INTRODUCTION:

The oral route is the robust and impeccable route for the administration of therapeutic agents because the economical therapy and easy in administration cause high levels of patient compliance¹. Oral dosage forms are well liked than other dosage forms because of ease of administration, explicit dosage, self- medication, pain avoidance, patient compliance, etc^2. Inspite of noble advancement in drug delivery system the oral drug delivery is the foremost technique of administration of drug for systemic effect³. Commonly pediatric, geriatric, and bedridden patient encounter struggle in swallowing the conventional oral dosage form. To conquer this challenge a novel formulation was evolved i.e. oral fast dissolving films.

Oral fast dissolving films are kind of oral drug delivery system for the oral delivery of the drug, was developed based on the technology of the transdermal patch. This delivery system consists of a thin film, which is easily put on the mucosal tissue or patient’s tongue, instantly wet by saliva; then it rapidly disintegrates and dissolves to release the medication for oral mucosal absorption⁴.

Strategy in oral fast dissolving film:

· The system of this delivery consists of a thin film.

· On placing the film on the top of the tongue, the film rapidly dissolves within seconds, avoiding first pass metabolism as compared to tablet and other immediate release oral solid dosage forms, and thus increase the bioavailability of drug⁵.

· OFDF dissolves in the mouth like a cotton candy.

Essential Properties

Oral fast dissolving film having following properties⁶

· Available in various size and shape

· Rapid release

· Thin elegant film

· Fast disintegration or dissolution

· Un-obstructive

Advantages of oral fast dissolving film (OFDF)

· Comprehensibility of larger surface area that leads to quickly disintegrate and dissolution in the oral cavity within seconds⁷.

· Oral film dosage form allows rapid wetting by saliva due to available large surface area in the film thus rapidly disintegrate and dissolve and absorbed directly to the systemic circulation by avoiding first-pass hepatic metabolism and on increase the bioavailability⁸.

· OFDF is flexible so they are not as fragile and not need any kind of special package for protection during transportation and storage as compared to fast dissolving tablet⁹.

· No fear of chocking as compared to fast dissolving tablet.

· No use of water has led to better satisfactoriness amongst the dysphasic patients.

· The dosage form can be taken at any time and any place as per convenience of the individual.

Disadvantages of oral fast dissolving film

· Oral films are hygroscopic in nature so it must be kept in dry places.

· It also expresses the fragile, granule property.

· High amount of doses cannot be incorporated into the oral film.

· It requires special packaging for the products stability and safety¹⁰.

Development of oral solid dosage form¹¹

Fig.1: Development of oral solid Dosage form

Method of preparation of oral fast dissolving films

Oral Fast dissolving film can be prepared by

a. Solvent casting method

b. Semisolid casting method

c. Hot melt extrusion

d. Solid dispersion extrusion

e. Rolling method

Solvent casting method¹²

Semisolid casting method:

Solution of water soluble film forming polymer is prepared

Resulting solution is added to a solution of acid insoluble polymer

(Examples: cellulose acetate phthalate, cellulose acetate butyrate, etc.).

Then the appropriate amount of plasticizer is added to obtain a gel mass.

Gel mass is then casted in to the films or ribbons using heat controlled drums.

The thickness of the films should be about 0.015-0.05 inches.

The ratio of the acid insoluble polymer to film forming polymer should be 1:4

Film is prepared

Hot melt extrusion:

Hot melt extruder is used in this process. This technique involves shaping a polymer in to film via the heating process^13,14.

