Rapid Dissolving Film as Platform for Drug Delivery Systems: A Review

Fast dissolving drug delivery systems were first developed in late 1970 to serve as an alternative to conventional dosage forms, for instance, fast disintegrating tablets and capsules for geriatrics and pediatric patients having difficulty in swallowing conventional dosage forms. A typical ODF is usually equal to the size of a postage stamp ^[1]. Fast dissolving drug delivery systems include orally disintegrating tablets (ODTs) and Rapid dissolving films (RDFs). The Centre for Drug Evaluation and Research (CDER) defines ODTs as a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue” ^[2]. USFDA defines OTFs as, “a thin, flexible, non-friable polymeric film strip containing one or more dispersed active pharmaceutical ingredients which is intended to be placed on the tongue for rapid disintegration or dissolution in the saliva prior to swallowing for delivery into the gastrointestinal tract” ^[3]. RDFs are coming into their own as mainstream pharmaceutical products. Statistics have shown that four out of five patients prefer orally disintegrating dosage forms over conventional solid oral dosages ^[4]. These factors, coupled with convenience and compliance advantages, have been (and will continue to) pave the way for ODT and RDF drug product growth. This review highlights the various types of polymers, the different types of manufacturing techniques and evaluation tests for the oral films.

Need for preparing fast dissolving oral thin films:

Oral dosage forms are the most common drug administration method due to the ease of administration, high patient convenience and compliance, minimum aseptic conditions, and flexibility in designing the dosage forms. However, there are several limitations for geriatric, pediatric, or dysphagic patients, people with difficulty in swallowing, and even animals. As an alternative method to overcome these limitations, orally disintegrating systems were developed, aiming for a fast release of the drug without water ingestion, also enabling drug absorption directly through oral mucosa to enter systemic circulation, avoiding first-pass hepatic metabolism ^[5]. There is no need for water or measuring and upon melting; the dose of medicine is swallowed. Absorption of drug by oral mucosa into systemic circulation is an attractive approach because it is highly vascularized and hence highly permeable. Therefore, fast dissolving films have become a popular oral dosage form for various medicaments which provide rapid disintegration due to large surface area and hence improve patient compliance. Thus, fast dissolving oral thin film drug delivery systems are being developed ^[6].

Advantages of RDF: ^[7-8]

An RDF should have the following ideal features:

1. It should taste good.

2. Drugs should be very moisture resistant and soluble in the saliva.

3. It should have appropriate tension resistance.

4. It should be ionized in the oral cavity pH.

5. It should be able to penetrate the oral mucosa.

6. It should be able to have a rapid effect.

Advantages of RDF:

1. RDF should be thin and flexible, but stable to guarantee a robust manufacturing and packaging process and ease of handling and administration.
2. Does not require water use - Can be used safely even when access to water is not possible (such as travel).
3. Surface of the FDF should be smooth and uniform
4. Ease of administration for patients who are mentally ill disabled and uncooperative.
5. There is little or no residue in the mouth after application
6. Bypasses the gastrointestinal tract and thus increasing bioavailability
7. Low dosage and low side effects
8. It provides more accurate dosage when compared to liquid dosage forms
9. No need to measure, which is an important disadvantage in liquid dosage forms
10. They should provide an acceptable taste and a pleasant mouth-feel
11. Improves the absorption rate and amount of drugs
12. Provides enhanced bioavailability for less water-soluble drugs, especially via giving a large surface area while rapidly dissolving

Disadvantages of RDF: ^[7,9]

1. Dose uniformity is difficult to maintain
2. Only those active pharmaceutical ingredients having small dose can be incorporated.
3. Require expensive packaging.
4. Since RDFs dissolve quickly, dose termination is impossible.
5. RDFFs are not official in any pharmacopoeia.
6. - Is hygroscopic by nature. For this reason, it causes difficulties for long-term protection.

Classification of RDF: ^[10].

There are three subtypes of oral fast dissolving films:

1.Flash release.

2.Mucoadhesive melt?away wafer.

3.Mucoadhesive sustained release wafers.

Formulation Of Fast Dissolving Oral Thin Films:

Numerous excipients used in the formulation of mouth     dissolving     film     are     film  formers, plasticizers, sweetening agents, saliva stimulating agents, flavouring   agents, colouring agents, etc. ^[11]. ODFs are fast disintegrating thin films having an area ranging from 5 to 20 cm2 in which drug is incorporated in the form of matrix using hydrophilic polymer.  Active pharmaceutical ingredient can be incorporated up to 15 mg along with other excipients i.e., plasticizers, colorants, sweeteners, taste masking agents etc. Plasticizer increases workability, spread-ability and flexibility of films thereby reducing the glass transition temperature of polymers ^[12]. From the regulatory point of view, all the excipients used should be generally regarded as safe (GRAS) listed and should be used as per Inactive Ingredients Limit (IIG limit). Various components of fast dissolving oral thin films are shown in Table 1.

Table 1: General composition of fast dissolving Rapid dissolving films ^[8]

Drug Selection:

The ideal key characteristics for a drug candidate are that it shall have low molecular weight, low dose, high solubility and permeability (BCS – Class I drug). At present, researchers are exploring oral thin films of BCS – Class II drugs as well as organoleptic character like ‘taste’ plays a pivotal role in formulating a drug as RDFs to gain the subject or patient compliance ^[14]. The amount of active agent used in the film is about 65 % by weight ^[15], and may broadly range from 0.01 % to about 80 % by weight of the dried RDFs ^[16].

