INTRODUCTION:

Oral route of drug administration is the most common and popular route of drug delivery. About 60% of all dosage forms available in market are oral solid dosage forms, but effectiveness of certain drugs get reduced when administered through the per-oral route. The problems associated with oral route of administration are first pass metabolism, drug degradation in variable pH condition of gastrointestinal tract, inadequate absorption and slow onset of action. Therefore to improve the efficacy of such drugs, reconsideration of their delivery strategies is essential. ^[1,2]

Research and developments in oral drug delivery has evolved to changeover of solid dosage forms from conventional solid tablets/capsules to modified release tablets/capsules, to fast dissolving tablets, to wafers, to recent development of fast dissolving films or strips. ^[1]The concept of mouth dissolving drug delivery system (MDDDS) arose from the need to provide patients with more conventional means of taking their medication.

For the patients suffering from dysphagia, repeated emesis, motion sickness, and mental disorders swallowing a dosage form with large quantity of water is a difficult task. European Pharmacopoeia has used the term orodispersible tablet for a tablet that disperses within 3 minutes in mouth before swallowing. While dissolving or dispersing the tablet in the saliva, some amount of drug may get absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. From this, theory of orotransmucosal drug delivery can be proposed. ^[3,4]

Now days, there has been significant interest and developments in transmucosal routes of drug administration. Drug can be directly transported to the systemic circulation through mucosal surface. In transdermal drug delivery, keratinized outermost layer of the skin i.e. stratum corneum can act as a permeability barrier for the transportation of the drug to the systemic circulation. Mucosal surface has low level of keratinization than skin. Oral mucosa, depending on the site, is between 4 - 4000 times more permeable compared to the skin. Also compared to several mucosal surfaces such as nasal, rectal, vaginal, and ocular, oral mucosa has attracted particular attention because rectal, vaginal and ocular route for systemic drug delivery possess lack of patient compliance and are more suitable for local drug delivery. In nasal transmucosal drug delivery, limitations such as small dosing volume, mucocilliary clearance, disruption of physiological function and irreversible damage to cilia on chronic therapy makes it less feasible for transmucosal drug delivery.^[^2,5] In contrast, following characteristics make the oral mucosa ideal site for drug delivery.

1. Accessible

2. Self-administrable

3. Highly hydrated environment to dissolve drug

4. The oral mucosa being highly vascularized (Arterial supply: Ext. carotid artery, buccal artery, facial artery, infra orbital artery, posterior alveolar artery, sublingual artery) and of lower thickness, drugs can be directly enter to the systemic circulation without undergoing first-pass hepatic metabolism which in turn can improve bioavailability and onset of action of drug.

5. Sustained drug delivery possible

6. Oral mucosa repairs rapidly, less responsive to allergic and irritant materials ^[5]

Overview of oral mucosa

Oral cavity is made up of the lips, cheek, tongue, hard palate, soft palate and floor of the mouth. Oral cavity is lined by oral mucosa. Surface of the oral mucosa is formed by stratified squamous epithelium lined on basement membrane. (Fig.1). Basement membrane separates epithelium from underlying lamina propia and submucosa layer. Submucosa layer contains blood vessels and nerves. The top quarter to one-third of the oral epithelium is made up of closely compacted epithelial cells. The main function of the oral epithelium is to guard the underlying tissue against potential unsafe agents in the oral environment and from fluid loss. ^[2]

Oral mucosa can be divided into lining mucosa, masticatory mucosa and specialized mucosa. Lining mucosa mainly found on buccal (vestibule of the mouth) and sublingual region (floor of the mouth), masticatory mucosa found on gingiva (gums) and hard palate region, specialized mucosa found on dorsal surface of tongue. ^[2]

Fig 1: Schematic Diagram of Buccal Mucosa

Buccal and sublingual mucosae commonly have application in drug delivery as they possess more suitable properties over gingival and palatal surface. Sublingual mucosa is thinner and more superior in terms of permeability compared to buccal mucosa. Therefore sublingual mucosa is more suitable site for drug delivery when rapid onset of action is needed. Tongue movement and constant washing by saliva makes this site less suitable for retention of dosage form. A thin film fabricated using hydrophilic polymers that rapidly dissolves beneath the tongue or in buccal cavity and dissolved drug gets absorbed through the oral mucosal surface to reach to the systemic circulation.^[^2,6]

Advantages of buccal/sublingual films

Oral strips are thin and flexible dosage forms having larger surface area which rapidly wets and dissolves in the moist buccal environment. Drug dissolved in saliva get easily transported from oral mucosal surface to the submucosa layer containing blood vessels ultimately to the systemic circulation. Therefore drugs susceptible for first pass metabolism, degradation in acidic environment can be formulated into oral strips.

