INTRODUCTION:

Bigels can be defined as a mixture of an aqueous hydrogel phase and a lipophilic organogel phase in a definite ratio^[1,2]. Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids^[3]. However, they are highly susceptible to microbial contamination and also possess poor mechanical strength^[4]. Organogel is a thermodynamically stable, visco-elastic system of a nonpolar (non-aqueous) phase where gelation is induced by specific concentration of gelator (any substance capable of forming gel) at a definite temperature^[5,6]. Organogels were being investigated since early1990s^{[7, 8]}.

Microscopy of the organogels showed that the three dimensional network of needle aggregates of gelator is responsible for immobilizing the apolar solvent. Non-ionic surfactants such as sorbitan esters or Spans are being currently employed for crippling the non-polar phase in pharmaceutical, food and cosmetic industries^[9^]. Owing to their low cost and stability over a wide range of temperature, sorbitan esters are quite often being used as an alternative to the phospholipids for various topical preparations^[10]. Sorbitan esters are generally classified according to the presence of fatty acid chain in their chemical structure. Presence of long saturated hydrocarbon chains within the sorbitan ester molecules result in the formation of solid esters [e.g., sorbitan monopalmitate (Span 40) and sorbitan monostearate (Span 60)] whereas, the short hydrocarbon chains form liquid esters (e.g., sorbitan monolaurate or Span 20). Span 40 and Span 60 have been found to be biocompatible, odorless, and form opaque, thermoreversible semi-solid organogels with apolar liquids such as vegetable oil, dichloro methane, n-decane, isopropyl myristate etc.^[5]. But due to their stickiness and oily residues, organogels have been less appreciated by consumers. Moreover, the leaching of the internal oil phase from these gels on long-term storage has forced scientists to look for stable formulations^[11]. To overcome this problem, the concept of bigels was introduced in 2008 by Almeida et al ^[1]. Several studies have reported bigel formation with natural and synthetic hydrophilic polymers such as guar gum, Carbopol, HPMC (Hydroxypropyl methylcellulose), PVPK30 (Polyvinyl pyrrolidone)^{[2, 12-}¹⁴^].

Bigels, unlike emulsions, creams and emulgels, do not show demixing of the two phases on storage at room-temperature for a period of up to 6-12 months although they are devoid of any stabilizer^[15,16]. As a pharmaceutical formulation, bigels possess many advantages over other semi-solid systems owing to the synergistic effect of both the gel phases, ease of preparation, satisfactory stability, viscosity, spreadability, microarchitecture, absence of surfactant related skin toxicity and possible delivery of both lipophilic and hydrophilic drugs ^[17].

There are reports of studies on organogels of vegetable oils such as soybean oil, sun flower oil, mustard oil, ground nut oil, olive oil etc. using Spans as gelators^[18-21]. However, no attempt has been made to develop bigels of soybean oil with HPMC as the hydrophilic gelling agent with Span 40 or Span 60 as the gelator.

Hydroxypropyl methylcellulose (HPMC) is a semi-synthetic linear polymer comprised of etherified anhydroglucose rings derived from cellulose. HPMC as gelling agent yields consistent properties and exhibits reproducible controlled release performance in contrast to polymers like guar, shellac, and other botanical extracts. Since they are nonionic, they minimize interaction problems when used in acidic, basic, or other electrolytic systems.^[22,23].

The difference in molecular weight of various commercially available HPMC grades is reflected in the viscosity of an aqueous solution of a standard concentration. The hydrophilic nature of HPMC provides for better polymer-water contact, thus increasing the overall rate at which complete polymer chain hydration and gelation occurs, compared to other cellulosics. This leads to the formation of an effective protective gel barrier essential to the controlled drug release from hydrophilic matrix. As a result, drug-release rates have been sustained longer with HPMC than with equivalent levels of methylcellulose (MC), hydroxyethylcellulose (HEC), or carboxymethylcellulose (CMC). For these reasons, HPMC is very often the polymer of choice over other cellulosics^[24].

