Review on: Oral dissolving film: An Emerging Platform for Rapid Drug Delivery

In 1970s fast dissolving drug delivery system were developed as an alternative to traditional drug delivery system like syrup, tablet ,capsule. Recent technology advancement have diverted many drug company to explore new prospective in this technology tom provide  fast, accurate dosing that is expected to increase compliance, particularly among Children.This method provide a number of significant advantages over the traditional solid dosage form such as tablet, capsule and syrup. Oral dissolving film is one amongst the new approach to increasing patient acceptance dissolution.[2,14,21]

It is a novel drug system for the oral delivery of drug.this delivery system consist of very thin oral strip.It is used for geriatric and paediatric patient who had difficulty ingestion typical oral solid dosage form. The oral film placed on the patient tongue or oral mucosal tissue, the film hydrate rapidly and adhere on to the location of action. Oral dissolving film which disintegrate or dissolve within second when placed in the mouth without drinking of water or chewing it dissolve rapidly  and release active pharmaceutical ingredients for systemic absorption. Oral mouth  dissolving film improve patient compliance fast dissolving film easy to use especially for the patient who have difficult swelling pill such as child elderly.The ability of oral film dissolve quickly on require and the dosage can be administered directly. The film designed to disintegrate within a second upon contact with the environment of the oral cavity provide quicker onset of therapeutic effect. The large surface area of the film expose to the moist oral environment accelerate the disintegration process,Ensuring that the drug is quickly available for absorption, either through[for directly enter to the blood stream]. Oral film avoids swallowing Issue . There’s for fast dissolving film have become a popular oral dosage form for various medicaments.[1,12,13] 

United state food and  drug administration [USFDA] define the fast dissolving film as a thin , flexible , non friable polymeric film strip containing one or more dispersed dissolve active pharmaceutical ingredients .  The objective of the  present research work was to develop fast dissolving oral film disintegrating within few second to enhance the convenience of administration to the patient to improve compliance. Mouth dissolving film also know as an fast dissolving film , quick dissolving Film , rapid dissolving film , oral thin film [OTC] etc. The formulation developed was simple , easy to prepare and economical with great applicability and also giving faster in-vitro drug dissolution rate as compare to tablet. Oral dissolving film should have ability to promote through oral mucosal layer. Fast dissolving film are preferred in hydrophilic in nature [41,62]

Oral thin film are less sensitive to environmental condition like temperature and humidity. Oral thin film provides excellent mouth feel produced by use of flavour and sweeteners . Various hydrophilic polymers which provide rapid dissolution acceptable mechanical properties and good mouth feel quality are used a film forming agent.[63]

Water soluble polymer are used film formers as they provide rapid disintegration , good mouth feel , and mechanical strength to the films.   Variety of polymers are used for  preparation of film like gelatin , xanthum gum , hydroxyl propyl methyl cellulose , modified starch , hydroxyl ethyl cellulose etc.[35,45]

Fig-1: oral fast dissolving film

Special feature of mouth dissolving film

1-mouth dissolving film are thin and elongated .

2-it show a fast disintegration within 1 minute .

3-films are available in various size and shape.    

4-oral film are excellent mucoadhesion.                        

5-fast disintegration and rapid release [3,4,5

Ideal characteristics of suitable drug candidate

1-the drug have pleasant taste.

2-the drug with smaller and moderate molecular weight are preferable.

3-the drug should have good solubility and stability in water as well as saliva .

4-it should be partially ionized at the PH of oral cavity .

5-it should have ability to permeate oral mucosal tissue [6,7,8]

Advantage

1- No need of water swallow

2- Available in various size and shape

3-Hydrate and dissolve oral cavity within a fraction of second

4-Fast disintegration and dissolution

5-Taste masking

6-Improved patient compliance

7-Improved oral absorption and bioavailability

8-Rapid onset of action

9- Enhanced stability      

10 - Minimised first pass metabolism [8,9]

Disadvantage

1-It is hygroscopic in nature so it must kept in dry places

2-Packing of films require special equipment and it difficult to packing

3-Need special packing has they must be protected in to oral film

4-Eating and drinking may become restricted

5-It takes moisture from atmosphere

6-Dose uniformity is a challenge [10,11]

 Overview of oral cavity

The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The oral mucosa in general is intermediate between that of the epidermis and intestinal mucosa in terms of permeability. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. There are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa.[42,46,47]

Sublingual gland

Salivary gland are present in the floor of the mouth underneath the tongue. Sublingual gland are also know as the salivary gland that are located beneath the tongue secrete saliva which get mixed with food , so get food gets lubricated , formed in to a soft bogus and can be easily swallowed. Absorption of the drug is directly  from the site in to systemic circulation owing to its relatively lesser thickness, high permeability and rich blood supply the are also known as sublingual gland. They produce mucin in turn produce saliva.oral cavity is lined with mucous membrane which comprises of squamous cell and mucus gland. Salivary gland contain the group of cell which secrete saliva in to the mouth through salivary duct. Salivary gland includes comprise of parotid , submandibular and sub maxillary glands . The fluid which is produced by the gland get mix with food , so the food gets easily chewed , so it can be said the absorption is directly proportional to layer thickness .[23,64]

The absorption of drug follow in this way sublingual > buccal > gingival > palatal . Due to high permeability and rich blood supply , the sublingual route can produce rapid onset of action so the drug with can short delivery period can be delivered.

