Preeti K Suresh et al.

/ Pharmacie Globale (IJCP) 2011, 9 (08)

Available online at www.pharmacie-globale.info

ISSN 0976-8157

Research Article

PHARMACIE GLOBALE INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY

FORMULATION AND In-vitro CHARACTERIZATION OF SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM OF CINNARIZINE

Preeti K Suresh* and Sudhanshu Sharma
University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur, Chhattisgarh, India. Received: 26 June 2011; Revised: 24 August 2011; Accepted: 28 August 2011; Available online: 5 September 2011

ABSTRACT

The oral drug delivery is fraught with low and erratic bioavailability owing to enzymatic degradation of drug, poor permeability, poor solubility and dissolution, intestinal efflux and pre-systemic metabolism in the intestine and liver. The objective of the present investigation was to develop and characterize SNEDDS of cinnarizine, a BCS class II for improved oral delivery. The components for nanoemulsion were identified by solubility studies and tendency for self-emulsification in various excipients. Oleic acid, Tween 80 and Capmul MCM C-8 were selected as oils, surfactants and cosurfactants respectively. The effects of varying ratios of surfactant:cosurfactant:oil ratios of SNEDDS were studied. Droplet size and zeta potential of the formulations were investigated and found to be in the range of 59.7 - 317.3 nm and -23.9 - 52.2 mV respectively. The SNEDDS exhibited good efficiency for selfemulsification. The in vitro dissolution profile was studied in 0.1 N HCl and phosphate buffer (pH 6.8). SNEDDS with (mix) surfactant : cosurfactant ratio (2:1) and (mix)-oil ratio (6:1) showed the highest drug release. Keywords: Self-emulsifying systems, nano-emulsion, Capmul MCM C8, oleic acid, SNEDDS.

INTRODUCTION

In recent years, much attention has been focused on lipidbased formulations to improve the oral bioavailability of poorly water-soluble drug compounds. In fact, the most popular approach is the incorporation of the active lipophilic component into inert lipid vehicles such as oils1, surfactant dispersions2, emulsions3, liposomes4, selfemulsifying formulations5, self-nanoemulsifying systems6-9 and self-microemulsifying systems10. Most of them increase surface area of the drugs to improve solubilisation behaviour as well as permeation. Lipids have been extensively studied as components of various oily liquids and dispersions that are designed to increase solubility and oral bioavailability of BCS class II and IV drugs.11, 12 Some of the potential advantages of self-emulsifying lipid formulations include physicochemical stability, enhanced oral bioavailability enabling reduction in dose, consistent temporal profiles of drug absorption, selective targeting of drug towards specific absorption window in GIT, control of drug delivery profiles, ability to increase Cmax, AUC, and reduced tmax, linear AUC-dose relationship, reduced variability including effect of food, protection of sensitive drug substances, high drug payloads and flexibility of designing liquid or solid dosage forms. SNEDDS are isotropic mixtures of oil, surfactants and cosurfactants that form fine oil-in-water nanoemulsions upon mild agitation, followed by dilution with aqueous media, such as GI fluids.13 SNEDDS can be orally
*Corresponding Author: Preeti K Suresh University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur-492 010, Chhattisgarh, India. Contact no:- +91-9827938427 Email: preeti_venugopalan@yahoo.co.in, suresh.preeti@gmail.com

administered in soft or hard gelatin capsules due to the anhydrous nature. They typically produce nanoemulsions with droplet sizes between 20 and 200 nm upon dilution. When compared with emulsions, which are sensitive and metastable dispersed forms, SNEDDS are physically stable formulations that are easier to manufacture, and may offer an improvement in dissolution rates and extents of absorption, resulting in more reproducible bloodtime profiles due to the nanometer sized droplets present. Droplet size has been widely proposed as a key factor for the efficiency and fate of SNEDDS.6,7,9,13 SNEDDS are particularly useful when the poorly water soluble compounds are to be pre-dissolved in a suitable solvent and filled into capsules. The main benefit of this approach is that pre-dissolving the compound overcomes the initial rate limiting step of particulate dissolution in the aqueous environment within the GI tract. However, a potential problem with this system is that the drug may precipitate out of solution when the formulation disperses in the GI tract, particularly if a hydrophilic solvent is used (e.g. polyethylene glycol). But alternatively, if the drug can be dissolved in a lipid vehicle there is less potential for precipitation on dilution in the GI tract, as partitioning kinetics will favor the drug remaining in the lipid droplets.11 The bioavailability enhancing property has been associated with a number of in-vivo properties of lipidic formulation including:

