AbstractFinasteride and silodosin are potential combinations for management of benign prostatic hyperplasia (BPH). Simultaneous transdermal delivery can overcome reasons of their poor oral bioavailability. This was achieved via menthol-based microemulsion (ME) which can undergo thermoresponsive phase transition. Pseudoternary phase diagrams were constructed at room temperature and 32 °C using menthol (oily phase) and Tween 80 (surfactant) in absence and presence of ethanol or propylene glycol as cosurfactants. In absence of cosurfactant, phase behavior depended on temperature with part of liquid crystal (LC) zone changing to microemulsion at 32 °C. Cosurfactant abolished LC/gel zones irrespective to temperature. Microemulsion formulations were selected from the area undergoing LC/ME thermoresponsive transition. These were evaluated for viscosity, droplet size, drug release and skin permeation. Characterization confirmed nanosized droplet and viscosity measurement confirmed thermoresponsive behavior in absence of cosurfactant. MEs showed lower release compared to saturated aqueous solutions. MEs resulted in significant increase in transdermal flux of finasteride and silodosin compared to aqueous control with ethanol containing system producing the highest flux. Simultaneous loading of finasteride and silodosin in microemulsions modulated thermodynamic activity. However, their flux remained significantly higher than aqueous suspension. Thus, the study introduced thermoresponsive microemulsion as efficient system for simultaneous delivery of finasteride and silodosin.
IntroductionBenign prostatic hyperplasia (BPH) is an advancing disease affecting older men. Its symptoms include enlarged prostate and affected urinary system1. Prostatic hyperplasia can cause pressure on the urethra resulting in its incomplete or even complete obstruction, interrupting regular urination. Several pharmaceutical therapies have been used to manage lower urinary tract symptoms resulted from BPH including "1- adrenergic antagonists, 5- reductase inhibitors, anticholinergic agents, and phytotherapies1. The main pharmacological options for men with symptomatic BPH are 5a-reductase inhibitors (e.g. dutasteride, finasteride) and a1-adrenergic receptor antagonists (e.g. tamsulosin, terazosin, alfuzosin, doxazosin) either alone or in combination2. Combined therapy of dutasteride-tamsulosin and finasteride-doxazocin showed promising results in numerous literatures using different routes of administration1,2,3.Finasteride is a competitive inhibitor of 5α-reductase which has been used in benign prostatic hyperplasia (BPH)4. Oral finasteride has been widely used for BPH with high reported efficacy. However, only 63% of the drug is absorbed in the gastrointestinal tract5. Consequently, several topical formulations have been developed to enhance its bioavailability. These include the utilization of chemical enhancers6, liposomes7, polymeric nanoparticles8,9, PLGA microspheres10 and microemulsions11. Finasteride was reported to have higher efficacy and better clinical outcomes in management of BPH when used in combinations with alpha-1A adrenoceptor blockers. Higher pharmacological efficacy of finasteride and doxazocin combination was reported compared to monotherapy when administered as oral dosage forms or topical gel formulations1,12.Silodosin is a very selective alpha-1A adrenergic receptor blocking agent which is used orally to treat the symptoms of benign prostatic hyperplasia. Silodosin is the most uroselective α-blocker offering less side effects13. The oral bioavailability of silodosin is nearly 32% with extensive drug metabolism via glucuronidation in the liver14. Taking these into consideration, silodosin can be considered as a good candidate for combination with finasteride in a suitable topical formulation to enhance bioavailability of both drugs achieving higher clinical outcomes.The organizational structure of human skin hindered its utilization as a pathway for systemic delivery of large number of drugs15. Research studies were thus directed to develop strategies for breaching this firm organization of skin strata. These tactics include modulation of lipid and cellular architecture by chemical agents to create a space for passage of molecules16. Other tools may utilize weak electricity or ultrasonic waves to perform the same function17,18,19. Researchers also optimized the chemical potential and fabricated supersaturated recipes which provide greater input rate through intact cellular organization20. Modern techniques introduced nanosized carriers into the field starting with vesicular lipid systems with successive literature modifying the composition to control the characteristics of vesicle membrane to more flexible highly penetrating system21,22,23,24. The advantage of flexibility was extended to hire eutectic premixes for increased permeation via skin25,26. Encouraging findings have been reported for microemulsion and self-microemulsifying systems27,28. Transdermal microemulsions has been investigated and studied