INTRODUCTION:

Human skin acts as a vital protective barrier against water loss and harmful substances, primarily thanks to the stratum corneum. Throughout history, skin has been a preferred route for drug delivery due to its benefits, including patient compliance and enhanced drug absorption¹. However, traditional dermal formulations like creams and patches have limitations, such as poor skin contact, rub-off, and discomfort, leading to inconsistent drug delivery and reduced patient compliance.

To address these issues, Film Forming Systems (FFS) have gained attention as a promising penetration enhancement approach.

FFS creates a thin, nearly invisible film on the skin by incorporating an active ingredient into a liquid or semisolid formulation. The core components of FFS include the drug, a film-forming polymer, and solvents². As the solvent evaporates upon contact with the skin, it leaves behind a drug-containing film, facilitating therapeutic action³. FFS offers various advantages, including dosing flexibility, elasticity, adhesiveness, and streamlined development, making it appealing to formulation scientists. Patients find FFS easy to apply, and it maintains an inconspicuous appearance with resistance to rub-off and faster drying times. Overall, FFS represents a versatile and effective solution for delivering drugs through the skin, with the potential to improve patient compliance and treatment outcomes in various conditions, from skin diseases to pain management and more.

Mechanism of film formation and dermal permeation:

The fundamental design of Film Forming Systems (FFS) involves a dispersion or solution where the primary ingredient is a volatile solvent, serving as the foundational carrier for the entire formulation. Upon application to the skin, this volatile solvent rapidly evaporates, leaving behind both an active drug and a film-forming excipient⁴. This transformation of a topical solution or gel into a film leads to a significant concentration of the drug remaining on the skin surface, resulting in drug supersaturation within the skin or stratum corneum. This, indeed, constitutes a key advantage of FFS⁵ The creation of a supersaturated system to enhance drug permeation has historically presented challenges. Nevertheless, the formulation of such systems results in an increased drug flux through the skin, achieved by elevating the thermodynamic activity of the formulation without affecting the skin's protective barrier. This, in turn, leads to a reduction in potential side effects or discomfort associated with drug delivery²(Figure 1).

Figure 1: Mechanism of film formation and dermal permeation

Advantages of film-forming systems^6,7

Using the skin as a drug delivery route offers numerous benefits, including avoiding first-pass metabolism, rapid establishment of supersaturated drug levels upon skin application, easy application for patient convenience, lower required dosages, no gastrointestinal compatibility issues, improved patient adherence, consistent drug levels within the therapeutic range, comprehensive target site coverage, and reduced dosing frequency, making it an attractive option for patients and healthcare providers.

Limitation of film-forming systems⁷

While utilizing the skin as a drug delivery route presents notable advantages, it is essential to consider potential drawbacks. Skin irritation and contact dermatitis may arise, underscoring the importance of formulation safety and skin tolerance. Additionally, drugs with minimal plasma concentrations might not be suitable for this approach, as therapeutic levels can be challenging to achieve for certain substances. Furthermore, the limitation of this method lies in its inability to effectively deliver high molecular weight drugs, as their absorption through the skin is limited. These considerations emphasize the need for careful drug selection and formulation design when opting for transdermal drug delivery.

Topical film-forming system design:

Topical drug delivery entails the application of therapeutic formulations onto the skin's surface or specific pathological areas within the skin. Conditions like psoriasis, eczema, and fungal infections such as tinea pedis are prime examples of dermal treatments involving topical delivery. A standard FFS topical formulation typically comprises essential components, including an active drug, a solvent, a polymer, and a plasticizer.

Transdermal film-forming system design:

Transdermal drug delivery involves the absorption of drugs through the skin and their subsequent entry into the bloodstream and circulation. An illustrative example of transdermal delivery is the use of fentanyl for the management of severe pain. In transdermal formulations, the addition of a plasticizer may be necessary to attain the desired mechanical properties of the film. Additionally, when permeation enhancers are incorporated into transdermal formulations, they can potentially impact the drug release from the polymeric film.

