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Article

Topical Pentravan® Based Compositions with Naproxen and Its Proline Ester Derivative—A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin

by
Ewelina Kopciuch
1,
Paula Ossowicz-Rupniewska
1,
Urszula Adamiak-Giera
2,
Anna Nowak
3,
Katarzyna Wilpiszewska
1,
Monika Białecka
2,
Łukasz Kucharski
3,
Anna Muzykiewicz-Szymańska
3,
Maciej Miernik
4,
Mirosław Halczak
4,
Maciej Romanowski
4 and
Ewa Janus
1,*
1
Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Pułaskiego 10, 70322 Szczecin, Poland
2
Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70111 Szczecin, Poland
3
Department of Cosmetic and Pharmaceutical Chemistry, Pomeranian Medical University, Powstańców Wielkopolskich Ave. 72, 70-111 Szczecin, Poland
4
Department of General Surgery and Transplantation, Pomeranian Medical University, Powstańców Wielkopolskich Ave. 72, 70-111 Szczecin, Poland
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(3), 1338; https://doi.org/10.3390/app15031338
Submission received: 2 December 2024 / Revised: 18 January 2025 / Accepted: 24 January 2025 / Published: 27 January 2025
(This article belongs to the Special Issue Bioactive Composite Materials: From Preparation to Application)
Browse Figures
Versions Notes

Abstract

:
The compositions based on Pentravan® vehicle were prepared with (S)-naproxen, and its salt —(S)-naproxenate of L-prolinium isopropyl ester as active pharmaceutical ingredients, and two penetration enhancers from the group of sensates—menthol and Capsicum Tincture. Thermophysical properties of the mixtures of each naproxen form with enhancers were determined by DSC method. The stability of the prepared compositions after one- and three-month storage and the rheological properties were investigated. The permeation of active ingredients through the human skin was evaluated based on the in vitro study in Franz diffusion cells using the prepared compositions with each naproxen form. Increase in the permeability of the naproxen salt, especially in the presence of Capsicum Tincture, provides much faster and greater penetration of the skin by the drug. It seems to be promising the use of the developed composition in the form of pain relief and anti-inflammatory creams, occlusive compresses or topical patches. Moreover, the developed compositions can be crucial for the topical compositions made in compounding pharmacies by physicians’ recipes in individual pain pharmacotherapy.

1. Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are immensely popular and the most frequently prescribed group of analgesics. However, oral administration of drugs from this group is often associated with many side effects. The adverse effects include, among others, cardiovascular and gastrointestinal complications, which significantly limit their use [1,2]. Therefore, an administration route should be carefully chosen while considering the clinical status of patients, comorbidities, and age. Topical routes have become increasingly popular, because of a high efficacy with a beneficial profile of adverse effects. After the topical skin application, the NSAID penetrates the skin layers to target sites within the skin or below it, creating the local anti-inflammatory and analgesic effects. Various enhancers’ approaches, allows for enhanced drug concentration mainly locally in tissues, e.g., in the structures of joint, in tendinous cots, and in the bursa [3,4,5]. Advantages associated with the skin application include non-invasive delivery and low levels of the drug in the plasma, which minimizes a first-pass metabolism and enables easier termination the drug exposure at any time as well as reduced drug toxicity [2].
It is estimated that the plasma concentration of NSAIDs after topical skin administration states that only 5% of the concentration is achieved after systemic administration. However, concentration of NSAIDs in the joint cartilage and synovial fluid is higher after topical than after oral administration [6]. Besides the skin barrier, important factors, limiting the permeation of drugs through the skin, include the physicochemical properties of the drug (molecular weight, ionization, solubility, and lipophilicity) as well as the properties of the drug vehicle and excipients [2].
(S)-Naproxen, i.e., (+)-(2S)-2-(6-methoxynaphth-2-yl)propionic acid, classified as an NSAID, has analgesic and antipyretic properties. Its skin administration is recommended in rheumatic diseases or degenerative changes in both peripheral joints and the spine. Applied on specific area of the human body surface, it can effectively reduce the symptoms of post-traumatic changes or inflammation of the tissues in this area. Various attempts are being made to increase the permeation rate and amount of permeated naproxen through the skin for greater therapeutic efficacy. Both the chemical form of the drug and the composition of formulation, i.e., the vehicle and excipients, affect the penetration through the difficult-to-penetrate barrier of the skin, and above all the stratum corneum layer [7,8,9,10,11].
Salt formation is one of the important and simple solutions that not only increases the solubility of ionizable compounds, as naproxen, but also increases the drug permeation through the skin barrier. The type of counterion is important in this matter [7,10]. Various neutralizing agents, such as alkali metal hydroxides, ammonia, diethylamine, triethanolamine, and any combinations thereof were used with naproxen in topical gel compositions to produce the corresponding salt form of naproxen in situ. Among all used, the ammonia and diethylamine have been found to enhance significantly the permeation and the accumulation of naproxen in human skin [8].
Recently, we have shown that salts of the naproxen with alkyl esters of amino acids such as Gly, Ser, Leu and Pro increase the solubility of drug in water and PBS pH 7,4 solution. Moreover, the combining of glycine isopropyl ester and L-proline alkyl esters with (S)-naproxen has been found to be the highest beneficial for a significant increase in drug permeability through pig skin compared to the free acid form of (S)-naproxen [12,13].
In addition to appropriate selection of active compound form, searching for formulations and appropriate compositions is advisable to ensure better release and penetration of naproxen. Selecting the appropriate vehicle can increase penetration and obtain an immediate therapeutic effect. Microemulsion formulations based on isopropyl myristate in oil phase and different surfactants increased the topical delivery of naproxen [7]. Topical gel formulations with naproxen sodium were also developed using a different type of gel forming agents that revealed a better release and permeation of naproxen with a decrease in concentration of gel forming agent with inclusion of certain enhancers [8,10]. In recent years, various carriers with specific compositions have been proposed to increase drug permeation. One such vehicle is Pentravan®, an oil-in-water (o/w) emulsion base. Despite the relatively high water content, this medium has the consistency of a thick, yellowish cream with a pH of 4.0–5.5. The composition of this vehicle includes components that facilitate the permeation of the drug through the skin, improve its hydration, and preserve, stabilize, and improve the rheology of ointments and creams [2]. Pentravan® is a registered pharmaceutical raw material, comprising ingredients approved by regulatory agencies for pharmaceutical uses worldwide. It is used as a vehicle in topical skin compositions on prescription that are made in compounding pharmacies. Prescription analgesic and anti-inflammatory drug topical compositions are developed by physicians to individualize pharmacotherapy for patients with pain of various origins, primarily chronic, e.g., in musculoskeletal and rheumatic diseases and soft tissue pain. Selecting the appropriate form of the active substance as the best possible carrier and excipient in topically administered NSAIDs plays a crucial role in the increase of drug permeation and allows for improved analgesia and anti-inflammatory effects.
In our previous studies, we have shown that Pentravan® is an excellent vehicle for (S)-naproxenate of L-prolinium isopropyl ester [ProOiPr][NAP]. The cumulative mass of permeated naproxen from this composition through the model STRAT-M® membrane was statistically several times higher than for both the acid naproxen incorporated into the same vehicle and commercially available topical gels with either the acid form of naproxen or the sodium salt form [13].
Considering that the penetration of the active ingredient may be modulated by the specific ingredients of topical compositions, our efforts in the presented studies were focused on the effect of penetration enhancers from the group of sensates as menthol and capsaicin on the naproxen permeation. Moreover, menthol or capsaicin have analgesic effects confirmed in experimental and clinical models. Our studies are crucial for the development of topical compositions used in individual pain pharmacotherapy using physicians’ own recipes made in compounding pharmacies.
In the presented studies, in vitro permeation tests were performed in Franz diffusion cells using human skin, instead of the artificial STRAT-M® membrane which was used in our previous studies [13]. Human skin penetration studies are necessary to progress to clinical trials. Additionally, the stability of prepared compositions and their rheological properties were assessed.

