INTRODUCTION:

Drugs having poor aqueous solubility show low bioavailability. In pharmaceutical science, solubility is commonly related to bioavailability of compound. It was reported a couple of decades ago that more than 40% of failures in new drug development have been attributed to poor biopharmaceutical properties, including water insolubility¹. Poor water solubility led to ineffective absorption at site of administration, which has been designated as an important part of the high clinical failure due to poor pharmacokinetics².

Poor aqueous solubility of drugs also affect their therapeutic performance in following ways: high intra and intersubject variability, lack of dose proportionality, shows performance limitations, incomplete or fickle absorption, poor bioavailability, slow onset of action.

Through the years of diligent and intelligent research by pharmaceutical scientists, many techniques dealing with the formulation issues of water insoluble drugs have been developed like pH adjustments, co solvents, micelles, liposomes, polymerimeric modification (polymorphs), particle size reduction, complexation, carriers, solid solutions/dispersions, lipid formulations⁷.

There are many approaches for dissolution rate enhancement is alteration of the solid state of drug substance: polymorphs, solvates, and amorphous forms. Also lipid formulations like microemulsions, self emulsifying systems. Others like solid dispersions for poorly water soluble drugs, particle size reduction, complexation, solid solutions/dispersions, prodrug for improved solubility and nanoparticles⁸. SEDDS and SMEDDS have the advantage of easy dispersion and which leads to rapid absorption and reduced variability.

The pre-epithelial unstirred water layer presents a barrier to passive absorption of poorly water soluble drugs. Ingested food containing lipids can significantly alter postprandial drug absorption and its bioavailability⁹. Biological lipids are not large macromolecular polymers but many of them are formed by chemical linking of several small constituent molecules. The lipids can be classified into a few major groups: Fatty acids, fatty acid derivatives, cholesterol and its derivatives and lipoproteins.

The lipid based drug delivery system for oral use are designed to presently a poorly soluble drug in a solubilised form to eliminate dissolution of crystalline material as the rate limiting step to absorption¹⁰. The major advantage of the lipid delivery system is that drug can be present in a stable liquid solution. This eliminates the time required to dissolve solid particles. The lipids used in formulation may facilitate the transport of drug substance across the intestinal membrane and further improve the absorption of drugs from lipid formulations¹³.

SEDDS is an isotropic mixture of natural or synthetic oils, solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and co-surfactants, which upon mild agitation like gastro-intestinal motility followed by dilution in aqueous media e.g. gastro-intestinal fluids forms fine oil in water (o/w) emulsions or microemulsions²¹. SEDDS is thus a formulation that represents an efficient vehicle for in vivo administration of emulsions as their thermodynamic stability offers advantages over unstable dispersions such as emulsions. Self emulsifying formulations spread readily in GI tract, and digestive motility of GI tract provide agitation necessary for self emulsification. Solid SEDDS has advantages like pharmacokinetics provide a large interfacial area, maintaining drug in solution, consistent gastric emptying similar to aqueous solutions, faster and more uniform distribution, minimizing the irritation. Improvement in rate and extent of absorption, resulting in reproducible plasma profiles. Telmisartan has half life of 24 hours; peak plasma levels are obtained approximately 0.5 to 1 hour after oral administration. It is a potent, long lasting, nonpeptide antagonist of angiotensin II type1 (AT1) receptor indicated for treatment of essential hypertension. Hence, it was envisaged to develop a solid SEDDS of poor water soluble drugs like telmisartan.

MATERIALS AND METHODS:

Materials:

The telmisartan was procured from Dr. Reddy’s Lab. The lipids Captex 355, Capmul MCMC8, Tween 80 were obtained from Signet Chemical Corporation. Other like chemicals potassium hydroxide, sodium hydroxide, ethanol, diethyl ether, acetonitrile were obtained from Rankem, methanol, calcium chloride from S.D. Fine chemicals, potassium dihydrogen orthophosphate, potassium chloride, sodium chloride were purchased from Loba chemical and concentrated hydrochloric acid from Samar Chemicals, hard gelatin capsules from Macleod’s Ltd.

