A Review on Film Forming Drug Delivery Systems

 

Hayder Yahya Mansoor Al-Jarsha*, Mowafaq M. Ghareeb, Ahmed A. Hussein

Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq.

 

ABSTRACT:

Conventional dosage forms for topical and transdermal drug delivery have several disadvantages related mainly to its poor skin permeation and patient compliance. Many approaches have been developed to improve these dosage forms. Film forming drug delivery systems represents a recent advancement in this field. It provides improved patient compliance with enhanced skin permeation of drugs. In its simplest form, these consist of a polymeric solution, usually in a supersaturated state, in a suitable solvent. A plasticizer is usually added to improve the flexibility and enhance the tensile strength to the film. It is also possible to control and sustain the drug release from the films by controlling the polymeric content, concentration of plasticizer, or formulation with other additives. In this review, we are summarizing the mechanism of formation of these films as well as its types and possible applications. The main ingredients, properties, and evaluation of the various film forming delivery systems are also discussed.

 

 

 

INTRODUCTION:

Adult body skin has around 2 square meters of surface area and receives approximately ⅓ of total body’s circulating blood¹. Despite this rich blood supply, skin acts an effective barrier against permeation of most macro- and micro-molecules². This barrier is mainly due to stratum corneum which is about 10 μm in thickness and mainly consists of keratinized dead cells of the epidermis. Percutaneous drug absorption occurs principally through stratum corneum³.

 

Topical application of the drugs is needed either to achieve high local concentrations (topical treatments) or to bypass the skin and reach systemic circulation⁴. Despite hindered passage of drug particles through the skin, the topical route offers many advantages including self-administration (ease of application to a varied large surface) and acting as an alternative delivery route for hypodermic injections and some oral delivery drugs⁵.

 

The most commonly used dosage forms for topical applications are patches, ointments and creams. Patches ensure persistent drug contact with the skin surface providing a better rate and extent for drug absorption⁶. However, their application for curved surfaces can be cumbersome and they tend to irritate the skin and obstruct the sweat gland ducts (due to their occlusive properties). Pain associated with peeling off patches and their poor aesthetic appearance are additional well-known limitations⁷. Scale up for mass production is another challenge for patch dosage form and crystallization of drugs to stable forms usually encountered⁸. Creams, ointments and other semisolid preparations overcome some of the limitations associated with patches, but they cannot ensure persistent drug contact as they may easily be wiped off the surface with the patient’s clothes necessitating the need for repeated applications⁷. This vulnerability together with the post-application greasy or sticky feel account for the poor patient compliance associated with such preparations. Cross- infection can also take place when these dosage forms are applied to wounds using fingers⁹. The limitations mentioned earlier implicate the need for development of a new dosage form that increases patient compliance by reducing frequency of administration together with improved texture and appearance^10,11.

 

Film forming system (FFS) is an innovative alternative to conventional formulations which produces in situ film after its application on the body surface. It is a non-solid dosage form consisting of a vehicle into which the film forming additives and the drug are incorporated. The vehicle evaporates rapidly after application on the skin leaving a thin, well-adhered film in which the drug is incorporated. The excipients can be varied to produce a sustained release film in a form of matrix. Additionally, other types of films can be produced as needed such as those in a form of thin liquids having a high penetration ability into stratum corneum¹².

 

FILM FORMING MECHANISM:

Upon applying the FFS on the skin, in situ film formation takes place after solvent evaporation (figure 1). In case of solution FFS, chains of the polymer intercalate, passing through a gel form to the thin film. Certain concentration of the polymer is required for the interpenetration of its chains to take place. This concentration is   inversely proportional to the viscosity of the applied solution¹³.

 

Figure 1. Film formation mechanism¹⁴.

 

The residual thin film on the skin surface therefore reaches a saturated or even supersaturated level with respect to drug concentration. This result is increased thermodynamic activity of the formulation which improves drug permeation without eliciting irritation or other local side effects^12,14.