The major aim of the current study is to investigate the effect of adding different grades of HPMC (HPMCK4M and HPMCK15M) and two different Spans (Span 40 and Span 60) on the rheological and drug release behavior of soy-bigels and thus establish a novel topical base for drug delivery.

MATERIALS AND METHODS:

Materials:

Food grade soybean oil (Emami Ltd., Kolkata) was purchased from local market. Paracetamol IP (PCM) was received as a gift sample from enlisted vendor. Span 60 (sorbitan monostearate) and Span 40 (sorbitan monopalmitate) was purchased from Loba Chemie Pvt. Ltd., Mumbai. HPMCK4M was of AR grade and obtained from Colorcon Asia Pvt. Ltd. as gift sample. All other reagents were of analytical grade. For hemocompatibility study, fresh goat blood was collected in heparin coated tube and stored at -4ºC.

Methods:

Method of preparation:

The organogel was prepared by adding required quantity of Span in soybean oil maintained at 60℃ with continuous stirring (500 rpm). The hot dispersion turned into organogel when left undisturbed and cooled down to 25℃. The drug loaded organogel was prepared by addition of paracetamol (PCM) followed by addition of Span.

The hydrogel was prepared by stirring definite quantity of HPMC in warm distilled water (65℃) at 500 rpm to obtain a viscous dispersion. The organogel in sol state was added to HPMC aqueous dispersion maintained at 60-70℃ under stirring at 500 rpm^[25].

The stirring was continued until a homogenous mixture was obtained. The mixture formed bigel when cooled to 25℃. Propyl paraben (0.02% w/v) was added to prevent bacterial contamination of the hydrogel. Composition of the various formulations are provided in Table 1.

Method of characterization:

FTIR spectroscopy:

FTIR analysis of blank organogel and hydrogel as well as drug loaded formulations along with its individual components was carried out using Fourier Transformed Infrared Spectrometer (ALPHA-II, Bruker, Bellerica, MA, USA) operated in Attenuated Total Reflectance (ATR) mode. Samples were scanned in the range of 4000 to 500 cm^-1[25].

Organoleptic evaluation:

Formulations were observed visually for their colour, odor and texture^[26].

Determination of pH:

The pH of the formulations was determined using digital pH meter (Fisher Scientific-Accumet AE 150)^[26].

Applicability parameters:

Applicability parameters of organogels and bigels include determination of extrudibility and spreadability^[27,28]. Extrusion was studied by measuring the distance travelled by the ribbon of gel extruded from a collapsible tube in 10 s. Approximately 1 g of the gel was placed between two glass slides of equal weight, area and thickness. Initial spreading diameter (D_i) was noted. Thereafter, a load of known weight of 10, 20, 50, or 100 g was applied individually on the upper slide for 1min and the final spreading diameter (D_f) of the gel was noted in each case. Extrudibility and spreadability are expressed in cm/s and percentage respectively and the corresponding equations are given below:

Extrudability = Distance travelled by the gel (cm) /10 s (1)

% Spreadability = [(D_i-D_f)/D_i] ×100 (2)

Where, D_i= initial spreading diameter, D_f= final spreading diameter

Rheological study:

The viscosity of the blank gels (organogels and bigels) was studied in Brookfield Digital Viscometer (Model LVDVI+, Brookfield Engineering Laboratories Inc, USA) with spindle no. 6 (for Span 40-based gels) and 7(for Span 60-based gels) at 25°C^[14]. The apparent viscosity of organogel and bigel formulations of different compositions were measured as a function of shear rate varying from 1 to 5 rpm. Ostwald-de wale Power law model has been employed to analyze the flow behavior of the gel formulations:

Ʈ=k*ɤⁿ (3)

where relationship between stress (Ʈ) and shear rate (ɤ) provides the values for flow consistency index (k) and flow behaviour index (n). The flow may be stated as non-Newtonian pseudo plastic/shear thinning if n is
< 1^[29,30].