by many authors and claimed to boost transdermal drug delivery of different model drugs either alone or as fixed drug combinations27,29. The unique feature of microemulsion is its phase transition in response to dilution with water or evaporation of volatile constituents. The effect of this feature was probed in transdermal delivery with supersaturation being suggested as an additional mechanism for enhanced transdermal delivery from microemulsion30. Thermoresponsive phase transition of microemulsion is possible but no literature report was published on this subject.Consequently, the purpose of this research was to test the potential of menthol based microemulsion as thermoresponsive system for simultaneous transdermal delivery of finasteride and silodosin as combined therapy for BPH.Materials and methodsMaterialsFinastride was donated by Adwia Pharmaceuticals, Cairo, Egypt. Silodosin was generously provided by Alandalous Pharmaceutical industries, Cairo, Egypt. Pharmaceutical grade ethanol, propylene glycol, Tween 80 and KH2PO4 were provided by El Nasr Pharmaceuticals Chemicals Co., Cairo, Egypt. Menthol was obtained from Bhagat Aromatics Ltd, India. Acetonitrile (HPLC grade) was from Fisher Scientific UK, Loughborough, Lecis, United Kingdom.Construction of pseudoternary phase diagramMenthol was employed as oily phase; Tween 80 was utilized as surfactant in absence or presence of ethanol or propylene glycol as cosurfactants. The surfactant and cosurfactant were mixed at 1:1 weight ratio. The pseudo-ternary phase diagram was constructed at ambient temperature and at 32 °C employing water titration method. Different weight ratios (0.5:9.5, 1:9, 1.5:8.5, 2:8, 2.5:7.5, 3:7, 3.5:6.5, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1) of oil and surfactant/cosurfactant system were mixed to provide homogenous mixtures. Water was gradually added to these mixtures followed by gentile mixing using magnetic stirrer. After equilibration, the developed systems were inspected visually to determine the phase change upon increasing water concentration. Transparent fluid systems were characterized as microemulsion while viscous systems showing oil strokes were specified as liquid crystals. None flowable systems after 45° tilting were taken as gel phase. Turbid milky fluid phase was described as coarse emulsion.Preparation of microemulsionMicroemulsion was selected from the microemulsion/liquid crystal border of the phase diagram of menthol/Tween 80 and water at room temperature. The same composition was used in other phase diagrams which contained cosurfactants. The composition of the selected microemulsion formulations is presented in Table 1. For preparation of the selected formulation the menthol was solubilized in Tween 80 in presence or absence of ethanol or propylene glycol at 32 °C. Water heated to 32 °C was added while magnetic mixing. Finasteride and/or silodosin were added with mixing to develop 1% w/w of each drug. The transdermal drug delivery potential of the selected formulation was evaluated with saturated aqueous solutions of individual drugs and their combination being employed as control.Table 1 The composition of the tested microemulsion formulations.Full size tableCharacterization of the tested microemulsionsThe thermoresponsive phase transition of cosurfactant-free formulation was monitored visually at different temperatures and the formulation was photographed at different temperatures (10, 22, 25, 32 °C). In addition, the viscosity of the selected formulation was determined at room temperature and at 32°C using a RheoWin HAAKE Visco Tester IQ Thermo Fisher “Vane geometry and universal conminer holder” SN 15,063,200,722,241,020 (Germany). The type of microemulsion was distinguished using conductimetric measurements. The electrical conductivity was recorded by an electrical conductivity meter (HQD portable meter, DOC 022.97.80017, HACH, USA). For quantifiable conductance, NaCl (0.1% w/v) was solubilized in microemuslion before recording the conductance. In addition, the conductivity of individual components of microemulsion was recorded as controls.Morphology and size determinationMicroemulsion droplets were assessed for their size and morphology utilizing transmission electron microscopy (JEM-1400 Plus, Jeol, Tokyo, Japan). The undiluted sample of each microemulsion was dropped on a carbon cupper plate and left to dry. After being dried, it was stained by saturated ethanolic solution of uranyl acetate and fixed on the sample holder before examination by TEM. The captured micrographs were used to monitor the morphology and measure droplet size.Droplet size, size distribution and zeta potential determinations utilized zetasizer (ZetaPALS, Brookhaven instruments crop., Malvern, New York, USA). This involved direct measurement of microemulaions without dilution to avoid phase transition. The equipment provides laser beam at 90◦ and was operated at 30 °C to guarantee fluidity of cosurfactant free formulation. Droplet size was computed as Z-average obtained as the mean of 5 runs. The