2. Materials and Methods

2.1. Materials

Pentravan® (Pen), menthol (p.a.), Capsicum Tincture (TinCap) and ethanol 96% were pharmaceutical raw materials of the appropriate properties and the required purity necessary for the preparation of prescription drugs in the pharmacy, purchased from Fagron (St. Paul, MN, USA). TinCap was a standardized tincture, containing alkaloids: 0.02–0.06% per capsaicin; Acetic acid (99.5%), potassium dihydrogen phosphate, and phosphate-buffered saline (PBS; pH 7.40 ± 0.05) were from Chempur (Piekary Slaskie, Poland), whereas acetonitrile for HPLC was from J.T. Baker (Berlin, Germany). All chemicals were of analytical grade. (+)-(2S)-2-(6-Methoxynaphthalen-2-yl)propanoic acid, (S)-naproxen (NAP) (≥98%), was purchased from AmBeed (Arlington Heights, IL, USA). (S)-Naproxenate of L-prolinium isopropyl ester, [ProOiPr][NAP] was obtained according to the methodology described previously [12,13].
Pentravan® is an oil-in-water emulsion. The unique character of this vehicle is attributed to its specific components. According to the information provided by the manufacturer, the water content is 62%. Moreover, Pentravan® contains the following ingredients: a complex named LIPOIL, butylated hydroxytoluene (BHT), dimethicone, urea, potassium sorbate (SORB), polyoxyethylene stearate (40), cetyl alcohol, stearyl alcohol, stearic acid, glycerol monostearate, benzoic acid, carbomer, and hydrochloric acid.

2.2. Skin

Skin specimens were harvested from abdominal skin of patients who underwent plastic surgery. The study was approved by the Ethical Committee of Pomeranian Medical University in Szczecin (KB0012/02/18). The skin of 0.5 mm in thickness was divided into about 2 cm × 2 cm pieces. The fresh human skin was washed in PBS buffer pH 7.4 several times. The skin samples were wrapped in aluminum foil and stored in a freezer at −20 °C until use, not longer than three months. Human skin retains its barrier properties even when stored frozen up to one year, and can be used for in vitro skin permeation tests, which is widely accepted by advisory and regulatory agencies [14,15]. On the test day, the skin samples were slowly thawed at room temperature for 30 min and hydrated with PBS pH 7.4 [16,17,18].
Skin electrical impedance was performed by LCR meter 4080 (Voltcraft LCR 4080, Conrad Electronic, Hirschau, Germany), operated in parallel mode at an alternating frequency of 120 Hz (error at kΩ values < 0.5%). The measurements were made by placing the tips of the measuring probes in both the donor and the receptor chamber filled with PBS pH 7.4 buffer and separated with a skin sample. Skin samples with impedance above 10 kΩ, corresponding to the electrical resistance of human skin, were used in the permeation tests [19].

2.3. Differential Scanning Calorimetry

DSC analyzer model Q-100 (TA Instruments, New Castle, DE, USA) was used for thermal analysis of single ingredients (NAP, [ProOiPr][NAP], menthol) and mixtures of each naproxen form with enhancers. Samples of substance or mixture were weighed in the aluminum pan which was then hermetically sealed to prevent vaporization. Each sample was heated in the temperature range of 20–200 °C, at the heating rate of 10 °C/minute, under nitrogen atmosphere.
Mixtures of each naproxen form with the menthol were prepared by weighing the respective amount of each substance in the Eppendorf tube and mixing on a single tube vortex mixer for 5 min. The remaining mixtures, i.e., the drug with TinCap and three components comprising the drug, menthol, and ethanol, were prepared by weighing and grinding substances in a mortar. The mass proportions of ingredients in the mixtures were the same as in the compositions (Table 1), but these mixtures did not contain the Pentravan®.

2.4. Preparation of the Compositions Based on the Pentravan®

Six different topical compositions were prepared using Pentravan® as the vehicle (Table 1). Both naproxen forms—NAP and [ProOiPr][NAP] were incorporated into the vehicle, as well as various pharmaceutical components, i.e., ethanol, menthol, and the TinCap. NAP or [ProOiPr][NAP] was dissolved in ethanol, placed in a mortar and mixed with a small portion of Pentravan®. Next, the remaining vehicle portion was added while gently mixing. Menthol was micronized with ethanol in a mortar and the vehicle was added in portions. TinCap was directly introduced into the vehicle. In each composition, the concentration of naproxen as the active ingredient was 10% (w/w).

2.5. Characterization of the Topical Compositions

The stability of the prepared topical compositions was assessed visually after one- and three-months of storage in darkness, at a temperature of 25 °C.
The rheological properties of the topical compositions were determined on the day of preparations, using rheometer Discovery HR-1 (TA Instruments, USA) with TRIOS software for data acquisition, equipped with a lower Peltier plate for temperature control. The measurements were carried out in rotation mode at 30 °C using a stainless steel, 25 mm upper plate.

2.6. Skin Permeation Tests

The permeation experiments were performed in Franz diffusion cells (Phoenix DB-6, ABL&E-JASCO, Wien, Austria) with diffusion area of 1 cm2 each. The volume of the receptor chamber was 10 cm3, and it was filled with PBS solution (pH 7.4). Each diffusion unit was kept at the constant temperature of 37.0 ± 0.5 °C [20]. The receptor chamber fluid was stirred with a magnetic stirring bar at the same speed (350 rpm) for all cells. The skin was mounted on the donor chamber. Skin integrity tests were performed as described in Section 2.2. Only undamaged skin samples with an even thickness were chosen for tests. The permeation tests were carried out for 24 h. The tested topical compositions of 1 g, were uniformly applied to the diffusion area of the skin in each donor chamber. At scheduled time intervals (0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, and 24 h), portions of the receptor fluid (0.5 mL) were withdrawn for determination of naproxen concentration by HPLC method. The cumulative mass of the permeated naproxen (in µg NAP·cm−2) was calculated based on this concentration. The receptor fluid was replenished with a fresh PBS solution (0.5 mL) after each sampling. The measurements in the Franz diffusion chamber were performed in triplicate for each topical composition.
The profiles of in vitro percutaneous absorption for infinite dose of drug are most often characterized by Fick’s laws of diffusion [21,22]:
Jss = dQ/Sdt
where Jss is the steady-state flux in µg NAP cm−2 h−1; dQ is the change in the quantity of permeated NAP (in µg NAP) through the skin to the receptor chamber in time interval dt; S is the active diffusion area in cm2.
The steady state flux of naproxen through the human skin into receptor fluid was determined as the slope of the linear portion of the plot of cumulative mass of NAP (Q) in the receptor fluid versus diffusion time (t).