The drug is mixed with carriers in solid form

Extruder having heaters melts the mixture

Finally the melted mixture is shaped in films by the dies

Solid dispersion:

The term solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier in a solid state in the presence of amorphous hydrophilic polymers ^[15]

Drug is dissolved in a suitable liquid solvent

Incorporated solution into the melt of polyethylene glycol, below 70ºC

Solid dispersions are shaped into the films by means of dies

Table 2: Generalized detail of different ingredients of oral fast dissolving films¹⁶

S. No.	Ingredients	Amount (w/w)
1	Drug (API)	5-30%
2	Water soluble polymer	40-50%
3	Plasticizer	0-10%
4	Saliva stimulating agents	2-6%
5	Sweetening agents	3-6%
6	Surfactant	Quality sufficient
7	Flavors, colors, Fillers	Quality sufficient

Table 3: List of few drugs that can be incorporated in oral fast dissolving film ^[17,
18]

Drug	Dose	Therapeutic action
Azatidine Maleate	1mg	Anti histaminic
Nicotine	2mg	Smoking cessation
Loperamide	2mg	Anti diarroheal
Ondensetron	2.5mg	Anti emetic
Triplodine hydrochloride	2.5mg	Anti histaminic
Zolmitritpan	2.5mg	Anti migraine
Salbutamol	4mg	Anti histaminic
Chlorpheniramine Maleate	4mg	Anti allergic
Cetrizine	5-10mg	Anti histaminic
Acrivastine	8mg	Anti histaminic
Loratidine	10mg	Anti histaminic
Omiprazole	10-20mg	Proton pump inhibitor
Famotidine	10mg	Antacid
Ketoprofen	12.5mg	Analgesic
Dicyclomine hydrochloride	25mg	Muscle relaxant
Diphenhydramine hydrochloride	25mg	Anti allergic
Sumatriptan succinate	35-70mg	Anti migraine

Film forming polymers:

Oral fast dissolving film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made. “Water soluble polymers” are used as film formers for fast dissolving films. The water-soluble polymers get quick disintegration, good mouthfeel and mechanical properties to the films. The disintegration rate of the polymers is decreased by increasing the molecular weight of polymer film bases¹⁹.

Ideal properties of the film forming polymers

· The polymer employed should be non-irritant, non-toxic and devoid of leachable impurities.

· The polymer should be readily available.

· It should have excellent spread and wetting ability property.

· The polymer should exhibit sufficient shear, peel and tensile strengths.

· It should have good shelf life.

· It should not aid in cause secondary infections in the oral region.

· It should have a good mouth feel property^{20, 21}.

Table 4: Polymers used in preparation of oral fast dissolving film²²

Natural Polymer	Synthetic Polymer
Pullulan	Hydroxypropylmethyl cellulose
Starch gelatin	Polyvinyl pyrrolidone
Pectin	Polyvinyl alcohol
Sodium alginate	Carboxy methyl cellulose
Maltodextrin	Poly ethylene oxide
Polymerized rosin	Kollicoat
LycoatNG 73	Hydroxypropyl cellulose
Xanthan	Hydroxyl ethyl cellulose

Plasticizer:

The role of plasticizer is beneficial for preparation of oral fast dissolving film. Plasticizer helps to improve of flexibility of the film and reduce brittleness of the film and enhance the strength of the polymer. Plasticizer may affect the absorption rate of the drug and plasticizer should be compatible with drug some commonly used plasticizer are^23,24.

Table 5: Commonly used Plasticizer

S. No	Plasticizer
1	Glycerol
2	Propylene glycol (PG)
3	Poly ethylene glycol (PEG)
4	Phthalate derivatives
5	Citrate derivative
6	Castor oil

Surfactant:

Surfactant are used as solubilizing or wetting or dispersing agent so that the films gets dissolve within seconds and release active agent instantly. Sodium lauryl sulfate is used in the formulation of mouth dissolving film of Amlodipine and one most important surfactant is poloxamer 407²⁵.

Colours:

A full range of colour is available, including FD&C colors, EU Colors, Natural colors and custom Pantone matched colours²⁶. Pigments such as titanium dioxide or FD & C approved coloring agents are incorporated (not exceeding concentration levels of 1 percent; w/w) in Oral film when some of the formulation ingredients or drugs are present in insoluble or suspension form²⁷.