system also provides graphical presentations of droplet size distribution and computes the polydispersity index (PDI).High pressure liquid chromatography (HPLC)Finasteride/silodosin concentration was determined by HPLC (1260 infinity, supplied with a VWD1260 UV detector and a TCC 1260 autosampler, Agilent technologies, Deutschland, Germany). The stationary phase was 5μm, C18 solid held in 150 mm × 4.6 mm column (Intersil®, GL Sciences Inc., Tokyo, Japan). Agilent Open LAB ChemStation software was used for controlled operation. Analysis of finasteride and silodosin utilized the same chromatographic conditions with the mobile phase being a mixture of 10 mM phosphate buffer (adjusted to pH 6.8 with potassium hydroxide) and acetonitrile (55:45). The flow rate of the mobile phase was adjusted to be 1.2 ml/minute. The drug content in the effluent was determined at 210 nm. The samples were diluted with 40% propylene glycol aqueous solution and 30 µl of each was injected into HPLC system.In vitro drug releaseThe release of drugs from the selected formulations was investigated using vertical glass Franz diffusion cells. The diffusional area of these cells was 2.27 cm2 with a receptor fill volume of 14.5 ml. Release was through cellulose membrane (Cellulose tubing, M.W cutoff 14 KD, Sigma Diagnostics, St. Louis, MO) which was employed as an artificial membrane and mounted between the donor and receptor chambers. For sink status, 40% (v/v) propylene glycol in distilled water was used as the receptor media. For simulating the in vivo condition, surface temperature of the membrane was adjusted to be 32 ± 1 °C. This was achieved by incubating the cells into temperature regulated water bath. After an overnight equilibration, the selected formulation (2 ml) was introduced to the donor chamber which was tightly covered. Receptor was sampled occasionally followed by refill with fresh receptor. Drug concentration was recorded by HPLC. The release rate was determined from the release profiles which were obtained by plotting the cumulative amount of drug released as a function of time.Preparation of skin samplesThe skin of freshly cut albino male rabbit ear which was obtained from local animal house was utilized as a skin model due to lack of human skin. This model is accepted for monitoring transdermal delivery of alternative drugs from other microemulsion systems23,27. Animal treatment and skin preparation were conducted according to relevant guidelines and regulations. All methods comply with the ARRIVE guidelines. These procedures were approved by the Ethical Committee of Faculty of Pharmacy, Tanta University (approval number, TP/ RE/ 9/ 23 p-0046). Inner ear whole skin was isolated after incision around the tips of ears followed by gentle skin separation from the cartilage.Skin permeation studiesThese investigations involved the same diffusion cells as in the release studies with cellulose membrane being replaced with full thickness rabbit ear skin. The skin was fixed between the donor and the receptor compartment in a way to expose the stratum corneum surface with the dermis touching the receptor. The receptor was 40% v/v propylene glycol in distilled water to act as sink for the permeant. The cells were incubated in a water bath with the temperature being adjusted to mimic physiological skin surface temperature (32 ± 1 °C). After overnight equilibration, the donor compartments were loaded by tested formulations (2 ml) then occluded using aluminum foil. Samples (5 ml) were withdrawn periodically up to 10 h at which 10 ml sample was collected. The receptor was replenished after each collection and the study continued for 24 h. Finasteride/silodosin levels in the samples were quantified via HPLC. Skin samples were distributed among formulation to ensure representation of each rabbit in the tested formulations31. The cumulative quantity permeated was plotted against time intervals. The resulting profile was hired to compute the transdermal flux (slope of the linear part). The lag time was also extracted from the intercept of the linear part with the time axis.Statistical analysisThe Kruskal Wallis test was used for statistical analysis. To compare between means, Tukey`s multiple comparison was employed as post hoc test.Results and discussionPseudo-ternary phase diagramThe phase diagrams were constructed at ambient temperature and at 32 °C. Menthol was elected as oily phase due to its reported remarkable skin permeability enhancing effect for different model drugs32,33. Tween 80 was probed as surfactant due to its ability to solubilize menthol. Ethanol or propylene glycol were employed as cosurfactant. The surfactant/cosurfactant ratio was adjusted to 1:1 w/w. This adjustment was based on the reported phase diagram utilizing the same surfactant and cosurfactant system27,29. The pseudo-ternary phase diagrams of menthol, Tween 80 and water system in the presence and absence of ethanol or propylene glycol as cosurfactants are shown in Figs. 1–2. Figure 1a shows the pseudo-ternary phase diagram constructed at