2.7. High-Performance Liquid Chromatography (HPLC)

The concentration of NAP in the receptor fluid was determined using a liquid chromatography system (HPLC, Agilent, Poland). The HPLC system consisted of HP 1100 model UV-VIS DAD detector, HP 1100 model pump and HP 1100 model autosampler. The detector was operated at 270 nm. The 125 × 4 mm chromatographic column filled with Hyperisil ODS (C18), particle size 5 µm, was used. The mobile phase was 60/40 (v/v) mixture of 0.02 M potassium dihydrogen phosphate and acetonitrile with a 1 mL/min flow rate. The column temperature was 25 °C, and the injected sample volume was 20 μL.
Retention time for NAP and [ProOiPr][NAP] was 3.450 min. Linearity of the response (Y) to drug concentration (X) within the range of 0.00156–0.05000 mg/mL: Y = 143,850 X − 0.3669 (R2 = 0.9999) for NAP; Y = 167,673 X − 7.1052 (R2 = 0.9995) for [ProOiPr][NAP]. Precision: RSD < 1%; Accuracy: 100% ± 2.0%; For NAP: LOD 0.142 µg/mL and LOQ = 0.426 µg/mL. For [ProOiPr][NAP]: LOD = 0.156 µg/mL and LOQ = 0.468 µg/mL.

2.8. Statistical Analysis

Results were presented as mean ± standard deviation (SD). A one-way analysis of variance (ANOVA) was used. The significance of differences between individual groups was evaluated with Tuckey’s test (α < 0.05). A cluster analysis was carried out to determine similarities between all compositions tested. On this basis, groups of compositions with a similar permeation of naproxen were presented. Statistical calculations were done using Statistica 13 PL software (StatSoft, Kraków, Polska).

3. Results

3.1. Drug-Enhancer Mixtures Thermal Testing

At first, the acid (S)-naproxen (NAP), its salt with L-proline isopropyl ester [ProOiPr][NAP], and the mixtures of each form of NAP with two permeation enhancers menthol and TinCap were tested using DSC. Selected DSC thermograms of drug, enhancer and their mixtures, optionally also with ethanol, are shown in Figure 1 and Figure 2 for NAP and [ProOiPr][NAP], respectively. DSC thermograms of single ingredients, menthol and NAP (Figure 1a) showed sharp endothermic peaks at 45.67 °C and 159.18 °C, corresponding to their melting points. For mixtures of NAP with menthol or with both menthol and ethanol, the endothermic peaks were also registered. However, they were slightly broadened, especially the menthol peak and shifted towards lower temperatures by approximately 1 to 3 °C, what can be attributed to decrease in the purity of each component by the mixing process. Thus, the melting peak of NAP occurs at a temperature of 156.24 °C and 157.14 °C, for the two-components menthol + NAP mixture, and the three-components mixture menthol + NAP + ethanol, respectively. However, by the mixing of NAP with TinCap (Figure 1b), the temperature of the endothermic peak of NAP decreased much less, only by 0.5 °C. These results excluded any incompatibility of NAP with both menthol and TinCap.
Moreover, DSC analysis of [ProOiPr][NAP] as a single ingredient, showed a sharp endothermic peak at temperature of 74.15 °C (Figure 2). For the mixture of [ProOiPr][NAP] and the menthol, no endothermic peak was observed in the range of 60–200 °C (Figure 2a). There was also no sharp endothermic peak corresponding to the melting point of menthol. However, a broad endothermic peak at 48.83 °C was observed. This temperature is a little higher than the melting point of menthol and lower than melting point of [ProOiPr][NAP]. It can be due to the interaction of naproxen salt with menthol creating a kind of eutectic mixture. No peak is visible in the DSC thermogram of the three-components mixture [ProOiPr][NAP] + menthol + ethanol. However, a comparison of DSC thermograms of two-components mixture [ProOiPr][NAP] + TinCap and the single component [ProOiPr][NAP] (Figure 2b) showed the presence of the endothermic peak corresponding to the melting point of [ProOiPr][NAP] for both. The registered temperature of this peak was about 3 °C lower in the mixture [ProOiPr][NAP] + TinCap. TinCap comprised the ethanol inside, and despite this, its mixture with naproxen salt retains the explicit melting point of the salt, in contrast to the mixture of this salt with menthol. Hence, the observed changes in the thermograms for mixture of menthol with [ProOiPr][NAP], compared to the thermograms of single components, can indicate intermolecular interactions between the salt and menthol. The possibility of eutectic mixture formation should be confirmed by more detailed studies. However, the low viscosity eutectic solvents comprising menthol were reported recently [23,24,25,26]. The strategy of combining two solids to obtain a liquid is very useful and is gaining increasing interest especially in the pharmaceutical products.

3.2. Stability and Rheological Evaluation of the Topical Compositions

Topical compositions based on Pentravan® as vehicle comprised one of the (S)-naproxen forms, i.e., acid naproxen NAP or its salt [ProOiPr][NAP]. They were prepared without and with penetration enhancer—menthol or TinCap. The topical compositions had a total concentration of naproxen 10% w/w.
The compositions with acid naproxen were a slightly yellowish emulsion, like the Pentravan® vehicle. However, the compositions with [ProOiPr][NAP] were orange in color. The composition comprising menthol and [ProOiPr][NAP] began to separate into two phases almost immediately after preparation, while almost all compositions remained homogenous after three months of storage at room temperature. The exception was the composition comprising acid naproxen and menthol, in which separation of a liquid phase from the emulsion was observed after one month of storage. These observations indicate that menthol reduces the stability of Pentravan® based topical compositions.
Figure 3 shows a plot chart of the viscosity versus shear rate for the Pentravan® and the prepared topical compositions. The viscosity of Pentravan® was 31.143 Pa s at 30 °C. The viscosities of the compositions with naproxen salt, [ProOiPr][NAP], at this temperature, were just 0.523 Pa s and 0.427 Pa s, without and with TinCap, respectively and were one order of magnitude greater than viscosities of typical oils [27,28]. The viscosity of the Pentravan® based topical compositions comprising the acid form of naproxen without any enhancer, was above twofold lower than for the vehicle itself and was 12.496 Pa s. The addition of the enhancer decreased even more the viscosity, which was 8.249 Pa s and 3.125 Pa s with TinCap and menthol, respectively. For the Pentravan® itself and all topical compositions comprising the acid form of naproxen, the viscosity decreased as the shear rate increased. These compositions and the vehicle itself showed typical Bingham plastic behavior. However, two compositions containing naproxen salt showed almost Newtonian fluid behavior. The viscosity of the prepared compositions may affect the sensory properties and film thickness when the composition is applied to the skin. The sensations experienced during application are partly due to the flow properties of the emulsion. The dependencies of viscosity with increasing shear rate show that the sensation during application and rubbing on the skin for each composition can be similar.

