Essay: Drug administration

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The administration of active pharmaceutical ingredient via oral route is the most convenient and acceptable route of drug administration (Christiansen et al., 2014). However, the bioavailability of drugs via this route is the major issue for a formulator. In addition, the 40% of new APIs that reaches to a formulator are with poor water solubility, drug precipitation in the upper intestine, intestinal p-glycoprotein drug efflux and food effect (Miller and Dahan, 2012). Efavirenz is amongst those APIs, approved for HIV infection. Efavirenz (EFV) is chemically (S)-6-chloro-4(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. It is a non-nucleoside reverse transcriptase inhibitor approved by USFDA for the treatment of HIV type 1 (Young et al., 1995). The root cause of decreased oral bioavailability of Efavirenz (EFV) is its lower intrinsic dissolution rate (i.e. 0.037 mg/cm2/min) and poor aqueous solubility (3-9 µg/mL) inspite of its high lipophilicity (Log P = 5.4) and high permeability (BCS Class II drug) (Boffito et al., 2003). This further cause high intra (55-58%) and inter (19-24%) subject variability (Senapati et al., 2016) that may additionally be associated with food effect. Overall, the very low solubility of EFV affects its administration, absorption, bio-distribution and bioavailability to large extent. The solubility of EFV was largely influenced by its solubility in gastro-intestinal fluids and permeability across intestinal wall. Custodio et al., (2008) reported that the solubility of API is changed with the environment of intestinal fluids eg: level of surfactant, volume, pH and lipophilicity, whereas, the permeability of API is influenced with its lipophilicity, molecular size of API, efflux transporter protein or affinity to influx. Further, the absence or presence of food materials can change the gastrointestinal environment (such as pH, gastric enzymes, gastric emptying time, and increase in volume of upper intestine and enhanced bile secretions) that leads to affect the solubility of poorly water soluble drugs. Hence, the solubility characteristics of poorly water soluble drugs are mostly affected that in turn influence permeability characteristics (Christiansen et al., 2014; Custodio et al., 2008; Kostewicz et al., 2002; Fleisher et al., 1999). Thus, a strategy should be based on enhancement in the solubility of EFV employing a method that not only resolves the issue of oral bioavailability but also reduces food associated variability.

Few attempts have been made to tackle the “solubility related low bioavailability issue and food effect” issue of EFV. This includes formulation and development of EFV loaded bi-continuous nano-structured lipid crystalline particles (Avachat and Parpani, 2015), micronization via spray drying (Tshweu et al., 2014), solubility enhancement using hot melt extrusion, solid dispersion, co-micronization (Koh et al., 2013; Sathigari et al., 2012), self microemulsifying drug delivery system (Reddy et al., 2014; Deshmukh and Kulakrni, 2012) and self nanoemulsifying drug delivery system (Kamble et al., 2015). These techniques have been reported to improve solubility, bioavailability, dissolution profile and physical stability. However, satisfactory and complete solution to the problem of EFV “solubility related low oral bioavailability issue and food effect” is still missing in the literature. Further, lymphatic route provides the successful delivery of therapeutic molecules for the treatment of cancer and immunodeficiency virus that made their place in the lymphatic system (Alex et al., 2011; Xie et al., 2009). The intestinal lymphatic system is a pathway made for food-derived lipids, water-insoluble peptide and fat soluble vitamin (Yáñez et al., 2011). The added advantage of drug transported through lymphatic system is that they can bypass the liver and thus neglect hepatic first pass metabolism (Pokharkar et al., 2017; Trevaskis et al., 2009; Trevaskis et al., 2008). The drug molecules administered by oral route has to cross enterocytes barrier and entered the portal circulation that deliver drugs to liver via portal vein, this causes first pass effect. However, for drugs having log P>5, entered into lymphatic system in solubilized lipid formulation and reduces movement into portal circulation (Porter et al., 2008; Jannin et al., 2008).

The aim of present investigation was to load EFV in an isotropic mixture (IM) that have a capability to deliver EFV in lymphatic circulation that could possibly enhances bioavailability and neglect food effect along with its associated variabilities. The isotropic mixture (IM) consisted of Maisine 35-1 (long chain triglyceride), Cremphor RH40: Labrasol (surfactants) and Transcutol-HP (co-surfactant) was optimized employing QbD approach. Further, the developed isotropic mixture was evaluated for its in-vitro, in-vivo pharmacokinetic and tissue distribution studies.