Table 1: Comparison of oral mucosa with different mucosae of GIT ^[2]

Absorptive Site	Estimated surface area	Mean fluid volume (mL)	Relative enzyme activity	Relative drug absorption capacity
Oral cavity	100 cm²	0.9	Moderate	Moderate
Stomach	0.1-0.2 m²	118	high	Moderate
Small intestine	100 m²	212	high	High
Large intestine	0.5-1 m²	187	Moderate	Low
Rectum	200-400 cm²	-	Low	Low

Table 2: Characteristics of oral mucosa^[^2]

Tissue	Structure	Thickness (µm)	Surface area (cm²±SD)	Permeability	Blood flow In rhesus monkeys (ml/min/100 g tissue)
Buccal	Nonkeratinized	500-600	50.2 ± 2.9	Intermediate	20.3
Sublingual	Nonkeratinized	100-200	26.5 ± 4.2	Very good	12.2
Gingival	Keratinized	200	-	Poor	19.5
Palatal	Keratinized	250	20.1 ± 1.9	Poor	7.0

The disadvantage associated with most of the ODTs is they are fragile and brittle which demands special packaging during storage and transportation. The films are flexible therefore compared to most of the ODTs they are not as fragile. Hence, there is ease of transportation during consumer handling and storage.

Compared to liquid formulations, precision in each dose is more for each of the strips.

Better patient acceptability due to ease of swallowing and no water required while administering therefore can be consumed at anyplace and anytime as per convenience of the individual.

Convenient dosage form for the patients suffering from dysphagia, repeated emesis, motion sickness and mental disorders. Since the first pass effect can be avoided and drug directly reaches to the systemic circulation there can be enhanced bioavailability with dose reduction. ^[6]

Table 3: Properties of the commonly used film forming agents ^[8,9]