Components and considerations for transdermal and topical film-forming system:

The components utilized in transdermal and topical Film Forming Systems (FFS) exhibit similarities. However, it's important to note that the target site for transdermal applications presents a greater challenge to access compared to topical use. Consequently, transdermal FFS often necessitates the inclusion of penetration enhancers as an integral part of the formulation.

Drug:

Topical and transdermal drug administrations face challenges in crossing the skin's barrier, the stratum corneum. Factors such as solubility, molecular weight, structure, and lipophilicity affect drug penetration^8,9. The ability to achieve drug penetration depends on factors such as solubility, molecular weight, structure, and lipophilicity. In this context, molecular weight plays a significant role, with smaller compounds exhibiting greater ease of diffusion through the skin layers compared to larger molecules⁵. In the formulation of Film Forming Systems (FFS), a fundamental consideration is the solubility of the drug within the film-forming polymers. This solubility leads to drug saturation and the creation of a drug reservoir on the skin's surface. For topical formulations, particle size typically falls within the range of 1 to 50μm, with the requirement that topical suspensions should have a particle size of less than 35μm to prevent any tactile grittiness¹⁰. Ideally, both topical and transdermal formulations should aim for lower doses to achieve efficacy (less than 10 mg), shorter half-lives (less than 10hours), lower molecular weights (less than 500 Da), and intermediate octanol/water partitioning coefficients (log P: 1 – 3). Research indicates that the solubility of the drug within the polymer is a critical factor in controlling drug permeation through the skin⁴. When considering transdermal delivery using FFS, specific drug properties should be optimized in terms of dosage, molecular weight, and partition coefficient, as discussed earlier¹¹.

Polymer:

Polymers are essential in creating film-forming systems for topical and transdermal applications, forming transparent, flexible films that match skin temperature. They stabilize supersaturated systems, enhance drug permeation, and improve formulation mechanical properties¹². Polymers can be used alone or in combination to achieve desired film properties. The chosen polymer must be non-toxic, non-irritating, and free of leachable impurities. Both natural and synthetic polymers are useful in film preparation¹³. The selection of polymers depends on solubility and polymer concentration, and designing an effective FFS requires a delicate balance.

Solubility of Polymer:

The choice of polymer depends on its solubility, which determines the drug reservoir's location within the skin. Water-soluble polymers are used to produce thin films that disintegrate quickly while maintaining mechanical strength. The solubility of water is crucial in film-forming systems, as it determines the reservoir's location¹⁴. Hydrophilic film-forming polymers require a drug reservoir within the skin for effectiveness due to their low water resistance, resulting in short-term persistence. Hydrophobic films have greater water resistance and form an external drug reservoir both on and within the skin. Adhesion to the skin is influenced by interactions with proteins and lipids. Cationic polymers, due to the skin's net negative charge at physiological pH, exhibit greater substantivity than neutral or anionic polymers¹⁵_.

Concentration of Polymer:

Polymer concentration plays a vital role in film-forming systems (FFS), affecting viscosity, film thickness, and drug release characteristics. Low concentrations can cause weak films, while high concentrations can cause thick, inflexible films and delay drug release. Common natural and synthetic polymers used in FFS include Eudragit and HPMC¹⁶. Eudragit, a polymethacrylate, is known for its well-defined composition, solubility profile, and swelling properties, especially when ethanol is used as a solvent¹⁷. HPMC, a hydrophilic polymer, improves solubility and dissolution rates of poorly water-soluble drugs and aids in solubility improvement for crystalline and poorly water-soluble medications¹⁸. Klucel HPC, an under-explored polymer, has unique properties like solvent solubility, thermoplasticity, and suitability for organic solvent-based applications¹⁹.

Table 1: Polymer used in FFS and its properties.