Drug content determination:

Definite amount of drug-loaded gel was added to phosphate buffer (pH 5.8) which was kept undisturbed for 48 h for complete leaching of drug^[31]. The dispersion was filtered through Whatman filter paper No. 1. An aliquot of filtrate was suitably diluted and absorbance measured spectrophotometrically at 249 nm (Shimadzu UV-VIS 1800 spectrophotometer)^[32]. The drug content of formulations was determined from calibration curve of the drug in the said buffer.

In-vitro drug diffusion study and modelling of release kinetics:

In vitro drug release from organogels and bigels was performed through dialysis membrane (HIMEDIA^® LA 330-5MT) in modified Franz diffusion cell^[33]. Accurately weighed drug-loaded sample was placed in the donor compartment and the receptor chamber containing phosphate buffer (pH 5.8) was maintained at 32±0.5 ℃. An aliquot of 1 ml was withdrawn every hour, replenished with fresh buffer and study was continued for 7 h. The aliquot was analyzed spectrophotometrically at 249 nm (Shimadzu UV-VIS 1800 spectrophotometer)^[32]. Drug release data were subjected to mathematical modeling by using zero order, first order, Higuchi and Korsmeyer-Peppas models^[34].

Determination of steady-state flux and permeability co-efficient:

The measurement of flux across human skin provides a valuable insight into the formulation development of any dermatological product ^[35]. The steady-state flux of PCM from both organogels and soy-bigels across the artificial dialysis membrane is defined as follows.

SS_flux = dQ/dt*1/A (4)

where,

SS_flux= steady-state flux of drug (mg/cm².hr);

dQ/dt= slope of the linear portion of the curve i.e. cumulative amount per unit time (mg/hr);

A = diffusional area (cm²)

Permeability co-efficient is quantified by the following equation.

K_p= SS_flux / C_app -(5)

where, C_app = initial concentration of the drug in the gel formulation. In the present study, it was expressed as %w/v i.e. weight of drug actually present in the volume of gels taken for permeation study.

Hemocompatibility study:

Accurately weighed amount of blank organogel and bigel was placed in dialysis tube filled with 50ml normal saline (0.9% w/v NaCl solution) and continuously stirred in a magnetic stirrer for 1 h at 37℃ in order to enable leaching of the gel components. Leachant (0.5ml) was withdrawn, diluted to 10ml with normal saline and 0.5 ml diluted goat blood (4ml of goat blood diluted with 5ml of normal saline) and incubated at 37ᵒC for 1 h. It was then centrifuged at 3000rpm for 10 min. The supernatant was measured spectrophotometrically at 542 nm. Positive control was prepared by taking 0.1 (N) HCl solution in lieu of leachant. In negative control, normal saline was used instead of leachant^[36]. Normal saline was taken as the corresponding blank and percent haemolysis may be calculated as follows:

% Hemolysis =

(OD _test-OD _negative) / (OD _positive-OD _negative) × 100 (6)

Where, OD _test= Absorbance of the test sample

OD _positive= Absorbance of the positive control

OD _negative=Absorbance of the negative control

Thermal stability study:

The stability analysis of the pharmaceutical products may be carried out either by a thermo cycling process or by incubating the samples at a specific environment for a longer period of time^[14].

Thermal stability studies of organogels and soy-bigels was carried out by thermocycling method^[16]. Freshly prepared samples were subjected to 5 consecutive freeze-thaw cycles. During each cycle, organogels were heated to 65℃ and then immediately kept overnight at 4℃. Change in gelation time was noted on exposure to each thermocycle.

Statistical analysis:

All the experiments were performed in triplicate. All data were expressed as mean ± standard deviation (S.D.). ANOVA was used to calculate significant differences between the experimental data. The p-value less or equal to 0.05 was considered to be statistically significant^[37].

RESULT:

Organoleptic evaluation:

Organogels and bigels of soybean oil were characterized for their organoleptic properties such as colour, odor and appearance (Table 2).