3.3. Permeation Studies of Naproxen from the Topical Compositions Based on Pentravan®

In vitro permeation tests evaluated the effect of two naproxen forms used in the Pentravan® based topical compositions and two penetration enhancers—menthol and TinCap, on the penetration of the drug through human skin using Franz diffusion cells. Permeation parameters, including the cumulative permeation mass of naproxen (Q), a steady-state flux (JSS), and the quantity of permeated naproxen as percentage of the applied dose over 24 h (%AD), were determined for five topical compositions (Table 2). The permeation profiles are presented in Figure 4. Only the topical composition Pen + menthol + [ProOiPr][NAP] was not used in these tests due to its instability and the liquid phase separation immediately after preparation, as described above.
As shown in Figure 4A when the topical compositions comprising the acid form of naproxen were applied, both enhancers increased the percutaneous permeation of naproxen compared with the control (Pen + NAP). In the initial five hours, the drug penetrated the skin in the largest amounts from the composition Pen + menthol + NAP comprising the menthol. When the composition Pen + TinCap + NAP was used, in the first two hours, the percutaneous permeation of NAP was like the control, but after that time, the permeation increased with TinCap significantly. Thus, after eight hours the cumulative amount of NAP, with use of menthol and TinCap in topical composition, was similar, 243.4 ± 16.8 µg NAP cm−2 and 252.8 ± 22.1 µg NAP cm−2, respectively. However, without any enhancer, the acid naproxen permeated much slower and after eight hours, the cumulative mass was twice lower (116.1 ±7.6 µg NAP cm−2). Finally, after 24 h, when the topical composition with TinCap was used, the cumulated mass of naproxen in the receptor fluid was 1079.1 ± 137.1 µg NAP cm−2 and was over three times higher than without any penetration enhancer 339.7 ± 16.3 µg NAP cm−2 (Table 2).
It can be assumed that for each topical Pentravan® composition comprising NAP, the dependence of cumulative mass of naproxen on time has a typical J-shape, and steady-state flux was reached after three hours. The steady-state flux for the time interval from three to 24 h are presented in Table 2. The ascending order of flux for the topical compositions with NAP is as follows Pen + NAP < Pen + menthol + NAP < Pen + TinCap + NAP (12.9; 34.5 and 47.9 µg NAP cm−2 h−1 respectively).
Different permeation results of drug through human skin were obtained when naproxen salt [ProOiPr][NAP] was used instead of acid naproxen (Figure 4B). The application of the composition Pen + [ProOiPr][NAP] on the skin ensured the highest flux 91.14 ± 2.7 µg NAP cm−2 h−1, during the first five hours. However, after five hours of permeation, the diffusion of the naproxen from Pen + [ProOiPr][NAP] composition through the skin slowed down and continued, but with a significantly lower flux. The addition of the TinCap to the composition comprising [ProOiPr][NAP] caused only a slightly decreased amount of the drug to permeate into the receptor fluid within the first five hours compared to the composition without tincture. However, from the third hour following application to the skin up to the 24 h limit of the test duration, the naproxen permeates through the skin from the composition Pen + TinCap + [ProOiPr][NAP] with a steady-state flux 66.8 µg NAP cm−2 h−1. Ultimately, with the addition of TinCap, the cumulative mass of naproxen in the receptor fluid after 24 h was twice as high (1613.2 ± 114.3 µg NAP cm−2) compared to the one (791.2 ± 83.8 µg NAP cm−2) without enhancer in the composition (Table 2, Figure 4B).
Figure 5 shows cluster analysis in which the cumulative mass of compounds from all-time points during the 24 h experiment was considered. The cluster analysis distinguished three groups that differed significantly from each other. The largest group, ensuring the similar penetration, are the compositions: Pen + [ProOiPr][NAP], Pen + Men + [NAP] and Pen + TinCap + [NAP]. On the other hand, the composition Pen + TinCap+[ProOiPr][NAP] comprising naproxen salt, constitutes a separate group characterized by the highest penetration, considering all time points”.
Figure 6 presents a box plot of the mean flux (in µg NAP cm−2 h−1) calculated for time intervals between subsequent experimental points during the 24 h study—for example, between the first and second hour of the experiment, between the second and third hour of the experiment, and so on. The mean flux value for each composition is shown in the graph as a point within a box, the standard error as an area, and the standard deviation as a pair of “whiskers”. These results clearly indicate that the compositions containing the naproxen salt provided the highest naproxen permeation rate over the entire time range. However, for the composition Pen + TinCap + [ProOiPr][NAP], each individual flux values at subsequent experimental points during the 24 h study tends to be clustered closer to the mean than for Pen + [ProOiPr][NAP]. This means that the permeation rate is more uniform over the entire time range for Pen + TinCap + [ProOiPr][NAP]. Moreover, a higher standard deviation for Pen + [ProOiPr][NAP] means that the permeation rate is uneven in different experimental time ranges and as is shown in Figure 4B, is initially high and then decreases after 5 h.
For the composition comprising the acid form of naproxen, the mean values calculated from the fluxes in the individual time intervals are similar for both Pen + menthol + NAP and Pen + TinCap + NAP, but lower than for compositions comprising naproxen salt. However, the dataset for composition containing TinCap indicates a little spread that means a more uniform flux of naproxen during the entire 24 h permeation experiment.
The results show that for faster action of the drug, for example rapid pain relief, the composition Pen + [ProOiPr][NAP] can be superior among all prepared topical compositions with Pentravan® as the vehicle. TinCap provided a significantly increase in permeated drug when the composition with naproxen salt remains on the skin for a longer time. Therefore, it may be best to apply the developed composition Pen + TinCap + [ProOiPr][NAP] on the skin and cover with occlusion foil, which ensures a longer effect associated with the gradual and sustained high level of naproxen penetration through the skin. Moreover, it seems to be promising for use of Pen + TinCap + [ProOiPr][NAP] in the form of pain relief and anti-inflammatory topical patches. Patches remaining on the skin for a longer time could provide a therapeutic effect throughout this period.
Furthermore, the amount of permeated naproxen expressed as the percentage of the applied dose, was from 0.33% for Pen + NAP to 1.61% for Pen + TinCap + [ProOiPr][NAP]. These results clearly show that the most significant increase in naproxen penetration was achieved when its salt was included in the Pentravan® based composition. These findings showed the impact of different naproxen forms and enhancers on the permeation dynamics, providing valuable insights into the optimization of compositions for topical anti-inflammatory and pain relief creams or patches.