The formation of fine dispersions and micellar suspensions to prevent precipitation and recrystallization of the drug compound. The ability of certain lipid compounds and their metabolites to initiate changes in the gastrointestinal Pharmacie Globale (IJCP), Vol. 02, Issue 09

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fluid to favor improved drug absorption. The inhibition of cellular efflux mechanisms and preabsorptive metabolism by gut membrane-bound cytochrome enzymes, further augmenting the absorption enhancing properties of these formulations.14, 15 Certain lipidic excipients are associated with selective drug uptake into the lymphatic transport system, thereby reducing the effect of first-pass drug metabolism in the liver.16 The potential of SNEDDS to improve the dissolution rate and bioavailability have been investigated for ibuprofen17, ezetimibe18, lactamase19, probucol20, tamoxifen citrate21, all-trans-retinol acetate22 and indomethacin23 with encouraging results.

Solubility studies An excess amount of CNZ was added to various oils, surfactants and cosurfactants, and mixed by vortexing. The mixture was kept at ambient temperature for 72 hr to attain equilibrium. The equilibrated sample was centrifuged at 1000 rpm for 10 min to remove the insoluble drug. An aliquot of the supernatant was diluted with methanol and CNZ was quantified by UV spectroscopy. Screening of oils The oils were selected on the basis of their tendency for self emulsification. The oils selected for this investigation were oleic acid, castor oil, olive oil and soyabean oil. The oils and surfactant (tween 80) were mixed in a ratio of 1:1. The mixture was then checked for self emulsification by adding 1 mL from each mixture to 5 mL of water and followed by agitation. The turbid solution obtained was observed under microscope for emulsion formation. Preparation of self nanoemulsifying systems A series of SNEDDs were prepared using oleic acid as the oil, Tween 80 as surfactant and Capmul MCM C-8 as the cosurfactant (Table 1). In all the formulations, the amount of CNZ was kept constant. Accurately weighed CNZ was placed in beaker and oil, surfactant, and co surfactant were added. The components were mixed by gentle stirring with magnetic stirrer and the resulting mixture was heated at 40C, until the drug was completely dissolved. The homogenous mixture was stored at room temperature until further use.
F-4 3:1 6:1 435 145 96 25 F-5 3:1 4:1 405 135 135 25 F-6 3:1 2:1 336 112 225 25 F-7 4:1 6:1 464 116 96 25 F-8 4:1 4:1 432 108 135 25 F-9 4:1 2:1 360 90 225 25

Cinnarizine (CNZ), a piperazine derivative with antihistaminic activity and high affinity to H1 receptors is currently used for the treatment of cerebral arteriosclerosis, cerebral thrombosis, and subarachnoid hemorrhage. A poorly water-soluble Class II drug, the oral delivery of CNZ is precluded due to variable dissolution and low bioavailability. The aim of the present study was to develop and evaluate SNEDDS of CNZ to improve its oral bioavailability.

MATERIALS AND METHODS

Cinnarizine was kindly supplied by Hikal Ltd, Bangalore, India as a gift sample. Capmul MCM C8 and Acconon MC82 were kindly donated by Abitec Corporation, Janesville, WI. All other chemicals were purchased from Loba Chemie Pvt Ltd, Mumbai, India and were used as received. Table 1. Composition of various SNEDDS formulations of Cinnarizine
Formulation (mix) S:Co-S (mix) : oil Tween-80 (mg) Capmul MCM C-8 (mg) Oleic acid (mg) Cinnarizine (mg) F-1 2:1 6:1 386 193 96 25 F-2 2:1 4:1 360 180 135 25 F-3 2:1 2:1 300 150 225 25

