AN OVERVIEW ON ORAL THIN FILMS–METHODOLOGY, CHARACTERIZATION AND CURRENT APPROACH

The pharmaceutical sector is looking for new ways to deliver drugs, and one such way is through thin films. It has been said that thin films offer an alternative to traditional dosage forms. They offer rapid, local, or systemic effects and are a very flexible platform. Furthermore, patients with dysphagia, elderly, paediatrics, or bedridden patients, as well as those who have difficulty accessing water, can easily utilize these systems on their own. There are several ways to administer these drug delivery systems, including transdermally, ocularly, buccally, sublingually, and orally. One of the most creative and patient-focused novel drug delivery systems is Orodispersible Thin Films (OTF). Numerous pharmaceutical companies and academic experts worldwide are currently investigating the potential of these films for delivering drugs derived from both synthetic and natural sources. The beauty of this special drug delivery method is that, as we can see from the subjects' consumption of conventional dosage forms (tablets, capsules), they don't require water to be consumed. Furthermore, these delivery methods do a great job of encouraging patient compliance in general, especially in the case of both older and pediatric patients. This review shows a detailed review of oral thin film its applications and method of preparation; mainly focus of this research is thin film introduction to researchers and last 10 y of research on thin film with drugs and polymers used in research.


INTRODUCTION
The oral route is the most preferred route for the delivery of drugs to date as it bears various advantages over the other routes of drug administration, but oral drug delivery systems still need some advancements to be made because of their drawbacks related to particular classes of patients which include geriatric, pediatric and dysphasic patients associated with many medical Conditions as they have difficulty in swallowing or chewing solid dosage forms.Many pediatric and geriatric patients are unwilling to take solid preparations due to fear of choking.Even with fast-dissolving tablets, there is a fear of choking due to the tablet-type appearance.One study showed that 26% of 1576 patients experienced difficulty in swallowing tablets [1].The most common complaint was tablet size, followed by surface form and taste.The problem of swallowing tablets was more evident in geriatric and pediatric patients, as well as traveling patients who may not have ready access to water.So, fast-dissolving drug-delivery systems came into existence in the late 1970s as an alternative to tablets, capsules, and syrups for pediatric and geriatric patients who experience difficulties in swallowing traditional oral solid dosage forms [2,3].These systems consist of solid dosage forms that disintegrate and dissolve quickly in the oral cavity without the administration of water.Research and development in the oral drug delivery segment has led to the transition of dosage forms from simple conventional tablets or capsules to modified release tablets or capsules to oral disintegrating tablets (ODT) to wafers to the recent development of oral fast dissolving films (OFDFs).Amongst the plethora of avenues explored for rapid drug-releasing products, oral strip technology is gaining much attention [4].
The film is an ideal intraoral fast-dissolving drug delivery system, which satisfies the unmet needs of the market, is easy to handle and administer, maintains a simple and convenient packaging, alleviates unpleasant taste, and is straightforward to manufacture [5].The film is placed on the top or the floor of the tongue.It is retained at the site of application and rapidly releases the active agent for local and/or systemic absorption.Oral fast-dissolving film (FDF) is one such novel approach to increase consumer acceptance by rapid dissolution and self-administration without water or chewing.The need for non-invasive delivery systems continues due to patients' poor acceptance and compliance with existing delivery regimes, limited market size for drug companies and drug uses, coupled with high cost of disease management [6,7].
Numerous pharmaceutical preparations are administered as liquids, tablets, granules, and powders.A tablet design is typically given to patients in a form that allows them to chew or swallow a specific dosage of medication.However, swallowing or chewing solid dosage forms can be challenging for patients, especially those who are elderly or young [8].Because of their fear of asphyxiation, many elderly and children are unwilling to take those solid dosage forms.To address this need, oral dissolving tablets, or ODTs, have been developed.Short dissolution/disintegration times do not, however, eliminate the risk of asphyxiation and the nervousness of swallowing the solid form of medication (tablet, capsule) for some patient populations.In these circumstances, oral thin film (OTF) drug delivery systems are a better option [9,10].
Approximately one-third of the population, primarily the geriatric and pediatric populations, has swallowing difficulties, resulting in poor compliance with oral tablet drug therapy, which leads to reduced overall therapy effectiveness [11].A new oral fastdissolving dosage form such as the fast-dissolving tablet or fastdissolving film, has been developed, which offers the combined advantages of ease of dosing and convenience of dosing in the absence of water or fluid.Most of the existing fast-dissolving drug delivery systems are in the form of solid tablets and are designed to dissolve/disintegrate in the patient's mouth within a few seconds or minutes without the need to drink or chew.However, the fear of taking solid tablets and the risk of choking for certain patient populations still exist despite their short disintegration/dissolution times [12].The film overcomes the danger/fear of choking1.The development of a fast-dissolving film also provides an opportunity for a line extension in the marketplace; a wide range of drugs (e. g., neuroleptics, cardiovascular drugs, analgesics, antihistamines, antiasthmatic and drugs for erectile dysfunction) can be considered candidates for this dosage form [13].