Methods:

Estimation of drug content in oils and in vitro drug release studies:

A stock solution of telmisartan was prepared by dissolving accurately weighed quantity in specific volume of methanol. The stock solution was again diluted to obtain a series of dilutions in 0-40 µg/mL concentration range. The absorbance of solutions was measured at 301 nm using double beam UV-Visible spectrophotometer (1700, Shimadzu, Japan). A standard curve of Beer’s law was plotted. This graph was used for the estimation of DC content in various oils and for in vitro drug release studies. The calibration curve of drug was constructed using various solvents like methanol, 0.1N HCl and methanol in 1:1 ratio, Phosphate buffer pH 3.2 and methanol in 1:9 ratio, Phosphate buffer pH 6.4 and methanol in 1:9 ratio.

Solubility studies:

The solubility of telmisartan in various oils, co-solvent and surfactants was studied in order to screen components for formulation development. The solubility of drug in various components (oils, surfactants, and co-surfactants) was determined as follows. Two ml of each of selected vehicles was added to screw capped vial containing an excess of DC (100 mg). After tightening the cap, the mixture was heated at 40 ºC in a water bath to facilitate the solubilisation. Mixing of the systems was performed using ultra sonicator (PCI Analytics Pvt. Ltd., India) for 2 hours with 10 minute intervals at every 15 minutes of sonication. Vials were again shaken with water bath shaker at 25 ºC for 48 hours. After reaching equilibrium, each vial was centrifuged at 3000 rpm for 20 minutes, and excess insoluble drug in supernatant was discarded by filtration using a Whatman filter paper (#35). Aliquot of sample was taken and diluted with methanol to specific volume to give specific point concentration in calibration curve. Analysis of drug was carried out on double beam UV-Visible spectrophotometer (1700, Shimadzu, Japan) at 301nm wavelength. The quantification was done according to calibration curve and column graphs were plotted taking solubility in mg per mL as ordinate axis.

Phase diagram studies:

Ternary phase diagram was constructed with one axis representing oil, the second representing surfactant and the third representing co-surfactant. All components were weighed out on analytical balance. The maximum proportion of oil studied for generation of microemulsification phase boundary was 50 per cent. The system was agitated until a clear SEDDS solution was obtained. Then, 1 g of solution was diluted with 250 ml distilled water with gentle stirring on magnetic stirrer (Remi Equipment Pvt. Ltd., India) to form oil in water emulsion or microemulsion and phase boundary was determined. The phase diagrams were then constructed using software Grapher v7. The proportion of lipid components studied were oil (10-50), surfactant (0-90), cosurfactant (0-90).

Preparation of dosage form:

Preparation of liquid SEDDS:

Based on solubility studies and ternary phase diagram studies, series of self emulsifying drug delivery systems consisting of different drug concentrations were prepared by keeping proportion of surfactant and co-surfactant at constant value. The oils were chosen according to solubility studies. The formulation amount of drug was dissolved initially with pre-weighed co-surfactant (Capmul MCM) in screw caped glass bottles. Oil and surfactant (Tween 80) were accurately weighed and added to drug co-surfactant mixture. The components were homogenized by gentle shaking and sonicated for 10 minutes. The homogeneous mixture was stored at room temperature until used. For preparation of final dosage form this pre-concentrate was filled into size 00 hard gelatin capsules. The volume of pre-concentrate filled was kept constant at 0.8 mL. The filled capsules were stored at room temperature until used in subsequent studies.

Preparation of solid SEDDS:

The solid SEDDS was prepared by mixing liquid SEDDS and different adsorbent by trituration method. Various adsorbent and there ratios are given in table 1. Required quantity of adsorbent was weighed and transferred to mortar and trituration was performed by adding liquid SEDDS in drop wise manner. Material was triturated thoroughly to ensure proper adsorption.