Ideal characteristics of APIs to be incorporated into fast dissolving oral thin films:

1. Low dose
2. Palatability
3. Small molecular weight
4. Solubility and stability in saliva

Some of the suitable candidates for incorporation into thin film formulation are given in Table 2.

As per, BCS, USFDA designates Class II for compounds that are highly permeable and are low soluble; Class IV is designated for compounds whose solubility and permeability are low. For compounds that belong to class II or IV obtaining a bioavailability that is compatible with the therapeutic effect requires formulating the active ingredient in the form of a solution or solid dispersion in a polymer. However, stabilizing such solutions or dispersions is difficult thus leading to recrystallisation and eventually loss of bioavailability over time. One alternative to this problem in dealing with poorly soluble active ingredients is size reduction (by milling or other know techniques) of the compound to augment the rate of solubilization, Noyes-Whitney equation – a classical equation developed relative to the speed of dissolution of a substance in a solvent, and thus maximize its in-vivo absorption. For instance, a nanosuspension of active ingredient can be prepared by adding film forming polymers just before they are incorporated into the RDF formulation. Preparing them just before incorporation helps in fixing the issues associated with Ostwald maturation – a phenomenon that occurs during the aging of suspensions. Therefore, nano-suspension of an active ingredient helps in obtaining homogeneous films stable over time ^[17].

 Masking Unpleasant Taste of the API:

Another extremely challenging part of delivering a drug via thin film formulation is to deliver it without the user experiencing unpleasant taste. The film formulation once it gets easily dissolved in oral cavity it enables a drug to be absorbed in the oral cavity, causing bitter taste during drug absorption and the perception of the same happens via the taste receptors. Accordingly, new ideas for blocking or masking such nasty taste are required. Obscuration is an act of hiding or concealing something. In the present review, obscuration methodologies to conceal the bitter taste of the drug in RDF’s are discussed.

1. The bitter tasting drug Sildenafil Citrate was successfully taste masked using sodium hydroxide and sodium bicarbonate. The ratio of sodium hydroxide to sodium bicarbonate is 3:6.4 to 12.8 % (w/w) of the drug [18].
2. Similarly, Ketoprofen has unpleasant bitter taste with a burning sensation. It even irritates the throat mucosal membrane during swallowing. Masking the taste of such a drug is definitely a hard-core challenge for the formulator. Initially, the researchers attempted taste masking using alkaline agents. However, those attempts could not completely mask the taste [19].
3. Taste masking for the active agents could also be achieved using a film composition; (i) a film forming polymer and (ii) an active composition including a granulated particle with taste masking coat of a reverse-enteric polymer composition and a water-insoluble polymeric composition, each present in an amount of about 9:1 to about 1:9 by weight of the coating composition and the coated active is insoluble at a neutral pH[20].

Attempts to mask the taste of active ingredient may further reduce maximum drug load. Nonetheless, obscuration for highly bitter active ingredients is almost impossible.

Film forming polymers: ^[10]

A variety of polymers are available for preparation of fast dissolving oral films. The use of film forming polymers in oral films has attracted considerable attention in medical and nutraceutical applications. The selection of film forming polymers, is one of the most important and critical parameters for the successful development of film formulation. The polymers can be used alone or in combination to provide desired film properties. The polymers used in oral film formulation should be:

Ideal properties of polymers:

1. Nontoxic and nonirritant
2. Devoid of leachable impurities
3. Should not retard disintegration time of film
4. Tasteless.
5. Should have good wetting and spread ability property
6. Should have sufficient peel, shear, and tensile strength
7. Should not alter properties of the active pharmaceutical ingredient or other excipients of the formulation
8. Inexpensive
9. Should not aid in causing secondary infections in oral mucosa.
10. Should have optimum peel strength and tensile strength

Fig. 1. Oral films for drug delivery.

Natural polymers:

Gum polysaccharides:

Gum polysaccharides like gum arabic, κ-carageenan, and sodium alginate are some of the potential polymers for film formation. They can be used in combination with others so as to provide primary film structure and rapid dissolving characteristics. Some examples are shown in Table 5.

Advantages:

1. Addition of these can improve can improve dissolution of films in mouth
2. Reduces tensile strength only to a minimal extent

Table 5: Film composition and the resulting dissolution time

Gelatin:

Gelatin is set up by the thermal denaturation of collagen, detached from animal skin, bones, and fish skins. Gelatin is a conventional term for a blend of filtered protein divisions acquired either by partial acid hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin) of animal collagen and additionally may likewise be a blend of both ^[22]. It is readily soluble in water above 40ºC and it forms viscous solution of randomly coiled polypeptide chains. Mammalian gelatins have better physical properties and thermostability than most of the fish gelatins due to their higher amino acid content. The properties and film forming ability of gelatin is directly related to the molecular weight of the gelatin, i.e., the higher the average molecular weight, better the quality of the film. The molecular weight distribution depends mainly on the degree of cross-linking of collagen fibers and the extraction procedure used. Gelatin films could be formed from 20-30% gelatin, 10-30% plasticizer (glycerin or sorbitol) and 40-70% water followed by drying the gelatin gel ^[23].

Advantages of gelatin films:

1. Dissolve rapidly
2. Films are excellent carriers for flavors
3. Films produce a smooth mouth feel ^[24]

Ghorwade et al. formulated Montelukast sodium fast dissolving films using gelatin as a film base (3.54% w/w). It was observed that films had desired tensile strength and optimum in vitro dissolution time ^[25].

