Hypromellose functionality in film-forming solutions: In vitro characterization and in silico optimization for topical administration of ketoprofen

Abstract

This study investigated the development of hypromellose-based film-forming solutions (FFSs) containing ketoprofen, aiming to elucidate how key formulation variables (concentration and type of hypromellose (high-viscosity grades 2910 and 2208), plasticizers (macrogol 400 and propylene glycol) and volatile solvents (water and water/isopropanol mixtures)) influence FFSs performance and film properties. The FFSs were characterized in terms of pH, transparency, and rheological behavior, while the resulting films were evaluated for weight, stickiness, and mechanical properties. All FFSs exhibited pH values ranging from 4.10 to 5.83, high transparency (transmittance >90%), and shear-thinning behavior.

The results demonstrated a critical role of polymer and plasticizer selection, with hypromellose 2910 outperforming hypromellose 2208 in both FFS and film properties, and macrogol 400 yielding films with superior mechanical performance compared to propylene glycol. The performance-defining characteristics and further in silico optimization of plasticizer concentration using a second-order polynomial regression model based on tensile strength, Young’s modulus, and elongation at break, enabled identification of an optimal FFS composition (2% hypromellose 2910, 1.52% macrogol 400, 2.5% ketoprofen, and a 1:1 water/isopropanol mixture up to 100%). The optimized formulation formed a transparent film with favorable mechanical properties, including tensile strength (10.94 ± 2.26 MPa), elongation at break (75.97 ± 6.12%), and Young’s modulus (33.79 ± 4.76 MPa). In vitro drug release was significantly enhanced from the optimized FFS compared to commercial gels, reaching 82.66% after 6 h and following the Korsmeyer–Peppas model, indicating its potential as a carrier for topical administration of ketoprofen.

Introduction

Although recent decades have seen intensive efforts to optimize percutaneous drug delivery, maintaining prolonged retention of formulations on the skin and thus ensuring consistent drug availability remain major challenges, particularly for drugs whose efficacy relies on achieving regional or transdermal delivery (e.g. nonsteroidal anti-inflammatory drugs (NSAIDs) and hormones, respectively) [1], [2]. Conventional topical formulations, such as ointments, creams, gels and cutaneous sprays, are easy to apply but prone to rapid removal, may require frequent reapplication, and often provide limited control over the treated area and suboptimal sensory or cosmetic properties, which can compromise patient compliance and therapeutic outcomes. In response to these recognized limitations, film-forming solutions (FFSs) have emerged as promising alternative carriers of active pharmaceutical ingredients [3], [4]. FFSs typically contain drug substance and one or more film-forming polymers dissolved in a mixture of volatile solvents and non-volatile solvents (plasticizers), which allows the formation of a thin, preferably invisible film on the skin due to the relatively rapid evaporation of the volatile solvents [5], [6], [7]. In FFSs, film-forming polymers are essential because they create a polymeric matrix on the skin, directly influencing both the mechanical properties of the film and the drug delivery [7], [8]. In general, earlier studies on FFSs employed synthetic polymers such as povidone and methacrylic acid–acrylate copolymers, due to their favorable effects on film characteristics, including bioadhesion, drying rate, and mechanical properties [9], [10], [11]. In recent years, particular attention has shifted toward the use of biocompatible and biodegradable polymers derived from renewable sources, such as cellulose derivatives, starches, and alginates, as sustainable alternatives to synthetic polymers [12].

Among cellulose derivatives, hypromellose has attracted significant interest due to its excellent film-forming ability and safety profile [13], [14]. Its amorphous nature also may contribute to the stabilization of FFS by preventing crystallization of the drug after the solvent evaporates and (super)saturation is achieved [13]. As a polysaccharide, hypromellose possesses significant bioadhesive potential, which is particularly important for films as it ensures prolonged retention on the skin [15]. Both the European Pharmacopeia (Ph. Eur.) and the United States Pharmacopeia (USP) classify hypromellose into four types marked with four-digit numbers (1828, 2208, 2906, and 2910) according to the percentage of methoxy groups (the first two digits) and hydroxypropoxy substituents (the last two digits). Although hypromellose has been recognized as a promising film-forming polymer for topical FFSs, its potential remains insufficiently explored, as only a limited number of studies have investigated its use in such systems. Low-viscosity hypromellose 2910 (5 mPa·s) was used in FFSs at concentrations of 1–5% for formulations containing black pepper extract (Piper nigrum L.) to enhance the local effect of piperine, with 2% selected as the optimal concentration for forming films with the best appearance [16]. Similarly, Nagathan and Hallikeri [17] used low-viscosity hypromellose 2910 (5 mPa·s, 15 mPa⋅s and 50 mPa⋅s) at concentrations of 3.5–5.7% in FFSs containing diclofenac sodium (0.12%), ethanol (90%) as a volatile solvent, and dibutyl phthalate (3.5%) as a film plasticizer, with 3.5% selected as the optimal concentration due to the shortest drying time and the highest cumulative drug release. In the study by Monica et al. [18], high-viscosity hypromellose 2208 (4000 mPa·s) at concentration of 2% exhibited superior rheological, drug release, and film-forming properties compared to the synthetic polymer Eudragit® (15%) in FFSs containing mometasone furoate. As research on hypromellose-based FFSs remains limited and has so far focused predominantly on low-viscosity grades, further investigation is needed to comprehensively assess the potential of this polymer. In particular, studying the influence of high-viscosity hypromellose grades, different substitution types, and varying polymer concentrations on the properties of FFSs and the resulting films would provide a broader understanding of its applicability.

