Microemulsion-Based Polymer Gels with Ketoprofen and Menthol: Physicochemical Properties and Drug Release Studies

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely applied in a number of medical conditions associated with pain, fever, and inflammation [1,2]. These active ingredients act by the inhibition of cyclooxygenase enzymes (COX-1 and COX-2), resulting in the reduction of prostaglandin synthesis. A significant area of NSAID application is musculoskeletal conditions affecting bones, joints, muscles, or larger areas including different tissues and anatomical structures [3]. The most common disorders comprise rheumatoid arthritis, osteoarthritis, low-back pain, neck pain, and gout, while the remaining musculoskeletal diseases are classified as other [4]. According to Global Burden of Disease, the data from 2019 indicate that about 1.71 billion people around the world are affected with different types of musculoskeletal problems, with a higher incidence in high-income countries [3]. It is noteworthy that these conditions may significantly contribute to a reduced quality of life. The affected patients may experience pain and limited mobility, leading to difficulties in performing daily activities.

The mentioned conditions may be considered as a significant socioeconomic burden, being an important cause of sick leave and generating enormous costs related to the treatment, rehabilitation, and disability pensions [5,6]. The therapeutic approach to musculoskeletal pain should be multi-directional, involving exercises, physical therapies, pharmacological treatment, and surgical interventions, depending on the condition type and severity, as well as occurring comorbidities [7,8]. NSAIDs are among the most frequently applied drugs employed in the management of pain related to different musculoskeletal conditions. It is noteworthy that oral therapies are the most common; however, oral administration may not be suitable for all patients because of adverse gastrointestinal, renal, or cardiovascular effects [5,9]. In some cases, topical therapies can be considered as an alternative to oral treatment, particularly at the early stages of a disease when the symptoms can be classified as mild to moderate [10,11]. The available literature studies [12,13,14] indicate that topical NSAIDs can be equally effective as oral formulations in pain alleviation. Moreover, topical administration offers numerous advantages over the oral route including a reduction in the mentioned side effect risks, reduced risk of interactions with other drugs administered orally, and avoidance or reduction of hepatic first-pass metabolism [15].

Ketoprofen (2-(3-benzoylphenyl)propionic acid; KET; Figure 1) is a drug with analgesic, anti-inflammatory, and antipyretic activity resulting from non-selective reversible inhibition of both cyclooxygenase 1 and 2 isoenzymes. It occurs in the form of a racemic mixture with the S-isomer displaying pharmacological activity, while the R-isomer is inactive. KET can be applied in numerous conditions with associated pain and inflammation, including musculoskeletal disorders, postoperative pain, and many others [16]. KET can be administered orally or parenterally. However, the systemic action of the drug is associated with an increased risk of side effects, including gastrointestinal problems. It is noteworthy that these adverse reactions can be avoided with topical formulations. KET, diclofenac, and ibuprofen are three popular NSAIDs applied externally and the existing evidence indicates that all of them can be employed in some less-severe conditions with good efficacy and minimized risk of adverse reactions [17].

One of the most important challenges related to the administration of pharmacologically active ingredients to the skin is its low permeability associated with its physiological barrier function. In order to overcome these difficulties, numerous strategies can be employed. One of the possible approaches frequently applied to increase the amount of the drug permeating across the stratum corneum, the most external skin layer playing a crucial role in preventing exogenous substances from entering the deeper tissues, is the selection of an appropriate drug carrier. Among the most extensively investigated ones, different types of nanocarriers, like submicron emulsions [18,19,20], vesicular systems [21], solid lipid and polymer nanoparticles [22,23], and drug nanocrystals [24], should be mentioned. Microemulsions are a type of submicron systems, composed of polar and non-polar phases stabilized with a surfactant and usually also a co-surfactant, which have an important role in the reduction of the interfacial tension between the phases to ultra-low values typical for these systems.

Microemulsions are characterized by a spontaneous or low-energy formation process, which is an enormous advantage from a practical point of view. Numerous studies indicate that microemulsions can effectively enhance the permeation of the active ingredient across the stratum corneum, allowing for obtaining a better therapeutic effect [25,26,27,28,29]. Moreover, their composition, involving both polar and non-polar components stabilized with surfactants and low molecular weight co-surfactants revealing good solubilizing properties, allows for the incorporation of both lipophilic and hydrophilic compounds, comprising drugs and other components, like permeation enhancers [25,26]. It is also important to notice that microemulsions as low-viscosity media can be inconvenient for topical application and are frequently transformed into semisolid products, like polymer gels. It is noteworthy that mechanical characteristics of such complex systems, which also affect their sensory properties, depend on the applied gel and microemulsion composition [30,31,32].

Menthol (M) is a cyclic monoterpenoid alcohol occurring naturally in a volatile peppermint oil. It is frequently used as an additional active agent in topical pain relief products, as it displays some analgesic properties. The mechanism of its action is not clear. Menthol interacts with transient receptor potential melastatin-8 (TRPM8), which is responsible for the cooling sensation, and also acts as a weak sodium channel blocker and a vasodilating agent. It is noteworthy that these actions are observed at relatively low concentrations, while at higher ones (exceeding 30%), menthol interacts with heat-activated vanilloid receptors TRPV3 and reveals irritating properties [33,34,35]. Apart from its own activity observed after topical administration, menthol can be considered as a skin permeation enhancer, increasing the absorption of the main active ingredient and improving its efficacy [36,37,38].

In this study, the formulation studies and a characterization of novel microemulsion-based gels with ketoprofen as an active pharmaceutical ingredient are presented. As an additional analgesic and permeation-enhancing agent, menthol was applied. The main objective of this study was the evaluation of the physicochemical properties of the obtained systems with special attention paid to the impact of the gels’ composition on their mechanical features, including rheological and textural parameters important for dermal application. Finally, the analyzed formulations were tested for drug release with vertical Franz diffusion cells, in order to evaluate the correlation between the gel composition and ketoprofen diffusion rate essential for the therapeutic efficacy of the product.

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Materials

Brij® O20 (Croda; Snaith, UK) and Carbopol® EZ-3 (Lubrizol, Wickliffe, OH) were kindly provided free of charge by Croda Poland sp. z o.o. and Lubrizol, respectively. Oleic acid, triisopropanolamine (TIPA), and phosphate-buffered saline (PBS) tablets (pH = 7.4) were purchased from Sigma-Aldrich (Saint Louis, MO, USA) and used as received. Ethyl alcohol (99.8%), HPLC-grade acetonitrile, acetic acid (99.5%), and sodium chloride were purchased from Avantor™ Performance Materials Poland S.A. (Gliwice, Poland). Ketoprofen was purchased from Glentham Life Sciences® (Corsham, UK). Menthol was purchased from Fagron (Rotterdam, The Netherlands) and potassium dihydrogen phosphate was obtained from Merck Millipore (Burlington, MA, USA). In all experiments, ultrapure water was used.

Otto, F.; Froelich, A. Microemulsion-Based Polymer Gels with Ketoprofen and Menthol: Physicochemical Properties and Drug Release Studies. Gels 2024, 10, 435. https://doi.org/10.3390/gels10070435

Read also our introduction article on Topical Excipients here: