EFFECT OF TRANS – ESTERIFICATION OF OIL ON NANOEMULSION GEL FOR TOPICAL DRUG DELIVERY

EFFECT OF TRANS - ESTERIFICATION OF OIL ON NANOEMULSION GEL FOR TOPICAL DRUG DELIVERY

Ashwini Anand Chikte, Milind Janrao Umekar, Minal N. Borkhade and Neha Sureshrao Raut^*

Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar, College of Pharmacy, Kamptee, Nagpur - 441002, Maharashtra, India.

ABSTRACT: The research investigated the modification of nano-emulsion by using transesterfied soyabean oil, to enhanced solubility and diffusion of voriconazole. Ternary phase diagrams of soyabean oil, acid / base esters of soyabean oil, Tween 80: PEG 400 (S/CoS) and water were developed. Ester value of soyabean oil increased from 214.04 to 261.5mg KOH/1g for acid ester and 293.58mg KOH/1g for base ester confirmed transesterification. The modified nanoemulsion batches E₄, E₅, E_A4, E_A5, E_B2 and E_B3 showed thermodynamic stability. Nanoemulsion of Soyabean oil (E₃ and E₄), acid ester (E_A4 and E_A5)_, and base ester (E_B2 and E_B3) were selected for in-vitro drug diffusion studies. The globule size of batch E₄, E_A4 and E_B2 nanoemulsion was found to be 185.6, 162.8 and 115.4 nm, respectively. Zeta potential of batch E₄, E_A4, and E_B2 was observed -35, -27 and -9mV respectively. The in vitro release release profiles from the E₄, E_A4 and E_B2 batches of nanoemulsion gel were fitted into Peppas kinetic model. Moreover, ‘n’ value of batch E₄, E_A4, and E_B2 was 0.8844, 0.8284, 0.8475 non-fickian diffusion. The soyabean oil and soyabean acid ester oil nanoemulsion found to be stable and a promising vehicle to enhance the permeation of voriconazole for topical delivery.

Voriconazole, Transesterification, Bioavailability, Globule size, Homogenization, Zeta potential, Nanoemulsion

INTRODUCTION: Nanoemulsion is a thermo-dynamically stable isotropically clear dispersion of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules. In addition to the surfactant the Co-surfactant / Co-solvent is used with the oil and water phase. The dispersed phase typically comprises small particles or droplets, with a size range of 5-200 nm, and has very low oil / water interfacial tension ^{1, 2}.

Unlike coarse emulsions micronized with external energy, nanoemulsion is based on low interfacial tension which is achieved by adding a co-surfactant, which leads to spontaneous formation of a thermodynamically stable nanoemulsion ^{3, 4}.

The nanosized droplets leading to increase in interfacial surface area associated with nanoemulsion would affect the transport properties of the drug ⁵. Nanoemulsions have a larger capacity for micellar solubilisation compared to simple solutions, give advantages in thermodynamic stability to unstable dispersions as it can be produced with less energy input, and have a greater shelf life a low viscosity, high kinetic stability against creaming or sedimentation, and large interfacial area make nanoemulsions of increasing use in different applications ⁶.

Nanoemulsions have been increasingly developed for use as drug-delivery systems for parenteral, oral, ocular, and topical administration ^{7, 8}. Specifically, in topical delivery, nanoemulsions offer several significant advantages including no skin irritation, powerful permeation ability, and high drug-loading capacity ^{9, 10}. Nanoemulsion-based cosmeceuticals have improved efficacy; whereby, the active ingredient will have better skin penetration and a higher rate in successful drug delivery to the target site due to its small particle size. Besides, the long-term colloidal stability of nanoemulsions can be achieved through high potential due to the increase of the repulsive force between droplets. Nanoemulsion is a non-equilibrium colloidal system where oil phase is dispersed as fine droplets, usually with particle size from 20–200 nm, throughout the aqueous phase stabilized by surfactants. Nanoemulsions can be prepared by high-energy emulsification or by low-energy emulsification methods. However, nanoemulsions are thermodynamically unstable colloidal systems that are highly dependent on their physicochemical properties, usually based on the preparation method ^{11, 12}.