Polymer	Type	Properties	Concentration	Ref
Hydroxypropyl methylcellulose	Semi-synthetic	Water-soluble, Biodegradable, biocompatible polymer, Non-greasy, and uniform film with good texture. Surface active agent adsorbing easily dispersed water, excellent lubricity when applied to the skin in an occlusive state. Compatible with other ingredients and with no interaction.	5-50%	20
Chitosan	Natural (Polysaccharide)	Improves penetration of drug compounds, Naturally occurring polycationic polysaccharides, Biocompatible, non-toxic, biodegradable, and imparts gel-forming property. Biopolymer for controlling the release rate of Transdermal Drug Delivery. Demonstrates paracellular permeability.	2-20%	12
Polyvinyl alcohol	Synthetic	Water-soluble, Adhesive properties, Biocompatible and non-toxic	20-50%	21
Eudragit (polymethacrylate copolymers) Eudragit RS 100, RL 100, NE, S 100, RS 30D	Synthetic	Compatible for use as pH-dependent and independent drug release. Moisture protectant, Transparent and elastic, Adhesive properties.	10–40%	22
Polyvinyl pyrrolidine (PVP)	Synthetic	Soluble in water and other solvents. Enhances Bioavailability, Acts as a binder, adhesive property.	10-40%	23
Ethylcellulose	Semi-synthetic	Forms water-soluble film. Generally used along with HPMC polymer. Non-irritating and non-allergic material. Tougher films.	5-50%	24
Acrylates copolymer Avalure® AC 118, AC 120	Synthetic	Water-soluble. Tough films.	6%	25
Klucel/ Hydroxypropyl cellulose (EF, LF)	Semi-synthetic	Nonionic, pH insensitive polymer, Water-soluble, Improve solubility	10-30%	26, 27
Silicone	Synthetic	Low surface tension, Film-forming ability, Forms durable film and is water vapour permeable	25-50%	28

Solvent:

The choice of solvent in film-forming systems (FFS) is crucial for formulation effectiveness. Two main categories include volatile solvents for film formation and nonvolatile solvents to prevent drug precipitation^29,30. This dual-solvent approach enhances drug diffusibility and skin permeability, aiding drug penetration. Organic solvents like ethanol and isopropyl alcohol are preferred for solubilizing film-forming polymers and acting as penetration enhancers. Other low-alcohol-content organic solvents can be used individually or in combination³¹.

Nonvolatile solvents are crucial drug carriers, promoting skin absorption and preventing drug crystallization. The choice of nonvolatile solvent can significantly affect drug permeation rates. For example, octyl salicylate optimized oxybutynin drug delivery in a film-forming system, while propylene glycol did not. Common nonvolatile solvents include ethyl acetate, oleic acid, and isopropyl myristate.Table 2 gives list of solvents that can be used individually or in combination.

Table 2: Examples of volatile solvents^11,15,32,33

Category	Examples
Alcohols	(C₂-C₄) alcohol, Lanolin alcohols, fatty alcohols, Ethanol, butanol, benzyl alcohol, Isopropanol
Glycol ethers	Polyethylene glycols (Derivatives - Capryol 90, Lauroglycol 90, Transcutol), propylene glycols, ethylene glycols
Others	Ethyl acetate, oleic acid, isopropyl myristate

Plasticizer:

Plasticizers are essential in film-forming systems, enhancing film flexibility and tensile strength³⁴. They mitigate brittleness by lowering the polymer's glass transition temperature. These molecules adapt to skin movements and reduce film-forming temperature below the skin's surface temperature^15,16. A suitable plasticizer should be compatible with the polymer, resulting in a clear, minimally noticeable film. However, the efficiency of the plasticizer varies depending on the specific polymer used, making it difficult to establish an ideal plasticizer concentration. Insufficient plasticizer leads to brittle films with poor adhesion, while excessive plasticizer results in a smooth, sticky film³⁴.

Beyond their impact on the film's physical properties, plasticizers also influence drug diffusion and release. They can increase the free volume and chain mobility of polymers, thereby enhancing drug release rates³⁵. Environmental moisture can also act as a plasticizer for hydrophilic polymers, further affecting drug diffusion and release¹⁶. The chosen plasticizer should be compatible and miscible with the specific polymers used and exhibit low skin permeability. Excessive leakage could compromise the film's integrity and adhesive properties.