Pullulan:

Pullulan is an exopolysaccharide produced on the surface of microbial cells. It is produced mainly by yeasts such as fungus Aureobasidium pullulans and other microorganisms like Cytaria darwinii, Cytaria harioti, Teloschistes flavicans, Tremella mesenterica, Rhodotorula bacarum, and Cryphonectria parasitic. In pullulan production, the main requirements are carbon source, nitrogen source, and other essential nutrients for A. pullulans' growth. Pullulan is a linear glucan with repeating units of maltotriose. Each maltotriose unit constitutes two α-(1 → 4) bonded glucopyranose rings interlinked by α-(1 → 6) linkage. When partial acid hydrolysis happens, there are rare forms of pullulan constituting panose and isopanose as repetitive units ^[5]

Advantages of pullulan:

1. It is non-hygroscopic
2. It is impermeable to oxygen
3. It is biodegradable, edible, odorless, tasteless ^[26]
4. No branching in structure in contrast to gum arabic, forming much stronger films
5. It is easily soluble in cold and hot water to make clear and viscous solution
6. It also has high adhesion and film forming abilities
7. It is a nonionic polysaccharide and is blood compatible, biodegradable ^[27]
8. It is non-toxic, non-immunogenic, non-mutagenic and non-carcinogenic
1. Pullulan films are thermally stable and possess anti-static and elastic properties
10. Pullulan films can be developed into compression molding
11. Pullulan films are highly water soluble, colorless, tasteless, odorless, transparent and flexible

In above formulation, hydroalchoholic vehicle was used ^[28].

Starch:

Starch, an abundant polysaccharide, presents two macromolecules: amylose and amylopectin. Amylose is a linear polymer of α-1,4 anhydroglucose units that forms a colloidal dispersion in hot water and has excellent film-forming ability. Amylopectin is a highly branched polymer of α-1,4 anhydroglucose chains linked by α-1,6 glucosidic branching points, being completely insoluble. Starch can be obtained from various sources such as botanical species like corn, wheat, potato, cassava, and rice, and the starch of each origin has specific compositions and different properties ^[5].

Advantages of starch:

1. Starch films are biodegradable
2. Starch films are transparent or translucent
3. Starch films are flavorless, tasteless and colorless ^[29]

Disadvantages of starch:

1. Starch films have poor mechanical strength
2. Film forming conditions have an effect on crystallinity of the starch films and their properties

Films of high-amylose corn starch or potato starch were more stable during aging, lost little of their elongation and had slight or no increase in tensile strength ^[38]. Films from cassava starch had good flexibility and low water permeability, indicating the potential application as edible film former ^[30]. Modified starch, due to its low cost, is being widely used in combination with pullulan.

Lycoat:

Lycoat is a novel granular hydroxypropyl starch polymer obtained from pea starch that has been designed especially for fast dissolving oral thin films. It is manufactured by Roquette Pharma.

Advantages of Lycoat:

1. Lycoat disperses easily in cold water without formation of lumps
2. It can be used alone as film forming polymer to formulate fast dissolving oral thin films with excellent functionality without the need of additional film forming agent
3. It is neutral in taste
4. It forms films without the use of organic solvents
5. APIs can be loaded in crystalline form or they can be solubilized in an organic solvent ^[31]

Maltodextrin:

Maltodextrin is a non-sweet nutritious oligosaccharide, used as a food additive, being easily digestible and absorbed. It is produced by hydrolysis from starch and is found commercially as a white hygroscopic powder. Three to nineteen units of D-glucose constitute maltodextrin. The bonds between the glucose units are mainly linked to the glycosidic bond α-(1 → 4). Maltodextrin is classified according to the dextrose equivalent (DE), ranging from 3 to 20. The smaller the glucose chain, the higher the DE and, consequently, more soluble . Maltodextrin has the following properties: good film former, odorless, good solubility, low hygroscopicity, excellent carrier, non-toxic, edible, soluble in water, and poorly soluble or even insoluble in anhydrous alcohol and maltodextrin is used in the range of 2-10% w/w ^[44].

Chitosan:

Chitosan is produced by partial deacetylation of chitin, a natural polysaccharide found in exoskeletons of arthropods such as insects and crustaceans, and fungi cell walls. Chitin is made up of Acetylglucosamine units, while chitosan is a cationic polymer consisting of a linear sequence of monomeric units of 2-acetamido-2-deoxy-Dglucopyranose 2-amino-2-deoxy-D-glucopyranose linked by β (1 → 4) glycosidic bonds. Chitin is insoluble in common solvents due to its highly crystalline structure ^[5].

Synthetic polymers:

Hydroxypropyl methyl cellulose (HPMC):

Hydroxypropyl methylcellulose (HPMC) and starch are among the polymers which could be used in the formulation of orally disintegrating films. Hydroxypropyl methylcellulose (HPMC) is a semisynthetic ether consisting of a cellulose chain with substituted methoxy (OCH3) and hydroxypropyl groups (OCH2CHOHCH3). The hydroxypropyl methylcellulose is a polymer used as a pharmaceutical excipient and is widely applied in the development of orally disintegrating films ^[32].  HPMC or Hypromellose is partly O-methylated and O-(2-hydroxypropylated) cellulose ^[34]. Depending upon the viscosity grades, concentrations of 2-20% w/w are used for film forming solutions ^[35]. Lower grades of HPMC like HPMC E3, HPMC E5and HPMC E15 are particularly used for film formation because of their low viscosity ^[36]. Lower grades are used with aqueous solvent. Additives are incorporated to improve specific properties of films. Several studies have been carried out to investigate the influence of additives on physico-chemical properties of HPMC films. Lipids such as waxes, triglycerides (tristearin), fatty acids (stearic acid, palmitic acid) result in decreased water affinity and moisture transfer due to their high hydrophobic properties ^[33].