Voriconazole is a triazole antifungal agent indicated for use in the treatment of fungal infections including invasive aspergillosis, esophageal candidiasis, and serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani. Voriconazole is lipophilic in nature and exhibit poor solubility, diffusion and bioavailability, which limits delivery of voriconazole via topical drug delivery system. Nanoemulsion based topical drug delivery is one of the effective approach to increase solubility, dissolution, improving diffusion, permeability, drug loading and bioavailability. Hence, to formulate nanoemulsion based gel of voriconazole. Beside this, to enhance the solubility and diffusion the oil phase of nanoemulsion modified by transesterification ¹³.

A large amount of active principle can be incorporated in the formulation due to high solubilizing capacity that might increase thermodynamic activity towards the skin ^{14, 15}. The nanosized droplets provide superior adherence to skin and have large surface area thereby providing high concentration gradient and improved active constituent permeation ¹⁶. The low viscosity of nanoemulsion restrains its clinical application due to inconvenient use, and therefore hydrogel thickened nanoemulsion systems were formulated with good stability, powerful permeation ability, and suitable viscosity for the topical delivery which provided longer contact with skin. Nanoemulsions could increase the topical delivery of voriconazol times compare with the control ¹⁷.

MATERIAL AND METHOD: Voriconazole was received as a gift sample from the Glenmark Pharmaceuticals Ltd.(goa M.S., India), Peanut oil (Gemini groundnut oil), Soyabean oil (Fortune Soyabean oil), Coconut oil (Fortune Soyabean oil), Sunflower oil (Parachute Pvt. Ltd) and Potassium hydroxide, Dichloromethane, Sodium Lauryl Sulphate, Potassium Chloride obtained from Fisher Scientific India Pvt. Ltd. Also Tween-80 and Hydrochloric acid from Merck Specialities Pvt. Ltd, Mumbai. Carbon tetrachloride, Methanol, Carbopol 934P purchased from Loba chemie Pvt. Ltd. All other chemicals and solvents were of reagent grade and were used without purification.

Preparation of Transesterified Oil Phase:

Reflux Condensation: Transesterification of oil done by different methods-

• By Using Base Catalyst: Heat 100ml of oil at 120 °C for 20 min, Add 40ml of methanolic NaOH (1.25g) and reflux condensate for 2 hr. By using acid catalyst - Heat 100ml of oil at 120 °C for 20 min, Add 40ml of methanolic H₂SO₄ (0.5ml) and reflux condensate for 2 hr.
• Phase Separation: The product obtained from above methods transferred into separating funnel and allowed to stand for 1 hr. After 1 hr, Fatty acid ester layer separated from Glycerol. Then the supernatant layer of fatty acid ester used for further process.
• Neutralization: The separated fatty acid ester layer obtained from base catalyst process neutralized by using 0.5% citric acid and from acid catalyst process neutralized by using 0.5% KOH.
• Washing: Ester layer may contain traces of NaOH, methanol, glycerol; to remove this residue the fatty acid ester layer treated with water at 50 °C - 60 °C for 4-5 times.
• Heating: After completion of washing process ester may contain same traces of water therefore in order to remove water residues ester was heated at 120 °C ^{18 - 20}.

Construction of Ternary Phase Diagram: Based on the solubility studies and the ternary phase diagram studies, series of nanoemulsion drug delivery systems (E₁, E₂, E₃, E₄ and E₅) for Soyabean oil and (E_A1, E_A2, E_A3, E_A4, EA₅) for Soyabean oil acid ester and (EB₁, EB₂, EB₃, EB₄, EB₅) for Soyabean oil base ester, consisting of Voriconazole, were prepared. A series of nano-emulsion formulations were prepared using Tween 80 and PEG 400 as the S/CoS combination and Soyabean oil, Soyabean oil Acid ester, Soyabean oil Base ester used as the oil phase ⁴.

Preparation of Oil in Water (O/W) Nanoemulsion: The water phase with or without an additional emulsifier and co-solvent was also heated. Then the components of oil phase and aqueous phase added at a slow rate with gradual stirring and vortex mixing at 40 °C on a magnetic stirrer. Further homogenization carried out to obtain the needed small droplet size range of the emulsion. Finally ultra sonicator used to achieve the desired range of dispersed globules ^{21, 22}.