2. Materials and methods

2.1 Materials

EFV was provided ex-gratia by Hetero healthcare Pvt. Ltd., Baddi, H.P. Transcutol HP (Diethylene glycol monoethyl ether), Plurol oleique (Polyglyceryl-3 dioleate), Labrafil M2125CS (Linoleoyl macrogol glycerides) and Labrafil M1944CS (Oleoyl macrogol-6 glycerides) were received as the kind gift samples from M/s Gattefosse, Saint-Priest, France. Captex 355 (Caprylic/Capric triglyceride) and Captex 200P (Propylene glycol dicaprylate/dicaprate) were received as the gift samples from M/s Abitec Corp., Wisconsin, USA. The solvents like methanol, acetonitrile etc. employed for liquid chromatographic studies were procured from Merck Life Sciences, Pvt. Ltd., Mumbai.

2.2 Methods

2.2.1 Equilibrium solubility of EFV

The equilibrium solubility of EFV was measured in various natural oils (watermelon seed oil, grape seed oil, almond oil, linseed oil, cotton seed oil and olive oil), synthetic/semi synthetic oils (Maisine 35-1, Labrafac lipophile WL 1349, Captex 200P, Labrafac PG, Captex 355, and Labrafil M2125CS), surfactants (Tween 80, Labrasol, Labrafil M1944CS, Cremophor RH40, Tocopherol acetate, Tween 20 and Span 80) and various co-surfactants (Capryol PGMC, Transcutol HP, Propylene Glycol, PEG 400 and Plurol oleique). For this purpose, an excess amount of EFV was transferred to each capped glass vial previously containing 1 g of oil phase and/or surfactant phase and/or co-surfactant phase and vortexed for 5 min after every 2 h for 24 h. Meanwhile in this duration, these vials were kept at a constant temperature in shaking incubator at 50 rpm and 25± 0.5°C. All the vials were subjected to centrifugation (3000 rpm for 10 min) after keeping them aside for 24h to attain equilibrium. The resultant supernatant was filtered using 0.45 µm membrane filter (Millipore, Darmstadt, Germany) and 0.1 mL of this supernatant was withdrawn, which was further diluted appropriately with mobile phase and was analyzed employing validated HPLC method.

2.2.2 Validation of analytical method

The analytical profile of EFV was validated for its quantification on high-performance liquid chromatography (HPLC) system. The samples obtained from solubility, in vitro dissolution tests, ex vivo permeation and in vivo animal pharmacokinetic study were quantitatively analyzed for EFV concentration using an isocratic HPLC system. The HPLC system comprises of 515 HPLC pump and 2489 UV detector (Waters Ges.m.b.H. Wien/Austria). The chromatograms were estimated with Empower 3 Software (Waters Ges.m.b.H. Wien/Austria). The analytical method was adjusted using ACN: 0.1 N formic acid (60:40 v/v) as mobile phase at 247 nm λmax; 1.0 mL/min flow rate; Spherisorb® 5µm ODS2, 4.6 x 250mm analytical column. Further, this assessment of EFV was validated for linearity (200 ng/mL- 100000 ng/mL), limit of detection (13.62 ng/mL), limit of quantification (45.40 ng/mL), Intra-assay and inter-assay Precision and Accuracy. The linearity equation (y = 72.26x + 3542; R² = 0.999, where ‘‘y’’ is the area un
der curve and ‘‘x’’ is the concentration in ng/mL) was then utilized to obtain unknown EFV concentration in various samples.