4. Discussion

Assessment of in vitro penetration is a crucial step in selecting the appropriate drug derivative, its dose, and the vehicle of topical composition. The degree of penetration of the active substance may vary depending on the properties of the compound, the vehicle, and additional components used [2,29]. The compositions applied on the skin containing NSAIDs allow for pain mitigation in the application area, simultaneously minimizing the risk of systemic adverse effects. To minimize the incidence of adverse effects of drugs with this group, especially when managing pain associated with osteoarthritis of the peripheral joints, drugs applied on the skin are recommended. One such drug is naproxen, characterized by high effectiveness for various inflammatory conditions [12,30]. Even though naproxen is a very popular topical drug, its poor solubility in water (0.051 mg cm−3 [31]) has limited its bioavailability.
Previous studies have shown that the structural modification of naproxen by forming its ion pair, in which the counterion is the L-proline alkyl ester cation, such as isopropyl ester L-prolinium (S)-naproxenate, [ProOiPr][NAP] and other salts of this drug ([ProOPr][NAP], [ProOBu][NAP], [ProOEt][NAP]) enhanced the penetration of pig skin compared to the control–unmodified naproxen [12,13]. Other studies also present that the ion pairs better permeate the lipids of the stratum corneum and then dissociate in the lower layers of the epidermis [12,32,33]. In our previous naproxen skin permeation studies, we used a PBS solution (pH 7.4) [12] or 70% ethanol [13] as a carrier of acid naproxen (NAP) and its amino acids ester salts. The compositions based on Celugel® or Pentravan® comprising acid or salt form of naproxen were also revealed. Furthermore, the significantly higher permeation of naproxen for composition comprising [ProOiPr][NAP], than for commercially available topical gels in the permeation studies through the artificial STRAT-M® membrane was disclosed [13].
Going further to obtain more realistic application conditions of topical analgesic compositions, we decided to check the penetration of naproxen through human skin and not as before through artificial STRAT-M® membrane [13]. Furthermore, to increase the penetration of naproxen through skin, in the presented studies we selected for testing two penetration enhancers as components of the topical compositions based on Pentravan® and comprising unmodified naproxen and its salt with L-proline isopropyl ester. The permeation of naproxen through human skin differs significantly in comparison with the naproxen permeation through STRAT-M® for the same compositions used in the permeation tests. For the Pen + NAP composition, the cumulative mass of naproxen in the receptor fluid after 24 h, was 434.2 ± 4.5 and 339.7 ± 16.3 µg NAP cm−2, respectively, when STRAT -M® and human skin were used in the tests. Greater differences in the amount of permeated naproxen with the change of membrane were observed for the Pen + [ProOiPr][NAP] composition applied, where the cumulative mass was 3338.9 ± 49.0 and 791.2 ± 83.8.µg NAP cm−2, respectively. Despite this difference, the naproxen salt still provides greater and faster permeation of naproxen compared with acid naproxen.
Pentravan® is a commonly used pharmacy oil-in-water emulsion base. Pentravan® is a liposomal cream base with a transdermal mechanism of active ingredient absorption. The key component of this medium is the LIPOIL complex, i.e., lecithin-based liposomes, which facilitates the penetration of drugs through the layers of the epidermis. After applying this medium to the skin, liposomes penetrate through the SC through intracellular channels into the deeper layer of epidermal tissue and the highly vascularised dermis. Lipids accumulated in the extracellular structure of the epidermis constitute the route of delivery of the active substance [4,17]. At first we demonstrated higher permeability of ibuprofen and its derivatives, with Pentravan® as vehicle compared to commercial preparations [2,29]. In other studies, Pentravan® was used as a vaginal delivery vehicle for hormonal medications [34].
The presented studies first allowed us to assess the possibility of combining naproxen and its salt with Pentravan® as a vehicle also with substances commonly used as penetration enhancers—menthol and TinCap. The menthol or capsaicin has an analgesic effect confirmed in experimental and clinical models. Both are sensates which provide a cooling (menthol) or warming (capsaicin) sensation when used in topical applications. They have been described previously in other studies [35,36]. Menthol is a specific terpene often used as an agent to increase skin penetration. The action of terpenes mainly involves changes in the SC barrier structure and interactions with intercellular lipids [37]. Terpenes loosen the ceramide structure, which is the main component of SC [38], thus increasing drug penetration [37,39,40,41,42]. Whereas capsaicin, classified as an alkaloid, stimulates sensory nerve endings, causes local skin hyperaemia and induces a warming sensation, which is beneficial in neuralgia pharmacotherapy [43].
It turned out that naproxen in the unmodified acid form is compatible with the Pentravan® vehicle used, also with the addition of both penetration enhancers. However, menthol shortens the time remaining the compositions homogeneous. The naproxen salt—[ProOiPr][NAP], also forms stable emulsions based on Pentravan®, without and with addition of TinCap, while with menthol the composition is unstable and the liquid phase separates from the emulsion immediately after preparation. Moreover, the viscosity of the compositions with naproxen salt were lower than with naproxen acid, which may also affect the spreadability and thickness of the composition layer on the skin. The influence of these factors should be verified by in vivo tests.
Our study showed that both unmodified NAP and [ProOiPr][NAP] combined with the Pentravan® vehicle are effectively released from the vehicle and penetrate through the human skin. However, the naproxen salt [ProOiPr][NAP] used in the Pentravan® based compositions provides much faster penetration the skin by the drug. Additionally, after 24 h, almost 2.5 times higher amount of permeated drug was demonstrated for salt than for the unmodified acid form of naproxen from Pentravan® based topical composition without any penetration enhancer. Moreover, the addition of TinCap to the composition comprising naproxen modified with proline isopropyl ester, significantly affects the steady drug permeation throughout the entire range of time tested. After 24 h, the cumulated mass of the drug in the receptor fluid was twice as high with TinCap as without it.
The developed topical compositions based on the Pentravan®, the registered pharmaceutical raw material, can be contribution for the prescription preparations prescribed by a physicians, made in compounding pharmacies for individual patients in the pharmacotherapy of pain of various origins, e.g., in diseases of the musculoskeletal system and rheumatic diseases and soft tissue pain. The presented results of the in vitro human skin permeation studies may be a starting point for the clinical trials and approving process.

5. Conclusions

The presented studies revealed significant correlations between the type of the composition ingredient and the stability and rheological properties of the composition, as well as permeation characteristics of the naproxen using the composition on the human skin in the in vitro test. The tested naproxen forms, both unmodified (S)-naproxen and its salt [ProOiPr][NAP], incorporated to the Pentravan® vehicle achieved a significantly higher cumulative mass after 24 h of permeation with Capsicum Tincture. These results underscore the importance of ingredient selection in topical administration of naproxen, especially regarding the optimisation of the composition and penetration properties. Additionally, the studies reveal that structural modifications of naproxen with amino acid ester and the use of penetration enhancing ingredients in the compositions can significantly impact therapeutic effectiveness of the naproxen after the skin administrations. The use of the developed composition in the form of pain relief and anti-inflammatory creams, occlusive compresses, or topical patches is promising. Moreover, the developed compositions can be crucial for the topical compositions made in compounding pharmacies by physicians’ recipes in individual pain pharmacotherapy.

Author Contributions

Conceptualization, E.J., P.O.-R. and U.A.-G.; methodology, E.J., P.O.-R., A.N., U.A.-G., M.M., M.H. and M.R.; validation, A.N. and E.K.; formal analysis, E.K., E.J., A.N. and U.A.-G.; investigation, E.K., U.A.-G., Ł.K., K.W. and A.M.-S.; resources, M.M., M.H. and M.R.; data curation, E.K., Ł.K., K.W. and A.M.-S.; writing—original draft preparation, E.J., A.N., E.K. and U.A.-G.; writing—review and editing, E.K. and E.J.; visualization, E.K., A.N. and K.W.; supervision, E.J. and M.B.; project administration, E.J. and P.O.-R.; funding acquisition, E.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Rector of the West Pomeranian University of Technology in Szczecin for Ph.D. students of the Doctoral School, grant number: No. ZUT/19/2022.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by Ethical Committee of Pomeranian Medical University in Szczecin (protocol code KB-0012/02/18, date of ethical approval 05 February 2018).