Polymer	Source/Composition	Reported Film Properties
Pullulan	It is a neutral linear polysaccharide consisting of α–1,6-linked maltotriose residues. It is a fungal (Aureobasidiumpullulan) exopolysaccharide made from starch.	Films made from pullulan are clear, water soluble, colourless, tasteless, odourless, transparent, flexible, elastic and heat sealable. Pullulan films are highly oxygen-impermeable, thermally stable with excellent mechanical properties.
Lycoat NG 73	Peastarch, prepared by chemical and physical treatments	Lycoat disperses easily in cold water without formation of lumps. Simple heating will develop its film-forming ability. It gives a homogenous solution as viscosity develops progressively by heating. It has excellent functionality without the need of additional film forming agent
Sodium alginate	It is the Sodium salt of alginicacid. Alginic acid is present in the cell walls of brown algae (Phaeophyceae, mainly Laminaria) as the calcium, magnesium and sodium salts. It is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-guluronic acid.	Films prepared from alginate are robust. Due to hydrophilic nature films exhibit poor water resistance. The water permeability and mechanical qualities can be measured as moderate compared to synthetic films.
Pectin	Pectin is a high-molecular-weight, complex anionic polysaccharide composed of β-1, 4-linked d-galacturonic acid residues, wherein the uronic acid carboxyls are either fully(high methoxy pectin) or partially (low methoxypectin) methyl esterified. Pectin is mainly prepared from citrus peel.	Film formers with good capacity to load drugs. It dissolves slowly in the oral cavity. It was observed that degradation of pectin reduces itsintrinsic viscosity from 4.9dl/g to 2.5dl/g making it moreappropriate for use in oral films
HPC	Partiallysubstituted poly (hydroxypropyl) ether of cellulose	Glass transition temperature of HPC is high (175-177°C).Films were shown to exhibit brittle fracture and found to be stiff, with a high elastic modulus and a very low percent elongation (less than 5%). Typically slow dissolving.
HPMC	HPMC is a partly O- methylated and O-(2-hydroxypropylated) Cellulose. Lower grades of the HPMC like E-3, E-5, E-15 are used as film forming agents.	Good film forming properties and excellent acceptability. Transparent, tough and flexible films can be fabricated from aqueous solutions.
PVA	Polymerization of vinyl acetate to poly vinyl acetate followed by hydrolysis of poly vinyl acetate to poly vinyl alcohol.	Films made up of PVA exhibit high tensile strength and flexibility.
Kollicoat	Kollicoat is a graftcopolymer of PVA and PEG.	Both the constituent molecules in the copolymer are hydrophilic therefore kollicoat is readily soluble in water. The PVA moiety act as a good film-forming agent and the PEG part acts as an internal plasticizer leading to film with excellent flexibility. Unlike other film formulations, the plasticizer cannot migrate because PEG is covalently bound in the molecule. Kollicoat is forming transparent film.
Gelatin	Partial acid hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin) ofanimal collagen and/ or may also be a mixture of both.	Film made up of gelatin dissolves rapidly, excellent carrier for flavors and possesses a smooth mouth feel
Maltodextrin	It is produced from starch by partial hydrolysis, made up of D-glucose units connected in chains of variable length. The glucose units are mainly connected with each other by α (1→4glycosidic bond. Malto dextrin is typically composed of a mixture of chains that made up of variable number of (three to nineteen) glucose units. Maltodextrins are classified by DE (dextrose equivalent) and have DE 3-20. Higher the DE value,shorter the glucose chains, higher the sweetness and higherthe solubility.	Maltodextrinswith lower DE values usually gives higher viscosity and better film formation while higher DE values produce films with more sweetness, solubility, plasticity, and hygroscopicity. Lower DE values offer several processing advantages over higher DE values. Lower DE values improve flexibility of the film which reduces cracking and flaking during slitting and cutting. Being less hygroscopic, lower DE maltodextrins pick up less moisture during slitting and cutting.

Permeability and Barrier properties of the mucosa

Epithelium of the oral mucosa composed of 4 types of cell layers keratinised layer, granular cell layer, spinous cell layer and basal cells. As supra-basal cells differentiate they form strong intercellular desmosomal junctions and form membrane coating granules on their apical surfaces. These membrane coating granules release lipophilic material into the intercellular spaces to ensure epithelial cohesion. This lipophilic material slows the passage of hydrophilic materials across the epithelium. ^[5]

The charge on the constituents of the basal lamina and high level of hydration of connective tissues may limit the rate of penetration of lipophilic compounds.There are three approaches of diffusion across the oral mucosa's permeability barrier (i) passive diffusion including trans-cellular(through cells) and para-cellular (where material passes through lipid rich domains around the cells), (ii) carrier mediated transport, and(iii) endocytosis/ exocytosis where material is actively taken up and excreted by cells via the endocytic pathway. ^[5,7]

Formulation consideration

Buccal /sublingual films are thin flexible polymeric strips intended to dissolve beneath the tongue or in buccal cavity. So mouth feel, taste masking, rapid dissolution, physical and mechanical characteristics have to be considered while formulating fast dissolving films. All excipients used in the formulation should be approved for use in oral pharmaceutical dosage forms and generally regarded as safe (i.e. GRAS-listed).^[^6]

Film forming polymer

Several polymers can be used for preparation of fast dissolving films (FDF) or oral strips (OS). To obtain the desired properties, polymers can be used alone or in combination. The film obtained should be of enough strength so that there won't be any damage while handling or during transportation, at the same time it should be thin and flexible and should have the property to disintegrate in seconds when placed in mouth to deliver the drug to the oral cavity promptly. As the strip forming polymer is the most crucial and main component of the OS, at least 45%w/w of polymer should be usually present based on the total weight of dry OS. ^[6] Properties of the commonly used film forming agents have discussed in following table 3.