Advantages of HPMC:

1. It has good film forming properties and excellent acceptability
2. HPMC forms transparent, tough and flexible films in aqueous solutions

• Nishimura et al. formulated Prochlorperazine oral disintegrating film using of HPMC (7.4% w/w) in combination with low substituted HPC (1.3% w/w). Films showed excellent stability and desired dissolution profile ^[36].
• Shimoda et al. prepared fast dissolving oral thin films containing Dexamethasone using HPMC (7.4% w/w) in combination with low substituted HPC (1.3% w/w). 90% of Dexamethasone was found to be dissolved within 5 minutes ^[37].
• Raju S et al. formulated and evaluated flash release oral films of Metoclopramide hydrochloride. The formulation released 99.40% of drug within 30 seconds ^[38].
• Joshi et al. formulated and evaluated mouth dissolving films of Domperidone. The film was prepared by solvent casting technique utilizing HPMC E15 as film forming agent and PEG 400 as plasticizer. The film containing HPMC E15 (500 mg) showed greater dissolution (more than 75% within 15 minutes), satisfactory in vitro disintegration time (45 seconds) and suitable physico-mechanical properties ^[39].
• Orally disintegrating film formulation of Diclofenac is shown in Table 7.

Poly (vinyl alcohol) (PVA), is one of the most widely used. It is a non-toxic, transparent synthetic polymer with high biocompatibility and biodegradability. It is also water soluble, has good film forming properties, highly polar, and forms numerous positive interactions through hydroxyl groups therefore, it shows a potential to interact and be blended with other polar polymers ^[41]

Advantages of PVA:

1. PVA has excellent film forming and emulsifying properties
2. It is resistant to oil and grease
3. PVA is odorless and nontoxic
4. PVA has high oxygen and aroma barrier properties
5. PVA has high enough tensile strength and satisfactory flexibility
6. High biodegradability ^[42]

Table 8: Ondansetron Rapid Film formulation.

Polyethylene oxide (PEO):

Polyethylene oxide is a synthetic polyether. It is available in a wide range of molecular weights. Usually 3-5% w/w solution is used for film formation ^[43].

Advantages of PEO:

1. PEO has a high melting point
2. It has good structural integrity
3. It has low glass transition temperature
4. It has low toxicity and biocompatibility
5. It is highly hydrophilic with good film forming capacity

Table 9: Formulation of Donepezil hydrochloride orally disintegrating film ^[44].

Polyvinyl pyrrolidone (PVP):

Polyvinylpyrrolidone (PVP), also called as Povidone, is a synthetic polymer obtained by radical polymerization of the monomer, N-vinylpyrrolidone. Soluble polyvinyl pyrrolidoneis synthesized by radical polymerization of N-vinyl pyrrolidone in 2-propanol. The soluble PVP products of pharmaceutical quality are designated as Povidone in the USP. Soluble PVP products are marketed under bran name Kollidon^®. PVP range comprises of products of different K-values. The K-value is associated with themean molecular weight.Itis included as part of the trade name and is calculated from the relative viscosity in water ^[33].

Table 10: Different grades of PVP and their mean molecular weight.

Advantages of PVP:

1. PVP is readily soluble in water and most other solvents
2. PVP has a very good film forming capacity
3. It has ability of to form a water-soluble complexes with insoluble APIs which can improve their release rate and solubility
4. It is non-toxic and chemically inert
5. It is temperature resistant, pH-stable and colorless
6. Films are clear, glossy and hard ^[45]

Major manufacturing companies of the polymers are shown in Table 11.

Table 11: Polymers and their manufacturers

Plasticizers:

Plasticizers are applied to enhance the pliability or elasticity which increases the automated holdings of film such as tensile potency and expansion of the mouth dissolving film (MDFs). Plasticizer reduces the brittleness of mouth dissolving film (MDFs) by enhancing the strength of the polymer. Selection of plasticizers depends on its similarity with polymers, drugs as well as other excipients. With the help of plasticizer, the flow properties of polymer will get superior and it also enhances the robustness of the polymer. Some examples of plasticizers used in preparation of mouth dissolving films (MDFs) are: - Polyethylene glycol (PEG), low molecular PEG, polypropylene glycol, dibutyl, castor oil, Glycerol, diethyl phthalate. Glycerol is better plasticizer for films prepared by using PVA. Polyethylene glycol (PEG) is used for both HPC and PVA films ^[46].

Surfactants are adopted to improve the wettability, solubility and dispersibility of the films so that the film gets dissolved within seconds and release the dynamic pharmaceutical agent rapidly. Most widely utilized surfactants are Sodium lauryl sulphate, Tween 80, Polaxamer 407. ^[46].

Sweetening agents:

A sweetener has begun to be essential components in both food products and in pharmaceutical products that are intended to be splinter or dissolved in the oral cavity. Sweetening agents are utilized to disguise the bitter taste of the drugs. Two types of sweeteners are adopted to enhance the savour of the mouth dissolving formulation they are natural sweetener and synthetic sweetener. Artificial sweetening vehicle has aquire more popularity in pharmaceutical formulation. Natural sweetening vehicle are ribose, glucose, mannose, fructose, galactose, sucrose, corn syrups or fructose. Whereas examples of artificial sweeteners are saccharin, sucralose and aspartames ^[46].   The use of natural sugars in such preparations needs to be restricted in the case of diabetic patients ^{[47, 48]}. Due to this reason, the artificial sweeteners are more popular in food and pharmaceutical preparations. Saccharin and aspartame are the first generation of the artificial sweeteners. These are found to be carcinogenic and are banned in some countries. Research is being carried out in order to prove find out the extent of carcinogenicity. Acesulfame-K, sucralose, alitame and neotame are the second-generation artificial sweeteners. Acesulfame-K and sucralose have more than 200- and 600-time sweetness respectively. Neotame and alitame have more than 2000- and 8000-time sweetening power as compared to sucrose. Rebiana is the herbal sweetener which is derived from plant Stevia rebaudiana. It has more than 200–300-time sweetness ^[49].

