INTRODUCTION:

Oral route of drug administration is considered as one of the most common routes of drug administration. With the aim of enhancing efficacy and safety of drug molecules newer dosage forms are designed. Quick disintegrating dosage forms are designed to produce faster drug absorption^1,2 than other oral dosage forms such as sublingual tablets and gained a point of importance in the pharmaceutical industry in this decade. Active pharmaceutical ingredients, polymer (s), plasticizer (s), saliva simulant, surfactant, sweeteners and flavors are components required for FDOF production³. Fast dissolving oral films disintegrate instantaneously after they are put on the tongue releasing the drug in the saliva and don’t require swallowing^4,5. The active pharmaceutical ingredients are swallowed orally with saliva which leads to absorption in the gastrointestinal tract or are absorbed from the vascular region in the oral cavity thus leading the drug to reach the blood circulation quicker. Thus either more or at least 90% drug is successfully delivered into the body⁶. The concentration of the polymers and the plasticizer on alteration can change the rate of drug release. Drugs with shorter half-life and having small intestine as its main site of absorption and maintenance of adequate plasma level of the drug can be achieved by systemic drug delivery⁷. For active pharmaceutical ingredients having high solubility and low permeability resulting in low bioavailability this dosage form can be a dosage form of choice⁸. After producing the fast dissolving oral films, they are to pass through a series of evaluations such as tensile strength, % elongation, thickness, folding endurance, unit surface area, average weight, drug content, and content uniformity by assay method, disintegration time and in drug release⁹. FDOF will continue its progression in the pharmaceutical market alongside other Pharmaceutical developments as it has some benefits such as self-medication, easy administration and more over avoiding pain present in parenteral route of administration¹⁰.

Table 1: Comparison between fast dissolving oral films and fast dissolving tablets¹¹

Sl. No.	Fast Dissolving oral film	Fast dissolving Tablet
1	It is a film	It is a tablet
2	Greater dissolution due to larger surface area	Lesser dissolution due to less surface area
3	Lower dose can only be incorporated	Higher dose can be incorporated
4	More patient compliance	Lesser patient compliance than film
5	No risk of choking	It has a chance of choking

Advantages of fast dissolving oral films are as follows:¹²

Avoiding first pass metabolism

Less time required for drug action

Avoiding invasive method of administration

Easy administration as it needs no trained professional.

Large surface area provides rapid disintegration and dissolution in the oral cavity.

Disadvantages of fast dissolving oral films are as follows:

Hydrophilic drugs are drugs of choice for fast dissolving oral films, but hydrophobic drugs are not able to formulate easily.

Drug loading capacity is low.

Hygroscopic dosage form¹³.

Dose uniformity is challenging.

Fig 1: Diagram of fast dissolving oral film on human tongue

Fig 2: Diagram of fast dissolving oral film

MATERIALS AND METHODS:

Materials:

API or Active pharmaceutical ingredient: 1 to 25% w/w of the total weight of the dry film is the main drug or active pharmaceutical ingredient. Small doses of API can be delivered through these oral films.

Multivitamins those are up to range 10% w/w of the weight of the dry films that achieve dissolution in less time fewer 60 seconds¹⁴.

Film forming polymers:Polymeric substances that form the film structure are the most important components. Quality of the oral film depends on the polymer quality, quantity and nature. Normally 45% W/W of the dry weight of the film are polymer. Choosing the most appropriate polymer for formulating the film leads to the changes in the tensile strength and the success of the film formation. As hydrophilic polymers readily dissolve in the saliva they are the polymer of choice for oral film formation. Swellable and hydrophilic polymers are polymers of choice for this purpose¹⁵.

Plasticizer:Plasticizers are chemical components of fast dissolving oral films that provide flexibility to the films along with elongation and tensile strength and are required in 0-20% of the total weight¹³. Plasticizers also help in reducing the brittleness of the films and thus protect them from breaking due to physical hazards. Plasticizers must be compatible with active pharmaceutical ingredients, polymers and excipients. Wrong choice of plasticizers may lead to cracking, splitting and peeling. Glycerol, propylene glycol, di-methyl phthalate are commonly used plasticizers.