ambient temperature in the absence of cosurfactants. Tween 80 formed microemulsion over a range of oil–surfactant–water ratios with the microemulsion zone representing about 32.7% of the total area of the pseudo-ternary phase diagram. The water content of microemulsion was maximized in systems containing the lowest oil concentration. Water content of microemulsion reduced progressively with increasing oil concentration. Systems containing surfactant (70%-40%) and oil (30%-60%) underwent thickening with increasing water content upon titration with water. These systems formed microemulsion which underwent increase in viscosity upon addition of water before transforming to liquid crystals followed by formation of gel that did not move upon tilting the container at 45°. These systems eventually transformed into coarse emulsion (Fig. 1a). The physical properties of LC and gel phase are identified based on the fluidity with LC being viscous system which can move upon tilting of the container. Moreover, polarized light microscopy of liquid crystals reveals the presence of opaque systems displaying birefringence, characterized by typical oily streaks, maltese crosses, or fan-like textures. The gel phase was shown as physically settled gel with rigid non-fluid structure. A similar description was shown in literature34. Incorporation of cosurfactants abolished the liquid crystalline and gel phases with direct transition from microemulsion to coarse emulsion system. This was the case in presence of ethanol or propylene glycol (Fig. 1b-c). Incorporation of ethanol as a cosurfactant increased the microemulsion zone to cover 35.8% of the area of the phase diagram relative to 32.7% in case of ethanol-free system (Fig. 1b). Incorporation of ethanol as a cosurfactant was reported previously to induce similar effects regarding enhancing microemulsion zone and abolishment of LC and gel phases29,35. Incorporation of propylene glycol as a cosurfactant had a similar effect to ethanol regarding breaking down of LC and gel phases with microemulsion zone covering 30.4% of the area (Fig. 1c). The effect of PG on altering the phase behavior during the construction of pseudo ternary phase diagram was reported previously 29. The vanishing of the liquid crystalline and gel phases is obvious in the presence of cosurfactant due to the expected fluidization of interfacial film together with extensive reduction in surface tension. These effects are expected to allow easy phase transition with unnoticeable formation of lamellar liquid crystalline intermediate phase29,30.Fig. 1Pseudoternary phase diagrams of menthol/water/Tween systems at room temperature in absence (a) and presence of ethanol (b) or propylene glycol (c) as cosurfactants.Full size imageConstruction of phase diagram at 32 °C which simulates skin temperature resulted in different phase behavior depending on the composition of the system (Fig. 2). For cosurfactant free system, increasing the temperature widened the microemulsion zone to reach 35.2% of total area compared to 32.7% at ambient temperature. In addition, liquid crystalline system exhibited smaller area of phase diagram with direct transition to coarse emulsion phase without formation of gel system (Fig. 2a). The recorded increase in microemulsion zone and the absence of gel phase in the constructed phase diagram at 32 °C compared with that constructed at room temperature can be accredited to increased solubility of menthol in the surfactant at higher temperature in addition to heat induced reduction in the interfacial tension. This effect was widely reported in literature36,37. The system employing ethanol as a cosurfactant did not exhibit significant changes in the phase behavior upon increasing the temperature (Fig. 2b). This can be accredited to the great impact of ethanol as cosurfactant in modulating the phase behavior which overshadows the effect of temperature. An early research article reported the lack of sensitivity of the interfacial tension between oily phase and aqueous phase containing mixture of surfactants to the impact of temperature. This research indicated no significant change in interfacial tension even after increasing the temperature from 30 °C to 80 °C38. The independence of interfacial tension on temperature in case of mixed surfactants can be extrapolated to surfactant/cosurfactant mixture in which the later provides significant reduction in interfacial tension with fluidization of interfacial layer. This effect is expected to overshadow the effect of temperature.Fig. 2Pseudoternary phase diagrams of menthol/water/Tween systems at 32 °C in absence (a) and presence of ethanol (b) or propylene glycol (c) as cosurfactants.Full size imageOn the other hand, propylene glycol containing system shows slight increase in microemulsion zone from 30.4% to 33% after increasing the temperature (Fig. 2c). This is expected as propylene glycol is less efficient than ethanol as cosurfactant39. The viscosity of propylene glycol is also a factor that can negatively contribute to the fluidity of the