 

According to Fick’s law of diffusion in sink condition, the flux (J) increases with increasing the concentration of the drug in the donor compartment (C_d)

 

          DKSC_d

J = –––––––––   ……………………… Equation 1

              h

 

Where J is the flux representing the amount of the drug passing through the skin having an area of S per unit time. D is the drug’s diffusion coefficient, K is the partition coefficient, C_d is the concentration of the drug in the FFS, and h is the thickness of the barrier (skin)¹⁴. It is clear that the flux is directly proportional to C_d. However, the value of C_d represents the dissolved part of the drug in the vehicle of the FFS. Therefore, a modified form of Fick’s law is used here:

 

          αD

J = ––––––  ………………………... Equation 2

          γh

 

where α and γ are the thermodynamic activities within the formulation and the membrane, respectively. Equation 2 demonstrates that the flux increases with increasing thermodynamic activity of the FFS that intern is correlated to the level of saturation. It should be mentioned that thermodynamic instability takes place if supersaturation is reached¹⁵. However, the supersaturated state created by FFS overrides the instability problem because it happens directly after application to the skin. Therefore, it FFS has an enhanced drug permeation compared to topical formulations¹⁴.

 

The rate of volatilization of the solvent is crucial for film development. If the rate of evaporation is slow, over-wetting and even dissolution of the surface substrates might take place. On the other hand, rapid evaporation of the solvent can result in drying of the droplets containing the polymer before contacting the surface (similar to the process of spray drying) or contacting the surface without spreading over it (called orange peel effect). The rate of volatilization of the solvent rely mainly on atmospheric temperature and pressure. Other factors can influence the rate such as air flow and humidity (if the solvent is water)¹³.

 

The ability of ethinylestradiol solution-based formulations to form a film was investigated in vitro using human epidermis under two conditions: with or without an enhancer. The standard to which the two formulations were compared to the marketed contraceptive patch (Evra®). The film forming formulations showed an increase of permeation by 4 and 7 times for those without and with enhancer, respectively¹⁶.

 

TOPICAL DRUG DELIVERY SYSTEMS:

FSS has the advantages of both semisolid dosage forms and transdermal patches as it basically represents a form in between those two systems¹⁴. Table 1 compares these topical delivery systems.  Additionally, the permeation models for the systems are illustrated in figure 2.

 

Table 1. Differences between of topical drug delivery systems¹⁴.

	Patches	Creams/ointments	Film forming system
Appearance	Highly visible	Visible	Almost invisible
Skin sensation	Comfortable, non-greasy, non-sticky	Can be greasy or sticky, inconvenient	Comfortable, non-greasy, non-sticky
Application	Easy, comfortable	Can be messy	Easy, comfortable
Modification of the dose	Uncommon, low	Common, high	Common, high
Frequency of administration	Variable (from twice daily to once weekly)	1 – 4 times daily	Once daily, once every other day also achievable
Prolonged release	Possible	Not possible in regular forms	Possible
Resistance to wipe off	Yes	No	Yes
Residues	Possible	No	Possible

 

In general, transdermal patches act either as a reservoir for slow drug release for systemic or localized drug delivery¹⁷. On the other hand, semisolid preparations deliver its active drug directly on the skin surface or to the underlying skin layers, but systemic drug delivery is restricted by multiple factors. FSS combines the functions of both patches and semisolids and can provide a transdermal delivery in addition to the topical as needed¹⁴.

 

Figure 2. Profiles of drug release from transdermal patches, semisolids, and film forming systems¹⁴.

 

APPLICATIONS OF FFS:

FSS were initially used in the field of wound care as tissues glues for operative wound closure. These film forming gels or solutions have natural or synthetic formers (e.g. fibrin, cyanoacrylates) and may or may not contain antimicrobial agents to prevent wound infections¹⁸.

 

Other proposed applications include peel off masks for treatment of skin hydration, acne and other non-medical uses (e.g. silicone FFS for cosmetic ointments and creams)^19,20. In ostomy, a possible application is by formation of a film around the wound to protect skin from the irritant body fluids¹⁸. In industry, hydrophilic/hydrophobic creams and ointments and UV protecting creams are examples of widely used barrier membrane substrates in which FFS can be utilized. Workers may use these barrier membranes for long-term protection from hazardous chemicals and UV/IR radiations²¹. In agriculture, film forming polymers can be applied to increase the soil integrity and raising its temperature. Therefore, spraying such polymers on the soil can help in protecting the crop²².