In FFS development, an additional challenge is that a polymer alone is often insufficient to produce films with adequate flexibility and mechanical strength, making the addition of a plasticizer essential [3]. The generally accepted view is that plasticizers exert their effect by forming interactions with specific functional groups of the polymer, thereby increasing the free volume within the polymer matrix and reducing intermolecular forces, which ultimately enhances the mobility and flexibility of the polymer chains [19], [20]. Plasticizers can also contribute to the stabilization of FFS by inhibiting the crystallization of the drug within the film, thereby influencing drug release and percutaneous penetration/permeation [4]. Additionally, some plasticizers, such as propylene glycol, may further enhance drug permeation by interacting with skin lipids [21], [22]. Since a plasticizer must be compatible with the polymer used, its selection mostly depends on the physicochemical characteristics of the film-forming polymer [23]. Commonly used plasticizers for hypromellose-based films include hydrophilic compounds such as propylene glycol, macrogol 300, macrogol 400, and triethyl citrate, which can also retain water from the environment and further improve film flexibility [16], [18]. Nevertheless, the effect of plasticizer type and concentration on the characteristics of hypromellose-based FFSs and the properties of the resulting films has not yet been systematically explored.

The choice of volatile solvents also plays a significant role in FFS formulation, as they directly influence polymer solubility, drying time, and the quality of the resulting film [24]. Solvent evaporation governs the transition from liquid to solid state, affecting film homogeneity, mechanical properties, and drug distribution [24]. Despite their importance, the impact of volatile solvent composition on the performance of hypromellose-based FFSs remains insufficiently investigated. Among commonly used volatile solvents, isopropyl alcohol (isopropanol) is particularly suitable due to its low surface tension (20.93 mN/m at 25 °C), high vapor pressure (4320 Pa at 20 °C), and good miscibility with water, which favor rapid and uniform film formation [25]. An important goal in formulation design is to minimize the content of flammable organic solvents that may increase the potential for irritation or sensitization, while ensuring that such reductions do not negatively affect critical product attributes such as drying time. Therefore, it is important to investigate not only the effect of adding a volatile solvent, but also the proportion of volatile solvent within the solvent mixture.

Ketoprofen, the model drug used in this study, is a widely used NSAID that belongs to the propionic acid derivatives group [26]. It is commonly prescribed for regional treatment of acute and chronic musculoskeletal pain conditions associated with inflammation, including arthritis-related pain, by topical application as suitable alternative to reduce the systemic side effects associated with oral administration. Due to its low molecular weight (254.28 g/mol), melting point (94 °C), and appropriate lipophilicity (logP 3.12), ketoprofen is considered the most suitable candidate among NSAIDs for passive percutaneous delivery [25], [27], [28], [29]. However, topical use of ketoprofen is compromised by the risk of photoallergic dermatitis upon sunlight exposure, which can be further worsened by transfer to clothing or other skin areas after application of conventional formulations [30]. Therefore, FFSs could be particularly advantageous for ketoprofen, ensuring the relatively rapid formation of a dry flexible film on the skin. Gennari et al. [31] highlight the potential of FFSs based on Eudragit® RL PO, with triethyl citrate and triacetin as plasticizers and a solvent mixture of acetone and isopropanol, for improving percutaneous delivery of ketoprofen. However, this study did not systematically address the impact of formulation variables on the physicochemical properties and film-forming behavior of the formulation, leaving important aspects relevant for formulation optimization insufficiently explored.

The present study aimed to systematically elucidate the influence of formulation parameters (type and concentration of high-viscosity hypromellose, plasticizers and volatile solvents) on the physicochemical properties and film-forming ability of FFSs as well as on the characteristics of the resulting films, including film weight, stickiness, and mechanical properties. In addition, in silico data analysis was performed to optimize hypromellose-based FFS composition for prospective use as a carrier for topical administration of ketoprofen.

Continue reading here

Materials

For the preparation of FFSs, hypromellose with a nominal viscosity of 4000 mPa·s (2% w/w aqueous solution at 20 °C) was used as the film-forming polymer. Two substitution types of hypromellose were used: hypromellose 2208 (Metolose® 90SH 4000, Shin-Etsu Chemical Co., Japan) containing 19.0–24.0% methoxy and 4.0–12.0% hydroxypropoxy groups, and hypromellose 2910 (Sigma-Aldrich Chemie GmbH, Steinheim, Germany) containing 28.0–30.0% methoxy and 7.0–12.0% hydroxypropoxy groups. Propylene glycol.

Sandra Milinković, Ana Ćirić, Erna Turković, Jelena Đuriš, Ljiljana Đekić, Hypromellose functionality in film-forming solutions: In vitro characterization and in silico optimization for topical administration of ketoprofen, International Journal of Biological Macromolecules, 2026, 153117, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2026.153117.

Are you looking for excipients in commercial quantities?