2.2.3 Fabrication of EFV loaded isotropic mixture

Ternary phase diagrams

The preliminary studies were conducted by constructing ternary phase diagrams to decide levels for three independent variables of D-optimal mixture design. Based upon the equilibrium solubility studies, Cremophor RH 40 and Labrasol were choosen as surfactant, their combinations were made in different ratio’s i.e. 1:1, 1:2, 1:3, 2:1 and 3:1. Ternary phase diagram of Maisine 35-1, Cremophor RH 40: Labrasol (different ratio) and Transcutol HP were plotted; each of them represents an apex of the triangle. Ternary mixtures by altering compositions of oil, surfactant and co-surfactant were prepared. For any mixture, the sum of oil, surfactant and co-surfactant concentrations was always make upto 100%. To explore the inherent properties of the developed isotropic mixture, droplet size, PDI and a visual experiment to determine the emulsification efficiency was organized (Cui et al., 2009; Kamboj et al., 2015). Aliquot (1 g) of the formulation was poured into 100 mL of purified distilled water at 37°C under a gentle agitation (50 rpm). The systems were determined visually in terms of the tendency to emulsify spontaneously and the final appearance of the microemulsion. The fraction of ingredients that coined to form clear microemulsion with a droplet size not more than 200 nm was considered as “isotropic mixture” region (Dokania and Joshi, 2014; Jain et al., 2014b). All studies were repeated triplicate, with similar observations being made between repeats.

Experimental design

In a classical mixture design where the composition is the factor of interest, the levels cannot be chosen arbitrarily, as all fractions of the components must sum up to unity. In a three-component mixture, all possible combinations may graphically be represented by an equilateral triangle. The range over which the components are varied may be restricted, resulting in a delimited area of interest. Such an area is usually an irregular polyhedron delimited by extreme vertices. The most superior design available in this case is a D-optimal design. On the basis of equilibrium solubility and ternary phase diagram, the selected levels of oil, surfactant mixture and co-surfactant were incorporated into a D-optimal mixture design and different formulations were prepared. D-optimal design is referred to as a computer-aided design, where the determinate information matrix is maximized and the generalized variance is minimized (Yin et al., 2009). The experimental design and statistical analysis were performed using Design Expert software (version 9, Stat-Ease, Inc.). The constrained region gained from the ternary phase diagram was further used to optimize the EFV loaded isotropic mixture composition. In this design critical material factors are proportion of Maisine 35-1 (X1, % w/w), Cremophor RH 40: Labrasol (50:50) (X2, % w/w) and Transcutol HP (X3, % w/w). Mathematical optimization of various critical response variables [droplet size (Y1), self-emulsification time (Y2), viscosity (Y3), %T (Y4) and % drug release in 60 min (Y5)] was conducted by altering the percentage of ternary components in isotropic mixture, which was considered as the critical material factors. Total sixteen formulations were formulated and represented in Table 1. The response surface methodology of three component system was performed with the constraints 0.2≤ (Maisine 35-1) ≤0.5; 0.4≤ (Cremophor RH 40: Labrasol (1:1)) ≤0.7 and 0.1≤ (Transcutol HP) ≤0.3. Design Expert® 9 software was utilized for the optimization study and contours plots of all the five critical response variables (droplet size (Y1), self-emulsification time (Y2), viscosity (Y3), %T (Y4) and % drug release (Y5)) were also constructed. The responses of all the 16 runs were then fitted in the quadratic, special cubic or cubic polynomial model. The polynomial equations were generated for each critical response variable using the Design Expert® 9 software. The appropriate fitting model for each response was selected based on the comparison of various statistical parameters such as r2, lack of fit, partial sum of square and sequential model sum of squares was provided by the analysis of variance (ANOVA) (Table 2). After the fitting of the mathematical model, the desirability function was studied for the optimization of independent variables for desirable responses. A numerical optimization criterion for isotropic mixture is also summarized in Table 3.

2.2.4 Evaluation of critical response variables

Droplet size (Y1)

The droplet size of the IM was determined after the reconstitution. Aliquot (1 g) of each pre-concentrate IM serially diluted (100 times) with purified distilled water, followed by stabilization for 2 h was measured by employing Zetasizer Nano ZS90 (Malvern Instruments, Worcestershire, UK) with dynamic light scattering droplet size analyzer at a wavelength of 633 nm and at a scattering angle of 90° at 25°C. (ZS 90, M/s Malvern Instruments, Worcestershire, UK). Each study was carried out in triplicate to ensure reproducibility and the values of z-average diameters were used. Zeta potential of the microemulsion formed after addition of IM into deionized water was measured using Zetasizer Nano ZS90 (Malvern Instruments, Worcestershire, UK).

Self-emulsification time (Y2)

The self-emulsification time of the IM formulations was evaluated in a US pharmacopoeia dissolution apparatus II paddle (Electrolab India, Mumbai, India). Briefly, an aliquot (1 g) of each isotropic mixture was poured into 500 mL of distilled water at 37°C under gentle agitation by a standard stainless steel dissolution paddle rotating at 100 rpm (Amin et al., 2015; Parmar et al., 2011). The emulsification time was assessed visually. The time required to disperse the isotropic system completely to obtain a clear uniform dispersion was recorded as the self emulsification time. Each study was carried out in triplicate to ensure reproducibility.

Viscosity (Cp) (Y3)

Various IM formulations were examined for viscosity using a Brookfield viscometer (Brookfield DV-1 Prime, Spindle no. SC4-18, Bruker, Berlin, Germany). Each study was carried out in triplicate to ensure reproducibility.

% Transmittance (Y4)

An aliquot (1 g) of the each IM formulations was serially diluted (100 times) with purified distilled water. Percentage transmittance was measured spectrophotometrically (Hitachi, Japan) at λmax 560 nm using water as a blank.

% Drug release (Y5)

In vitro release of EFV loaded IM was tested by employing dialysis bag method using USP dissolution apparatus-paddle II (Electrolab, Mumbai, India) at 37 ± 0.5°C using 500 mL of 0.5% SLS. IM formulation containing EFV equivalent to 200 mg EFV was filled in 6×3 cm dialysis bag (M. wt. cut off 12000Da, Hi-Media Industries Inc., USA) and diluted with the respective dissolution media. Both the ends of bag were tightly tied to prevent any leakage and dialysis bag was fixed to the rotating paddle. Samples were withdrawn at an interval of 5, 15, 30, 45, 60, 90, 120 minutes, respectively. At each time interval, aliquots of 5 mL was withdrawn and replaced by fresh dissolution medium and sample was diluted suitably whenever required with respective dissolution medium. At the end of the study the solution was used to determine the residual drug content of EFV in the IM. The amount of drug released was determined by validated HPLC method.

2.2.5 Drug Content measurements

The content of EFV in IM formulation was analyzed by extraction method. An aliquot (0.1 g) of each IM formulation was diluted (10 times) with methanol and the mixture was vortexed for 15 min to allow complete extraction of drugs in methanol. The resultant mixture was then centrifuged at 10,000 rpm for 10 min. The supernatan
t so obtain was suitably diluted with methanol and estimated by the in-house validated HPLC method.

2.2.6 Rheological measurements (Effect of dilution)

The rheology of IM formulation and effect of dilution with water was studied using MCR-52 Rheometer (Anton Paar, Germany) using Parallel plate geometry PP50 (50 mm diameter) with a 0.5 mm measuring gap. Temperature was maintained by Anton Paar, peltier system. The stress-strain correlation was determined by varying the shear rate (0-100 s-1) at controlled shear stress and varying shear stress (0-100 Pa) at controlled shear rate keeping at 25°C. Effect of dilution was observed using 1:1, 1:5, 1:7 and 1:10 proportion of IM with distilled water. The effect of temperature was evaluated by temperature ramping from 0-40°C.

2.2.7 Transmission electron microscopy

The morphological and structural behavior of the emulsion droplet of the optimized isotropic mixture was examined by using transmission electron microscopy (H 7500, Hitachi, Tokyo, Japan, with an operating voltage of 100kV) in order to study the shape, uniformity and droplet size of the reconstituted isotropic mixture. An aliquot (0.1 g) of each IM formulation was diluted (10 times) with purified distilled water and stabilized for 2 h. A 0.5 mL droplet of the reconstituted IM formulation was directly positioned on the film coated copper electron microscopy grids followed by staining with 0.5% aqueous solution of phosphotungstic acid for 30 s, and the excess was siphoned off. The image was magnified and focused on a layer of photographic film. Combinations of different bright-field imaging at increasing magnification were used to expose the structure as well as the size of the formed microemulsion.