Flavors:

These are most important agents which are to be added to pharmaceutical oral preparations, preferably up to 10%w/w flavors are added in the formations. Flavor can be alone or combination. Peppermint oil, cinnamon oil, oil of nutmeg are example of flavor oils while vanilla, cocoa, coffee, chocolate and citrus are fruity flavors. Apple, raspberry, cherry, pineapple are few examples of fruits essence type²⁸.

Saliva stimulating agent:

Saliva stimulating agents is used to increase the saliva production rate that would support in the faster disintegration of the rapid dissolving strip formulations. Generally Citric acid, malic acid, lactic acid, tartaric acid can be used as salivary stimulants²⁹.

Sweetening agent

Sweeteners are the important part of the food products as well as pharmaceutical products intended to be disintegrated or dissolved in the mouth and provide acceptable taste. Natural and artificial sweeteners are used to improve drug taste^30,
31.

Table 6: List of sweeteners.

Natural sweetener (water soluble)	Artificial Sweetener (water soluble)
Xylose	Sodium or calcium saccharin salts
Ribose	Cyclamate salts
Glucose	Acesulfame-k

Method of preparation of oral fast dissolving films^[32]

Oral Fast dissolving film can be prepared by

f. Solvent casting method

g. Semisolid casting method

h. Hot melt extrusion

i. Solid dispersion extrusion

j. Rolling method

Hot melt extrusion^{33, 34}

Hot melt extruder is used in this process. This technique involves shaping a polymer in to film via the heating process^35,
36.

The drug is mixed with carriers in solid form

Extruder having heaters melts the mixture

Finally the melted mixture is shaped in films by the dies

Rolling method:

In rolling method, drug in a solution or suspension is rolled on a carrier. The solvent is mostly water and mixture of water and alcohol. The film is dried on the rollers and cut in to desired shapes and sizes. Other ingredients with active agent are dissolved in small portion of aqueous solvent using high shear processor. Water soluble hydrocolloids dissolved in water to form homogenous viscous solution^37,38.

Patented Technologies:

a. XGel: XGel film technology is developed by BioProgress which is the heart of Meldex international’s intellectual properties used in all its film system and its ingestible delivery technologies. X Gel film, potentially enhanced the product stability. It has also been developed for non-ingestible application such as cosmetic, ostomy pouches, sanitary and healthcare devices^39,40.

b. Soluleaves: In this technology the film is produced in order to release the active ingredients on coming in contact with saliva. This applied flavor release products such as mouth fresheners, vitamins product⁴¹. This delivery used in cough/cold and release active ingredients slowly over 15 minutes.

c. Wafertab: Wafertab is a drug delivery system that incorporates pharmaceutical actives into ingestible films. This used in topical or oral application and itself to many possibilities for innovative drug design, enabling multiple films with different actives to be bonded together⁴².

d. Foamburst: Foamburst is an oral film patent granted in September 2004 which is for capsule made foamed film. Gas is blown into the film during production. It is used in releasing flavor.

e. Micap: Micap signed an option agreement in 2004 to combine its expertise in microencapsulation technology with the Bio Progress water-soluble films. The development aimed at providing new delivery mechanisms⁴³.

f. Rapid film™: It is a novel thin film technology developed by Applied Pharma Research (APR). It is a thin film containing drug with area of 1-10 cm². Disintegration occurs completely within 20 seconds. For example: Donepezil Rapidfilm®, Olanzapine Rapidfilm®^{44, 45}.