Oral cavity
The mucus produced by the 40-50 cell layer of the oral tissue epithelium is composed of proteins and carbohydrates.The mucosal thickness varies between 100 and 200 μm at the base of the mouth, the tongue, and the gums.Mucus, a small gel-like fluid secreted by the submucosal layer, is composed of 90%-99% water, 1%-5% water-insoluble glycoprotein, and other components like proteins, enzymes, electrolytes, and nucleic acids [15,16].In contrast, saliva and parotid are secreted by lobules within the salivary glands from the salivary duct in the vicinity of the sublingual canals and submandibular teeth.Most frequently, small salivary glands are located on the mucosa of the cheeks and lips.About 1-2 ml of saliva is secreted in total in a minute [17][18][19][20].
The mucus, water, the enzymes lysozyme and amylase, mineral salts, immunoglobulins, and blood clotting factors make up saliva [21].Saliva and mucin function as barriers for the oral mucosa as well.There are two distinct regions in the mucosal epithelial structure: the lipophilic space between cells and the lipophilic membrane of the stratified epithelium and the more hydrophilic region.In terms of substance permeability, the oral mucosa can withstand conditions that the intestinal mucosa and the epidermis cannot [22].The buccal mucosa is thought to have 4-4000 times greater permeability than the skin.There are two primary drug absorption pathways provided by the mucosal epithelium: the transcellular (intercellular) and paracellular (intercellular) pathways (fig.).While more hydrophilic molecules can enter the intercellular space due to their polarity, particles with a high partition coefficient can more easily pass through the lipophilic structure that makes up cell membranes.The drug's absorption depends on whether it is hydrophilic, hydrophobic, or amphiphilic [23,24].The ideal characteristics of the drug to be selected The drug should have a pleasant taste.The therapeutic dose of the drug should not be greater than 40 mg [13].The drug should have small molecular size and low molecular weight.The drug should have good solubility and stability in water as well as in saliva.It should be partially unionized at the pH of the oral cavity.The drug should exhibit low sensitivity to environmental conditions.It should have the ability to permeate oral mucosal tissue [13,16,17].

Advantages of oral thin films
Rapid onset of action with increased bioavailability due to bypassing the hepatic first-pass effect [18].Convenient for pediatric, geriatric, and dysphasic patients having difficulty in swallowing.Rapid disintegrating and dissolution in the oral cavity due to the larger surface area of films.Reduce dose, enhances the efficacy and safety profile of the drug with reduced side effects.Beneficial in cases such as motion sickness, acute pain, sudden allergic attack, asthmatic attack, and coughing, where an ultra-rapid onset of action is required [19].No need for water for administration.Flexible and portable, they provide ease of handling, transportation, and storage.Ease of administration to mentally ill, disabled, uncooperative patients and patients who are on reduced liquid intake plans or are nauseated [20].Beneficial in cases such as motion sickness, acute pain, sudden allergic attack, asthmatic attack, and coughing, where an ultra-rapid onset of action is required.
Stability for a longer duration of time since the drug remains in solid dosage form till it is consumed.Accuracy in dose as compared to liquid formulations.Pleasant mouthfeel, leaving negligible or no residue in the mouth after administration.

Disadvantages of oral thin films
High doses of 40-50 mg cannot be incorporated.Drugs which irritate the oral mucosa cannot be administered by this route [25].Excessive bitter drugs are not feasible [26].Dose uniformity is a technical challenge.They require special packaging for the product's stability and safety.

Ideal characteristics of drug for oral thin film
The therapeutic dose of the drug should not be greater than 40 mg.The drug should have a pleasant taste.The drug should have small molecular size and low molecular weight.It should be partially unionized at the pH of the oral cavity.The drug should have good solubility and stability in water as well as in saliva.It should have the ability to permeate oral mucosal tissue.The drug should exhibit low sensitivity to environmental conditions [28].