2.2.8 In vitro dissolution

Without dialysis bag

In vitro release of EFV loaded IM and pure EFV suspension was tested. In vitro release of EFV loaded IM was carried out using USP dissolution apparatus-paddle II (Electrolab, Mumbai, India) at 37±0.5°C using 500 mL of 0.5% SLS, pH 6.8 or in biorelevant dissolution media’s (FaSSIF and FeSSIF) with stirring speed of 50 rpm (da Silva Honório et al., 2013). The FaSSIF (Fasted state simulated intestinal fluid) and FeSSIF (Fed state simulated gastric fluid) were prepared as per the method reported by Jantratid and Dressman, 2009. The amount of drug released was determined by validated HPLC method. Further, dissolution data was compared using similarity factor (f2) and dissimilarity factor (f1) approach

With dialysis bag

IM formulation containing EFV equivalent to 200 mg EFV and pure 200 mg EFV powder as mentioned above were filled in 6×3 cm dialysis bag (M.wt. cut off 12000Da, Hi-Media Industries Inc., USA) and diluted with the respective dissolution media. Both the ends of bag were tightly tied to prevent any leakage and dialysis bag was fixed to the rotating paddle. Samples were withdrawn at an interval of 5, 15, 30, 45, 60, 90, 120 minutes, respectively. At each time interval, aliquots of 5 mL was withdrawn and replaced by fresh dissolution medium and sample was diluted suitably whenever required with respective dissolution medium. At the end of the study the solution was used to determine the residual drug content of EFV in the IM. The amount of drug released was determined by validated HPLC method. Further, dissolution data was fitted into various release models to evaluate its release kinetics.

2.2.9 Stability testing of reconstituted EFV loaded isotropic mixture (IM)

The stability of reconstituted optimized isotropic mixture was assured by observing cloud point, thermodynamic stability and self emulsification time as per the method reported by Bandyopadhyay et al., (2012); Elnaggar et al., (2009); Kamboj et al., (2015).

2.2.10 Animal Pharmacokinetic studies

Tissue distribution studies

For biodistribution and in vivo pharmacokinetic, female Wistar rats weighing 160–180 g were used. The protocol was duly approved by the Institutional Animal Ethics Committee (IAEC) of Punjabi University, Patiala, India (107/99/CPCSEA-2016-27). The animals were divided into two groups (n = 3, six time points).

Groups I: Oral administration of EFV suspension (40 mg/kg of EFV)

Group II: Oral administration of EFV loaded IM (40 mg/kg of EFV)

The formulations were administered to rats orally using an oral feeding cannula. The blood sample (1 mL) each was withdrawn from retro orbital vein and, collected into heparinized microcentrifuge tubes at different time intervals (2, 3, 4, 6, 8,12 and 24 h). Plasma was separated by centrifuging the blood samples at 4000 rpm for 10 min at 4°C. After centrifugation, the plasma obtained was stored at -20˚C until analysis. The animals were sacrificed thereafter and the organs of interest (heart, spleen, kidney, brain, liver and lymph nodes) were collected immediately after cervical dislocation at different time points. The tissues were homogenized in ice-cold phosphate buffer saline solution. To this 1:2 ratio of diethyl ether for EFV extraction was added and vortexed for 5 min followed by centrifugation at 3500 rpm for 15 min. The organic phase was separated and evaporated under reduced pressure in a vacuum oven. The residue was reconstituted in 500 µL of methanol injected into HPLC column. The amount of EFV in the blood plasma and tissues was determined by validated HPLC method. Statistical analysis of in vivo pharmacokinetic data was conducted using one-way ANOVA followed by post hoc Tukey’s multiple-comparison test, with P values of <0.05 were considered as significant.

In vivo pharmacokinetic performance of EFV loaded isotropic mixture (IM)

In vivo pharmacokinetic studies were conducted using New Zealand male rabbits. All animal experiments were executed out after approval of the protocol by the Institutional Animal Ethical Committee (IAEC), Panjabi University, Patiala, India, (107/99/CPCSEA-2016-26) guidelines for the use and care of experimental animals.

New Zealand male rabbits, weighting 2.2-2.5 kg were fasted for 24 h before drug administration. The fasted group of animals was allowed to free access of water and remained in fasted state during the study. However, fed state group was given access to standard fatty meal throughout the study. Animals were divided into different groups, according to two way cross over design and receive the following treatments.