Plasticizers are characterized as nonvolatile compounds with low molecular weight, and they can exist in various forms such as liquids, plastics, elastomers, or resins³⁶. Commonly employed plasticizers include glycerine, polyethylene glycol, sorbitol, dibutyl phthalate, propylene glycol, triethyl citrate, and others.

Permeation enhancer:

A critical component of transdermal formulation is the utilization of penetration enhancers, which are substances employed to facilitate the penetration of substances through the skin. The incorporation of chemical permeation enhancers is a fundamental aspect of formulation design for this purpose³⁷. It's important to recognize that skin permeation depends not only on the physicochemical properties of the drug but also on the composition of the vehicle used. These enhancers serve to augment drug solubility within the skin and enhance its diffusivity across the various layers of the skin, effectively altering the drug's diffusion coefficient. They achieve this by interacting with intracellular keratin, influencing the lipids and proteins present in the stratum corneum, the outermost layer of the skin. Among the most commonly employed excipients for penetration enhancement, water and surfactants play pivotal roles. It's worth noting that an increase in the water content within the stratum corneum typically results in an enhancement of transdermal drug delivery through the skin³⁸.

Some prominent examples of penetration enhancers include octadecenoic acid, dimethyl isosorbide (DMI), diethylene glycol monoethyl ether (DGME), propylene glycol, oleic acid, and laurocaprane (Azone), among others. These substances are frequently utilized to enhance the permeation of drugs through the skin.

THERAPEUTIC APPLICATIONS:

Film-forming systems have been successful in various skin conditions, particularly in topical and transdermal applications. They enhance penetration through the creation of supersaturated solutions or high drug thermodynamic activity. Film-forming preparations have traditionally been used in surgery and wound care, with two main groups: those without pharmaceutical agents and those combined with antimicrobial compounds. They are also used in ostomy care to protect the skin surrounding the wound from the potentially aggressive effects of bodily fluids. Film-forming preparations have been found to be effective in reducing infections and preventing infections.

Liquid film-forming products are widely used for topical therapy, primarily for managing conditions like warts and calluses, and nail mycoses. However, they are particularly important in treating chronic dermatological diseases like atopic dermatitis and psoriasis, which require daily management. A recent development in film-forming preparations is a cream for localized delivery of Lidocaine and Tetracaine in a eutectic mixture, primarily for pre-surgical anesthesia. This film-forming system offers both local and systemic effects, making it effective for the topical administration of antibacterial, antifungal, and steroidal drugs. For instance, a study conducted by Ranade et al.³⁹ showcased the fabrication of topical metered-dose film-forming sprays for pain management using Ropivacaine as the drug, Eudragit S100 as the polymer, and Ethanol and Isopropyl alcohol as key components. The formulation of a topical film-forming spray was evaluated for factors such as spray type, pattern, angle, droplet size, film washability, appearance, and drying time. Results showed that drug diffusion through the stratum corneum was sufficient to induce latency in response in rats, indicating the potential of this method for local anesthetics. Clinical studies by Li et al. demonstrated the efficacy of a single application of a 1% terbinafine film-forming solution for treating tinea pedis in the Chinese population, offering potential benefits for patients and public health⁴⁰.

Transdermal therapy has been utilizing a novel film-forming approach to deliver drugs, such as testosterone, hormones, and COX inhibitors. A study by Mori et al. demonstrated the development of a film-forming transdermal spray containing voriconazole for fungal infections. The spray, which includes voriconazole, Eudragit RLPO, Ethylcellulose, and Eudragit polymers, and a eutectic mixture of camphor and menthol as penetration enhancers, showed significant potential for treating fungal skin infections while enhancing patient compliance. The careful adjustment of polymer concentration and use of the penetration enhancer eutectic mixture offer a promising approach to combat fungal infections. Examples of marketed film-forming formulations include Axiron, Cutimed Gel, and Lamisil Once Spray.