Table 1 Proportions of liquid SEDDS and adsorbent

Batch code	Solid : Liquid	Solid composition
F₁	1 : 2	Al.Mg.Silicate (100%)
F₂		Al.Mg.Silicate + Flowac (70:30%)
F₃		Al.Mg.Silicate + MCC PH101 (70:30%)
F₄	3 : 4	Al.Mg.Silicate (100%)
F₅		Al.Mg.Silicate + Flowac (70:30%)
F₆		Al.Mg.Silicate + MCC PH101 (70:30%)
F₇	1 : 1	Al.Mg.Silicate (100%)
F₈		Al.Mg.Silicate + Flowac (70:30%)
F₉		Al.Mg.Silicate + MCC PH101 (70:30%)

Characterization of SEDDS:

Physicochemical characterization:

Physicochemical characterization of systems serves as primary means of product characterization. The parameters studied are shown below.³

Visual isotropy studies:

A series of SEDDS were prepared and their self emulsifying properties on dilution were observed visually. Second visual observation was carried out after dilution of system as mentioned in self emulsification time evaluation.

Self emulsification time analysis:

Visual test can be a measure of an apparent spontaneity of emulsion formation. A visual test to assess the self emulsification properties reported by Craig et al. (1995) was modified and adopted in the present study^4. One mL of formulation was introduced into 250 ml of distilled water in a glass beaker at 37±1 °C and contents were continuously mixed with a magnetic stirrer (Remi Equipment Pvt. Ltd., India).

Emulsion droplet size analysis:

The droplet size of emulsion was measured after dilution of system. For this, 500 mg of the powder was added to 200 ml distilled water. Diluted sample were filtered and subjected to particle sizing system. Particle sizing system (Malvern particle size analyzer) was operated at temperature of 24⁰C. The SEDDS formulation before adsorption and after adsorption was subjected to particle size analysis.

Study of powder flow properties:

Flowability was determined by using the Kawakita analysis (Kawakita et al 1970). The method involves pouring a 2 g of powder and formulations into a 10 ml glass measuring cylinder and the heap of particles in cylinder was leveled off horizontally with a thin metallic spatula, and bulk volume V_O was accurately measured. The tapping was started mechanically and change in volume of powder column V_N was noted after N no. of taps. The Kawakita equation used for assessing the flow properties of powders, is given by;

N/C = N/A + 1/ab

Where, a and b is constant; a describes the degree of volume of reduction at the limit of tapping and is called compactibility; 1/b is considered to be a constant related to cohesion and called cohesiveness, C, the degree of volume reduction which is calculated from the initial volume V₀ and tapped V_N as:

C = (V₀– V_N) / V₀

Numerical value for constant a and b are obtained from the slope, of plot of N/C versus number of taps N (N= 5, 10, 15, 20….)

Drug content of SEDDS:

The Beers plots were prepared at specific concentration range for different drug concentrations in methanol as said earlier. A capsule prepared as final dosage form of each batch of the SEDDS was placed in a 100 mL volumetric flask. The flask was subjected to sonication energy for 30 minutes with intermittent shaking. The flask was made up to volume with the methanol. Necessary dilutions were made with methanol. The solutions were filtered through filter papers (Whatman #35) and analyzed spectrophotometrically at the appropriate predetermined analytical wavelength using double beam UV-Visible spectrophotometer (1700, Shimadzu., Japan).

In vitro drug release study:

The in vitro drug release study was performed in USP dissolution test apparatus type I using modified dissolution medium at 50 rpm of rotating speed. Filled hard gelatin capsules (size 00) of SEDDS were subjected to dissolution at temperature of 37±0.5 ⁰C. The 10 ml of sample was withdrawn at 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes of time intervals. Each time same aliquot of sample was replaced with appropriate medium. The concentration of drug was determined by spectrophotometric analysis using Beer’s curve. Each study was done in triplicate. Dissolution profiles of each dosage form were compared with telmisartan. Scattered line graphs were plotted showing comparison of cumulative per cent drug release against time in minute.⁵

Stability studies

The final dosage forms developed were subjected to two months stability study. Samples were subjected to controlled condition of 40⁰C and 60 % RH. Samples were analyzed for integrity, phase separation and drug precipitation if any. The drug content of samples was determined after test period. The per cent drug loss for samples was components used in system should have high solubilization capacity for drug, ensuring solubilization of drug in resultant dispersion. Solubility profile of drug is shown in figure below. The solubility of telmisartan was in alcoholic NaOH than methanol.