Group A: Oral administration of suspension of EFV (40 mg/kg of EFV)

Group B: Oral administration of EFV loaded IM (40 mg/kg of EFV)

Group C: Oral administration of EFV loaded IM (20 mg/kg of EFV)

Group D: Oral administration of EFV marketed formulation

At different time intervals, blood samples (0.5 mL) was withdrawn from peripheral ear vein of each rabbit with an aid of 26 gauge needle and transfer it to the vacuum micro-centrifugation tubes having disodium EDTA (40 µL). After the separation of plasma using centrifugation (6000 rpm, 10 min), the acetonitrile (0.9 mL/0.1 mL of plasma) treatment was given to precipitate proteins. The mixture was centrifuged (4000 rpm, 10 min) again and supernatant layer was collected and evaporated. The residue was reconstituted with mobile phase (ACN: 0.1 N formic acid; 60:40 v/v) and the amount of EFV in the blood plasma was determined by validated HPLC method. Standard non-compartmental pharmacokinetic parameters (± SD) were estimated using the in house pharmacokinetic program. Statistical analysis of in vivo pharmacokinetic data was conducted using one-way ANOVA followed by post hoc Tukey’s multiple-comparisons test, with p values of <0.05 were considered as significant.

3. Results and discussion

3. 1 Solubility determination

In a search to find a suitable component of isotropic mixture for EFV, solubility was chosen as the primary step to screen components. For this purpose, a random selection of o
il phase, surfactant phase and cosurfactant were made as available in the literature. The oil phase may be chosen from natural origin or from oils available after pretreatment (i.e Semi synthetic oils). The results of solubility in individual microemulsion components are shown in Figure 1. Amongst natural oils (Watermelon seed oil and grape seed oil) and semi synthetic oils (Labrafac PG, Maisine 35-1, Labrafac WL 1349) was found to have more than 250 mg/g of oil solubility. In a surfactants (Labrasol, Cremophor RH40, Caproyl PGMC, Labrafil M 1944 CS) was found to have more than 340 mg/g of surfactant solubility. In a co-surfacatnt category (Lauroglycol, and Transcutol HP) solubilize EFV more than 250 mg/g of co surfactant. Thus, for EFV isotropic mixture based formulation constituting oil (Maisine 35-1), surfactant (Labrasol, Cremophor RH40) and co-surfactant (Transcutol HP) were selected as they showed maximum solubility, decreased emulsification time, high level of clarity and miscibility.

3.2 Preparation of ternary phase diagram

The combination of Maisine 35-1, Labarsol, Transcutol HP (mixture 1) and Maisine 35-1, Cremophor RH 40, and Transcutol HP (mixture 2) were studied to prepare ternary phase diagrams (Figure 2). The results indicated individual mixtures 1 and 2 have low area for microemulsion. So, a need was felt to enhance the microemulsion region, for that purpose, various mixtures of Cremophor RH 40: Labrasol were prepared in ratio 1:1, 1:2, 1:3, 2:1 and 3:1 were studied for ternary phase diagrams taking Maisine 35-1 as oil and Transcutol HP as co-surfactant. An enhancement in the microemulsion region was observed when a combination of surfactants was used (Kogan and Garti, 2006; Senapati et al., 2016). However, the combination Cremophor RH 40: Labrasol 1:1 showed higher microemulsion area. The area where the ternary mixture showed clear microemulsion with low globule size (200 nm) was choosen for further optimization studies (Dokania and Joshi, 2014; Jain et al., 2014a; Kamboj and Rana, 2016; Kamboj et al., 2015). The ternary phase diagram showed that 2-5 g Maisine 35-1 (oil), 4-7 g of Cremophor RH 40: Labrasol (1:1) (surfactant) and 1-3 g of Transcutol HP (co-surfactant) ternary mixture (total 10 g) exhibited an area which could be used further to optimize isotropic mixture of EFV by utilizing D-optimal mixture design approach.