Solvent casting method
The most widely used technique for creating OTFs is solvent casting, which has low processing costs, straightforward application, and easy preparation [32].To put it briefly, components that dissolve in water are made by combining them in a heated magnetic stirrer.To create a viscous solution, the medication and additional excipients are then added to this mixture.This method's solution is put into a petri dish, and the solvents are left to evaporate.These are stored for 20-25 or 24-48 h at room temperature or for a shorter time at 40-50 °C in the oven, according to the solvent system that was used.After the solvents evaporated, 15-20 mm diameter and 0.2-0.3mm thick films were carefully removed from the petri dishes.[33].They are cut into the appropriate size pieces based on the concentration of active ingredients they contain.1,7Using gel-forming polymers, the semisolid gel mass is dried after being poured into appropriate molds in the solvent casting technique.After that, they are ready by being cut into the appropriate sizes [34,35].They have about 90%±used this technique for the formulation of OTF.The advantage of this method is to get film of uniform thickness and it is quite flexible.The cost of this method is also very low [36,37].

Hot-melt extrusion method
Transdermal delivery methods, sustained-release pills, and granules have all been produced using Hot Melt Extrusion.It takes its cues from the plastics manufacturing sector.To achieve desired drugrelease profiles, oral film manufacturing components, including combinations of drugs, polymers, and plasticizers, are extruded into various end forms [42].
It is distinct due to the heat treatment and lack of solvent.After the API and additional excipients are combined in a dry condition, heat is delivered through the extruder's heaters to create a molten mass that is forced out of the orifice.After allowing the films to cool, the necessary size is cut from them.Hoffmann had discussed using this method in continuous-release oral films despite ongoing issues with the films' thickness and breakdown [43,44].The HME procedure has the following drawbacks: it works best with pharmaceuticals that are thermostable, and finding heat-resistant film-forming polymers might be challenging.

Solid dispersion method.
Solid dispersion refers to the dispersion of one or more solids (such as drugs or therapeutic actives) utilizing techniques like HME into another solid, the inert carrier (such as an amorphous hydrophilic polymer).To create a solution, the medicine is first dissolved in an appropriate liquid solvent.Subsequently, the solution is mixed into the polyol melt, such as polyethylene glycol, without eliminating the liquid solvent [45][46][47][48].It's possible that the medicine or solvent of choice won't mix well with the melted polyethylene glycol.As it cools, a solid dispersion forms and the drug's immiscible components are forced through dies to produce the structure of the film.The drug's polymorphic form that precipitates in the solid dispersion may change depending on the type of liquid solvent utilized [49].

Rolling method
In the rolling process, film is created by first preparing the pre-mix, then adding the active ingredient, and then forming the film.The pre-mix batch is introduced to the main batch feed tank together with additional materials such as polar solvent, film-forming polymer, and API.The first metering pump and control valve then feed a predefined amount of the masterbatch [50].Once the mixer is filled with the proper amount of medication, it is combined long enough to create a homogenized matrix.The second metering pump feeds a certain amount of matrix into the pan.The film thickness was measured by the metering roller.At last, the film is produced on the substrate and removed by the support roller.Controlled bottom drying is used to dry the wet material [51][52][53].

Organoleptic test
A fast-dissolving product (OTF) should have the following required organoleptic qualities: taste, flavour, and colour.The formulation should have appropriate organoleptic pleasant properties because it will dissolve in the oral cavity [55].Patients find a formulation more agreeable when it is coloured, and when oral films are given to children, they should also be colourful.Therefore, the formulation's hue should be consistent and appealing.Visual inspection is one method of evaluating colour.The smell is the other organoleptic feature [56].The taste that is incorporated into the recipe should give it a pleasant scent.The addition of a flavoring compound should disguise the smell of the polymer, medication, and any other excipient.Another crucial component that needs to be considered is taste [57][58][59][60].

Thickness
Digital Vernier Callipers that have been calibrated or a micrometer screw gauge are used to measure the thickness of the film [61].
The ideal range for film thickness is 5-200 µm.Assuring uniformity in the film's thickness is crucial since it directly affects the precision of the dosage distribution in the film.The thickness should be measured at five separate locations-four at the corners and one in the middle.[62] A minimum of five films from every formulation are measured at five separate places to determine the optimal thickness of buccal thin films, which is between 50 and 1000 µm.10 The results are reported as the mean along with the standard deviation (x̄ and SS) [63].