Plasticizer

Plasticizer is an important ingredient of the OS formulation. It assists in improving the flexibility of the strip and decreases the brittleness of the strip. When Plasticizer added to polymer it gets incorporated in between polymer chains and spaces them apart from each-other which results into easy movement of the polymers chains. Plasticizer significantly reduces the glass transition temperature of the polymer therefore polymer chains can slide over each other at lower temperature, thus improves the strip properties. Plasticizer due to its properties improves the flow of polymer and enhances the strength of the polymer. The compatibility of plasticizer with the polymer and type of solvent used in the casting of strip determines the selection of plasticizer. Some of the frequently used plasticizer excipients are glycerol, propylene glycol, low molecular weight PEGs, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, citrate derivatives such as tributyl, triethyl, acetyl citrate, triacetin and castor oil. Usually plasticizers should be used in the concentration of 0–20%w/w of dry polymer weight otherwise inappropriate use of plasticizer may lead to film cracking, splitting and peeling of the strip. Use of certain plasticizers may also influence the absorption rate of the drug. The Plasticizer incorporated in the strip should impart long-lasting flexibility to the strip. Generally it depends upon the volatile nature of the plasticizer and type of its interaction with the polymer. It should be noted that the properties of plasticizer are significant to decrease the glass transition temperature of polymer in the range of 40–60ºC for non-aqueous solvent system and below 75ºC for aqueous systems. Plasticizers should have compatibility with drug as well as other excipients used for preparation of strip. Certain drug molecules themselves can act as a plasticizer. For example, ibuprofen interacted with Eudragit RS 30 D and played the role of a plasticizer. In this case, the glass transition temperature of Eudragit RS 30 D decreased and smooth film formation was observed due to the hydrogen bonding between the drug and the polymer. There are two mechanisms proposed for plasticization effect namely internal plasticization (involving chemical interaction) and external plasticizing effect. Formulators prefer the latter mechanism as it does not involve chemical alterations in the product. The chemical structure and concentration of plasticizers play an important role in alleviating the glass transition temperature of the polymers. Cellulosic hydrophilic polymers were easily plasticized with hydroxyl containing plasticizers like PEG, propylene glycol, glycerol and polyols. In contrast, less hydrophilic cellulosic polymers were plasticized with esters of citric acid and phthalic acid. Glycerol acts as a better plasticizer for PVA while diethylene glycol can be used for both HPMC as well as PVA films. ^[6,10]

Active Pharmaceutical Ingredient

Though fast dissolving oral strip dosage form has the capacity to deliver variety of API’s, size of the dosage form limits the use of the drugs to be incorporated. Oral strips are delivered as thin, flexible films with area up to 8 cm²which dissolves within several seconds therefore drug molecules with high dose and low solubility are not preferable. Generally 5%w/w to30%w/w of active pharmaceutical ingredients can be incorporated in the OS. Water soluble API’s are in the dissolved state in oral strip or they form solid solution means homogenous one phase system with polymer. Incorporation of water insoluble drug in water miscible polymers can be achieved by micronization or nanonization of drug. Micronization of the drug helps to improve the texture of the film also uniformity and dissolution. Taste masking is an important part while incorporating bitter tasting drugs in fast dissolving films. Complexations with cyclodextrins and resins, polymeric coating, microencapsulation are the important techniques of taste masking. ^[6]

Saliva stimulating agents

Saliva stimulating agents increase the rate of production of saliva that would assist in the faster disintegration of the fast dissolving strip. Generally acids like citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid can be utilized as salivary stimulants. ^[1]

Sweeteners

Low molecular weight carbohydrates and specially sucrose are most commonly used sweeteners. Sucrose is very soluble in water and being colourless does not impart any undesirable colour to the final formulation. It is stable over the pH range 4-8. It mask the taste of both salty and bitter drugs. Polyhydric alcohols such as sorbitol and mannitol also exhibit sweetening capacity and suitable for diabetic patients. Mannitol is half as sweet as sucrose and sorbitol has 50-60% of sweetness of sucrose. Sorbitol and mannitol have negative heat of solution therefore impart cooling sensation in mouth. Artificial sweeteners also termed as intense sweeteners. They are several hundreds to thousands times more sweeter than sucrose. Therefore they are hardly required at a concentration more than 0.2%.Only six artificial sweeteners are permitted for oral use within the European Union, the most widely used is sodium or calcium salts of saccharin. Both the salts exhibit high water solubility and are chemically and physically stable over wide pH range. Less widely used artificial sweeteners are aspartame, acesulfame potassium, thaumatin, sodium cyclamate, neohesperidine. Main disadvantage associated with artificial sweeteners is metallic or bitter aftertaste. ^[11,12]A quite new sweetening agent in U.S. market is stevia powder, It is obtained from the extract of the leaves of the plant Stevia rebaudianabertoni. It is natural, nontoxic and safe and 30 times as sweet as sweet as sucrose. It is heat stable. ^[11]