RESULTS:

Figure 1 Solubility profiles of telmisartan

Phase diagram studies:

The SEDDS has an important characteristic of drug precipitation on dilution with water due to loss of solvent capacity. Selection of oil and surfactant, and the mixing ratio of oil to other components, play an important role in formation of the SEDDS. Therefore, the phase behavior of each SEDDS needs to be carefully studied using the phase diagram as a guide. The microemulsion phase was identified as the area in the phase diagram where clear and transparent formulations were obtained on dilution based on visual inspection of many samples. Four ternary phase diagrams of SEDDS consisting of Tween 80, Capmul MCM, and different compositions of oils were obtained to evaluate their structural differences after dilution to distilled water, as shown in figure 2 and figure 3. Among the various phases formed by these three component system, a field with clear micro emulsion on dilution was identified as grade shade (ME). Dark shaded region shows lyotropic liquid crystalline phase (LC). Remaining area near to microemulsion region was supposed to form emulsion (E) with varying stability.

Figure 2 Ternary phase diagram for Captex 355, Capmul MCM and Tween 80

Figure 3 Ternary phase diagram for Myvacet 9 K45, Capmul MCM and Tween 80

Preparation of dosage form:

All the formulations of SEDDS with different drug concentrations were successfully prepared. All the formulation passed the preliminary tests self emulsification time and visual isotropy. Solid SEDDS with least number of the excipients were prepared to give simplest yet effective formulation. The theoretical drug loading in optimized liquid SEDDS was 500 (mg/mL). Different adsorbent and there combinations are shown in table 2.

Table 2 Formulation batches of solid SEDDS

Batch code	Solid : Liquid	Solid composition
F₁	1 : 2	Al.Mg.Silicate (100%)
F₂	--	Al.Mg.Silicate + Flowac (70:30%)
F₃	--	Al.Mg.Silicate + MCC PH101 (70:30%)
F₄	3 : 4	Al.Mg.Silicate (100%)
F₅	--	Al.Mg.Silicate + Flowac (70:30%)
F₆	--	Al.Mg.Silicate + MCC PH101 (70:30%)
F₇	1 : 1	Al.Mg.Silicate (100%)
F₈	--	Al.Mg.Silicate + Flowac (70:30%)
F₉	--	Al.Mg.Silicate + MCC PH101 (70:30%)

Characterization of SEDDS:

Physicochemical characterization:

Physicochemical characterization of the systems was carried out by evaluating the time of emulsification and visual isotropy.

Visual isotropy studies:

All the formulations prepared from Capmul MCM as co-surfactant and Tween 80 as surfactant were clear, isotropic solutions with no signs of precipitation or separation. Some formulations at higher concentration of oils (> 50 %) showed hazy appearance and demanded more amount of co-surfactant. Formulations prepared from Myvaset 9 K45, Capmul MCM and Tween 80 showed haziness when proportion of Capmul MCM was below the 15 %w/v of total system. SEDDS formed the fine oil in water emulsions with only gentle agitation, upon their introduction into aqueous media. Since the free energy required to form an emulsion is very low, the formation is thermodynamically spontaneous. After 250 times dilution with water, formulations yielded varied quality emulsions depending upon their compositions. As seen in phase diagram studies, compositions selected from ME region yielded good quality microemulsion having 10 % showed least stability and immediately separated out oil phase after short time span of 10 minutes. Emulsion behaviours based on compositions were further discussed in phase diagram studies.

Self emulsification time analysis:

As discussed in phase diagram studies, self emulsification time for given system mostly contingent to the proportion of surfactant and co-surfactant used in the system. It was observed that increasing the concentration of Capmul MCM in SEDDS formulation has increased the spontaneity of the self emulsification. This was due to increased miscibility achieved by the system. Further clarifying, when a co-surfactant is added to the system, it further lowers the interfacial tension between the oil and water interface and also influences the interfacial film curvature, which thereby readily deforms around oil droplets.⁸ Increase in the proportion of Tween 80 in the composition beyond 70 % w/w caused system to form a gel like phase on dilution which delayed self emulsification time. Final formulation showed self emulsification time less than 30 sec.