Sweetening agent:Sweeteners are chemical components that induce the sweet taste in the fast dissolving oral films when they come in contact with the tongue in the oral cavity. Sodium saccharin¹⁶, sucrose, fructose, dextrose, aspartame, sorbitol and mannitol are some commonly used sweeteners. The sweeteners of choice must be compatible with polymers and active pharmaceutical ingredients and must not produce any undesirable color to the final product. It is required in 3 to 6% weight respect of total weight¹³.

Flavoring agent:Flavoring agents are chemical components that produce a specific taste when used in films. These flavoring agents increase the patient's compliance towards the oral dosage form. The flavoring agents must be compatible with polymers and active pharmaceutical ingredients. It is required in 0 to 10% weight respect of total weight¹³.

Saliva stimulating agents, coloring agents and surfactants are also used in formulating fast dissolving oral films.

Methods:

Various methods are followed for producing fast dissolving oral films. Among which the most promising five are described below:

Solvent casting: Volatile solvents are used to dissolve active pharmaceutical ingredients (API), polymer and plasticizer producing a homogeneous mixture. Magnetic stirrers can be used for laboratory grade production. The choice among aqueous and non-aqueous solvents is based on the solubility of the polymers and API. Entrapped air during the mixing is eliminated using a vacuum pump. The mixture is then poured into a glass petri dish or mold and kept in the oven or dryer until it gets completely dried and is cut to required shape and size^17,18.

Hot melt extrusion:This process dates back to the 1930s and is best to be practiced in industrial grade production. In this process heat and pressure is applied resulting in melting of polymer and passing through a fixed orifice continuously¹⁹. Uniform density, thickness and shape of film is produced through this process²⁰. This is an anhydrous process.

Semi Solid casting: Polymers that are soluble in water are dissolved in water and a uniform mixture is made out of it. On the other hand, acid insoluble polymers are made into a soluble solution. Then the first is put into the latter in a 1:4 ratio plasticizer is added to a fixed amount and mass of gel is obtained. Later heat controlled drums are used to make films of diameter ranging between 0.05-0.015 inches out of them.

Rolling:

Film forming polymers dissolved in polar solvents and mixed homogeneously with drugs added to it. Stable matrix is fed to the roller and with support of roller wet films are produced and are dried. Films are next cut into required size and shape.

Solid dispersion extrusion:Hydrophobic crystalline drug added to organic solvent with hydrophilic carrier. Solvent is removed by vacuum. Solid dispersion is made at the molecular level. Amorphous drugs are dispersed in hydrophilic carrier matrices²¹. Dies are used to produce films by dispersion methods.

An overview of past works:

Oral fast dissolving films are chosen for drug delivery designing by various researchers throughout the world in recent years.

Rao U V et.al chooses to develop orally dissolving films for delivering Zolpidem for treatment of short term insomnia. They tried various concentrations of polymers and plasticizers affecting properties like change in disintegration times, and in vitro dissolution studies. The films were produced by the method of solvent casting and were evaluated for folding endurance, average weight, dissolution, disintegration and tensile strength. HPMC E5 and HPMC E15 as polymers and glycerol for plasticizers were used in formulating standard films with 80% drug release in 2 minutes and disintegration in 60 seconds⁹.

Kaur P et.al intheir in their review article Oral dissolving film: present and future aspect states that oral fast dissolving films are able to develop NSAIDS, antihistamine, antiulcer, antipsychotic, sedative, hypnotic, antiparkinson, antiemetic, antidepressant and anti-migraine drugs. They also state that these dosage forms are able of fast drug release and on using saliva stimulating agents like citric acid, lactic acid, tartaric acid and ascorbic acid the oral fast dissolving films can show quicker drug absorption due to fast disintegration because of more saliva production due to saliva stimulation¹⁴.

Reddy S P et.al in their research of developing faster onset of action to a poorly soluble drug Ezetimibe chose oral fast dissolving films as the dosage form. Solvent casting method using petri plates was followed by then for film production. They used HPMC E5, HPMC E6, HPMC E15, Transcutol Hp and pectin for this purpose. They concluded that Transcutol Hp proved its efficacy in providing faster rate of drug delivery and immediate onset of action within 10 minutes when used in formulation²².

Prabhu P et.al in their research of developing levocetirizine dihydrochloride fast dissolving films for achieving a quick release antihistamine medication. They followed the solvent casting method for film production with polymers HPMC 15 cps and PVA. They stated that there is a significant increase in the dissolution rate by these films which were prepared using HPMC as polymer, when compared to conventional tablets. They have concluded that these films were suitable to use to treat allergic rhinitis and other allergic conditions²³.