Evaluation of Nanoemulsion:

Thermodynamic Stability Studies (Freeze-Thawing Cycle): The formulations were subjected to 3-4 freeze-thaw cycles, which included freezing at 4 °C for 24 hours followed by thawing at 40 °C for 24 hours. Centrifugation was performed at 3000 rpm for 5 minutes. The formulations were then observed for phase separation ³.

Dispersibility Test: The efficiency of nano-emulsion was assessed by using a standard USP XXII dissolution apparatus type II. 1.0ml of each formulation was added to 900ml of water at 37 ± 0.5 °C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vitro performance of the formulations was visually assessed using the grading system ²³.

Percent Transmittance Study: The samples prepared for nanoemulsion were subjected to % transmittance analysis using double beam UV-Visible spectrophotometer at wavelength of 255nm ²⁴

%Transmittance = 1×100 / Antilog {A}

Where, {A} =Absorbance at 300nm.

In vitro Drug Diffusion Studies: Each 1ml of the formulations were placed on france diffusion cell by placing dialyzing membrane 110 having width 32.34mm and diameter 21.5mm on it in 7.4 pH  buffer as dialyzing medium. 1ml of aliquote was taken after each 1 hr interval for 12 hrs and volume was make up upto 10ml and then it was analyzed spectrophotometrically at 255nm ²⁵.

Partical Size and Zeta Potential Determination: The droplet surface charge (zeta potential) was determined by photon correlation spectroscopy (PCS) using a Zetasizer (1000 HS, Malvern Instruments). The formulation (0.1ml) was dispersed in 50ml of water in a volumetric flask, mixed thoroughly with vigorous shaking and light scattering was monitored at 25 °C at 90 ° angle. Zeta potential values were determined from the electrophoretic mobility of the oil droplets via in-built software. The measurements were carried out on diluted emulsion formulations. 1:250 dilutions were made of formulation for the determination of zeta potential with the help of photon correlation spectroscopy ^{26, 27}.

Stability Studies: The stability study of selected formulation was done at 40 °C with 75% RH room temperature and in freezing temperature. The test parameters such as integrity, phase separation and drug precipitation were determined for 4 week. The data were subjected to calculate the stability of nanoemulsion ²⁸.

Formulation of Nanoemulsion Based Gel:  From the evaluation of nanoemulsion, E₄ (Smix: oil, 6:4) formulas of oil, E_A4 (Smix: oil, 6:4) acid ester, E_B2 (Smix: oil, 4:6). Base ester selected for formulation in gel. For preparation of nanoemulsion based gel, 3gm of carbopol 934 added in 87ml of water, stirred till homogenous mixture was formed, kept it aside for overnight. Then 13ml of nanoemulsion was added drop by drop up to 100ml. The pH values were subsequently regulated to 6-9. Then other ingredient like PEG-400 added to obtain a homogeneous dispersion of gel ²⁹.

Evaluation of Nanoemulsion Based Topical Gel:

Physical Appearance: The prepared nanoemulsion gel was inspected visually and using clarity tester for their color, homogeneity and consistency.

Viscosity and pH Determination: The viscosity of all prepared nanoemulsion gel was measured by model (DV-E) Brookfield viscometer using spindle no. 63. The pH of nanoemulsion based topical gel was determined at room temperature using digital pH meter, model NIG-333. pH meter was calibrated using 9.2 and 4.0 pH buffer solutions ³⁰.

Spreadability: An excess of gels (about 2g) sandwiched between two glass plates having fixed the dimensions. A 300g weight was placed on the top of two plates for five minutes to expel air and to provide a uniform film of the gel between the plates. Excess of the gel was scrapped off from the edges. The top plate was then removed and the time (in sec) required by the top plate to separate out from above plate should be noted. A shorter the time interval indicates better spreadability ³¹.

Drug Content Detrmination: Gel formulations (100mg) was dissolved in methanol and filtered and the volume was made to 100ml with methanol. The resultant solution was suitably diluted with methanol and absorbance was measured at 255 nm using Shimadzu - 1700 UV Visible spectro-photometer. Drug content was determined from calibration curve for Voriconazole ³².