Aromatic oils include caraway, clove, dill, lemon, orange, pepper-mint etc. Synthetic sweeteners, chloroform, vanillin, benzaldehyde etc. and variety of organic compounds like alcohols, aldehydes, esters, ketones, fatty acids and lectones can be used alone or combined with essential oils. ^[13]Flavour acceptance is also affected by age. In general, children like fruit flavoured syrup; adults prefer a more acid taste, while many old people find mint or wine flavours more agreeable.

Table 4: Comparison of sucrose with saccharin and aspartame ^[11]

	Sucrose	Saccharin	Aspartame
Source	Sugar cane, sugar beet	Chemical synthesis; phthalic anhydride, a petroleum product	Methyl ester dipeptide of phenylalanine and aspartic acid
Relative sweetness	1	300	180-200
Bitterness	None	Moderate to strong	none
Aftertaste	None	Moderate to strong; sometimes metallic or bitter	none
Calories	4/g	0	4/g
Acid stability	Good	Excellent	Fair
Heat stability	Good	Excellent	Poor

Flavouring agents

Flovours used in the formulation must be non-toxic, soluble, stable and compatible with the excipients. ^[13]

Table 5: Preferred flavours as per the type and taste of the drug ^[13]

Drug	Preferred Flavour
Antibiotics	Cherry, maple, pineapple, orange, raspberry, banana-vanilla, butterscotch, coconut-custard, fruit-cinnamon, strawberry, vanilla
Antihistamines	Apricot, cherry, cinnamon, grape, honey, lime, peach-orange, peach-rum, raspberry, wild cherry
Barbiturates	Banana-pineapple, banana-vanilla, cinnamon-peppermint, orange, peach-orange, grenadine-strawberry
Decongestants & Expectorants	Anise, apricot, butterscotch, cherry, coconut-custard, custard-mint- strawberry, grenadine-peach, strawberry-lemon, gooseberry, orange-lemon, coriander, pineapple, raspberry.
Electrolyte-solutions geriatrics	Cherry, grape, lemon-lime, raspberry, wild cherry syrup, grenadine-strawberry, lime, portwine, cherrywine, wild-strawberry.
Salt taste drugs	Butterscotch, maple
Bitter taste drugs	Wild cherry, walnut, chocolate-mint, licorice
Sweet taste drugs	Fruit, berry, vanilla
Acid taste drugs	Citrus

Motor drive

Rotating screw

Fig 2: Schematic diagram of Hot melt extruder

Response to the flavour may not be the same in health and disease while a flavour acceptable for a short time may become objectionable if the treatment is prolonged. ^[13]

Colouring agents

When drug is present in the film in a suspension or insoluble particulate form, colouring agents have to be incorporated in the oral film. Pigments such as titanium dioxide or FD&C approved colouring agents are generally used (not exceeding concentration levels of 1%w/w). ^[1,6]

Manufacturing of Oral films

Casting Method

It includes mixing of drug, polymers, plasticizers and other components in water, suitable solvent or solvent system. Solvents used for the preparation of solution or suspension should be selected according to ICH solvent classification. Formed solution or suspension is casted on the suitable surface of desired area and dried at appropriate temperature. ^[1]

Hot melt extrusion

Hot melt Extrusion is a continuous process. The extruder is usually composed of a feeding hopper, barrels, single or twin screws, the die, screw driving unit and downstream processing equipment (Fig.2). Generally mixed blend of drug, polymer and plasticizers added to the barrel through hopper. The heat required to melt or fuse the material is supplied by the heat created by friction as the material is sheared between the rotating screws and the wall of the barrel in combination with electric or liquid heaters. It facilitates intense mixing and agitation of material which causes distributive and dispersive mixing of drug particles in the molten polymer. Hot melt extrusion processing results in a more uniform dispersion of particles at molecular level. ^[14]