Determination of pH:

pH of the formulations were found to be in the range of 5.8 to 6.1 at 25℃ which was close to skin pH (4.5-6.5).

Applicability parameters:

Extrudability and spreadability data of both organogels and bigels are presented in Table 2.

Rheological study:

Viscosities of the gel formulations are graphically represented (Figure 2). The flow behavior index ‘n’ was found to be less than 1 in all the cases.

Figure 2: Viscosity profile of organogels and soy-bigels at 25ºC

Drug content determination:

Drug content was found to be in the range 85-92% in soy-bigels.

In vitro drug diffusion study with kinetic modeling:

Better drug release was observed in all the bigels compared to their respective organogels (OG1 and OG2). Span 40 based soy-bigels with either grade of HPMC revealed superior performance than soy-bigels of Span 60 and HPMC.

Figure 3: Drug release profile of organogels and soy-bigels in phosphate buffer (pH 5.8) at 32±0.5ºC. Data presented as mean±standard error of mean from n=3. p<0.05 indicating statistically significant differences

Kinetic modeling of drug release from organogel (OG1 and OG2) revealed zero order kinetics with both non-Fickian and Fickian type of diffusion respectively. Bigels developed from Span 60 (OHS1 and OHS2) were found to follow Higuchi model with non-Fickian and quasi-Fickian diffusion. The best fit model for bigel with Span 40 and HPMCK15M was found to be Higuchi however soy-bigels developed from HPMCK4M followed Korsmeyer-Peppas kinetics with non-Fickian type of diffusion.

Table 3: Kinetic modelling of drug release from organogels and soy-bigels

Batch	Kinetics followed	Mechanism of diffusion
OG 1	Zero	Non-Fickian
OG 2	Zero	Fickian
OHS 1	Higuchi	Non-Fickian
OHS 2	Higuchi	Quasi-Fickian
OHP 1	Higuchi	Non-Fickian
OHP 2	Korsmeyer-Peppas	Non-Fickian

Drug diffusion parameters of the gels are presented in a tabular form (Table 4).

Table 4: Drug diffusion parameters of organogels and soy-bigels

Batch	t₅₀ (h)	SS_flux(mg/cm².h)	K_p (cm²/h)
OG 1	ND*	0.90±0.5	0.45±0.7
OG 2	6±0.1	2.68±0.5	1.34±0.4
OHS 1	ND*	1.36±0.6	0.68±0.5
OHS 2	7.6±0.3	0.47±0.3	0.23±0.7
OHP 1	5.2±0.5	2.60±0.6	1.33±0.5
OHP 2	6±0.2	2.65±0.7	1.32±0.8

*ND : could not be determined as < 50% drug released during 7 h of drug release study

Hemocompatibility study:

The % hemolysis of all the formulations were found to be less than 5% in presence of organogel and bigel leachant and thus hemocompatible (Table 2).

Thermal stability study:

All the formulations except the soy-bigels developed from Span 60 (OHS1 and OHS2) were found to be stable up to five consecutive thermocycles (Figure 3).

Figure 4: Change in gelation time of organogels and bigels of soybean oil on exposure to 5 freeze-thaw cycles

DISCUSSION:

Soy-bigels developed with HPMC (K4M or K15M) and Span 40 or Span 60 were found to possess non-greasy, smooth feel and appearance and are expected to spread uniformly over affected area of skin on being extruded without loss of structural integrity. The smooth and creamy texture may be attributed to the uniform mixing of otherwise two immiscible but compatible phases owing to the presence of the gelators (Span 60/Span 40), a surface-active agent^[38]. Compatibility among the formulation ingredients was confirmed by FTIR analysis ^[^25].