In vitro Drug Release: About 1-2gm of each batch of prepared gel were placed on dialyzing membrane containing diffusion cell, phosphate buffer 7.4 in its receptor compartment, 1ml of phosphate buffer was taken after 1 hr interval up to 12 hr. Mention steady state condition in diffusion cell by placing 1ml of fresh phosphate buffer after removal of 1ml of sample from receptor compartment ³³.

RESULT AND DISCUSSION:

Preformulation Studies:

Identification Test for Voriconazole:

Melting Point: The melting point of the Voriconazole was found to be 129 °C, which also complies with melting point reported in United state Pharmacopoeia 2011.

Infrared Absorption Spectrophotometry: All the prominent and primary peaks were observed in FTIR spectrum of Voriconazole Fig. 1.

TABLE 1: FTIR PEAKS OF VORICONAZOLE AND PHYSICAL MIXTURE OF VORICONAZOLE WITH CARBOPOL

FIG. 1: OVERLAIN OF FTIR SPECTRUM OF VORICONAZOLE AND VORICONAZOLE + CARBOPOL

As shown in Table 1 the FTIR spectra of Voriconazole, and its combination with Carbopol, Show prominent characteristic peak. Therefore an FTIR spectrum of physical mixture of voriconazole with carbopol exhibited all functional group of voriconazole suggested compatibility of voriconazole with carbopol 93P Table 1.

UV Spectrophotometric Analysis: The λ_max of Voriconazole was found to be at 255 nm ³⁴, which also complies with the specification of United state Pharmacopoeia 2011.

Plot of Calibration Curve: UV spectroscopy can be utilized for qualitative and quantitative analysis of compounds. The Beer’s curves of Voriconazole were prepared in Methanol and 7.4 pH buffer and the calibration curves as shown in Fig. 2.

A                                                                                     

B

FIG. 2: CALIBRATION CURVES OF VORICONAZOLE IN (A) METHANOL (B) 7.4 pH BUFFER

Coefficient of regression (R²) value of Voriconazole in Methanol and 7.4 pH buffer were 0.999 and 0.999 respectively which are very near to the unity. So, it showed that a good linear relationship between these two variables.

Excipients Evaluation: All the excipients i.e., lipids (Peanut oil, Coconut oil, Sunflower oil, Soyabean oil), were evaluated by studying the parameters such as acid value, saponification value, ester value, iodine value and peroxide value, as given in Table 2.

As shown in Table 2, acid value, saponification value, iodine value, peroxide value and ester value of oils was in the range of given standards. From the data obtained by characterization of lipid/oil, soyabean oil acid and base ester show higher ester value than other oil and their esters.

TABLE 2: EVALUATION OF OILS / LIPIDS PHASE USED IN VARIOUS LIPIDS, SURFACTANTS AND CO SOLVENT

Solubility Determination: The solubility of Voriconazole was found to be more in soyabean oil (102.5mg/ml). The solubility of voriconazole was observed increases in esters of soyabean oil (105.5 and 111.3mg/ml), suggests that ester of oil act as a super solvent for highly voriconazole ³⁵.

Pseudo Ternary Phase Diagram: The data obtained from evaluation and solubility study of sunflower, soyabean, coconut, peanut oil and its esters, substantiate proper trans-esterification and improved solubility of voriconazole in soyabean oil and its esters ^{4, 36}.

From prepared Smix ratio, all type I (where surfactant concentration constant) and 2:1, 3:1 ratio of type II (where co-surfactant concentration constant) was shown phase separation after addition of water beside this Smix also immiscible with oil. Therefore, 4:1, 5:1 and 6:1 Smix ratio of type II which showed stable phase continued for further studies. Pseudoternary phase diagrams were plotted according to different batches of Soyabean oil and its acid as well as base ester. The dots shown in figures indicate the nanoemulsion region.

As shown in Fig. 3 the maximum emulsification region was obtained in Smix (4:1) with Soyabean oil, Smix (5:1) with acid ester and Smix (4:1) with Soyabean oil base ester concentration in respectively ³⁷.