Table 7: Some oral fast dissolving films which are available in marketed^{46, 47}

Brand name	Manufactured	API	Uses
Klonopin wafers	Solvay Pharmaceuticals	Clonazepam	Anxiety
Listering cool mint pocket packs	Pfizer, Inc	Cool mint	Mouth fresheners
Sudafed	Wolters Kuwer Health Inc	Phenylepinephrine	Congestion
Suppress	Innozen, Inc	Menthol	Cough suppressant
Triaminic	Novartis	Diphenhydramine HCL	Antiallergic
Theraflu	Novartis	Dextromethorphan HBR	Cough suppressant
Orajel	Del	Menthol	Mouth ulcer
Gas –X	Novartis	Simethicone	Anti Fluctuaing
Chloaseptic	Prestige	Benzocaine	Sore throat
Benadryl	Pfizer	Diphenhyramine HCl	Anti -allergic

Table 8: Supporting research for development of oral fast dissolving film

Author name	Year	Method	Drug / polymer and other formulation ingredients	Result
Dangre P.V. et al	2019	Solvent casting Method	Clonidine HCL, HPMC E15, PEG-400, Xylitol, Sodium lauryl sulphate (SLS), Citric acid.	The optimized formulation showed fast drug dissolution (>90%) within8 min, and solid state characterization by DSC, XRD revealed excellent film characteristics ^[48].
Maddela S. et al	2019	Solvent casting method	Zolmitriptan, Hydroxy propyl methyl cellulose (E3, E5, and E15), PEG 400, PVP K30, SLS, Pine apple, Aspartume, Glycerol, Methanol.	Formulation showed quicker disintegration (within 11 s) and ZOL release rates (within 180 s) along with good physico-mechanical properties. These results indicated that the disintegration and drug release of ZOL can be enhanced to a greater extent by optimizing formulation variables in Mouth dissolving films^[49].
Joshi Pratikkumar et al	2019	Solvent casting method	Domperidone and β-cyclodextrin (1:3), Tween-80, HPMC E15, PEG-400, Citric acid, Methanol	The promising film showed the greatest drug dissolution (more than 75% within 15 min), satisfactory in vitro disintegration time (45 sec) and physico - mechanical properties that are suitable for mouth dissolving films ^[50].
Pooja RD et al.	2018	Solvent casting method	Oxcarbazepine, HPMC E5 LV, HPMC E50 LV, PEG 400, PEV K30, Menthol, Mannitol, Citric acid.	The results obtained showed no physical chemical incompatibility between the drug and the polymers. The prepared films were clear, transparent and smooth surface. D4 formulation showed maximum in-vitro drug release 94.35%, following first order kinetics (r2=0.9791) ^[51].

Evaluation of fast dissolving oral films

a. General appearance⁵²

Visual evaluation of translucent and semitransparent strip tests fast dissolving films.

b. Weight of films⁵³

On analytical balance, oral fast dissolving films can be weighed, and average weight can be calculated for each film. Films should have almost constant weight, is desirable. It's important to make sure a film includes the right amount of excipients and APIs.

c. Organoleptic evaluation⁵⁴

For many pharmaceutical products, color is a essential means of identification, and is also typically necessary for customer acceptance. The product's color has to be consistent within the dosage form. Odor is also important for the acceptance of the oral dosage form by the user and can provide an indicator of the quality of the films as the presence of an odor in a lot may imply a problem of stability. The odor can, however, be indicative of the product (e.g. vitamins), added ingredients (e.g. flavoring agents), etc. Taste is also an important element for the approval of the customer and many businesses use taste panels to determine the interest of various rates of flavors in product growth. Unique monitored human taste panels are used for evaluating psychophysical assessment of the drug. In-vitro methods of utilizing taste sensors, specially designed apparatus are being used for this purpose.

d. Film thickness⁵⁵

A film thickness should be measured using the micrometer screw gauge or digital calibrated Vernier callipers. Film should be measured at five points, i.e. from the middle and from all four corners and then determined as mean thickness. The uniformity of thickness must be calculated, as it is directly related to the consistency of the dose in the film.

e. Mechanical properties⁵⁶

Three mechanical properties namely tensile strength, percentage elongation and Young’s modulus are calculated.

i. Tensile strength:

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. It is calculated by formula:

Load at failure X100

Tensile strength = ------------------------------------

Film thickness X film width

ii. Percent Elongation:

When stress is applied, a film sample stretches and this is referred to as strain. Strain is basically film deformation separated by the original sample dimension. Generally elongation of film increases as the plasticizer content increases.