Informed Consent Statement

The patients/participants provided their written informed consent to participate in this study.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Acknowledgments

E.K. would like to thank the Rector of the West Pomeranian University of Technology for the financial support in purchase of naproxen, reactants for salt synthesis, and ingredients of topical compositions.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. McCarberg, B.; D’Arcy, Y. Options in Topical Therapies in the Management of Patients with Acute Pain. Postgrad. Med. 2013, 125, 19–24. [Google Scholar] [CrossRef]
  2. Ossowicz-Rupniewska, P.; Nowak, A.; Klebeko, J.; Janus, E.; Duchnik, W.; Adamiak-Giera, U.; Kucharski, Ł.; Prowans, P.; Petriczko, J.; Czapla, N.; et al. Assessment of the Effect of Structural Modification of Ibuprofen on the Penetration of Ibuprofen from Pentravan® (Semisolid) Formulation Using Human Skin and a Transdermal Diffusion Test Model. Materials 2021, 14, 6808. [Google Scholar] [CrossRef]
  3. Marwah, H.; Garg, T.; Goyal, A.K.; Rath, G. Permeation Enhancer Strategies in Transdermal Drug Delivery. Drug Deliv. 2016, 23, 564–578. [Google Scholar] [CrossRef] [PubMed]
  4. Roberts, M.S.; Cheruvu, H.S.; Mangion, S.E.; Alinaghi, A.; Benson, H.A.E.; Mohammed, Y.; Holmes, A.; Van Der Hoek, J.; Pastore, M.; Grice, J.E. Topical Drug Delivery: History, Percutaneous Absorption, and Product Development. Adv. Drug Deliv. Rev. 2021, 177, 113929. [Google Scholar] [CrossRef] [PubMed]
  5. Mohammed, Y.; Holmes, A.; Kwok, P.C.L.; Kumeria, T.; Namjoshi, S.; Imran, M.; Matteucci, L.; Ali, M.; Tai, W.; Benson, H.A.E.; et al. Advances and Future Perspectives in Epithelial Drug Delivery. Adv. Drug Deliv. Rev. 2022, 186, 114293. [Google Scholar] [CrossRef]
  6. Derry, S.; Wiffen, P.J.; Kalso, E.A.; Bell, R.F.; Aldington, D.; Phillips, T.; Gaskell, H.; Moore, R.A. Topical Analgesics for Acute and Chronic Pain in Adults—An Overview of Cochrane Reviews. Cochrane Database Syst. Rev. 2017, 2020, CD008609. [Google Scholar] [CrossRef]
  7. Üstündağ Okur, N.; Yavaşoğlu, A.; Karasulu, H.Y. Preparation and Evaluation of Microemulsion Formulations of Naproxen for Dermal Delivery. Chem. Pharm. Bull. 2014, 62, 135–143. [Google Scholar] [CrossRef] [PubMed]
  8. Bayer Healthcare LLC. Topical Gel Compositions of Naproxen. WO2020159676 A1, 6 August 2020. Available online: https://patentimages.storage.googleapis.com/21/d0/5b/1b07902db0937c/WO2020159676A1.pdf (accessed on 3 April 2024).
  9. Bonina, F.P.; Puglia, C.; Barbuzzi, T.; De Caprariis, P.; Palagiano, F.; Rimoli, M.G.; Saija, A. In Vitro and in Vivo Evaluation of Polyoxyethylene Esters as Dermal Prodrugs of Ketoprofen, Naproxen and Diclofenac. Eur. J. Pharm. Sci. 2001, 14, 123–134. [Google Scholar] [CrossRef]
  10. Attia, D.A. In Vitro and in Vivo Evaluation of Transdermal Absorption of Naproxen Sodium. Aust. J. Basic Appl. Sci. 2009, 3, 2154–2165. [Google Scholar]
  11. Noreen, S.; Pervaiz, F.; Ashames, A.; Buabeid, M.; Fahelelbom, K.; Shoukat, H.; Maqbool, I.; Murtaza, G. Optimization of Novel Naproxen-Loaded Chitosan/Carrageenan Nanocarrier-Based Gel for Topical Delivery: Ex Vivo, Histopathological, and In Vivo Evaluation. Pharmaceuticals 2021, 14, 557. [Google Scholar] [CrossRef] [PubMed]
  12. Świątek, E.; Ossowicz-Rupniewska, P.; Janus, E.; Nowak, A.; Sobolewski, P.; Duchnik, W.; Kucharski, Ł.; Klimowicz, A. Novel Naproxen Salts with Increased Skin Permeability. Pharmaceutics 2021, 13, 2110. [Google Scholar] [CrossRef]
  13. Kopciuch, E.; Janus, E.; Ossowicz-Rupniewska, P.; Nowak, A.; Duchnik, W.; Kucharski, Ł.; Adamiak-Giera, U.; Lendzion-Bieluń, Z. Characterization of Naproxen Salts with Amino Acid Esters and Their Application in Topical Skin Preparations. Eur. J. Pharm. Biopharm. 2024, 204, 114505. [Google Scholar] [CrossRef] [PubMed]
  14. Barbero, A.M.; Frasch, H.F. Effect of Frozen Human Epidermis Storage Duration and Cryoprotectant on Barrier Function Using Two Model Compounds. Skin Pharmacol. Physiol. 2016, 29, 31–40. [Google Scholar] [CrossRef] [PubMed]
  15. Badran, M.M.; Kuntsche, J.; Fahr, A. Skin Penetration Enhancement by a Microneedle Device (Dermaroller®) In Vitro: Dependency on Needle Size and Applied Formulation. Eur. J. Pharm. Sci. 2009, 36, 511–523. [Google Scholar] [CrossRef]
  16. Haq, A.; Goodyear, B.; Ameen, D.; Joshi, V.; Michniak-Kohn, B. Strat-M® Synthetic Membrane: Permeability Comparison to Human Cadaver Skin. Int. J. Pharm. 2018, 547, 432–437. [Google Scholar] [CrossRef]
  17. Kuntsche, J.; Bunjes, H.; Fahr, A.; Pappinen, S.; Rönkkö, S.; Suhonen, M.; Urtti, A. Interaction of Lipid Nanoparticles with Human Epidermis and an Organotypic Cell Culture Model. Int. J. Pharm. 2008, 354, 180–195. [Google Scholar] [CrossRef] [PubMed]
  18. Simon, A.; Amaro, M.I.; Healy, A.M.; Cabral, L.M.; de Sousa, V.P. Comparative Evaluation of Rivastigmine Permeation from a Transdermal System in the Franz Cell Using Synthetic Membranes and Pig Ear Skin with in Vivo-in Vitro Correlation. Int. J. Pharm. 2016, 512, 234–241. [Google Scholar] [CrossRef]
  19. Davies, D.J.; Ward, R.J.; Heylings, J.R. Multi-Species Assessment of Electrical Resistance as a Skin Integrity Marker for in Vitro Percutaneous Absorption Studies. Toxicol. Vitr. 2004, 18, 351–358. [Google Scholar] [CrossRef] [PubMed]
  20. Bertges, F.S.; da Penha Henriques do Amaral, M.; Rodarte, M.P.; Vieira Fonseca, M.J.; Sousa, O.V.; Pinto Vilela, F.M.; Alves, M.S. Assessment of Chemical Changes and Skin Penetration of Green Arabica Coffee Beans Biotransformed by Aspergillus Oryzae. Biocatal. Agric. Biotechnol. 2020, 23, 101512. [Google Scholar] [CrossRef]
  21. Scheuplein, R.J.; Blank, I.H. Permeability of the Skin. Physiol. Rev. 1971, 51, 702–747. [Google Scholar] [CrossRef]
  22. Higuchi, T. Physical Chemical Analysis of Percutaneous Absorption Process from Creams and Oint-Ments. J. Soc. Cosmet. Chem. 1960, 11, 85–97. [Google Scholar]
  23. Ribeiro, B.D.; Florindo, C.; Iff, L.C.; Coelho, M.A.Z.; Marrucho, I.M. Menthol-Based Eutectic Mixtures: Hydrophobic Low Viscosity Solvents. ACS Sustain. Chem. Eng. 2015, 3, 2469–2477. [Google Scholar] [CrossRef]
  24. Barani Pour, S.; Jahanbin Sardroodi, J.; Rastkar Ebrahimzadeh, A.; Avestan, M.S. Structural and Dynamic Properties of Eutectic Mixtures Based on Menthol and Fatty Acids Derived from Coconut Oil: A MD Simulation Study. Sci. Rep. 2022, 12, 5153. [Google Scholar] [CrossRef]
  25. Martins, M.A.R.; Crespo, E.A.; Pontes, P.V.A.; Silva, L.P.; Bülow, M.; Maximo, G.J.; Batista, E.A.C.; Held, C.; Pinho, S.P.; Coutinho, J.A.P. Tunable Hydrophobic Eutectic Solvents Based on Terpenes and Monocarboxylic Acids. ACS Sustain. Chem. Eng. 2018, 6, 8836–8846. [Google Scholar] [CrossRef]
  26. Jin, Y.; Jung, D.; Li, K.; Park, K.; Lee, J. Mixing of Menthol-Based Hydrophobic Deep Eutectic Solvents as a Novel Method to Tune Their Properties. J. Mol. Liq. 2020, 301, 112416. [Google Scholar] [CrossRef]
  27. Brummer, R.; Godersky, S. Rheological Studies to Objectify Sensations Occurring When Cosmetic Emulsions Are Applied to the Skin. Colloids Surf. A Physicochem. Eng. Asp. 1999, 152, 89–94. [Google Scholar] [CrossRef]
  28. Diamante, L.M.; Lan, T. Absolute Viscosities of Vegetable Oils at Different Temperatures and Shear Rate Range of 64.5 to 4835 s−1. J. Food Process. 2014, 2014, 234583. [Google Scholar] [CrossRef]
  29. Klebeko, J.; Ossowicz-Rupniewska, P.; Nowak, A.; Janus, E.; Duchnik, W.; Adamiak-Giera, U.; Kucharski, Ł.; Prowans, P.; Petriczko, J.; Czapla, N.; et al. Permeability of Ibuprofen in the Form of Free Acid and Salts of L-Valine Alkyl Esters from a Hydrogel Formulation through Strat-MTM Membrane and Human Skin. Materials 2021, 14, 6678. [Google Scholar] [CrossRef] [PubMed]
  30. Welton, T. Ionic Liquids: A Brief History. Biophys. Rev. 2018, 10, 691–706. [Google Scholar] [CrossRef]
  31. Kumar, L.; Suhas, B.; Pai, G.K.; Verma, R. Determination of Saturated Solubility of Naproxen Using UV Visible Spectrophotometer. Res. J. Pharm. Technol. 2015, 8, 825. [Google Scholar] [CrossRef]