interfacial film. Taking the temperature induced reduction in viscosity into consideration, the phase behavior of propylene glycol containing system can depend on temperature. This clearly explains the recorded modulation in the phase diagram of such system at 32 °C compared to the corresponding phase diagram constructed at ambient temperature.It is important to note that various types of liquid crystals are documented in literature. These include thermotropic which undergo transition by heat, lyotropic which can change in response to temperature and concentration of amphiphilic molecule and metalotropic which is sensitive to the proportion of inorganic and organic components40,41. These types are further subclassified into different phases depending on their appearance and physical characteristics42,43. The current phase diagram included a phase transition system which is sensitive to both water content and temperature depending on the composition and relative proportions. Additional characterization is required for type verification. The applications of LC systems as drug delivery systems are documented in literature with promising results being reported in enhanced transdermal and ocular delivery31,44.Characterization of formulationThe selected microemulsion formulation contained menthol oil and water (20% each) with 60% of the system being surfactant or surfactant/cosurfactant mixture at a ratio 1:1 w/w. The cosurfactant free formulation underwent thermoresponsive phase transition as shown in Fig. 3. At 10 °C, the formulation was in the form of firm gel. Increasing the temperature to 22 or 25 °C developed liquid crystalline system which formed clear microemulsion at 32°C (Fig. 3). The viscosity values at room temperature were 1476, 81.2 and 21.1 cps for cosurfactant-free system, propylene glycol containing system and ethanol containing system, respectively. The viscosity was also determined at 32 °C. The recorded viscosity values at 32 °C were 165.5, 48.3 and 20.5 cps for cosurfactant free system, propylene glycol containing system and ethanol containing system respectively. The viscosity values depended on the temperature and the presence of cosurfactant. The reduction in viscosity at higher temperature reflects the thermoresponsive phase transition. The reduction in the viscosity values after increasing temperature is expected with the higher thermal energy of the molecules and weak intermolecular forces. The more viscous the fluid, the more sensitive it is to temperature change which explains the small reduction in ethanol containing system45. The reduction in the viscosity values after the addition of cosurfactants can be explained based on their ability to increase the system fluidity with ethanol showing more intense fluidizing effect than propylene glycol. The fluidizing effect of interfacial film after incorporation of cosurfactant has been shown with similar rank of efficiency being recorded for ethanol and propylene glycol29. Noteworthy, the thermoresponsive phase transition of cosurfactant-free system provides the formulator with a chance to prepare viscous liquid crystalline formulation at storage temperature which can form fluid microemulsion after application to skin surface. The fluidity of the developed system allows for intimate contact with the microarchitecture.Fig. 3The effect of temperature on the phase behavior of microemulsion comprising menthol, water and tween at ratio of 20, 20 and 60, respectively.Full size imageThe electrical conductivity values of the tested microemulsion formulations were measured after being prepared using 0.1% w/v sodium chloride solution as an aqueous phase. The recorded values were 15.11, 46.8 and 36.6 µs cm-1 for TW ME, TW-Ethanol ME and TW-PG ME respectively. These recorded electrical conductivity values were small compared to that recorded with pure 0.1% w/v sodium chloride solution (2267 ± µs cm-1). This indicates the entrapment of water as the internal phase of the formed microemulsion providing W/O microemulsion system. To confirm this finding the electrical conductivity of starting materials were determined, and the recorded values were 3.75, 1.99, 0.68, 0.03 and zero µs cm-1 for pure distilled water, ethanol, Tween 80, propylene glycol and melted menthol, respectively. These values together with the conductivity of sodium chloride solution confirm absence of significant contribution of the internal aqueous phase of ME in conductivity providing clear indication that the developed ME systems were in the form of w/o type.Morphology and size determinationThe TEM micrographs of menthol based microemulsion are shown in Fig. 4, confirming the existence of spherical droplets in the nanoscale with an average size of 86.6 ± 27.5, 80.3 ± 13.4 and 107.3 ± 19 nm for the cosurfactant free microemulsion, ethanol containing microemulsion and propylene glycol containing system. The recorded droplet size was similar to that reported in literature for microemulsion systems46.Fig. 4Representative transmission electron micrographs and zetasizer