 

CHARACTERISTICS OF FFS:

Unlike other semisolid preparations, FFS remain on skin for long period of time, can be applied to several sites of the body regardless to their area or shape. Other unique properties of FFS include rapid drying and transparency of the formed film as shown in figure 3 – A. Additionally, a flexible, non-tacky and comfortably peelable film is obtained after film drying (figure 3 – B). Excellent adhesion and resistance to wipe off of the film reduces the possibility of transmission of ingredients to the clothes or other people¹⁴.

 

Figure 3. Visual appearance of FFS. A: Thin transparent film formation, B: Flexible, non-sticky, and removable film upon drying¹⁴.

 

FORMULATIONS OF FFS:

1. Solutions/sprays:

The FSS formulations have four main ingredients which include solvent (nonvolatile and volatile components), drug, polymers and penetrability enhancers. The non-volatile component will prevent precipitation of the drug upon vaporization of volatile solvent. This nonvolatile component is selected to have an intrinsic ability to partition itself and aid in drug partitioning into the stratum corneum of the skin. It should also enhance drug permeation and diffusivity through alternation of intercellular lipids. The result is an invisible drug depot within the stratum corneum that slowly releases the drug into the systemic circulation through the skin layers. Therefore, once daily application is possible to accomplish the desired therapeutic effects in many FFS^23,24.

The preparation of such FFS is performed by dissolving the polymer in the vehicle with overnight stirring to reach maximum solubilization of the polymer. A clear solution should be obtained into which other excipients are added such as plasticizer, cross linker, etc. After that, the solution should be stirred for at least 24 hours²⁵. The selected polymers are selected to have properties of anti-nucleating agents and crystallization inhibitors to maximize physical stability of the drug even after evaporation of solvent. Therefore, polymers such as polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) are usually added to FFS¹⁴.

 

FFS can be applied using an applicator and left to dry. Alternatively, spray containing FFS with metered dose dispending pump can be used²⁶. In solution film forming dosage form, the polymeric solution is sprayed or applied as a liquid on the skin which upon evaporation of its solvent, forms a transparent film. The film can be peeled off at any time to eliminate the therapeutic regimen (figure 4). Therefore, this might be considered as an attractive alternative to transdermal drug delivery¹⁶.

 

Figure 4. Skin application of FFS¹⁴

 

In 1996, the first generation of FFS was developed by Misra et al²⁷. The liquid FFS was prepared using a mixture of polyvinyl alcohol (PVA) and PVP dissolved in isopropyl alcohol with liquid paraffin (plasticizer) and Tween 20 (surfactant). Wistar rats and were used in permeation studies. A biphasic film forming solution releasing testosterone showed excellent skin adherence with adequate amounts of the hormone diffusing in a slow release pattern following the first burst release^27,28. Other FFS of ketorolac solution was prepared utilizing PVP and Eudragit dissolved in ethanol²⁵. Spray formulation of fluconazole was prepared using Eudragit® RS100 and ethyl cellulose with a mixture of methanol and of camphor as penetrability enhancers²⁹. Similarly, the antifungal voriconazole was incorporated into a spray FFS using ethyl cellulose and Eudragit® RLPO³⁰. A spray FFS containing estradiol using different types of plasticizers and polymers. Optimization of the formulation was done to obtain a FFS having more efficient and lasting for longer time compared to available patch and gel formulations³¹.

 

2. Gels:

Gels are semisolids with liquid and solid components. The liquid component can be hydrophilic or hydrophobic. The solid part of the gel interconnects and immobilizes the liquid part by forming a three-dimensional network³². If the liquid component of the gel contains polymers that are hydrophilic in nature, it is then termed “hydrogel”³³.