  32. Zillich, O.V.; Schweiggert-Weisz, U.; Hasenkopf, K.; Eisner, P.; Kerscher, M. Release and in Vitro Skin Permeation of Polyphenols from Cosmetic Emulsions. Intern. J. Cosmet. Sci. 2013, 35, 491–501. [Google Scholar] [CrossRef]
  33. Benson, H. Transdermal Drug Delivery: Penetration Enhancement Techniques. Curr. Drug Deliv. 2005, 2, 23–33. [Google Scholar] [CrossRef] [PubMed]
  34. Haddad, C. Treatment of Refractory Endometriosis-Related Pain with Vaginal Gestrinone in Pentravan Associated with Pinus Pinaster Extract and Resveratrol: A Preliminary Study. Gynecol. Obstet. 2014, 4, 9. [Google Scholar] [CrossRef]
  35. Kunta, J.R.; Goskonda, V.R.; Khan, M.A.; Brotherton, H.O.; Reddy, I.K. Effect of Menthol and Related Terpenes on the Percutaneous Absorption of Propranolol across Excised Hairless Mouse Skin. J. Pharm. Sci. 1997, 86, 1369–1373. [Google Scholar]
  36. Degim, I.T.; Uslu, A.; Hadgraft, J.; Atay, T.; Akay, C.; Cevheroglu, S. The Effects of Azone and Capsaicin on the Permeation of Naproxen through Human Skin. Int. J. Pharm. 1999, 179, 21–25. [Google Scholar] [CrossRef]
  37. Nowak, A.; Duchnik, W.; Makuch, E.; Kucharski, Ł.; Ossowicz-Rupniewska, P.; Cybulska, K.; Sulikowski, T.; Moritz, M.; Klimowicz, A. Epilobium angustifolium L. Essential Oil—Biological Activity and Enhancement of the Skin Penetration of Drugs—In Vitro Study. Molecules 2021, 26, 7188. [Google Scholar] [CrossRef]
  38. Aqil, M.; Ahad, A.; Sultana, Y.; Ali, A. Status of Terpenes as Skin Penetration Enhancers. Drug Discov. Today 2007, 12, 1061–1067. [Google Scholar] [CrossRef]
  39. Chen, J.; Jiang, Q.-D.; Wu, Y.-M.; Liu, P.; Yao, J.-H.; Lu, Q.; Zhang, H.; Duan, J.-A. Potential of Essential Oils as Penetration Enhancers for Transdermal Administration of Ibuprofen to Treat Dysmenorrhoea. Molecules 2015, 20, 18219–18236. [Google Scholar] [CrossRef]
  40. Wan, G.; Dai, X.; Yin, Q.; Shi, X.; Qiao, Y. Interaction of Menthol with Mixed-Lipid Bilayer of Stratum Corneum: A Coarse-Grained Simulation Study. J. Mol. Graph. Model. 2015, 60, 98–107. [Google Scholar] [CrossRef]
  41. Wang, H.; Meng, F. The Permeability Enhancing Mechanism of Menthol on Skin Lipids: A Molecular Dynamics Simulation Study. J. Mol. Model. 2017, 23, 279. [Google Scholar] [CrossRef]
  42. Huang, C.; Wang, H.; Tang, L.; Meng, F. Penetration Enhancement of Menthol on Quercetin through Skin: Insights from Atomistic Simulation. J. Mol. Model. 2019, 25, 235. [Google Scholar] [CrossRef] [PubMed]
  43. Adamiak-Giera, U.; Nowak, A.; Duchnik, W.; Ossowicz-Rupniewska, P.; Czerkawska, A.; Machoy-Mokrzyńska, A.; Sulikowski, T.; Kucharski, Ł.; Białecka, M.; Klimowicz, A.; et al. Evaluation of the in Vitro Permeation Parameters of Topical Ketoprofen and Lidocaine Hydrochloride from Transdermal Pentravan® Products through Human Skin. Front. Pharmacol. 2023, 14, 1157977. [Google Scholar] [CrossRef]
Applsci 15 01338 g001
Figure 1. Comparison of DSC thermograms for: (a) (S)-naproxen (NAP), menthol and two- and three-components mixtures of NAP with menthol and with menthol and ethanol, (b) NAP and mixture of NAP with TinCap.
Figure 1. Comparison of DSC thermograms for: (a) (S)-naproxen (NAP), menthol and two- and three-components mixtures of NAP with menthol and with menthol and ethanol, (b) NAP and mixture of NAP with TinCap.
Applsci 15 01338 g001
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Figure 2. Comparison of DSC thermograms for: (a) [ProOiPr][NAP], menthol and two- and three-components mixtures of [ProOiPr][NAP] with menthol and with menthol and ethanol, (b) [ProOiPr][NAP] and mixture of [ProOiPr][NAP] with TinCap.
Figure 2. Comparison of DSC thermograms for: (a) [ProOiPr][NAP], menthol and two- and three-components mixtures of [ProOiPr][NAP] with menthol and with menthol and ethanol, (b) [ProOiPr][NAP] and mixture of [ProOiPr][NAP] with TinCap.
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Figure 3. The plot of viscosity (at 30 °C) vs. shear rate for the Pentravan® and the topical compositions comprising acid naproxen (NAP) or its salt [ProOiPr][NAP], with and without permeation enhancers.
Figure 3. The plot of viscosity (at 30 °C) vs. shear rate for the Pentravan® and the topical compositions comprising acid naproxen (NAP) or its salt [ProOiPr][NAP], with and without permeation enhancers.
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Figure 4. Permeation profiles of naproxen through human skin from topical compositions based on Pentravan®: (A)—with acid form of naproxen, NAP; (B)—with salt of naproxen, [ProOiPr][NAP], in the presence of chemical enhancers: menthol (green line), TinCap (red line) or without enhancer (dark blue line).
Figure 4. Permeation profiles of naproxen through human skin from topical compositions based on Pentravan®: (A)—with acid form of naproxen, NAP; (B)—with salt of naproxen, [ProOiPr][NAP], in the presence of chemical enhancers: menthol (green line), TinCap (red line) or without enhancer (dark blue line).
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Figure 5. Cluster analysis graph for the mean cumulative mass of naproxen (for all-time points) during 24 h permeation study from topical Pentravan® based compositions comprising two forms of naproxen and without or with penetration enhancers. Compounds with similar permeation are marked with various separate circles (blue circle—the greatest permeation, green circle—the lowest permeation).
Figure 5. Cluster analysis graph for the mean cumulative mass of naproxen (for all-time points) during 24 h permeation study from topical Pentravan® based compositions comprising two forms of naproxen and without or with penetration enhancers. Compounds with similar permeation are marked with various separate circles (blue circle—the greatest permeation, green circle—the lowest permeation).
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Figure 6. The box plot of the dataset of naproxen flux for all time intervals during the 24 h skin permeation study with Pentravan® based topical compositions.
Figure 6. The box plot of the dataset of naproxen flux for all time intervals during the 24 h skin permeation study with Pentravan® based topical compositions.
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Table 1. Ingredients of topical compositions based on Pentravan® as vehicle *.
Table 1. Ingredients of topical compositions based on Pentravan® as vehicle *.
CompositionIngredient
Pentravan®NAP[ProOiPr][NAP]MentholTinCapEthanol
Pen + NAP8010–––10
Pen + menthol + NAP7010–10–10
Pen + TinCap + NAP8010––10–
Pen + [ProOiPr][NAP]73.2–16.8––10
Pen + menthol + [ProOiPr][NAP]63.2–16.810–10
Pen + TinCap + [ProOiPr][NAP]73.2–16.8–10–
* The number represents amount of the ingredient as weight percent (wt %) of total composition weight.
Table 2. Permeation parameters of naproxen through the human skin from different compositions.
Table 2. Permeation parameters of naproxen through the human skin from different compositions.
FormulationQ
(µg NAP cm−2)		%ADJSS,
(µg cm−2 h−1)
Pen + NAP339.7 ± 16.3 a0.33 ± 0.02 a12.9 ± 0.6 *, a
Pen + menthol + NAP847.9 ± 117.1 b0.85 ± 0.12 b34.5 ± 1.6 *, b
Pen + TinCap + NAP1079.1 ± 137.1 b1.08 ± 0.12 b47.9 ± 1.9 *, c
Pen + [ProOiPr][NAP]791.2 ± 83.8 b0.79 ± 0.08 b91.14 ± 2.7 **, d
Pen + TinCap + [ProOiPr][NAP]1613.2 ± 114.3 c1.61 ± 0.11 c66.8 ± 1.0 *, e
Q—the cumulative mass of naproxen permeating through the human skin after 24 h; %AD—Q as the percentage of the applied dose; JSS—steady-state flux determined from the slope of the linear portion of the profiles; flux determined for permeation interval time: * 3–24 h; ** 1–5 h; a, b, c, d, e different letters indicate significant differences p < 0.001, α = 0.05, mean ± SD, n = 3. The statistically significant difference was estimated by ANOVA using the Tuckey’s test.
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Kopciuch, E.; Ossowicz-Rupniewska, P.; Adamiak-Giera, U.; Nowak, A.; Wilpiszewska, K.; Białecka, M.; Kucharski, Ł.; Muzykiewicz-Szymańska, A.; Miernik, M.; Halczak, M.; et al. Topical Pentravan® Based Compositions with Naproxen and Its Proline Ester Derivative—A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin. Appl. Sci. 2025, 15, 1338. https://doi.org/10.3390/app15031338