Table 13: Role of Magnasweet^® and its concentration ^[82]

 Table 14: Sweetening agents, their brand name, manufacturer and concentration

Saliva stimulating agents:

The motive to utilize saliva brace agent is to raise the rate of blossoming of saliva as this direct enhance the disintegration time of mouth dissolving films (MDFs) and the film will dissolve faster in the oral cavity. Generally, food grade acids can be used as saliva stimulating agent ^[46]. Among them, citric acid is the most preferred one and is most widely used. These can be used alone or in combination. The stimulation of salivation can be measured by comparing the amount of resting flow and stimulated flow at equal time under same conditions ^[91].

Super-disintegrants:

 One of the most attractive aspects of films is their quick disintegration/ dissolution after contact with saliva in the mouth, leading to improved acceptance and compliance among pediatric, geriatric, and dysphagic patients ^[30]. Super-disintegrants provide quick disintegration as a result of combined effect of both swelling and water absorption, when they are added in the formulation. Super-disintegrants absorb water and swell which promotes the dispersibility of the system, thereby enhancing disintegration and dissolution. Strong interaction with water is essential for disintegration. Mechanism of disintegration includes swelling, wicking, deformation or combinations of any of these ^[92].

Food, Drug and Cosmetic (FD&C) has consent to the use of coloring agents while formulating mouth dissolving films (MDFs), the colour incorporated should not exceeding 1% w/w of the formulation, e.g., Titanium dioxide is most commonly used ^[29].

Flavoring agents:

The selection of flavor depends on the type of drug to be incorporated. The acceptance of the oral disintegrating or dissolving formulation by an individual depends on the initial flavor which is perceived in first few seconds after the dosage form is consumed and the after taste of the formulation, which lasts for at least about 10 minutes ^[95]. The following flavours are used in pharmaceutical preparation: menthol, cinnamon, clove, orange, mint, lemon, vanillin peppermint, apple and pineapple. They act by imparting flavours and odour of their own and have anesthetic effect on sensory receptors associated with taste ^[29].

Table 16: Flavors used for taste masking of different tastes ^[96]

Manufacturing processes overview: from the conventional to the innovative:

The two main techniques used to prepare oral films are solvent casting ^{[20, 21]} and hot melt extrusion. However, during the past few years some developments and innovative techniques have emerged. Some variants of these manufacturing methods of casting and extrusion have also been described and used alone or in combination, such as semisolid casting and solid-dispersion extrusion ^[23]. Inventive manufacturing processes as the rolling or printing ^[22]. methods have also been described.

Manufacturing Process Overview ^[29]

Solvent casting:

This is the most widely used method for manufacturing of fast dissolving oral thin films. Figure 3 indicates equipment used for solvent casting method.

Steps

1. Water soluble polymers are dissolved in water
2. Other excipients and APIs are dissolved in aqueous solution under high shear
3. Both the mixtures are combined to give viscous homogenous solution
4. The solution is deaerated and transferred to the casting station where solution is cast into film on a release liner of thickness 30-120 cm

Film coating techniques include knife-over-roll, reverse roll, slot-die, gravure cylinder and Mayer rod coating

5. Casted film is dried in oven
6. Dried films are cut into desired shape
7. Film product is investigated for desired qualities
8. Final inspection is done
1. Product is sent for packaging

The preferred finished film thickness is 12-100 μm, although various thicknesses are possible to meet API loading and dissolution needs. Solvents used for manufacturing oral thin films should be selected from ICH Class III solvents list ^[26].

Process parameters: ^[10]

1. Mixing temperature: 20- 90^o C
2. Agitation time: 40-120 minutes
3. Rotating speed: 1000-2000 RPM
4. Flow rate while defoaming: 80 litres/hour
5. Passage time during casting: 2-8 minutes
6. Drying temperature: 50-130^o C

Advantages:

1. The method is cost-effective
2. Preferred over hot melt extrusion as it involves no exposure of API to elevated temperature, which may cause degradation of heat-sensitive APIs
3. Films have better uniformity of thickness and better clarity
4. Films have fine gloss
5. Films are free from defects such as die lines
6. Films have flexibility and better physical properties

Disadvantages:

1. The polymer must be soluble in a volatile solvent or water
2. A stable solution with a reasonable viscosity should be formed
3. Formation of a homogeneous film and release from the casting support must be possible

Hot melt extrusion:

Figure indicates hot melt extruder.

Steps

1. The mass is prepared under controlled temperature and steering speed by mixing API with excipients
2. Mixture is melted in the extruder
3. The film is coated and dried in a drying tunnel
4. Then slitting is done
5. The films are punched, pouched and sealed ^[7]

Process parameters:

1. Screw speed: 15 rpm
2. Processing temperature: 650-1150^o C
3. Extrudate temperature: 650^o C
4. Final film thickness: 200 μm

Advantages:

1. No use of solvent or water
2. Fewer processing steps
3. Better alternative for poorly soluble drugs
4. Less energy required compared with high shear methods
5. More uniform dispersion because of intense mixing and agitation

Disadvantages:

1. Thermal degradation due to use of high temperature can take place
2. Flow properties of the polymer are essential for processing

Some recent technologies:

Electrospinning:

Electrospinning (ES) technology is mainly applied in the textile or filtration industry. The ES technology involves impact of high electric field on polymer solutions, thereby generating polymer fibers of submicron size when the surface tension of polymers is overcome by electric forces. The setup consists of a solution feeder and a high voltage power supply which is connected to a spinneret and a collector electrode. The solution on the spinneret electrode forms a droplet which can interact with electrostatic field. The droplet gains a cone-shape and thin jet can emerge from the tip of the cone. Fibers are drawn by electrostatic forces between the two electrodes and the solvent evaporates, resulting in solid nanofibers. The prepared non-woven web is removable from the grounded collector as a sheet. Immediate release from nonwoven system of electrospun nanofibers is also known as mat or web. The method involves mixing API with the liquefied polymer and electrospinning the solution onto a collecting element.