Fig : 2 - overview of oral mucosa

Mechanism of absorption

Sublingual administration 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 braciocephalic vein and are then drained into the systemic circulation. Upon sublingual administration drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth.

The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane .The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route and is only surpassed by hypodermic injection.[15]

Classification of fast dissolving film and there property

[16,17]

Classification of the fast dissolving technology

Fast dissolving technology can be divided in to three group [^3,18]

1: Lyophilised system

The technology behind these systems entails forming tablet-shaped units from a drug suspension or solution with other structural excipients using a mould or blister pack. In the pack or mould, the units or tablets are frozen and lyophilised. The resulting units are extremely porous, allowing for rapid water or saliva penetration and disintegration.

2: Compressed tablet- based system

This system is made using standard tablet technology and excipients that are compressed directly.Tablet technologies vary in hardness and friability depending on the manufacturing method. When compared to a standard tablet, the speed of disintegration for fast dissolve tablets is achieved by formulating with either water soluble excipients super disintegrant or effervescent components, allowing rapid penetration of water into the core of the tablet

3: Thin film strip

Oral films, also known as oral wafers, evolved from the confection and oral care markets in the form of breath strips over the last few years and became a novel and widely accepted form by consumers for delivering vitamins and personal care products. FDFs are now a proven and accepted technology for the systemic delivery of APIs in over-the-counter (OTC) medications, and they are in the early to mid- development stages for prescription drugs.

This has been attributed to the consumer success of breath freshener products like Listerine Pocket Paks in the US consumer market. To create a 50-200 mm film, such systems employ a variety of hydrophilic polymers. The film is made in large sheets and then cut into individual dosages units for packaging in a pharmaceutically acceptable format.

Comparison between oral film and oral disintegrating tablet

                                                                                                                                      [18,19,20]

Formulation of fast dissolving film

Fast dissolving oral film includes various ingredient for its formulation such as as :

 Active pharmaceutical ingredient

 Film forming polymers

 Plasticiser

 Super disintegrates

 Sweetening agent

 Saliva stimulating agent

 Surfactants

 Flavouring agent

 Colouring agent

 Stabilising and thickening agent

Formulation of FDFs involves the intricate application of aesthetic and performance characteristics such as taste masking, fast dissolution, physical appearance, mouth feel etc. From the regulatory perspectives, all excipients used in the formulation of OS should be Generally Regarded as Safe (i.e. GRAS-listed) and should be approved for use in oral pharmaceutical dosage forms. A typical composition includes various ingredients which are described in the Table

A typical composition contain the following ingredients.

Active pharmaceutical ingredients

The film composition contains 1-30% w/w of the active pharmaceutical ingredient. Always use low dose active pharmaceutical ingredients because high dose of drug are difficult to incorporate in fast dissolving film. A number of drugs can be used as fast dissolving oral film including anti-histamine, anti- diarrheal, anti-depressants, vasodilators, anti-asthmatic, antiemetic, mouth ulcer etc. [24,56]

Film forming polymer

Polymer is the major and most essential component of FDOFs. A variety of polymers are available for preparation of oral film and these are used in the concentration of about 40-45% w/w of total film weight but can be increased up to 65%w/w of film weight alone or in combination to obtain desired properties of oral film.

The film obtained should be tough enough so that there may not be any damage while handling or during transportation. The robustness of the film depends on the type of polymer and the amount in the formulation. The polymer used should be non-toxic non-irritant and goo wetting and spreading properties .the polymer should be reasonable price and widely available.[25,26,54,55]

Plasticisers

Plasticiser is an essential component of the oral film formulation. It aids in the improvement of the strip's flexibility and decreases its brittleness. Plasticisers play an important role in improving strip properties by lowering the polymer's glass transition temperature. The plasticiser chosen will be determined by its compatibility with the polymer as well as the type of solvent used in film casting. The use of plasticiser improves the flow of polymer and increases the polymer's strength. Plasticisers that are commonly used include glycerol, propylene glycol, di-butylpthallate, and polyethylene glycols, among others. Incorrect plasticiser use can cause film splitting or cracking.The use of certain plasticisers may affect the rate of drug absorption. The permanent should be imparted to the strip by the plasticiser used.Plasticisers should be compatible with the drug as well as other excipients used in strip preparation. With hydroxyl-containing plasticisers such as PEG, propylene glycol, glycerol, and polyols, cellulosic hydrophilic polymers were easily plasticised. Glycerol is a better polyvinyl alcohol plasticiser than diethylene glycol, which can be used for both hypromellose and polyvinyl alcohol films [27,57]