particle size distribution for microemulsions comprising menthol/water/Tween systems in absence (a) and presence of ethanol (b) or propylene glycol (c) as cosurfactants.Full size imageThe size of prepared formulation was measured using zetasizer and the results were recorded as 155.5 ± 18.7, 125.4 ± 11.1 and 127.2 ± 9.3 nm for TW ME, TW-Ethanol ME and TW-PG ME respectively. Despite monomodal distribution of droplet size (Fig. 4), the PDI values reflected heterogenicity recording 0.58, 0.44 and 0.30 for the same formulations, respectively. The recorded size values indicate droplet size reduction in presence of co-surfactants which is believed to be related to fluidization of the interfacial film and reduction of interfacial tension. Similar findings and explanation were presented in previous research29.HPLC analysis of finasteride and silodosinSimultaneous quantification of finasteride and silodosin was achieved using HPLC. The mobile phase was refined to provide isocratic separation of both drugs. Figure 5 shows representative chromatogram showing clean separation of both drugs with no interference. Silodosin was eluted first after a retention time of 2.6 min. Finasteride was subsequently eluted after a retention time of 5.5 min.Fig. 5Representative chromatogram showing elution of silodosin and finasteride after 2.6 and 5.5 minutes, respectively.Full size imageIn vitro drug releaseThe experimental conditions of in vitro release were the same as for the permeability study with the skin being replaced with semipermeable membrane to correlate between the data obtained from release experiments and skin permeation experiments29,31. The in vitro release plots of finasteride and silodosin are shown in Fig. 6 highlighting the existence of zero order release from the researched formulations. The computed release data are presented in Tables 2 and 3. The recorded release rate of finasteride from saturated aqueous control was higher than that recorded from different microemulsion formulations (Table 2). This can be explained by the high affinity of finasteride to microemulsion system. Similar release characteristics were shown with other candidates from microemulsion formulations27,29. Finasteride release rate from microemulsion cosurfactant free system was 8.4 ± 0.76 µg cm-2 h-1. Surprisingly, incorporation of cosurfactants (either ethanol or PG) in microemulsion formulation did not result in significant enhancement in finasteride release rate compared with cosurfactant free microemulsion despite of significant reduction in viscosity in presence of cosurfactant (Fig. 6a and Table 2). This data can be explained based on the fact that, the study employed fixed concentration of the drug. Taking this into consideration with the increased solubility in presence of cosurfactant, the cosurfactant free system will have higher thermodynamic activity and thus greater driving force for drug diffusion through artificial membrane. This was reflected by the existence of finasteride in the form of suspension in absence of cosurfactant with the existence of ethanol or propylene glycol forming clear solution at the same concentration. Another possible reason for no significant change in release after addition of cosurfactant is the increased affinity to the microemulsion which is parallel to increased solubility47,48,49.Fig. 6In vitro release profiles of finasteride (a) and silodosin (b) from simple aqueous suspension and different menthol-based microemulsion formulations. Formulation details are in Table 1.Full size imageTable 2 The transdermal permeation parameters and release rate of finasteride obtained from different microemulsion formulations and aqueous drug suspension.Full size tableTable 3 The transdermal permeation parameters and release rate of silodosin obtained from different microemulsion formulations and aqueous drug suspension.Full size tableWith respect to silodosin, a higher drug release rate was recorded from the saturated aqueous control followed by different microemulsion formulations (Fig. 6b and Table 3). Silodosin release rate from microemulsion formulations varied based on the composition of each system. The cosurfactant free microemulsion was specified by inferior release rate. Incorporation of cosurfactants (either ethanol or PG) in microemulsion formulation resulted in a significant (P < 0.05) increase in the release rate compared with cosurfactant free microemulsion. This data can be clarified with reference to viscosity data which reflected higher viscosity for cosurfactant free microemulsion compared with cosurfactant containing system (Fig. 6b and Table 3). The reverse correlation between the release rate and the viscosity of the delivery system was stated in literature50,51. Unexpectedly, the release rate silodosin from ethanol containing microemulsion was comparable to that containing propylene glycol despite its recorded lower viscosity value of the former. This can be accredited to the higher affinity of the drug to the microemulsion containing ethanol.Skin permeation studiesFigure 7 