Advantages:

1. Electrospun polymer is capableof disintegrating aqueous medium within less than a minute due to its large surface area ^[103]
2. Wide versatility for application to different polymers

Electro-spraying: ^[104]

Electro-spraying is a recent method which can be adopted for the preparation of RDFs. It involves spraying a solvent under the influence of a high electric field. Here, the polymer is dissolved in a liquid and it is subsequently electro-sprayed, the polymer will be dispersed inside small droplets. Polymer particles can then be deposited on a substrate to form a continuous film. The deposition of polymer depends on the surface energy of the substrate and the polymer, the droplet or particle size at deposition and the viscosity of the polymer/liquid mixture at deposition. In the case that the solvent and other parameters are chosen such that a stable electrospray is obtained, the viscosity and the size of the particle/droplet are the two major parameters to control film characteristics.  The droplet size of the spray can be controlled with liquid flow, surface tension and the conductivity. Since liquid flow is also an important parameter to control spray stability, the conductivity is the most convenient parameter to influence the droplet size. The viscosity of a droplets at deposition depends on the polymer itself, but also on the quantity of liquid still present with the depositing polymer. The liquid content depends on the initial concentration of polymer and solvent and on the evaporation before deposition on the substrate. If the concentration of polymer becomes too high, electrospray will change into electrospinning. This will result in completely different film morphologies.

Drying Of Films:

Drying helps to maintain overall low temperature inside the film. Even if the film surfaces are exposed to a temperature above which the API degrades, the film interior may not reach this temperature. Due to this temperature difference, the API does not degrade. The films are dried for 10 minutes or less. Drying the films at 80° C for 10 minutes produces a temperature difference between the atmosphere and the film matrix of about 5° C. This means that after 10 minutes of drying, the temperature of the inside of the film is 5° C less than the outside exposure temperature. In many cases, drying times of 4-6 minutes are sufficient. Due to this temperature difference between the atmosphere and the film matrix, the films may be dried at high air temperatures without causing heat sensitive APIs to degrade. Once a sufficient amount of the volatile liquid has evaporated, further exposure to heat leads to uniform heat diffusion throughout the film. The components desirably are locked into a uniform distribution throughout the film, and the final shape of the film is established. It may be desired to form a viscoelastic solid rapidly. Although minor amounts of water may remain subsequent to formation of the viscoelastic film, the film may be dried further without affecting the desired heterogeneity of the film. Further drying forms the final film wherein, solvent is further removedso that only less than 6% of the solvent remains in the final film formulation ^[105].

Patented Technological Platform of Orodispersible Films: ^[29]

Bema:

BEMA drug delivery technology consists of a small, bioerodible polymer film which quickly adhere to the oral mucosa less than 5 sec with a backing layer that assures the unidirectional flow of the drug. BEMA stands for bioerodible mucoadhesive drug delivery system. BEMA films were designed to rapidly deliver either local or systemic level of drug across mucosal membranes for time sensitive conditions or to facilitate administration of drug with poor oral absorption. The multilayer buccal film can rapidly deliver dose of a drug to oral mucosa and dissolved completely within 15-30 min. This technology is developed to deliver several drug substances especially if quick onset of the action is required or oral dosing is not optimal or intravenous injections are unable. The first product developed and marketed using BEMA technology was onsolis (fenatyl buccal soluble film) in 2009 for the management of cancer pain in opioid tolerant adults.

Smart Film:

Smart Film technology was developed by Seoul pharma, A south Korean pharmaceutical company, smart film has a high dose loading capacity about 140mg and are capable of incorporating both hydrophilic and hydrophobic drugs, bitter taste can be masked by taste masking agents. In 2012 the company launched Vultis(® containing 140.45 mg of sildenafil citrate, the sildenafil smart film is a fast-dissolving film its bitter taste is masked by sodium hydroxide and magnesium oxide.

Biodegradable transmucosal film:

Auxilium pharmaceuticals have developed biodegradable transmucosal films that adhere to the upper gum, preferably above the back molar, where it dissolves completely. Biodegradable transmucosal films is the most effective way to deliver drug substance and to achieve the same therapeutic levels with lower doses due to high rate of drug absorption when compared with the other conventional dosage forms, where drug absorption is lowers due to shorter onset of action or reduction of first pass metabolism and probably less frequent dosing.

Thinsol:^(TM)

Thinsol^(TM) is another patented technology developed by Paladin labs. It is a water based, enzymatically-digested carboxymethylcellulose film that is suitable for the rapid delivery of pharmaceutical and neutraceutical active ingredients. Thinsol may offer significant advantages over other edible film technologies as this technology allows development of products that other may not be able to formulate in a film strip format such as products that are heat sensitive and those that require high drug loads on each strip. Thinsol can accommodate active ingredients in a quantity of up to 60% of the overall weight of the films allowing for the development of a film strip containing over 100mg of the active ingredients like most film strip technology Thinsol doesn’t require heat during manufacturing process. Using Thinsol films can be dried at low temperature from the source such as hot air or infrared technology.