Figure 2: Film-forming drug delivery dosage forms

Solution: Sol Solutions are the first generation of film-forming systems, consisting of a drug, film-forming polymer, solvent, and occasionally a plasticizer or permeation enhancer. They offer a straightforward FFS design, with the volatile solvent being the primary component. Application can be direct or facilitated by an applicator^3,5. Evaluation of solutions considers pH, rheology, and dried film properties. Solutions offer advantages over conventional semisolid formulations. Researchers are exploring the use of polymers like PVP, PVA, Eudragit RLPO, and HPC to optimize solubility, stability, and release profiles for compounds like Testosterone, Ethinyl estradiol, and Ketorolac, potentially leading to improved pharmaceutical products or drug delivery methods^41-43.

Spray: Drug-containing films can be created using sprays, which offer contamination-free delivery and are easier to apply than traditional cutaneous solutions. Sprays can be categorized into pump sprays and aerosols, with pump sprays dispensed using mechanical force, and pressurized aerosols using propellants³. Film-forming spray formulations typically include organic solvents, film-forming polymers, plasticizers, penetration enhancers, propellants, and spray containers. Examples of film-forming sprays include pharmaceutical compounds like Methylphenidate hydrochloride, Ropivacaine, Testosterone, Fluconazole, Mupirocin, and Voriconazole, which have been successfully incorporated into these sprays using various grades of Eudragit. These formulations have yielded positive outcomes in drug delivery and application, demonstrating the versatility and effectiveness of Eudragit in this context^44-48.

The container's performance evaluation considers various factors like spray pattern, angle, volume, droplet size distribution, seal efficiency, and flammability testing. Other evaluations include viscosity, surface tension, drying time, and assessments to ensure the dried film meets desired properties.

Gels: Gels are semi-solid formulations with strong adhesion and user-friendly application, belonging to the second generation of film-forming systems. Gels, in particular, are semi-solid formulations that incorporate external solvents, rendering them either hydrophilic or hydrophobic in nature¹¹. They can be organogels, oleogels, or hydrogels depending on the liquid component. Recent research has identified other gel types suitable for dermal drug applications, including emulgels, proniosomal gels, aerogels, and bigels⁴⁹. A variety of film-forming gels have been created using suitable polymers for various medical purposes like pain management and hormone delivery, and these formulations are evaluated for viscosity, consistency, texture analysis, and spreadability. Traditional drugs such as Diclofenac, Sodium fusidate, Miconazole nitrate, and Terbinafine hydrochloride have been incorporated into topical film-forming gels in prior studies^50-53. In an innovative approach, silk fibroin was introduced as an in-situ gelling agent for the formulation of a film-forming gel⁵⁴.

Researchers have also delved into the transdermal utilization of film-forming gels with innovative drugs like Rotigotine for Parkinson's disease and Tolterodine for Overactive bladder, as documented in studies^55-57. Additionally, conventional drugs such as etoricoxib have been investigated for transdermal delivery through film-forming systems⁵⁸.

Emulsion: Film-forming emulsions find applications in the sustained release of lipophilic substances onto the skin. These emulsions typically include components such as medium-chain triglycerides (MCT), polyvinyl alcohol (PVA), a plasticizer, surfactant, and a matrix-forming polymer that encapsulates the oil-dispersed drug. To enhance formulation spreadability, a thickener is often incorporated⁵⁹. Furthermore, film-forming lotions have also been developed as part of film-forming systems. A study conducted by Ritu et al. highlights the formulation of film-forming lotions using a variety of excipients in conjunction with polymers⁶⁰. For a comprehensive overview, you can refer to Table 8, which provides details on the dosage forms of film-forming emulsions and their key components. In the realm of dermatological treatments, film-forming topical emulsions containing Nonivamide and utilizing Eudragit RS 30D have been documented as potential solutions for chronic pruritus, as reported in studies^59,61. Additionally, a topical film-forming lotion for hand dermatitis was developed using acrylate copolymers, featuring betamethasone dipropionate. Furthermore, an effective transdermal film-forming lotion for testosterone delivery was achieved through the utilization of PVP polymer, as described in studies^60,62_.