Characterization of SNEDDS separation or drug precipitation. Robustness to dilution: Robustness to dilution was Determination of emulsification time: Self-emulsifying studied by diluting the formulation with 100 times formulations can be graded for self-emulsification time, volumes of various dissolution media viz. 0.1N HCl and dispersibility and appearance.24 Visual assessment criteria phosphate buffer (pH 6.8). The diluted nanoemulsions for self nanoemulsion formed from different formulation is were stored for 12 h and observed for any signs of phase shown in Table 2. Table 2. Visual assessment criteria for self nanoemulsification
Grade I II III IV V Time for self-emulsification within 1 min within 2 min within 3 min Longer than 3 min Longer than 3 min Appearance Clear or slightly bluish Slightly less clear, bluish white Bright white, similar in appearance to milk Dull, grayish white emulsion, slightly oily appearance Large oil droplets present on the surface Dispersibility Rapid emulsification Rapid emulsification Rapid emulsification Slow to emulsify Poor or minimal emulsification

Transmission electron microscopy: The nanoemulsion globules were visualized by Transmission Electron Microscope (TEM) (MORGAGNI 2680 FEI, (Holland). Samples were dried on carbon-coated grid and negatively stained with aqueous solution of phosphotungstic acid. After drying the specimen was viewed under the microscope. Droplet size and zeta potential analysis: The droplet size and zeta potential of the emulsions was determined at 25C by dynamic light scattering (DLS) with Zetasizer Nano-ZS (Malvern Instrument Limited, UK) by monitoring at a scattering angle 173C. The nanometric size range of the globule was retained even after 100 times dilution with water which proves the compatibility of the system with excess water (Table 3).

Drug loading efficiency: 50 mg formulation was taken and to it methanol was added to make up the volume to 100 ml. The resultant solution was analysed spectroscopically following suitable dilution (Table 4). The drug loading efficiency was determined by the following formula: Stability study The physical stability study of the various SNEDDS formulations was performed at 4C, 25C and 45C for 60 days. The SNEDDS was evaluated by visual inspection for physical changes such as color and drug precipitation. In-vitro dissolution study Dissolution profiles of the SNEDDS were investigated Pharmacie Globale (IJCP), Vol. 02, Issue 09

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using the dialysis bag method according to dissolution apparatus 2 in USP 24 in 0.1N HCl and Phosphate buffer (pH 6.8) (900 mL). The formulation was placed in dialysis bag (MWCO 12000, Medicell International, UK) held to the bottom of the vessel using copper sinkers. The temperature was maintained at 370.5C during the study. At regular time intervals, 3 ml samples were withdrawn and replaced with equal volumes of fresh medium. The withdrawn samples were analysed spectrophotometrically for the drug content.

superior solubility, another benefit of using oleic acid is that it does not undergo lipolysis in GIT. Figure 1. Solubility profile of cinnarizine in various excipients

RESULTS AND DISCUSSION

Solubility studies Solubility of CNZ in components of SNEDDS is essential. The choice of surfactants is limited as very few surfactants are oraly acceptable. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules.25 The co-surfactant along with the surfactant, lower the interfacial tension to a very small, even transient negative value. At this value the interface would expand to form fine dispersed droplets, and subsequently adsorb more surfactant and surfactant/cosurfactant until their bulk condition is depleted enough to make interfacial tension positive again. This process known as spontaneous emulsification leads to the formulation of microemulsion. The selection of surfactant and co-surfactant is crucial not only to the formation of microemulsion, but also to solubilisation in microemulsions.

Screening of oils Oils can solubilize the lipophilic drug and is the most important excipient as it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract.26 The screening studies based on self emulsification indicated that all the oils used viz. oleic acid, castor oil, olive oil and soybean oil were efficient in selfemulsification and could be used for preparing SNEDDS. Robustness to dilution Robustness to dilution was studied by diluting the SNEDDS 100 and 1000-fold with various dissolution media viz. 0.1N HCl and phosphate buffer (pH 6.8). The diluted nanoemulsions showed no visible signs of phase separation or drug precipitation after storage for 24 h at 37.0+0.5C.