 

The current focus of transdermal delivery systems development is to utilize multiple polymers in combination with gelling agents to obtain gel FFS. Some commonly used gelling agents and their main properties are listed in table 2. The dose of the gel can be applied on the shoulders, arms, abdomen or internal parts of the thigh creating a bioadhesive film on the skin surface^34,35.

 

Table 2. Commonly used gelling agents³⁶

Gelling agents	Concentration used (%w/w)	Comments
Sodium carboxymethyl cellulose	3-4%	Withstands autoclaving and therefore, can be used in preparation of sterile gels
Carbopol 934	1%	Can promote sustained release of the drug
HPMC	2.5%	High stability and resistant to microbes
Combination of HPMC + Carbopol	1.2%	Combination enhances the stability
Pluronic® F127	1-3%	Improved transparency and solubility in cold water
PemulenTM	0.1-0.4%	Provides rapid release of oil phase, excellent stability

 

Together with the polymers, gelling agents, preservatives, plasticizers and other excipients are implemented in the formulation to confer the required properties of high flexibility, substantivity and complete skin contact with a good adhesion. In contrast to other forms of film forming dosage forms, gels are considered to be easier to apply and manufacture and have suitable adhesiveness, consistency, elasticity and flexibility³⁷.

 

FFS gel of terbinafine HCl was prepared using combination of two polymers: hydroxypropyl cellulose (HPC) and Eudragit. The resulted gel produced a matrix with a prolonged delivery time of terbinafine³⁵. Similarly, sustained release formulation of FFS gel containing rotigotine was prepared using carbomer 934 and HPC³⁸.

 

FFS of hydrogels are used mainly for wound healing. It is applied to the site to form a stress resistant film so that it is not affected by the physiological skin movement¹⁴. Tolterodine was formulated in such FFS hydrogel which produced a transparent film with a sustained release property³⁹. Transdermal testosterone was formulated using PVA to form a semisolid hydrogel inside the tubes. The surface energy and contact angel were reduce using an adhesive agent, polyisobutylene. The FFS produced a thin film within 2 – 3 minutes after spreading over the skin. The film was maintained on the skin for more than one day⁴⁰. A hybrid organic-inorganic gel was formulated to produce a flexible, thin, and transparent film. These characteristics improves the comfortability of the adhered film and make it more attractive from cosmetic point of view. PVA was used as a gelling agent, γ-(glycidyloxypropyl)trimethoxysilane as an inorganic-modifying agent, PVP as a thickening agent, and glycerol as a plasticizer. It is notably to mention that upon reduction of PVA crystalline regions, the permeability of the drugs (5-fluorouracil or ibuprofen) were increased³⁴. A unique application for gel FFS exists in wound healing. This is particularly important in skewed or uneven wounds compared to standard wound dressings. For instance, a gel FFS incorporating sodium fusidate showed enhanced in vivo healing of skin infections. The gel FFS constituted of water and ethanol. In addition, propylene glycol (PG), PVA and PVP was also incorporated to produce a thin flexible film with appropriate elasticity within 4 minutes³⁷.

 

3. Emulsions:

Emulsions are semisolid/liquid dosage forms which can incorporate both hydrophilic and lipophilic drugs. The stability of emulsions is usually obtained by employing one or more emulsifying agents. Emulsions are generally subdivided into water-in-oil (W/O) or oil-in-water (O/W) depending whether the dispersed phase (also called internal phase) is water or oil, respectively^41,42. The dispersion medium (also called continuous phase) is has an opposite water solubility to the dispersed phase. Emulsion type is mainly determined by the ratio of the internal to continuous phase as well as by the value of hydrophilic – lipophilic balance (HLB) of the emulsifying agent used. Several categories of emulsifying agents available including polymers, surfactant, finely divided solid particles (e.g. bentonite) and proteins (e.g. gelatin)¹⁴.

 

In addition to the abovementioned components, film forming emulsions also have polymer component to for the desired. The evaporation of the volatile ingredients from the emulsion allows absorption of the drug into the skin⁴³. Film forming emulsions are superior to other semisolid formulations with respect to substantivity and extended contact time providing a more efficient sustained drug release for chronic diseases⁴⁴.