EVALUATION CONSIDERATIONS FOR FFS:

The fundamental aim of drug delivery is to achieve the optimal delivery of active drugs, thus enhancing patient treatment outcomes. In light of this objective, formulators consistently strive to conceptualize products with specific desired properties, aiming to optimize their performance for maximal efficacy. provides a concise overview of these desired properties for film-forming systems and the associated evaluation parameters that can be targeted. Comprehensive details regarding these evaluation parameters are beyond the scope of this article but can be readily found in reference articles.

Moreover, in addition to the film-related evaluation tests, film-forming systems (FFS) can undergo assessment for specific formulation-related parameters. The nature of these evaluations depends on whether the final FFS takes the form of a gel, spray, emulsion, or lotion.

Table 3: Desired properties of the Final Film

Sr.	Desired Property	Evaluated by
General Cosmetic and Appearance related properties of the Film
1	The film must be thin	Film thickness
2	The film should be Transparent	Transparency
3	It should not stick to the clothing	The tackiness of the film, Stickiness
4	The film should be non-irritant	Skin irritation test
5	The film surface should be uniform, smooth, homogenous, and clear, with almost no cracks	Surface Morphology by SEM
6	The film should ensure sufficient contact with the skin	Film wettability
Mechanical Properties of the Film
7	Dosage form should quickly dry on the skin, and the Minimum Film Forming Temperature (MFFT) should be below the skin surface temperature (∼32 °C). Short drying time of film-forming formulation	Drying Time
8	Total adhesion to the skin for the entire time of application	Adhesion testing
9	The mechanical properties of the formed film should overcome the tangential stresses by the body movement	Tensile Strength (Texture analyzer)
10	The film should be flexible enough to accommodate skin movements	Folding endurance film flexibility/Elongation test
10	In the case of hydrophilic polymers, the film needs to maintain its integrity for a prolonged time period in the presence of atmospheric moisture	Swelling study
12	It must give good spreadability when applied to the skin, and the surface tension of the formulations is generally low to provide good spreadability	Surface tension
Film performance parameters
13	Film after application should be able to achieve supersaturation and thus reservoir in the skin	Drug content
14	They must be resistance against washing to provide sustained protection to wounds	Stability against washing
15	The film should show desired drug release profile	In vivo skin permeation In-vitro Drug release
16	Water permeation characteristics of the film influence skin properties like stratum corneum hydration rate, blood flow, and skin temperature. Good water vapour permeability will make the film and thus skin breathable	Water vapour permeability
17	The drug diffusion and release can also be influenced by environmental moisture, which can act as a plasticizer of hydrophilic polymers.	Moisture uptake Water content
18	The pH of the formulation should be compatible with the skin should not cause any discomfort to the application area	pH
19	The film should be non-irritant	Skin irritation test

CONCLUSION:

Film-forming systems, a relatively innovative category within topical and transdermal drug delivery, have emerged as one of the most promising areas of research in this field. These systems play a pivotal role in maximizing drug bioavailability in topical formulations and enhancing patient compliance. The potential of film-forming systems to revolutionize drug delivery through the skin is truly remarkable, offering not only improved therapeutic outcomes but also high patient acceptability, a critical factor in the development of patient-centric treatment solutions. While film-forming systems have already demonstrated their value across a broad spectrum of applications, there remains a substantial opportunity for further refinement and expansion of their use across various drug classes. To unlock the full potential of film-forming systems, there is a need for a deeper understanding of how to effectively stabilize the supersaturated state and optimize the delivery of drugs and penetration enhancers. This ongoing research and development hold the promise of continuously enhancing the utility and impact of film-forming systems in modern pharmaceutical and healthcare practices.

CONFLICTS OF INTEREST:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Received on 31.10.2023 Revised on 22.05.2024

Accepted on 09.10.2024 Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):919-926.

DOI: 10.52711/0974-360X.2025.00135

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