Repka and co-workers used Killion melt extruder to produce HPC films. PEG 8000 2%, triethyl citrate (TEC) 2%, acetyltributyl citrate (ATBC) 2%, and PEG 400 1% were the plasticizing agents studied. In addition, either hydrocortisone 1% or chlorpheniramine maleate 1% was incorporated into the films as a model drug. ^[15]

Tensile strength

Tensile strength is one of the mechanical properties play significant role in defining physical integrity of the film. Strength of the film can be identified by tensile strength as diametric tension or tearing force. The sample for test is stretched/ stressed until it tears and the stress required represents the tensile strength means maximum stress applied at which the film specimen breaks called as Tensile strength. It is calculated by the applied load (force) at rupture divided by the cross-sectional area of the strip.^[^6,16]

A TA.XT2 texture analyser equipment furnished with a 5 kg load cell. Film strips were held between two clamps placedat a distance of 3 cm. Then the strips were dragged by the top clamp at a rate of 2 mm/s and the force at which film breaks is measured. In another method, Palem et al. used a microprocessor based advanced force gauze. ^[6,16]

Percent elongation

When stress is applied, a strip sample stretches or get elongated this is mentioned as strain. Per cent elongation is basically the deformation (increase in the length of strip) divided by original length of the sample. Generally elongation of strip increases with the plasticizer concentration.^[^6,16]

Tear resistance

Tear resistance of a film is a measure of its resistance to rupture and is calculated by subjecting the film to a constant rate of distortion. The maximum stress or force needed to tear the film is recorded in Newton's or pound–force. In a stress strain curve greater the area of stress strain curve, the higher the toughness of the film and amount of energy that a piece of the material can absorb. Mostly very low rate of loading 51 mm (2 in)/min is employed and is intended to measure the force to initiate tearing. The maximum stress or force required to tear the specimen is recorded as the tear resistance value in Newtons (or pounds-force). ^[6,16]

Young's modulus

Young's modulus or elastic modulus measures the stiffness of film. It is represented as the ratio of applied stress over strain in the region of elastic deformation. The methods used for the measurement of tensile strength could be utilized here. This measures resistance to deformation and can be observed by plotting the stress strain curve wherein the slope measures the modulus. The higher the slope, the greater is the tensile modulus. However, a gentle slope measures a low tensile modulus and low resistance to deformation. Moreover, films which are hard and brittle possess higher tensile strength and higher Young's modulus values. Hard and brittle strips demonstrate a high tensile strength and Young's modulus with small elongation. ^[16]

Folding endurance

Folding endurance is an important parameter to determine the flexibility of the oral strip. Folding endurance is obtained by repeated folding of the strip at the same place till the strip breaks or folded to 300 times without breaking. The number of times the film is folded without breaking is figured as the folding endurance value. ^[16]

Disintegration time

The disintegration time limit of 30 s or less for orally disintegrating tablets described in CDER guidance can be applied to fast dissolving oral strips. No official guidance is available about this. Pharmacopoeial disintegrating test apparatus may be used for this study. Typical disintegration time for strips is 5–30 s. ^[6]

Drop Method. In this method one drop of distilled water is dropped by a pipette onto the oral films. The films are placed on a glass slide and then the glass slide is placed planar on a petridish. The time until the film dissolved and caused a hole within the film is measured as disintegration time. ^[17]

Petridish Method. In this method 2mL of distilled water is placed in a petridish and film was added on the surface of the water and the time required until the oral film dissolved completely was measured. ^[17]

Dissolution test

In-vitro dissolution of the drug from the film is essential step to determine the permeability of the drug through buccal mucosa. Dissolution testing can be done using the standard basket orpaddle apparatus defined in any of the pharmacopoeia or with modification of dissolution apparatus.