Emulsion droplet size analysis:

The parameters for the emulsion droplet size analysis of the different formulations are as shown in table 3. Droplet size of both optimized liquid SEDDS and solid SEDDS i.e. before adsorption and after adsorption was performed. Results indicate that the Solid SEDDS is superior to liquid SEDDS in aspect of droplet size. As the amount of adsorbent is increased droplet size decreased. Water soluble agents i.e. spray dried lactose gives smaller droplet size with better stability of emulsion. Presence of water insoluble agent i.e. MCC PH 101 produces larger sized droplets.

Table 3 Droplet size

Batch	Mean diameter (nm)	Zeta potential (millivolts)
Liquid SEDDS without drug	178.2 ± 0.17	-3.17 ± 2.23
Liquid SEDDS with drug	191.5 ± 2.08	-5.70 ± 0.48
F₁	110.9 ± 1.74	-7.80 ± 0.20
F₂	110.4 ± 0.05	-15.4 ± 1.00
F₃	112.4 ± 0.75	-11.9 ± 0.50
F₄	88.2 ± 1.47	-7.57 ± 0.49
F₅	65.4 ± 0.05	-9.30 ± 1.30
F₆	86.6 ± 4.70	-9.90 ± 2.10
F₇	66.3 ± 0.25	-8.50 ± 0.43
F₈	58.6 ± 0.49	-13.20 ± 1.01
F₉	61.9 ± 0.97	-2.50 ± 0.12

Powder flow properties analysis:

Flow property of powder was studied by applying kawakita equation. It is observed that as the amount of adsorbent was increased, the flow property was also increased i.e. increase in adsorption surface area resulted in increase in flow behavior. Further, among all adsorbents used, aluminum magnesium silicate exhibited excellent adsorption property.

Drug content analysis:

The drug content in solid SEDDS was effectively measured by spectrophotometric method. The absorbance of all solutions were measured at 301 nm using UV-visible spectrophotometer (1700, Shimadzu, Japan). The drug content was found to be between 94-96%.

In vitro drug release comparison

Figure 4 Drug release studies of telmisartan solid SEDDS

In these studies it was observed that the entire drug was released within 5 to 30 minutes from each solid SEEDS formulated. The F9 SEDDS had shown much promising results by giving 92.4% release within 5 to 30 minutes. While that of telmisartan had shown only 20.7 % release in 20 minutes.

Stability studies:

Co-solvent used in the preparation of SEDDS was found to have deteriorating effect on the gelatin shell of the capsules and cause them to leak on storage and ultimately causing drug loss by physical means. Gelatin capsules filled with SEDDS did not show leakage and imperfections on storage at 40 ⁰C.

Results showed that there was no significant drug loss during the stability test periods, so systems overcome the probabilities of drug loss in presence of surfactants.

DISCUSSION:

The absorbance of telmisartan was increased with its concentration. Synthetic oils like Captex 355 and Capmul MCMC8 showed higher solubility than orthodox natural oils as they comprised of medium chain triglyceride and monoglycerides which have greater affinity for lipofilic compounds. Microemulsion area was increased as the surfactant and cosurfactant ratio was increased. Thus, the incorporation of surfactants and cosurfactants is encouraged considering the limitation of loss of flowability due to increase in viscosity. These compounds also lower the interfacial tension between the oil and water interface and influences the interfacial film curvature. All the formulations were successfully formed having clear, isotropic solutions. Thus percentage of surfactants were optimized and incorporated. This also has an effect on self emulsification time. Solid SEDDS is superior to liquid SEDDS in aspect of droplet size. Powder flow property is improved with the increased amount of adsorbent.

It could be manifested that the SEDDS formulation resulted in spontaneous formation of a micro emulsion with a small droplet size, which permitted a faster rate of drug release into the aqueous phase. Thus, this greater availability of dissolved drug from the SEDDS formulation could lead to higher absorption and higher oral bioavailability. These formulations showed no significant drug loss during the stability test periods, so systems overcome the probabilities of drug loss in presence of surfactants.

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Received on 24.08.2011 Modified on 20.09.2011

Research J. Pharm. and Tech. 4(10): Oct. 2011; Page 1581-1587