 

Emulsion drug delivery is affected by the emulsion type and the nature of the drug used. The lipophilic ethylhexyl methoxycinnamate (sunscreen agent) had a higher dermal delivery from W/O than from O/W emulsion and this was attributed to the nature of occlusive oily continuous phase of W/O type. However, other studies have found this statement to be inconsistent. It was shown that lipophilic parabens had enhanced skin permeation from O/W emulsions. The higher affinity of the parabens for the oil phase in emulsion compared to stratum corneum could explain the reduced skin permeation with the W/O emulsion⁴².

 

FDA recently approved Pliaglis® (Galderma Laboratories, USA) which is a cream FFS consisting of a mixture of lidocaine and tetracaine (7%/7%) indicated as a topical anesthetic for dermatological practices as pulsed dye or facial laser treatments, removal of tattoo with the aid of laser, or filler injections⁴⁵.

 

Nonivamide film forming emulsion having sustained delivery properties was prepared using Eudragit RS 30D and Eudragit NE as film forming polymers. Investigations on other nonivamide film forming emulsions in which the drug was incorporated in a polymeric matrix showed that diffusion of drug from the matrix affected the rate skin permeation. Consequently, the rate of permeation could be maintained constant for 12 hours if sufficient concentrations of the drug were employed^44,46.

 

CONSTITUENTS OF FFS:

1. Drug:

Initially, the solubility of the drug in the intended FFS polymers must be determined. This will give an idea about the saturation level of the drug retained on the skin and accordingly, its expected penetration level. For instance, the solubility of methylphenidate was shown to be higher in Eudragit® E compared to Eudragit® RS. Consequently, the level of saturation and drug release was higher from Eudragit® E-based FFS. Utilizing differential scanning calorimetry (DSC), one can determine the melting enthalpy of a drug at different ratios in the polymer. A linear relationship was found to exist between the solubility and enthalpy⁴⁷. Additionally, drugs utilized in FFS should be relatively stable to the epidermis enzymes with minimum skin irritation. High potency drugs having a reasonable skin permeability are other important prerequisites. Properties such as partition coefficient which will determine the drug pathway through the skin layers should also be determined. Finally, low molecular weight compounds are better permeated across the skin than large molecules and therefore, ideal drug should have relatively low molecular weight. The optimum drug properties to be a candidate for transdermal delivery are shown in table 3¹⁴.

 

Table 3. Optimum criteria of drug candidate for transdermal drug delivery⁴⁸.

Criterion	Description
Dose	Desired to be low (<10 mg/day)
Half-life	≤ 10 hours
Molecular mass	<400 Daltons
Partition coefficient (P)	Log P in octanol/water system is between 1 and 3
Skin permeability coefficient	> 0.5 x 10-3 cm/hr
Skin perception	Non-sensitizing and nonirritating
Oral bioavailability	Low

 

2. Polymers:

The film properties of the FFS depend on its polymeric foundation. A variety of polymers (whether implemented solely or in combination) constitute that foundation. These polymers should form the desired film properties required for each specific type of FFS (e.g. flexibility, transparency) at skin temperature⁴⁹. Table 4 shows examples of commonly used polymers in formulation of FFS with their respective properties.

 

Table 4. Examples of polymers used in film forming systems^49-52.