Saliva stimulating agent

The use of saliva stimulating agents is intended to increase the rate of saliva production, which will aid in the faster disintegration of the rapid dissolving strip formulations.In general, acids used in food preparation, such as citric acid, Malik acid, lactic acid, ascorbic acid, and tartaric acid, can be used as salivary stimulants. These agents are used alone or in combinations ranging from 2 to 6%w/w of the strip's  weight.[28]

Sweetening agent

Sweeteners have evolved into an essential component of formulations designed to be disintegrated or dissolved in the oral cavity. Natural and artificial sweeteners are both used in the formulation of fast dissolving films. Sweeteners are typically used in formulations at concentrations ranging from 3-6%w/w, either alone or in combination. Polyhydric alcohols such as sorbitol, mannitol, and isomalt can be combined to provide a good mouth-feel and cooling sensation. The classical source of the sweetener is sucrose , fructose , glucose ,liquid glucose and isomaltose . The sweetness of fructose is perceived rapidly in the mouth as compare to sucrose and dextrose.[29,30,59]

Surfactant

Surfactants are used as a solubilising, wetting, or dispersing agent, allowing the film to dissolve in seconds and release the active agent immediately. Sodium lauryl sulphate, benzalkonium chloride, bezthonium chloride, tweens, and other commonly used ingredients One of the most important surfactants is polaxamer 407, which is used as a solubiliser, wetting agent, and dispersant [6,58]

Flavouring agent

OFDF formulations should contain up to 10%w/w flavours. An individual's acceptance of an oral disintegrating or dissolving formulation is largely determined by the initial flavour quality observed in the first few seconds after the product has been consumed, as well as the after taste of the formulation, which lasts for at least 10 minutes. The flavour chosen is determined by the type of drug to be included in the formulation. It was discovered that age has a significant impact on taste fondness. The elderly prefers mint or orange flavours, whereas the younger generation prefer fruit punch, raspberry, and so on. Flavouring agents can be chosen from a variety of synthetic flavour oils, oleo resins, and extracts derived from various parts of the plant. Plants with leaves, fruits, and flowers Flavours can be used alone or in combination. Flavour oils include peppermint oil, cinnamon oil, spearmint oil, and nutmeg oil, whereas fruity flavours include vanilla, cocoa, coffee, chocolate, and citrus. Fruit essences include apple, raspberry, cherry, and pineapple, to name a few.[31,32,60]

Colouring agent

There is a wide variety of colours available, including FD&C colours, EU colours, Natural colours, and custom Pantone-matched colours. Some saliva stimulating agents may be added to improve disintegration and speed up release. Citric acid, tartaric acid, malic acid, ascorbic acid, and succinic acid are some of these agents. [33,34]

Stabilising and thickening agents

The stabilising and thickening agents are employed to improve the viscosity and consistency of dispersion or solution of the strip preparation solution or suspension before casting. Natural gums like xanthan gum, locust bean gum, carragenan and cellulosic derivatives can be used in the concentration up to 5%w/w as thickening agents and stabilising agents.[45]

Manufacturing method

1: Solvent costing method

2: Semi solid casting method

3: Hot melt extrusion method

4: Solid dispersion extrusion method

5: Rolling method

Solvent casting method

Fast dissolving buccal films are preferably formulated using the solvent casting method, whereby the water soluble ingredients are dissolved to form a clear viscous solution and the drug along with other excipients is dissolved in suitable solvent then both the solutions are mixed and stirred and finally casted in to the Petri plate and dried.[35,61]

Semi solid casting method method

In this method, a solution of water-soluble film forming polymer is prepared and added to a solution of acid insoluble polymer (e.g., cellulose acetate phthalate, cellulose acetate butyrate) prepared in ammonium or sodium hydroxide. The appropriate amount of plasticiser should then be added to form a gel mass. Finally, using heat-controlled drums, the gel mass should be cast into the films or ribbons. The thickness of the formed film will be between 0.015 and 0.05 inches. In this method, the acid insoluble polymer to film forming polymer ratio must be 1:4.[36,44]

Hot melt extrusion

In the hot melt extrusion method, as shown in Fig.9, the initial mass must be dried and obtained with carriers as the drug is mixed with carriers and obtained as solid mass, then the mass is introduced into an extruder divided into four zones with varying degrees of temperature, zone 1 at 800°C, zone 2 at 150°C, zone 3 at 1000°C, and zone 4 at 650°C. To process the granules inside the barrel of the extruder for 3-4 minutes, set the extruder speed to 15 rpm. After being pressed into a cylindrical calendar, the film is obtained. Hot melt extrusion has many advantages, such as limited operation units. It reduces waste and eliminates the need for the Because of intense mixing and agitation, the use of solvent or water (anhydrous) results in uniform content.[37,53]

Solid dispersion extrusion

Immiscible components are extruded with drug in this method, and then solid dispersions are prepared. Finally, dies are used to shape the solid dispersions into films.[41,52]