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Kopciuch E, Ossowicz-Rupniewska P, Adamiak-Giera U, Nowak A, Wilpiszewska K, Białecka M, Kucharski Ł, Muzykiewicz-Szymańska A, Miernik M, Halczak M, et al. Topical Pentravan® Based Compositions with Naproxen and Its Proline Ester Derivative—A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin. Applied Sciences. 2025; 15(3):1338. https://doi.org/10.3390/app15031338

Chicago/Turabian Style

Kopciuch, Ewelina, Paula Ossowicz-Rupniewska, Urszula Adamiak-Giera, Anna Nowak, Katarzyna Wilpiszewska, Monika Białecka, Łukasz Kucharski, Anna Muzykiewicz-Szymańska, Maciej Miernik, Mirosław Halczak, and et al. 2025. "Topical Pentravan® Based Compositions with Naproxen and Its Proline Ester Derivative—A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin" Applied Sciences 15, no. 3: 1338. https://doi.org/10.3390/app15031338

APA Style

Kopciuch, E., Ossowicz-Rupniewska, P., Adamiak-Giera, U., Nowak, A., Wilpiszewska, K., Białecka, M., Kucharski, Ł., Muzykiewicz-Szymańska, A., Miernik, M., Halczak, M., Romanowski, M., & Janus, E. (2025). Topical Pentravan® Based Compositions with Naproxen and Its Proline Ester Derivative—A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin. Applied Sciences, 15(3), 1338. https://doi.org/10.3390/app15031338

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