Haque E S et. al stated that in their research of developing polymer bound fast dissolving buccal films with disintegrants and metformin as the active pharmaceutical ingredient. They used microcrystalline cellulose, sodium starch glycolate as the disintegrants. Chitosan as the polymer. In in-vitro dissolution study films thus produced were found to dissolve within 30 minutes for all formulations. And 92.2% drug release in their formulation F6 in 6 minutes due to combined effect of sodium starch glycolate and microcrystalline cellulose⁷.

Bhavani M S et. al states that topiramate films were prepared by using HPMC 5, 15 and 50cps and 99.89% drug release is seen from the film produced by them²⁴.

Setouhy DA et. al stated the use of lycoat NG73 (granular hydroxypropyl starch) as a good quality film forming polymer alongside HPMC, PVA, PVP and lycoat RS780 (pregelatinizedhydroxypropyl starch). Orodispersible films which had lycoat NG73 showed great drug dissolution with promising in vitro disintegration time and physico-mechanical properties and were compared with a reference marketed product for bioavailability²⁵.

So it can be observed that the drug release rate is also very high from this dosage form.

Thus it is seen that due to changes in composition of polymers at various composition ratios the fast dissolving polymer films are formed with variability in drug holding amount and drug release rate. The fast dissolving oral polymer films are also seen to be enhancing drug release of drugs. Fast dissolving oral films are also efficacious in low solubility drug release.

Evaluation parameters:

General appearance:

Smoothness, evenness and transparent and semitransparent nature of the both sides of the film are to be observed.

Film forming capacity:

Performance of polymer in forming the desired film and holding the API in it. This is to be graded as very poor, poor, average, good, better, excellent as per their film forming capacity.

Thickness:

Uniform thickness of the film depicts uniform drug distribution. Screw gauge and Vernier calipers are normally used to measure the thickness of the film. 5 - 200µm is the range in between which the thickness of the fast releasing film must be. Average of three measurements at different spots of the same film states the thickness of the film²⁶.

Folding Endurance:

A strip of specific area (3cm* 2cm) was cut evenly and repeatedly folded at the same place till it broke. The number of times the film was folded at the same place without breaking gave the value of the folding endurance¹⁶.

Scanning electron microscopy:

Study of the morphology of the surface of the films made of different excipients and drugs is done by it. Scanning electron microscopes are used for this purpose.

Moisture uptake:

Part of dry film weighted and kept in desiccators with calcium carbonate at room temperature for 24hours. Then exposed to 84% relative humidity till a constant weight is achieved. Following formula is used for the calculation of % moisture uptake²⁷.

Moisture uptake = (initial weight - final weight / final weight) × 100

Percentage Moisture Content:

The prepared films were weighed individually and kept in a desiccators containing fused calcium chloride at room temperature for 24 h. After 24 h, the films were reweighed and determined the percentage moisture content from the below mentioned. Formula of Percentage moisture content is given below:

(Initial weight−Final weight)/Final Weight×100²⁸

In vitro disintegration test:

The films disintegrate when they come in contact with water. In USP disintegration apparatus phosphate buffer is used to study the disintegration time. A good fast dissolving oral film must disintegrate within 30 seconds^28,29.

In-vitro drug release test:

Drug release from the film into the dissolution media per unit time at standard solvent concentration and temperature in standard paddle type that is type II USP dissolution apparatus followed by sample collection at intervals of 5 minutes^{29, 30} and its UV spectrometric study leads to the study of in-vitro drug release test. Dissolution media that are the buffer solution choosing is based on sink conditions and the highest dose of the drug^{31, 32}.

CONCLUSION:

Fast dissolving oral thin films is an ultra-thin film made of hydrophilic polymer rapidly hydrates or adheres when placed on the tongue or in the buccal cavity. Orally fast-dissolving films are a new day oral delivery of the drugs. It is one of the safest, most convenient and most economical methods of drug delivery and has the highest patient compliance. These films are capable of disintegrate or dissolve within seconds releasing the active agent without drinking and chewing. Thus instant bioavailability is achieved bypassing first pass metabolism.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 22.11.2022 Modified on 12.06.2023

Research J. Pharm. and Tech 2023; 16(12):6100-6104.

DOI: 10.52711/0974-360X.2023.00990