Polymer	Properties
HPMC	·    Produce a smooth, non-sticky film with satisfactory texture ·    Non-ionic polymer with intermediate adhesive characteristics ·    Minimal interaction with other additives ·    Soluble in water, but insoluble in ethanol and chloroform ·    Stable over pH 3 to 11
Ethyl cellulose	·    • Inert and non-irritant ·    • Water insoluble but soluble in organic solvents ·    • Favorable for sustained release characteristics, usually in combination with HPC
Carboxymethyl cellulose	·    • Produce a clear or colloidal solution upon dispersion in water ·    • Has swelling property ·    • Good binding and adhesive properties
HPC	·    • Insensitive to the pH of the formulation because it is nonionic polymer ·    • Soluble in water and organic solvents ·    • Intermediate binding and adhesive properties
PVP	·    • Soluble in water and organic solvents ·    • Nonionic and biocompatible, therefore, used in wound dressing FFS ·    • Good binding and adhesive properties (due to Van der Walls and hydrogen bonds formation) ·    • Has high swelling property ·    • Can enhance the penetration of active ingredient ·    • Can enhance the adhesive properties if used as co-adjuvant
PVA	·    • Synthetic, non-ionic, water soluble polymer ·    • Intermediate adhesive and film forming characteristics ·    • Inert and nontoxic ·    • Films formed are of low elasticity and high rigidity, therefore, usually blended with PVP
Polyethylene oxide	·    • Non-ionic ·    • Increasing molecular weight increases the binding and adhesive properties
Chitosan	·    • Inert and biodegradable, therefore, used in wound dressing FFS particularly when mixed with PVP ·    • Insoluble in alcohol and sparingly soluble in water ·    • Particularly good film forming properties ·    • Can enhance the penetration of active ingredient ·    • Can be used in controlling the release of the drugs
Polymethacrylates copolymer (Eudragit)	·    • Films produced are elastic, flexible, and transparent ·    • Biocompatible ·    • Can be used in controlling the release of the drugs ·    • Good binding and adhesive properties

 

3. Solvents:

Solvents of the FFS influence drug permeation in addition to their drug-solubilizing action. The safety of these compounds has been demonstrated through their universal long-term use⁵³. Commonly used solvents for topical applications are mentioned in table 5.

 

Table 5. Example of solvents used in topical formulations (54)

Category	Examples
Alcohols	Ethanol, isopropanol, octanol, benzyl alcohol, butanol, fatty alcohols, lanolin alcohols
Glycols	Polyethylene glycols, propylene glycols, ethylene glycol monophenyl ether
Other solvents	Ethyl acetate, acetone, silicone oil, isopropyl myristate, octyl salicylate, dioxane, hexane, azone, butanone, oleic acid

 

4. Plasticizers:

FSS plasticizers provide flexibility and enhances the film’s tensile strength. The plasticizer has to be capable of lowering the glass transition temperature and enhancing the drug diffusion. Compatibility, low intrinsic skin permeability, and miscibility with polymers are important properties required for the plasticizers. Additionally, some plasticizers can increase the drug release by enhancing the mobility of polymeric chains⁵⁵. Skin adhesion can also be improved by plasticizer. Finally, it is important to use the optimum concentration of the plasticizer to give the film with the desired characteristics. Plasticizers in high concentration can produce smooth stocky films while those with insufficient concentrations will produce brittle films¹⁸. Commonly used plasticizers include PEG, sorbitol, silicone gums, acrylate polymers such as Eudragit® NE, PG, triethyl citrate dibutyl phthalate and others⁵⁶.

 

EVALUATION OF FFS:

1. Film Weight:

This is usually done by weighing one gram of the FFS and placing it on a Petri dish. After drying (usually overnight), the weight of the formed film is determined using an electronic balance¹⁸.

 

2. Surface morphology and topography:

Valuable information can be obtained using atomic force microscopy. The film’s mechanical and topographic characteristics is usually compared to these of skin. It provides a nanoscale photo showing the film surface roughness and homogeneity without any treatment of the film before measurement⁵⁷. Microscopic shape and surface roughness of the film can also be determined by transmission electron microscopy or scanning electron microscopy⁵⁸.

 

3. Film thickness:

A plate of Teflon can be used as a base on which the film is applied on an area of 5 cm² ¹⁸. Scalpel is used to cut the film after drying overnight. The average thickness of the film is ideally measured with a digital Vernier caliper at three distinct points on the film⁵⁹.

 

4. Phase transition time:

Phase transition time is the time required for the applied FFS (solution, gel, etc.) to form a film. In vitro evaluation is made using a Petri dish or skin obtained from pig’s ear. The quantity used is approximately one gram in case of Petri dish which is then kept at 37 °C using hot plate. The time recorded for the film to be formed¹⁸. Film formation is categorized as non-uniform formation, incomplete formation, or complete and uniform formation together with an indication about polymer behavior (with or without precipitation). The general appearance is also described in terms of opacity, dryness, stickiness, peelability)⁵⁵.