3.3 Optimization of EFV loaded isotropic mixture (IM)

From the phase diagram studies, 16 formulations were prepared as per D-optimal mixture design each containing 250 mg/g of EFV in IM. For this purpose, critical material factors (CMF) are Maisine 35-1 (X1), Cremophor RH 40: Labrasol (1:1) (X2) and Transcutol HP (X3) three constrains of these critical material factors were decided on the basis of ternary phase diagram investigations. The critical response variables (CRV) were taken as droplet size (Y1), self-emulsification time (Y2), viscosity (Y3), % transmittance (Y4), and % EFV release from IM (Y5) as these factors are expected to be essentially required to formulate good isotropic mixture. Various CMF and CRV of D-Optimal mixture design are shown in Table 1. The results of CMF variables were fitted to Design Expert® 9 software and statistical analysis provide different models and their polynomial equations of the CRV [droplet size (Y1), self-emulsification time (Y2), viscosity (Y3), % transmittance (Y4), and % EFV release from isotropic mixture (Y5)]. The values of the coefficients X1, X2 and X3 were statistically correlated with the response. A positive sign of coefficient indicates an agonistic effect while a negative term indicates an antagonistic effect of the coefficients. The larger coefficient means the critical material factors has more potent impact on the response. The model results confirmed that all the models used for various variables were adequate and satisfactory (Model p value>F is less than 0.01). The r2 values for all models varied between 0.95 and 0.99 indicating excellent fit of the generated polynomials to the response data (p < 0.0001 in all the cases). All the models were found to have insignificant values of “lack of fit” clarifying that the proposed model is appropriate. Close proximity in the magnitude of adjusted (Adj) and predicted (Pred) r2 to the actual model r2 also confirm excellent fit to the data.

Droplet size (Y1)

The equations procured after correlating droplet size with critical material factors are manifested in equation 1.

Droplet size (Y1) = +248.89X1 +103.84X2 +152.36X3 -51.18X1X2 -58.85X1X3-66.93X2X3 -260.18X1X2X3 +66.18X1X2(X1-X2) -86.14X1X3(X1-X3) -278.68X2X3(X2-X3) (Equation 1) r2=0.997; model = special cubic

It has been documented that droplet size distribution is considered to be as the important aspect influencing the in vivo fate of emulsions. The smaller the globule size, larger the surface area provided for drug absorption (Gupta et al., 2011). The droplet size of the emulsion also regulates the rate and extent of drug release. All the critical material factors were found to have significant effect (p<0.05) on the droplet size. It was evident from the correlation of droplet size with critical material factors that the role of proportion of Maisine 35-1 (X1) was more prominent as compared to proportion of surfactant mixture (X2) and co surfactant (X3) in enhancing the droplet size. Thus, an optimum proportion of X1 was required to achieve minimum droplet size. However, the contribution of surfactant mixture prepared by mixing proportion of Cremophor RH 40: Labrasol (1:1), proportion of Transcutol HP and proportion of Maisine 35-1 was inversely related to droplet size. This may be associated with inverse correlation of droplet size with any two combination i.e. X1X2, X2X3, or X3X1. Overall, the special cubic model proposed role of each component of microeemulsion in decreasing droplet size. This was also evident from response surface and contour plot.The ANOVA results between droplet size and critical material factors are illustrated in Table 2. The values of P>F less than 0.05 suggested model terms are significant. The software recommended model for droplet size showed F value of 504.99 implies the model is significant for special cubic model.

Self emulsification time (Y2)

Self emulsification time is the time needed by developed IM to convert into microdroplets or droplet dispersion (Zidan et al., 2007). This behaviour was depended on the critical material factors. Furthur, Singh et al., (2009) suggested self emulsification time is a dynamic non-equilibrium process involving interfacial phenomenon. Therefore, this could be treated as an essential response variable. The correlation between self emulsification time and critical material factors is shown in equation 2. The F-value of 25.52 implies that the lack of fit is not significant relative to the pure error. Non significant lack of fit is good for fitting data into the model.

Self emulsification time (SET) (Y3) = +67.66X1+54.59X2+44.38X3-28.47X1X2-12.71X1X3-58.99X2X3-222.27X1X2X3-3.68X1X2(X1-X2)+43.35X1X3(X1-X3)-76.25X2X3(X2-X3) (Equation 2) r2=0.958; model = cubic

From the equation it was evident that the correlation between self emulsification time and critical material factors follows cubic model. The factor influencing analysis of above equation suggested combination of X1, X2 and X3 had a highest effect on self emulsification time. The self emulsification time was found to decreased with increase in proportion of Cremophor RH 40: Labrasol (1:1) as well as proportion of Transcutol HP (Zidan et al., 2007). This was also evident from response surface and contour plot. However, analysis of role of individual component on self emulsification time, suggested more pronounced effect of proportion of oil (X1) in increasing self emulsification time (Bahloul et al., 2014).

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