechanical strength of tablets. Roche friabilator is used to determine the friability by following procedure. A preweighed tablet is placed in the friabilator. Friabilator consist of a plastic chamber that revolves at 25 rpm, dropping the tablets at a distance of 6 inches with each revolution. The tablets are rotated in the friabilator for 4 minutes for 100 revolutions. At the end of test, tablets are reweighed; the loss in the weight of tablet is the measure of friability and is expressed in percentage as; % Friability = Loss in weight / Initial weight x 100 i) Disintegration Time: The test is carried out using the disintegration apparatus. Phosphate buffer (pH 6.8) maintained at 37ºC ± 2ºC is used as a disintegration media and the time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus is measured. j) Wetting Time: A piece of tissue paper folded twice is placed in a small petridish containing 6ml. of distilled water. A tablet is carefully placed on the surface of the paper and the time required for water to reach the upper surface of the tablet is noted as the wetting time. Less is the wetting time, indicates more porous the tablet. k) Water Absorption Ratio: Water absorption ratio „R‟was determined using the equation: R=100 (Wb-Wa) / Wa Where, Wa is weight of tablet before water absorption and Wb is weight of tablet after water absorption. l) In vitro Drug Release Studies: The in vitro drug release is studied using USP dissolution apparatus II (paddle type) at 50 rpm in 900 ml of phosphate buffer (pH 6.8) at37±0.5ºC. At different time intervals, 10 ml of sample is withdrawn and filtered. An

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equal volume of the medium is introduced into the container after each withdrawal to maintain a constant volume. The absorbance of the samples is determined by UV Spectrophotometer at given max. The mean values of drug released are plotted as cumulative % drug release vs.time.

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Angina Pectoris 2018 http://www.pharmainfo.net/nandini/blog/introduction-tablets. 12. Atul Kumar Vats, H.G.Shivakumar, Chaudhari C.A., Sublingual Drug Delivery:An Extensive Review, International Journal for Pharmaceutical Research Scholars, 2016; 5(1): 9-19. 13. Al-Ghananeem AM, Malkawi AH, Crooks PA. Effect of pH on sublingual absorption of oxycodone hydrochloride. AAPS PharmSciTech, Mar 1, 2006; 7(1): E163-7. 14. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, Schiff E. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med., May 16, 2013; 368(20): 1867-77 15. Bredenberg S, Duberg M, Lennernäs B, Lennernäs H, Pettersson A, Westerberg M, Nyström C. In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci., Nov 30, 2003; 20(3): 327-34 16. Doelker E. Pharmaceutical dosage forms: Tablets: HA Lieberman, L. Lachman and JB Schwartz (Eds.), in three volumes, 2nd edn., revised and expanded, Marcel Dekker, New York, NY, 1989–1990, 1990, 592–616–560. 17. Giuseppina Sandri, Maria Cristina Bonferoni, Franca Ferrari, Silvia Rossi and Carla Caramella,” Differentiating Factors between Oral Fast-Dissolving Technologies”, Am J Drug Deliv 2006; 4 (4): 249-262. 18. Priyanka Nagar, Kusum Singh, Iti Chauhan, Madhu Verma, Mohd Yasir, Azad Khan, Rajat Sharma and Nandini Gupta,” Orally disintegrating tablets : formulation, preparation techniques and evaluation”, Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45. 19. https://en.wikipedia.org/wiki/Oral_mucosa 20. ASHISH MASIH, AMAR KUMAR, SHIVAM SINGH*, AJAY KUMAR TIWARI, “FAST DISSOLVING TABLETS: A REVIEW”, International Journal of Current Pharmaceutical Research Vol 9, Issue 2, 2017 , 8-18 21. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods: Chinna Reddy P, Chaitanya K.S.C., Madhusudan Rao Y, DARU Journal of Pharmaceutical Sciences, 2011; 19(6): 385-

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405. 22. Singh M, Chitranshi N, Singh AP, Arora V, Siddiqi AW, "An Overview on fast Disintegrating Sublingual Tablets." Int J Drug Deliv, 2012; 4: 407–17. 23. Patel P, Makwana S, Jobanputra U, Ravat M, Ajmera A, "Sublingual route for the systemic delivery of Ondansetron." Int J Drug Devlopment Res, 2011; 3(4): 36–44. 24. M A, Shakeel F, Jahangir MA, Anwar M, Mallick N, Ahmad FJ, A "Review on the strategies for oral delivery of proteins and peptides and their clinical perspectives." Saudi Pharm J. King Saud University, 2014 Jun; 1–16. 25. D Saporta, Sublingual immunotherapy: A useful tool for the allergic in private practice, Biomed research international, 2016; 1-7. 26. CQ Chan, LL Low, KH Lee: Oral vit B12 replacement for the treatment of pernicious anaemia, Frontiers in medicine, 2016; 38(3): 1-6. 27. https://pharmlabs.unc.edu/labs/tablets/molded.htm 28. Yutaka Okuda Yasunobu Okamoto, Yosuke Irisawa, Kazuto Okimoto Takashi Osawa, and Shinji Yamashita “Formulation Design for Orally Disintegrating Tablets Containing Enteric-Coated Particles” Chem Pharm Bull . 2014, 62(5), 407- 14. 29. Harita B, “A Short Review on Mouth Dissolving Tablets”, RRJPPS, 2015, 4 , 91- 103 . 30. Erno A. van Schaick, , Philippe Lechat, RPh, Bart M.M. Remmerie, Grant Ko, Kenneth C. Lasseter, and Erik Mannaert, “Pharmacokinetic Comparison of Fast- Disintegrating and Conventional Tablet Formulations of Risperidone in Healthy Volunteers” , Clinical Therapeutic, 2003, 25, 1687- 1699.

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