shows the permeation profiles of finasteride after its application alone or in combination with silodosin in the form of saturated aqueous solution or as 1% w/w in menthol based microemulsion formulations. The permeation plots showed linear pattern after a lag time. This is logic for saturated aqueous solution and cosurfactant free microemulsion which contained excess crystals that maintained saturation31. The linear profiles are not expected for ethanol/propylene glycol containing microemulsions which were in the form of solution. This may be due to possible back diffusion of the receptor fluid which may compromise the characteristics of the donor, but this requires verification. The permeation parameters including transdermal flux and lag time were calculated from the linear plots and were adopted to research the difference between formulations. These parameters are presented in Tables 2–3.Fig. 7Skin permeation profiles of finasteride alone (a) or after mixing with silodosin (b) in the form of simple aqueous suspension and different menthol-based microemulsion formulations. Formulation details are in Table 1.Full size imageThe recorded transdermal flux of finasteride form simple saturated aqueous solution was 0.47 µg cm-2 h-1. This flux is greater than recorded after permeation through human skin which is acceptable taking into consideration the difference in skin used52. Application of menthol oil based microemulsion formulations resulted in significant increase in the transdermal flux of finasteride compared to saturated aqueous control (p < 0.05) (Table 2 and Fig. 7a). This result simulates published studies which reported enhanced transdermal delivery of finasteride from cinnamon oil-based microemulsion in presence of oleic acid or Transcutol P11,53. Incorporation of ethanol or propylene glycol as cosurfactants in the microemulsion formulation significantly augmented finasteride transdermal flux through rabbit ear skin compared to the cosurfactant free formulation (P < 0.05) (Table 2 and Fig. 7a). Comparing ethanol and propylene glycol as cosurfactants, ethanol showed better augmentation in transdermal delivery of finasteride compared to propylene glycol (P < 0.05). The role of cosurfactant on transdermal absorption from microemulsion was established in literature. The superiority of ethanol over propylene glycol was indicated. The positive effect of cosurfactant was supposed to result from the significant reduction in the interfacial tension which allowed for more intimate contact between the formulation and skin surface with its microarchitecture29. Noteworthy, the rank of drug permeation does not agree with the rank of drug release as indicated from the inferiority of skin permeation from simple saturated aqueous suspension which showed the highest release rate. Similar pattern was reported in literature testing skin permeation from microemulsion.30,31Simultaneous delivery of finasteride with silodosin did not result in significant change in the transdermal flux of finasteride compared to its delivery alone in case of saturated aqueous suspension. Conversely, simultaneous delivery from microemulsions reduced the transdermal flux of finasteride compared to its delivery alone from the corresponding microemulsion system (Table 2 and Fig. 7b). This effect is unexpected and may be due to possible effect on the physical properties of the formulation with subsequent reduction in thermodynamic activity30,31. To verify this the solubility of finasteride in the tested microemulsion formulation both in absence and presence of silodosin (1% w/w) was determined. In absence of silodosin, the solubility of finasteride was 8.82, 22.17 and 40.65 mg/g for cosurfactant free microemulsion, propylene glycol containing microemulsion and ethanol containing microemulsion, respectively. In presence of silodosin, the solubility of finasteride was increased to reach 14.14, 23.39 and 52.07 mg/g for the same formulations, respectively. The increase in solubility confirms our supposition of reduced thermodynamic activity with subsequent decrease in transdermal flux of finasteride after simultaneous delivery with silodosin.Regarding the skin permeation of silodosin, the simple saturated aqueous solution of silodosin showed transdermal flux of 1.2 µg cm-2 h-1. Entrapment of silodosin in the different microemulsion systems was associated with significant elevation in transdermal flux (P < 0.05) compared with the control. The highest transdermal flux of silodosin was recorded for ethanol containing ME followed by PG containing formulation with cosurfactant free system producing the lowest enhancement (Table 3 and Fig. 8). Again, these results confirm the efficacy of microemulsion in transdermal delivery with inclusion of cosurfactant being beneficial. Noteworthy, the tested microemulsions contained fixed concentration (1% w/w) which is subsaturated and still showing significant increase in transdermal flux compared with fully saturated aqueous solution. This reflects potential benefits of microemulsion irrespective