Pharma film:

One of the pioneer companies in the oral film industry that owns a protected drug delivery technology is MonoSol Pharma film, their technology is more stable and robust when compared with other conventional dosage form with a loading capacity of 80 mg. the film is based on a polymeric matrix of hydoxypropyl methylcellulose dissolves rapidly and rapid drug absorption can be achieved. the company claims that the Pharma film can be used for both fast dissolving system and buccal delivery. Drugs like ondansetron hydrochloride, Montelukast sodium, rizatriptan, donezepil hydrochloride have been incorporated in pharma film.

Rapid films:

Rapid films® is a patented technology developed and commercialized by Labtec GmBH. Rapid films® are fast dissolving thin films made from water soluble polymers, non mucoadhesive, which can vary from single to multilayer design system. These films offer strong advantages to patients and combine the convenience of a liquid with the stability and dosing accuracy of a tablet. The film is based on a PVA-starch mixture which is plasticized by PEG. Up to 30 mg of the drug can be incorporate into Rapidfilms® . Ondasetron Rapidfilms® were the first oral films that have been approved worldwide, and there have been at least three more rapidfilms.

Quicksol:

SK Chemicals developed Quicksol® technology, a wide variety of drug substances can be accommodated by using quicksol® techniques. But only two drug available in the market produced by quicksol® techniques they are Montfree ODF (monteleukast) and Mvix-S ODF(mirodenafil). Mvix-S is a 50mg oral film which is thin and light. Mvix ODF absorption is 16.7% higher than Mvix tablet.

Bio-FX:

NAL Pharmaceuticals developed Bio-FX® fast onset oral cavity ODF, it is an oral film which is formulated with a BIOFX® absorption enhancer system which increases the sublingual and oral cavity absorption of the drug substance through oral mucosa. The aim is to increase the oral bioavailability of the drug by avoiding the first pass metabolism and gastrointestinal degradation. Bio-FX® films are formulated as single layers films with mucoadhesive polymers like polyvinylpyrrolidone. To improve the taste and mouth feel taste, masking agents has been incorporated. Currently there are no products in the market developed by Bio-FX® some are under development.

Packaging:

Expensive packaging, specific processing, and special care are required during manufacturing and storage to protect the fast-dissolving dosage forms. Single packaging is mandatory. An aluminum pouch is the most commonly used packaging material. APR-Labtec has developed the Rapid card, a proprietary and patented packaging system, which is specially designed for the Rapid films. The Rapid card has same size as a credit card and holds three films on each side. Every dose can be taken out individually.

The material selected must have the following characteristics

1. It must not be reactive with the product
2. It must protect the preparation from environmental conditions
3. It must be FDA approved
4. It must be tamper-resistant
5. It must be non-toxic

Packaging materials:

Foil, paper or plastic pouches:

The flexible pouch is can provide sufficient tamper resistance and high degree of environmental protection. A flexible pouch is formed during the product filling by either vertical or horizontal forming, filling, or sealing equipment. The pouches can be single pouches or aluminum pouches.

Single pouch and aluminum pouch:

Fast dissolving oral thin film drug delivery pouch is a peelable pouch for fast dissolving soluble films with high barrier properties. The pouch is transparent for product display. Using a two-structure combination allows for one side to be clear and the other to use cost-effective foil lamination. The foil lamination has essentially zero rate of transmission for both gas and moisture. The single dose pouch provides both product and dosage protection. Aluminum pouch is the most commonly used pouch.

Blister card with multiple units:

The blister container consists of two components

1. Blister, which is the formed cavity that holds the product
2. Lid stock, which seals the blister

The blister package is formed by heat softening a sheet of thermoplastic resin and then vacuums drawing the softened sheet of plastic into a contoured mold. After cooling,the sheet is released from the mold. Then it proceeds to the filling station of the packaging machine. The previously formed semi rigid blister is filled with the product and lidded with the heat sealable backing material. Generally, the lid stock is made up of aluminum foil. The material used to form the cavity is plastic, which can be designed to protect the dosage form from moisture.

Barrier Films:

Many drug preparations are extremely sensitive to moisture and therefore require high barrier films. Several materials may be used to provide moisture protection such as polychlorotrifluoroethylene film, polypropylene. Polypropylene does not stress crack under any conditions. It is an excellent barrier to gas and vapor. But the drawback is lack of clarity ^[107].

Evaluation Tests for Fast Dissolving Oral Thin Films:

Differential Scanning Calorimetry:

Differential Scanning Calorimetry is performed to indicate compatibility of drug with other excipients. Differential Scanning Calorimetry of plain drug and other excipients in the formulations can also be performed.  Film samples weighing approximately 5 mg are cut, sealed in aluminum pans, and analyzed in an atmosphere of nitrogen at flow rate of 25 ml/min. A temperature range of 0° C to 200° C is used, and the heating rate 10° C/min is used ^[108].

Morphology studies (Appearance):

Prepared films were visually inspected for colour, clarity, flexibility and smoothness. The morphology was carried out using Scanning Electron Microscope (SEM) ^[33].

Near Infrared (NIR) chemical imaging

NIR chemical imaging method complements SEM analysis. It is a more quantitative in nature as it aids in evaluating drug distribution in a larger surface area.

X-ray diffraction and Raman spectroscopy:

X-ray diffraction patterns and Raman spectra assist in determining the crystalline or amorphous nature of the unprocessed APIs and APIs incorporated in films ^[12].