Smix (4:1) + Soyabean oil                 

Smix (5:1) + Soyabean oil                    

Smix (6:1) + Soyabean oil

Smix (4:1)+Soyabean oil acid ester   

Smix (5:1)+Soyabean oil acid ester   

Smix (6:1)+Soyabean oil acid ester          

Smix (4:1)+Soyabean oil base ester   

Smix (5:1)+Soyabean oil base ester  

Smix (6:1)+Soyabean oil base ester

FIG. 3: PSEUDO TERNARY PHASE DIAGRAM OF RATIO (A) Smix (4:1) (B) Smix (5:1) (C) Smix (6:1) OF SOYABEAN OIL, SOYABEAN OF ACID ESTER AND SOYABEAN OIL BASE ESTER

Drug Loading in Nanoemulsion: Smix (4:1) with Soyabean oil, Smix (5:1) with Soyabean oil acid ester, Smix (6:1) with Soyabean oil base ester were selected for voriconazole loading in formulation. From the observation of solubility studies of Voriconazole in mixture of components of nanoemulsion it was revealed that solubility of Voriconazole increases with increasing in surfactant concentration. The maximum solubility of Voriconazole in Soyabean oil and its acid as well as base ester was found to be 121.3; 115.2 and 120.9 mg/ml respectively.

Characterization of Nanoemulsion:

Thermodynamic Stability Studies (Freeze-Thawing Cycle): The results obtained from thermodynamic stability studies, indicated that the formulations E₄, E₅, E_A4, E_A5, E_B2, E_B3, and E_B5 of Nanoemulsion of Soyabean oil and its acid and base ester were found to be stable. This attributes that all the components of the system observed compatible with each other and form a single homogeneous phase ³.

Dispersibility Test: The dispersibility of formulation increases with decreasing the proportion of oils with simultaneously increasing the ratio of S/CoS results in reduction of interfacial tension between oil globules and aqueous phase. The formulation E-4, E-5, E_A4, E_A3, E_A5, E_B2 and E_B3 has good dispersibility ²¹.

Percent Transmittance Study: The transparency indicates the good dispersibility of very finely or smaller globules of lipids in water. The results of percent transmitancy order was found to be 79.77, 49.47, 44.12, 42.66, 41.97 i.e. E-2>E-1>E-5>E-4>E-3 for Soyabean oil formulations and 77.37, 76.73, 69.73, 51.33, 43.12 i.e. E_A3>E_A1 >E_A5,> E_A4>E_A2 for soyabean oil acid ester formulations 55.83, 52.71, 50.30, 47.93, 42.86 i.e. E_B1.>E_B3> E_B4,>E_B5>E_B2. E2 formulation of Soyabean oil nanoemulsion, E_A3 formulation of acid ester nanoemulsion, E_B1 formulation of base ester nanoemulsion was found to be more transparent than other formulation.

Conductance Measurement: Condutance measurement of prepaired formulation indicated that there is no significant change in conductivities with oils proportion as well as surfactant / co-solvent proportions. Hence, the formulation was found to be stable in lipid phase due to the excellent absorptivity of surfactant / co-solvent as film on oil globules containing drug ²³.

Viscosity and pH Determination: The results indicate that increasing shear rate decreases the viscosity of formulation. Therefore, all these formulation represent the pseudoplastic flow (non-Newtonian system) ²¹. A viscosity of acid and base ester of soyabean oil was found to be in the range of viscosity of soyabean oil nanoemulsion. The pH of the all formulation was found to be in the range of 6-8, suggested applicable for topical application of skin.

Drug Content Analysis: The drug content analysis indicates that the quantity of drug of each formulation was observed more than 93.8% than the amount of drug loading. The percent drug content of Soyabean oil (E₄), acid ester (E_A4) and base ester (E_B2) was more i.e. 98.6 ± 0.054, 98.6 ± 0.042 and 98.2 ± 071 respectively. Therefore, it can be might be told that the entire drug is well uniformly distributed and there is no precipitation in the each. The percentage relative standard deviation (% RSD) is less than 2% indicates the reproducibility of process used for the formulation of nanoemulsion ²¹.

In vitro Drug Release Studies: In vitro drug release studies were performed to study the release behavior of formulation from lipid phase around the droplet. Fig. 4 indicates % drug release from Nanoemulsion through dialysis membrane. On the basis of Thermodynamic stability studies; Soyabean oil Nanoemulsion E-₃, E-₄, Soyabean oil acid ester Nanoemulsion batch E_A4, E_A5, Soyabean oil base ester Nanoemulsion batch E_B2E_B3 were selected for  in vitro drug diffusion studies ²³.