In rheological study, it was observed that on increasing shear rates, viscosity of all the formulations decreased indicating pseudoplastic or shear thinning behavior of the gels. Initially, the apparent viscosity decreased sharply at lower shear rates, but it was found to be steady at higher shear rates. This can be explained by the faster reduction in the size of the gelator molecule crystal aggregates as the shear rate was increased. The bigger crystals may break into smaller crystals (fragmentation) and may rearrange themselves into a parallel direction with shear. In general, at temperatures below the incipient gelation temperature, aqueous solutions of HPMC exhibit pseudoplastic flow. Pseudoplasticity increases with increasing molecular weight or concentration^[39]. The viscosities of the formulations may be established in the order of OHS1 > OHS2 > OHP1 > OHP2. Moreover, the flow behavior index was considerably less (n << 1) as expected from the rheological behavior of both organogels and soy-bigels^[40]. Thus, it is evident that HPMC of higher molecular weight as also Span with greater chain length imparted higher viscosity to the bigels. Formulations with higher viscosity may exhibit sustained or controlled drug release and presence of HPMC as the gelling agent may lead to formation of gel-matrix.

The superior performance of Span 40 based soy-bigels with either grade of HPMC over soy-bigels of Span 60 and HPMC in in vitro drug release studies may be attributed to the greater flexibility of Span 40 based organogels compared to Span 60. Moreover, higher MW of HPMC produces an increase in the entanglement of the polymeric chains resulting in the increase in the physical crosslink points. This not only decreases the spaces available within the inter-polymeric chains of the gelled matrices but also the hydration of the polymer matrices, promotes formation of an exterior drug diffusion barrier and finally may retard drug release^[41-^43].

Soy-bigels prepared from HPMCK15M with either of Spans (OHP1 and OHS1) demonstrated Higuchi model. Drug release can be assumed to occur by the gradual break-up of the swollen bigel matrix into smaller fragments as the gel skeleton is compromised by the influx of dissolution medium via the conduits offered by the tubular structure of Span molecules and finally diffusion of the drug-loaded oil droplets^[44-46]. Thus from the above discussion, soy-bigels of Span 40 based organogel with 3% HPMCK4M may be regarded as ideal topical base for drug delivery.

Thermal stability study of Span 40 based soy-bigels revealed its ability to withstand up to 5 thermocycles whereas the thermal stability of soy-bigels prepared with Span 60 could not be carried out due to phase separation at higher temperature.

CONCLUSION:

It may be concluded from the above study that gelator and grade of HPMC are major factors affecting the drug release pattern from soy-bigel. Soy-bigel matrix prepared with Span 40 and HPMCK4M having moderate viscosity and sustained drug release profile may help in development of a novel topical base for drug delivery.

CONFLICTS OF INTEREST:

All authors have none to declare.

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Received on 17.06.2019 Modified on 21.07.2019

Research J. Pharm. and Tech. 2020; 13(1): 353-360.

DOI: 10.5958/0974-360X.2020.00071.2

	Organoleptic properties			Applicability parameter		% Hemolysis
Batch	Colour	Odour	Appearance	Extrudibility(cm/s)	Range in % spreadability with application of individual load
*OG 1**	Yellowish white	Nil	Greasy	0.75±0.24	42-88	3.07±0.2
*OG 2**	Yellow	Nil	Smooth-oily	0.8±0.65	12-56	3.4±0.6
*OHS 1**	Milky white	Nil	Smooth, non-oily	0.77±0.19	34-92	2.54±0.5
*OHS 2**	Milky white	Nil	Smooth, non-oily	0.86±0.21	44-91	2.97±0.4
*OHS 1**	Creamy-white	Nil	Non- greasy	1.2±0.52	25-67	2.3±0.7
*OHS 2**	Creamy-white	Nil	Non- greasy	1.8±0.57	29-77	2.9±0.9

Composition (%w/v)	Batch
Composition (%w/v)	OG 1	OG 2	OHS 1	OHS 2	OHP 1	OHP 2
PCM	2	2	2	2	2	2
Span 60	18	-	18	18	-	-
Span 40	-	18	-	-	18	18
Soybean oil	80	80	80	80	80	80
HPMCK15M	-	-	3	-	3	-
HPMCK4M	-	-	-	3	-	3
Water	-	-	97	97	97	97