to the physicochemical properties of the drug. Microemulsions enhanced transdermal delivery of a range of drugs with varying partition coefficient to include very lipophilic, amphiphilic and even hydrophilic drugs27,29,31,54,55.Fig. 8Skin permeation profiles of silodosin alone (a) or after mixing with finasteride (b) in the form of simple aqueous suspension and different menthol-based microemulsion formulations. Formulation details are in Table 1.Full size imageAs for finasteride, silodosin microemulsions retained its superiority compared with saturated aqueous solution after simultaneous delivery but underwent reduction in transdermal flux from microemulsion after simultaneous delivery compared with its delivery alone. This finding can be explained based on the concept of reduced thermodynamic activity as reported above with finasteride.Explaining the transdermal flux results of finasteride in the light of the corresponding release rates, the data indicated comparable release from different microemulsion formulations, but transdermal flux depended on the formulation. Based on the flux TW-Ethanol ME was the best followed by TW-PG ME then TW ME with the control being inferior. This highlights a lack of dependence of finasteride transdermal permeation from microemulsion on its release. The same supposition is supported by the values of release rate which was larger than the transdermal flux in all cases. Similar pattern was noticed for lipophilic drug29. For the more hydrophilic silodosin, the transdermal flux values were even more than the release rate. This suggests that silodosin transdermal permeation did not involve diffusion of the free drug after release only, but other possibilities may take place. This possibility depends on the ability of the nanosized droplet with its minute surface tension to fill the surface microstructure of the skin. This provides intimate contact between skin and formulations with subsequent direct transdermal delivery from microemulsion to skin. This mechanism was previously postulated by other researchers27. Several other mechanisms were supposed for enhancing transdermal delivery from microemulsion. Modulation of stratum corneum integrity by microemulsion ingredients is considered as potential mechanism and can be applied here due to the reported enhancing effect of menthol25,56. Another alternative gets the benefit of entrance of microemulsion ingredients into the skin increasing drug partitioning into skin. Additionally, in situ phase transition due to evaporation or absorption of some microemulsion ingredients can hasten the rate of drug input into and via skin27,30. Overall, the research introduced a formulation which can be developed and applied in the form of liquid crystals which undergo phase transition to microemulsion at skin temperature maintaining the ability of enhanced transdermal delivery.ConclusionMenthol/Tween/water system undergoes thermoresponsive liquid crystal to microemulsion phase transition. Incorporation of ethanol or propylene glycol in this system abolishes the liquid crystal and gel phases. Finasteride and silodosin were separately and simultaneously incorporated in these microemulsion. Menthol -based microemulsions enhanced the transdermal delivery of each drug separately compared with the corresponding saturated aqueous control. Simultaneous loading of both drugs into microemulsions reduced the thermodynamic activity, but their transdermal flux remained significantly higher than the saturated aqueous solution. The enhanced transdermal delivery was achieved from 1% w/w even after challenging with saturated aqueous solution. The study introduces phase transition systems for hastened transdermal delivery of finasteride and silodosin.
Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
ReferencesPupe, C. G. et al. Development of a doxazosin and finasteride transdermal system for combination therapy of benign prostatic hyperplasia. J. Pharm. Sci. 102, 4057–4064. https://doi.org/10.1002/jps.23715 (2013).Article
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Download referencesAuthor informationAuthors and AffiliationsDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, EgyptHadir F. Marei, Mona F. Arafa & Gamal M. El MaghrabyDepartment of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi ArabiaMona F. ArafaDepartment of Pharmaceutics, Faculty of Pharmacy, Alsalam University, Tanta, EgyptGamal M. El MaghrabyAuthorsHadir F. MareiView author publicationsYou can also search for this author in
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PubMed Google ScholarContributionsHadir F. Marei: Investigation, Data curation, Visualization and writing original draft. Mona F. Arafa: Methodology, Data Curation, Visualization, Writing, Reviewing and Editing. Gamal M. El Maghraby: Conceptualization, Methodology, Visualization, Supervision, Writing, Reviewing and Editing.Corresponding authorCorrespondence to
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KeywordsFinasterideSilodosinThermoresponsiveMicroemulsionTransdermal flux