Thickness measurements:

The thickness of the film was measured by a micrometer screw gauge at five different places; an average of three values was calculated. This is essential to ascertain uniformity in the thickness of the film this is directly related to the accuracy of dose in the film. ^[31].

Palatability study:

This study is conducted on the basis of taste. All the batches are rated A, B and C grades as per the criteria. When the formulation scores at least one A grade, formulation is considered as average. When the formulation scores two A grades then it would be considered as good and the one with all three A grades, it would be the very good formulation.

Grades: A= Very good, B= Good, C= Poor ^[109]

Weight variation:

1 cm² samples representing five different regions is cut. Oral fast-dissolving films were weighed on an analytical balance and average weight can be determined for each film. Films should have nearly constant weight. It is useful to ensure that a film contains the proper amount of excipients and API ^[31]

Folding endurance:

Folding endurance of the film is essential to study the elasticity of the film during storage and handling. The folding endurance of the films was determined by repeatedly folding one film at the same place till it breaks. This is considered to reveal good film properties. A film (2 × 2 cm) was cut evenly and repeatedly folded at the same place till it breaks. All determinations were performed in triplicate ^[31].

Swelling Index:

The degree of swelling can be considered as an indicator of the film hydrophilicity and a measure of its interaction with the mucosal membrane. The swelling index (percentage of hydration) of the film samples were measured by weighing the samples over time while in contact with deionized water. Each film was weighed (W1) and placed onto a watch glass containing 1 mL of deionized water. The medium was removed at certain time points (10 s and 20 s), the film was lightly wiped and reweighed (W2). Experiments were performed in triplicates, and one sample was used for each time point. The swelling index was calculated using Equation ^[32]

Swelling index =W2-W1W1×100

Moisture uptake:

Films are cut in particular shape. The moisture uptake by the films is determined by exposing them to an environment of definite relative humidity and temperature for one week ^[111]. The uptake of moisture by the films is measured and calculated as % increase in weight by formula

% increase in weight= [(Final weight- Initial weight)/ Initial weight] x 100

Drug content determination:

The drug content is determined by any official assay method described for the particular API in any of the standard pharmacopoeias.

Content uniformity:

The content uniformity is determined using 20 films and estimating the API content in individual film spectrophotometrically. Content uniformity should be within 85-115% and relative standard deviation should be no more than 6 % ^[112].

Tensile strength:

The tensile strength is determined by the apparatus which has two clamps, the upper one is fixed and the lower is movable. The film sample (0.5×3 cm) is clamped between the two clamps. The force at tearing and elongation is determined.

The percent elongation (%E) is calculated using the following equation

% E = {(L_s-L_o) / L_o} x 100

Where, L_o = Original length

L_s = Length of the film after elongation

The modulus of elasticity of films was calculated from the equation

F/A = EM {(L_s-L_o) / L_o}

Where F = Breaking load (N),

A = Cross- sectional area of the film

EM = Modulus of elasticity ^[42]

Water vapor transmission rate:

For water vapor transmission rate study, vials of equal diameter can be used as transmission cells. Cells are washed thoroughly and dried in an oven. One gm of calcium chloride is taken in the cell and the polymeric films (two cm² area) are fixed over the brim with the help of an adhesive. The cells are accurately weighed and the initial weight is recorded. Films are then kept in a closed desiccator containing saturated solution of potassium chloride (80-90 % RH). The cells are taken out and weighed after 18, 36, 54 and 72 hours. From increase in weights, the amount of water vapor transmitted and the rate at which water vapor transmitted can be calculated by using the following formula

Water vapor transmission rate = WL/S

Where, W = Water vapor transmitted in mg

L = Thickness of the film in mm,

S = Exposed surface area in cm^{2 [113]}

Contact angle measurement:

Contact angle is measured by goniometer. A drop of distilled water is placed on the surface of the dry film and images are recorded with the help of digital camera within 10 seconds ^[114].

Surface pH of films:

The surface pH of fast dissolving films was determined in order to investigate the possibility of any side effects with in vivo. The films were allowed to swell in closed petri dish containing distilled water (5 ml) at room temperature for 30 minutes and the pH was determined with digital pH meter ^[33]

In vitro disintegration time:

In vitro disintegration time was determined visually in a beaker which contains 25 ml of phosphate buffer (pH 6.8) with swirling every 10 sec. The disintegration time is the time when the film starts to break or disintegrates ^[33].

In Vitro dissolution study:

The drug release studies are performed with USP dissolution test apparatus type II (Paddle method). All tests were conducted in 250 ml of Phosphate buffer pH 6.8. The dissolution medium was maintained at 37±0.5? C and the paddle rotation speed was 50 rpm. Aliquot of 5ml was withdrawn at specific intervals and were immediately filtered through Whatman filter paper and analysed by spectrophotometry. The absorbance values were transformed to concentration by reference to a standard calibration curve obtained experimentally measured on UV spectrophotometer ^[34].

Marketed Products:

Large number of OTF formulations is available in market. First, breath freshener films were introduced into market. Then, over-the-counter (OTC) and nutraceutical film formulations which incorporated active ingredients such as vitamins, herbal extracts and non-herbal extracts. Pfizer introduced Listerine^® pocketpaks^® in 2001 for as breath freshner. The brand augmentation started after this was fairly successful for several popular OTF products from Novartis and J&J Consumer (Triaminic^®, TheraFlu^®, Benadryl^®, and Sudafed^™). Biofilm is utilizing OTF for the brand extension of the existing products in pharmaceuticals as well as nutraceuticals with a range of aphrodisiac, energy boosters, vitamins and appetite suppressors. Some marketed OTC products of OTFs are shown in Table 17.