Percent elongation= L*100/L^o

L = Increase in length of film

L^o = Initial length of film

Young's Modulus:

Young's modulus or elastic modulus is the measure of stiffness of film. It is expressed as the ratio of applied stress over straining the region of elastic deformation as follows:

Slope X 100

Young’s Modulus=-------------------------------

Film thickness X crosshead speed

Brittle and Hard film demonstrates a high tensile strength and Young's modulus with small elongation.

f. Folding endurance:

It is determined by repeatedly folding the films at the same position of uniform cross sectional area and thickness before it splits.

g. Disintegration time:

The time of disintegration will be noted when the film starts to break down or decay. The Disintegration test was carried out in 10 ml phosphate buffer (pH 6.8) in a beaker at 37±0.5^oC.

h. pH value

PH is determined by dissolving an oral film in 10 ml of distilled water, and pH calculation of the solution obtained is supposed to have exactly the same pH.

i. Swelling property:

Each film sample is weighed and placed in a pre-weighed stainless steel wire mesh. The mesh of the film sample is then submerged in a plastic tub into a liquid of 15 ml (simulated solution of saliva). The weight of the film has been increased at the pre-set time interval up to constant weight.

Degree of swelling = Wt – Wo/ Wo

Where, Wt is weight of film at time t, and Wo is weight of film at time zero

j. Stability Studies⁵⁷

For the determination of the influence of temperatures and humidity on drug stability, stability tests on the engineered oral fast dissolving film are performed. The film is contained in an aluminium foil and is subject to room temperature stability. The sample can be removed at 3 months and 6 months and subjected to drug release and in vitro dissolution tests for cumulative percentage to assess disintegration period and disintegration check.

k. Assay/Uniformity of drug content:

This parameter can be calculated by continuous shaking, by dissolving known weight of film in 100 ml of simulated saliva of pH 6.8 for 30 min. Then the result is calculated by some standard assay method defined in any of the standard pharmacopoeia for the specific API. Content uniformity is determined by estimating the content of the APIs in individual strips. Limit regarding to content uniformity is 85-115%.

l. Dissolution test:

Dissolution is characterized as the amount of drug substance approaching the solution per unit time under uniform liquid / solid interface conditions, temperature, and concentration of the solvent. Dissolution testing can be performed using a standard paddle or basket defined in a pharmacopoeia of 37±0.5°C in a simulated saliva solution or pH of 6.8 phosphate buffers. Samples are withdrawn at regular time intervals and analyzed by UV-Visible spectrophotometer.

CONCLUSION:

Recently pharmaceutical companies discovered fast dissolving films as a practical and accepted alternative to traditional medicines. It is a new tool of treatment in the advanced drug delivery technology utilized the present drug to dissolve in the oral cavity and provides desired effect with rapid action. It is good for patient compliance those patients has difficult in swallowing tablets and capsule and also this technology is good tool to pharmaceutical company for product life cycle management for increasing the patent life of exiting products. Fast dissolving film is an ideal dosage form in the novel drug delivery system for the poorly water soluble drug. These novel opportunities offer many advantage over other dosage forms as well as they offer easy production and evaluation technique. This review is an effort to combine the knowledge available on oral fast dissolving films. A lot of research work is going on and will be started in near future on oral fast dissolving film.

CONFLICT OF INTEREST:

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENT:

Author wants to thanks Integral University for providing suitable research environment and facility. The University has also provided a manuscript communication number for further communication (IU/R&D/2020-MCN000809).

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Received on 02.12.2020 Modified on 12.01.2021

Research J. Pharm. and Tech. 2021; 14(4):2145-2152.

DOI: 10.52711/0974-360X.2021.00380