 

5. Film flexibility and tensile strength^14,60,61:

The capacity of the film to withstand the applied forces is known as tensile strength (TNS). The goal of measuring TNS is to measure the ability of the film to resist abrasion and to ensure its flexibility in order avoid its cracking or skin fixation upon skin movement. The following equation can be used to calculate the TNS:

 

 ………………………………... Equation 3

 

Where F_m is the maximum applied force (pressure) that can be accommodated by the film without cracking, L is the film thickness, and W is the original width of the film before applying any forces. The film elasticity can be estimated by measuring film elongation (FE) which can be calculated from the following equation

…………………….… Equation 4

 

The initial length of the film is I_o and I_max­ is the maximum length of the film before its tear.

Other way of measuring the film flexibility is to stretch the skin in 2–3 directions after the film formation. Upon stretching, non-flexible films exhibit cracking or skin fixation while flexible ones having no film cracking or skin fixation.

 

6. Drying time:

Volunteer’s forearm can be used to evaluate the drying time of FFS. The test is done by applying the film on the inner sides of the arm. Then, after a measured period of time, a glass side is allowed to touch the film without compression. The film is termed to be dry if no visible liquid was observed on the side of the glass. Otherwise, the test is repeated with an extension of the time period until obtaining the minimum time for dryness which is recorded to be the drying time of the film. A shorter drying time would increase patient compliance due to reduced waiting time for film formation⁶².

 

7. Bioadhesive Strength:

Determination of the stickiness of the film can be achieved by applying the FFS to the skin of a mouse (area of 2 x 5 cm). After drying and formation of the film, the force required to detach it from the skin (F) is measured. The bioadhesive strength per unit area (A) can be calculated from the following equation^60,63.

………… Equation 5

 

8. Stickiness of the film:

A piece of cotton wool is gently compressed against a formed film to determine its stickiness. Some of the fibers of cotton wool will be adhered on the film and by measuring its quantity the stickiness of the film can be rated. High, medium, or low film stickiness is termed if dense, thin, or occasional/no fibers are seen, respectively. This test is essential to optimize the formulation to have low/no stickiness in order to avoid sticking of the film to the clothes of the patient³⁵.

 

9. Water washability:

This is performed by applying the FFS on the skin and allow it to dry. Then washing the film with water and the easiness of washing is rated as poorly washable, moderately washable, or easily washable²⁹.

 

10. Homogeneity of the film:

Chemical composition can be investigated using Raman spectroscopy. The maps collected from spectra give an estimation of film chemical homogeneity. After topical application of FFS, tracking of permeation through the skin can also be done using Raman scattering technique⁵⁷.

 

11. Water vapor permeability (WVP):

WVP is the mass of water vapor permeating through the film per unit time per unit area⁶⁴. WVP can play a significant role in the permeability of wound fluids as well as microorganism growth. WVP of the film is affected by stratum corneum hydration, skin temperature as well as its blood flow⁶⁰.

 

To measure WVP, a plate of Teflon can be used as a base on which the film is applied and allowed to dry at room temperature for 72 hours. Circular film sheet of predetermined surface area (A, in cm²) is cut, and this is used to cover a glass vial prefilled with distilled water. Ring of silicon is used to aid in fixation of the sheet on vial’s opening together with aluminum cap. The vial is weighed before and after its placement for predetermined intervals into a desiccator with controlled relative humidity.  The entire duration of placement in the desiccator is approximately 72 hours⁵⁹. The wight loss (W, in grams) after each time interval (t, in hours) is calculated and the WVP is calculated from the following equation:

 

 …………………………… Equation 6 ¹⁴

 

12. Swab tests:

The resistance time of FFS can be measured using swab test. A glass is usually chosen to perform adhesion tests to simulate the hydrophilic polar substrate because of its strong adherence ability that mimics adherence to the skin⁴⁶. Both dry and wet swab tests should be performed. The dry swab test dictates the performance of FFS on the dry skin while the wet swab test indicates the behavior upon wetting by sweat or water on the skin. The dry test is usually performed on a plate made of glass. The plate is divided into six squares, each one having a dimension of 1 × 1 cm². The FFS is applied on the plate and samples are taken using dry cotton swabs from each square at 6 different times (at 0, 0.5, 2, 4, 6 and 8 hours). Extraction of the swabs’ content is the performed and the drug quantity in each swab is determined by appropriate methods. The we swab test is identical to the dry one except that the swabs are immersed in water before sampling¹⁴.