FIG. 4: % VORICONAZOLE RELEASE FROM SOYABEAN OIL NANOEMULSION, SOYABEAN OIL ACID ESTER  NANOEMULSION AND SOYABEAN OIL BASE ESTER NANOEMULSION

The % drug release of voriconazole from Soyabean oil-Nanoemulsion (E₃) (E-₄), Soyabean oil acid ester Nanoemulsion (E_A4) (E_A5) and Soyabean oil base ester Nanoemulsion (E_B2) (E_B3) at different sampling interval. In case of Soyabean oil acid and base ester nanoemulsion, E_B2 E_B3 of Soyabean oil base ester Nanoemulsion Show more drug release than E_A4, E_A5. From the above results it indicates that, as the concentration of oil increases and surfactant concentration decreases drug release decreases.

Release Kinetic: From the kinetic studies it was found that all the batches E₄, E₅, E_A4, E_A5, E_B2 and E_B3 shows the correlation coefficient value (r²) 0.9944, 0.9939, 0.9933, 0.9925, 0.9954 and 0.9911 by korsmeyer-peppas kinetics. The correlation coefficient obtained by korsmeyer-peppas kinetics more near to 1 as compared to other kinetics suggested prepared formulation exhibit korsmeyer-peppas kinetics release.

The ‘n’ value for batches E₄, E₅, E_A4, E_A5, E_B2 and E_B3 was found to be 0.8447, 0.7996, 0.8055, 0.7971, 0.8110, and 0.8088 respectively. The ‘n’ value for all batches are in the range of 0.5 – 1, hence it shows non Fickian diffusion which state that drug is release from nanoemulsion gel by diffusion manner.

Particle Size Analysis: It has been reported that the smaller particle size of the emulsion droplets may lead to more rapid absorption and improve the bioavailability particle size analysis was carried out for batch E₄, E_A4 and E_B2 was found to be 185.6, 162.8 and 115.4 respectively. Particle size of nanoemulsion of soyabean oil and its acid and base ester was found to be in the range of nanoemulsion. Soyabean oil acid and base ester nanoemulsion showed Particle globule size and proper distribution of particles which might be reduces particle size in formulation

Zeta Potential Determination: Particles with zeta potentials more negative than -45 mV are normally considered stable. (Ali et al., 2012). The zeta potential of the Soyabean oil (E₄), Soyabean oil acid (E_A4) Soyabean oil base (E_B2) nanoemulsion was found to be -35.5, -27.7and -9.15 respectively. These results indicated decrease in droplet size in trans-esterified oil containing nanoemulsion, shifted zeta potential from -35 mV to -27 mV and -9mV. The negative zeta potential of nanoemulsion suggested stability.

Stability Study: An accelerated storage testing was carried out to predict the long-term physical stability. No phase sepration occurred in Soyabean oil Nanoemulsion gel (E₄), Soyabean oil acid ester nanoemulsion gel (E_A4) as well as Soyabean oil base ester nanoemulsion gel (E_B2). Hence these nanoemulsion were physically stable ³⁸.

Characterization of Nanoemulsion Based Gel:

Homogeneicity, Appearance and Consistency: The prepared soyabaen oil based nanoemulsion and its acid base ester nanoemulsion gel (E₄, E_A4, E_B2) formulations were white, viscous, creamy preparations with a smooth and homogeneous appearance. They were easily spreadable with acceptable bioadhesion and fair mechanical properties.

pH and Viscosity Determination: The pH values of all developed formulae was in range 6-8 which is considered acceptable to avoid the risk of irritation upon application to the skin ²⁵. The prepared Soyabean oil, Soyabean oil acid ester, Soyabean oil-base ester nanoemulsion gel showed viscosity on 30 rpm 78.12, 72.83 and 78.58, on 50 rpm 63.45, 57.2 and 62.48, on 60 rpm 54.66, 49.2 and 49.5 respectively.

Viscosity results indicate that at Basic pH 7.4 phosphate buffer (equivalent to pH of skin) it changes into a highly viscous preparation. The viscosity value in the range of 50 cps to 100 cps significantly improves the contact time of the formulation on the skin surface and lower viscosity values offers no significant advantage. The viscosity study also show that the selected composition suitable for the use.