Percent elongation
Strain is the result of an example of stretching when tension is applied to a film.The definition of strain is the difference between the original and starting lengths of the film experiment and the change in film length.The quantity of plasticizer employed in the film formulation has a quantitative relationship with percent elongation.The strip elongates more readily when the plasticizer content in the film is higher.It is ascertained using the subsequent formula: [64][65][66].

Change in length
Initial length ˣ 100.

Folding endurance
The films' folding endurance was ascertained by folding a small, 2 x 2 cm² strip repeatedly at the same location until it broke; the value of folding endurance was calculated as the number of times the film could be folded at the same location without breaking; the three readings average and standard deviation of all films were computed [67,68].

Drug content uniformity
The uniformity of drug content can be ascertained using any standard testing method specified in a standard pharmacopeia for that specific API.By evaluating the API content in each strip, content consistency is ascertained.85-115% is the limit of content uniformity [69,70].

Swelling property
Tests for film swelling are conducted in a solution that resembles saliva.Every film sample is weighed before being inserted into a preweighed stainless steel wire mesh.The mesh that holds the film sample is immersed in a 15 ml medium within a plastic container.The weighing of the film has been raised at pre-arranged intervals until a consistent weight is noted.The values of the parameter wt-w0/w0, where wt. is the weight of the film at time t and w0 is the weight of the film at time zero, were used to calculate the degree of swelling [71].

Disintegration test
The amount of time (in seconds) that a film disperses when it comes into contact with water or saliva is known as the disintegration time.
The thin film starts to break down or disperse at the disintegration moment.The physical characteristics of water-soluble films are mostly determined by the film's weight and thickness [72].
The disintegration periods of OTFs can also be ascertained using the disintegration test equipment listed in pharmacopeias.The disintegration duration of the film composition typically ranges from 5 to 30 seconds, and this phenomenon is dependent on the formulation content.When determining the disintegration times of films that degrade quickly, no formal guide is available [73].

In vitro dissolution test
The quantity of drug material that dissolves under standard conditions of temperature, solvent concentration, and liquid/solid interface is known as the dissolution rate.Any of the pharmacopeia's conventional basket or paddle apparatuses can be used for dissolution testing.
Because paddle-type dissolving devices can float above the dissolving liquid, it is challenging to conduct an oral film dissolving study with one.The maximum dosage of the medication and the sink conditions dictate the choice of dissolving media.Throughout the dissolving inquiry, the medium should be held at 37±0.5 ˚C and 50 rpm [72][73][74][75].

Contact angle
Goniometers are used to measure contact at room temperature.Put a droplet of purified water onto the dry film's surface.A digital camera was used to capture pictures of the water droplets within ten seconds after their deposition.On both sides of the descent, the contact angle was recorded and an average was determined [73].

Scanning electron microscopy
One beneficial method for examining the surface morphology of a film between several excipients and drugs is scanning electron microscopy.A film sample was obtained and put in a sample holder, and several photomicrographs were made at a ×1000 magnification employing tungsten filament as the electron source [76].

Stability testing
OTF has been held for 12 mo at controlled temperatures of 25 °C/60% RH and 40 °C/75%, under ICH requirements.OTF should have their morphological characteristics, material thickness, reduction in film thickness, tensile qualities, water content, and dissolving behaviours thoroughly inspected before being stored [75,77].

CONCLUSION
OTFs are a more promising and advantageous administration method because of their improved therapeutic impact, responsiveness, and patient compliance.They have the potential to revive breath.Because oral films have a greater response than tablet formulations, many companies are now creating oral films instead.This type of technology has been investigated and has a lot of potential.
OTF dosage forms have demonstrated significant potential as a novel substitute for conventional dosage forms.This is attributed to their ease of administration for pediatrics, geriatric, and non-cooperative patients, as well as their cost-effective manufacture and convenient handling, storage, and transportation, including the potential to incorporate different medication ingredients, such as chemical medications, vaccinations, probiotics, and herbal extracts.Additionally, ODF is becoming more and more well-liked as a delivery system for treating conditions including oral inflammation, cardiovascular illness, pain management, nausea and vomiting, mental or emotional disorders, erectile dysfunction, pulmonary diseases, and more.When a quick onset impact is necessary and, in an emergency, it is one of the most significant dosage forms for oral administration that can be used.Thus, it can be said that OTFs with great patient compliance and numerous benefits have novel, forward-thinking prospects.

AUTHORS CONTRIBUTIONS
All the authors have contributed equally.