Table 6: Reported film formulations in literature ^[17-31]

Drug	Category	Composition of Fast dissolving film
Triclosan	Treating diseases of oral cavity such as plaque, caries and gingivitis	Methocel E5(2.2% w/v),Propylene glycol 1.35% w/v
Dexamethasone	Treatment of Nausea and vomiting induced by emetogenic anticancer drugs	Hypromellose (7.4%) L-HPC (1.3%), Microcrystalline cellulose (57%), PEG (15%), Polysorbate 80 (5.4%)
Prochlorperazine	Dopamine D2 receptor Antagonists effective in suppressing opioid analgesic-induced nausea and vomiting	Microcrystallinecellulose (57%), PEG (15%), Hypromellose (7.4%), Polysorbate 80 (5.4%) and 5% Low substituted HPC (1.3%).
Ondansetron Hydrochloride	Antiemetic	Poly vinyl alcohol, Poly vinyl pyrrolidone/ Carbopol 934P PEG 400
Tianeptine Sodium	Antidepressant effective against anxiety accompanying mood disorders	Lycoat NG73/Polyvinyl alcohol/HPMC/HEC/Maltodextrin/ Lycoat RS780/PVP K90
Nicotin	Smoking cessation	Maltodextrin (dextrose equivalent 6 and 12),Sorbitanoleate, Glycerol
Levocetrizine hydrochloride	Non-sedative antihistamine	Sodium alginate (1.25-1.75 %), Sodium starch glycolate as disintegrating agent
Levocetrizine di hydrochloride	Third-generation non-sedative antihistamine	HPMC E15/HPMC E 50/PVA (1-2%) Propylene glycol 1%
Salbutamol suphate.	Antiasthmatic	HPC/HPMC K100/Sodium Alginate(0.5-2)%
Rofecoxib	Nonsteroidal anti-inflammatory	HPMC E-15 (3-4%) /PVA (3-4%) Glycerin, Polysorbate 80
Allopurinol	Prevent and treat oral mucositis	Sodium Alginate (300 cps,500cps,1000 cps), Pullulan,(1.5-4)% Polygalacturonic acid
Desloratadine	Antihistaminic	Maltodextrine and HPMC E-5; PEG 400/glycerol
Sumatriptan Succinate	Antimigraine	HPMC E-5,HPMC E-15,PEG 400,PVP,
Cetirizine hydrochloride	Second generation Antihistaminic	Pullulan(0.5%), PEG 400 HPMC E-3/HPMC E-5/HPMC E-15 (1-4%); PEG 400
Amlodipine Besylate	Antihypertensive	HPMC E3,HPMC E5,HPMC E15,Methyl cellulose, Poly vinyl pyrrolidone K30

The dissolution medium selected should mimic the saliva. Many times the dissolution test can be problematic due to tendency of the strip to float onto the dissolution medium when the paddle apparatus is employed. ^[6]Murata et al. performed dissolution studies in plastic dish. Films were positioned in a plastic dish, and 10mL of the dissolution medium preheated to 37°C was added. The dish was shaken at 300 rpm in a shaker incubator at 37°C. ^[18]

Assay/drug content and content uniformity

This is determined by any standard assay method described for the API in any of the standard pharmacopoeia. Content uniformity is determined by estimating the API content in individual strip. Limit of content uniformity is 85–115% of average drug content. ^[6]Physical form (crystalline or amorphous) of the drug molecule inside the film can be easily determined by X-ray crystallographic analyses.^[^16]

Surface pH

The surface pH of fast dissolving strip should be determined to investigate the chances of any side effects in vivo. An acidic or alkaline pH may cause irritation to the oral mucosa; therefore it should be closer to the pH of the saliva i.e. 6.2–7.4. ^[16]

CONCLUSION:

Several ‘fast dissolving oral strips’ have already been entered in the market. Compared to some of the complicated and expensive process (like lyophilisation, spray drying) used in manufacturing various dosage forms, oral strips are relatively easy to fabricate. Being a consumer-friendly alternative, this delivery platform shows commercial potential capacity for future in pharmaceuticals.

ABBREVIATIONS:

MDDDS: Mouth dissolving drug delivery system

ODT: Orodispersible tablet

FDF: Fast dissolving films

OS: Oral strips

HPC: Hydroxy propyl cellulose

HPMC: Hydroxypropyl Methyl Cellulose

PVA: Poly vinyl alcohol

PEGs: Polyethylene glycols

DE: Dextrose equivalent

ICH: International Conference on Harmonization

TEC: Triethyl citrate

ATBC: Acetyltributyl citrate

SEM: Scanning electron microscopy

CDER: Centre for Drug Evaluation and Research

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