 

13. Diffusion tests:

In vitro diffusion tests are carried out to have an inspiration about permeation behavior of the drug in vivo. The release of drug from FFS is usually assessed using Franz cell which composed of two parts: the donor and receiver compartments. A diffusion membrane is placed between the two compartments (e.g. cellophane, egg membrane, etc.). The medium of diffusion is placed within receptor compartment from which the sampling arm is connected while the donor compartment is usually left uncovered to the atmosphere. The pH of the diffusion medium is either acetate (pH of 6) or phosphate (pH 7.4) at 37 °C⁶⁰. A predetermined amount of the film is applied on the donor compartment so that its drug content is known. The samples are collected at several time intervals from diffusion medium to determine spectrophotometry the percent drug release at each point³⁵.

 

14. Ex vivo skin permeation test:

Permeation tests are carried out ex vivo to assess the barrier effects of the skin on the FFS. Similar to diffusion tests, Franz diffusion cell can be used but the membrane is usually replaced with a skin of a rat with the stratum corneum and dermis are facing the donor and receptor compartments, respectively⁶⁵.

 

15. Skin penetration tests:

This test is simple yet particularly useful. A certain amount of FFS is applied on the skin using a spatula or a pipette. This amount contains a predetermined quantity of the drug. After application, the film is removed from the skin after specific time intervals (e.g. 10 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, etc.) and its drug content is determined. The quantity of the drug penetrated is calculated by subtracting the quantity of the drug remaining in the film from the original applied quantity at each time interval. A permeation profile can be obtained by drawing the quantity of the drug permeated versus time⁶⁶.

 

16. Skin Irritation Test:

This test usually performed in vivo using animals such as rabbits and mice⁶⁷. The animal’s skin is shaved and the FFS is applied. The skin reaction is observed over 24 hours for 7 days and a scoring system is used to document the type and degree of irritation (table 6)²⁴.

 

Table 6: Grading of skin irritation²⁴

Grade	Irritant response
0	No reaction
+	Weak reaction (application site has moderate erythema)
++	Moderate reaction (application site has erythema which might be spreading beyond application site)
+++	Strongly reaction (strong, usually spreading erythema with edema)

 

MARKETED FFS:

Several FFS products are available in market. Some examples are mentioned in table 7.

 

Table 7: Examples of marketed FFS (14, 68).

Brand name	Drug	Dosage form	Company
Axiron®	Testosterone	Solution in a metered-dose pump (or twist)	Eli Lilly and Company
Lamisil Once®	Terbinafine Hydrochloride	Solution	GlaxoSmithKline Consumer Healthcare
Medspray®	Terbinafine Hydrochloride	Solution as spray using “patch-in-a-can” concept	MedPharm Ltd.
Patented Technologies
Liqui-Patch	Testosterone, hydrocortisone	Solution as spray	Epinamics GmbH
Durapeel	Ropivacane	Gel	Crescita Therapeutics
PharmaDur®	Hydroquinone	Emulsion-gel	Polytherapeutics, Inc.

 

CONCLUSION AND FUTURE PROSPECTS:

FFS represent an innovative approach of drug delivery. It can be used to deliver drugs systematically or topically. FFS have several advantages over both semisolid and patch dosage forms. These include, but not limited to, simplicity, ease of application and removal, transparency, flexibility of dosing, and low skin irritation which eventually lead to increased patient compliance. Despite the works that has been accomplished on FFS, not much data is present about its efficacy and safety. Accordingly, the marketed products are few. The results obtained so far is encouraging to perform additional research to establish larger database and take this dosage form to a new level of applications

 

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Accepted on 01.12.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(10):5579-5588.