Spreadability: Spredability of developed oil nanoemulsion gel and acid base nanoemulsion gel were found to be 37.2, 36.6 and 34.71 respectively which indicate that all the polymers used gave gels spread by small amount of shear, revealed that increasing the concentration of any of the gelling agents was always associated with a decrease in the spreadability ²⁸.

Drug Contents Analysis: The drug content of the formulated gel was estimated and the results were in the official limits with range of 80 % to 99 %. The drug content determination also showed that the drug was uniformly distributed throughout the gel ²⁸. From the Fig. 5 showed % drug release of voriconazole at different sampling interval. An increased drug release rate was achieved in soyabean oil acid and base ester nanoemulsion gel as compared to soyabean oil gel. Voriconazole was released in a controlled manner from (E-₄), (E_A4), (E_B2) gel and 65.12%, 72.58%, 75.84% of voriconazole was released within 7 h.

In case of Soyabean oil acid and base ester nanoemulsion, E_B2 show faster drug release than E_A4. On basis of above graph it also concluded that ester nanoemulsion of soyabean oil has higher rate of release than soyabean oil nanoemulsion this is due to ester form of oil phase ^{16, 17}.

FIG. 5: % VORICONAZOLE RELEASE FROM SOYABEAN OIL NANOEMULSION BASED GEL AND SOYABEAN OIL ACID AND BASE ESTER NANOEMULSION BASED GEL

Release Kinetic: From the above kinetic studies it was found that all the batches E₄, E_A4, and E_B2 shows the correlation coefficient value (r²) (0.9974, 0.9955, 0.9964) more near to 1 as compared to other kinetics suggested prepared formulation exhibit korsmeyer-peppas kinetics release. The ‘n’ value for batches E₄, E_A4 and E_B2 was found to be 0.8844, 0.8284, 0.8475 respectively. The ‘n’ value for all batches are in the range of 0.5 – 1, hence it shows non Fickian diffusion which state that drug is release from nanoemulsion gel by diffusion manner.

CONCLUSION: Voriconazole nanoemulsion was prepared using spontaneous nanoemulsification method for improving its solubility and dissolution. Drug-excipient chemical compatibility facilitated to anticipate the potential degradation of vorinazole in various excipients and was helpful to design a suitable strategy for its stabilization in proposed formulation. Screening of surfactants and cosurfactants studies helped to identify the most suitable excipients, whereas the phase diagrams gave a good idea about the concentrations of the nanoemulsion components that should be employed to achieve self-nanoemulsifying formulations.

The Thermodynamic stability studies could differentiate the stability of different compositions and facilitated the selection of most stable formulation. The optimized voriconazole nano-emulsion could withstand the extensive dilution and exhibited 75% drug release in 10 hours irrespective of pH of medium. The results obtained in the present work also show that Nanoemulsion gel containing acid and base ester oil as oil phase is a suitable carrier system for the incorporation of voriconazole, and satisfies the best attributes for transdermal application i.e. Non-newtonian flow, good spreadability, and suitable release profile.

This debut study suggests that acid and base ester oil phase containing nanoemulsion gel could reduce the stratum corneum barrier effects and could enhance the transdermal permeation and penetration of voriconazole. The prepared nanoemulsion based gel of voriconazole exhibited stable formulation, whereas nanoemulsion with transesterified oil phase containing nanoemulsion based gel showed greater drug diffusion as compared with simple oil containing nanoemulsion based gel. The increase in voriconazole release from transesterified oil containing nanoeulsion gel suggested improved solubility of voriconazole in acid and base ester of soyabean oil. It is considered to be stable topical formulation of voriconazole.

ACKNOWLEDGEMENT: The authors are thankful to the research and development lab; analytical lab, Department of Pharmaceutical Chemistry at the Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India.

CONFLICT OF INTEREST: The authors declare no conflict of interest.

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    How to cite this article:

    Chikte AA, Umekar MJ, Borkhade MN and Raut NS: Effect of trans - esterification of oil on nanoemulsion gel for topical drug delivery. Int J Pharm Sci Res 2018; 9(2): 589-98.doi: 10.13040/IJPSR.0975-8232.9(2).589-98.

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