Droplet size and zeta potential analysis Droplet size distribution and zeta potential are important The solubility of CNZ was determined in various oils, characteristics of emulsion indicating the static electricity surfactants and cosurfactants and the results are repulsion and congregation of the droplets.27-29 And these presented in Figure 1. Solubility studies of drug in oil parameters are vital in determining the stability and in indicated that it was more soluble in oleic acid, Tween 80 vivo fate of emulsions. The droplet size and zeta potential and Capmul MCM C-8, and hence these excipients were were observed with the help of Malvern Zetasizer. The short listed for the preparation of SNEDDS as oil, results are shown in Table 3. surfactant and cosurfactant respectively. In addition to Table 3. Droplet size and zeta potential of formulations after 100 X dilution
Formulation Average size (nm) F-1 59.7 + 3.4 F-2 78.9 + 4.6 F-3 111.9 + 4.7 F-4 148.8 + 5.4 F-5 166.6 + 6.7 F-6 178.8 + 4.2 F-7 191.7 + 8.1 F-8 234.4 + 7.8 F-9 317.3 + 10.2 The values are mean + SD (n=3) Poly dispersity index 0.227 + 0.32 0.236 + 0.25 0.179 + 0.21 0.288 + 0.27 0.276 + 0.33 0.366 + 0.26 0.400 + 0.37 0.542 + 0.31 0.607 + 0.28 Zeta potential (mV) -52.2 + 2.3 -39.9 + 1.9 -35.0 + 2.1 -43.5 + 1.4 -30.0 + 1.1 -40.0 + 1.5 -24.1 + 2.4 -28.5 + 2.0 -23.9 + 1.0

Droplet size of CNZ nanoemulsion decreased with reducing the oil content in SNEDDS. When Smix:oil ratio was 2:1, the droplet formed was larger in comparison with ratios 4:1 and 6:1 of Smix : oil. Generally, at 2:1 ratio of surfactant and cosurfactant, smaller droplet was formed than 3:1 and 4:1 ratio of Smix. The smallest droplet size of nanoemulsion (59.70 nm) was obtained at the 6:1 ratio of Smix to oil. From the observations it is apparent that as the nano size range is dependent on concentration of oil, surfactant/co-surfactant ratio, these smaller sized droplets owing to increased surface area may allow more dissolution and drug release. The poly dispersity index below 0.3 was obtained for all formulations except F-6 to F-9. Poly dispersity index

below 0.3 indicates good uniformity in the droplet size distribution after dilution with water. Nanoemulsions are stabilised by a greater zeta potential (negative) by preventing droplet coalescence upon random collisions of particles leading to repulsive forces which can stabilize the formulation. The zeta potentials of the formulations F-1 to F-6 were less than 30, while F-7, F8 and F-9 formulations showed lower values. These observations appear to corroborate the results obtained. Determination of self-nanoemulsification The efficiency for self-emulsification was observed according to the emulsification time, dispersibility and visual appearance. The formulations were categorized into different grades on the basis of assessment criteria given Pharmacie Globale (IJCP), Vol. 02, Issue 09

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in Table 1. It was observed that with the increase in ratio of surfactant/co-surfactant the time of emulsification increases. Formulations F-4 to F-6 were bluish white and graded II, formulations F-7 to F-9 were white and graded III and all other formulations were clear or slightly bluish and graded I. Transmission electron microscopy TEM study indicated that the nanoemulsion generated from formulation F-1 appeared as bright spots on a dark background (Figure 2). The emulsion droplets generated were spherical and uniform in size with a large population of smaller droplets in the size range between 30 and 90nm. Figure 2. Transmission electron micrograph of SNEDDS (F-1) after 1,000-fold dilution with water

As the droplet size decreased, surface area increased allowing more dissolution and drug release. When Smix : oil ratio was 2:1, the droplet formed was larger in comparison with ratios 4:1 and 6:1 of Smix : oil. Generally, at 2:1 ratio of surfactant and cosurfactant, smaller droplet was formed than 3:1 and 4:1 ratio of Smix. Thus, the drug release from formulation F-1 was found to be highest at 74.25% and 96.89% after 6 and 24 hr respectively. The release of a drug occurs following its partitioning to aqueous fluids during droplet transport and disintegration along the GI tract. The effective delivery of a drug from SEDDS is proposed to be governed primarily by small particle size and the polarity of the resulting oil droplets, which permits a faster rate of drug release into the aqueous phase. The optimal polarity of the formulation is achieved by the appropriate combination of oil and surfactants. In o/w microemulsion formulations, the polarity of the oil phase is a less dominant factor, since the drug can reach the capillaries while still incorporated within the microemulsion droplets.30-32 Excess surfactant in a formulation may also promote the effective dispersion of drug in the lumen by the solubilization process, in addition to drug spreading in oil droplets.33,34 The solubilized drug may not precipitate in the lumen, and undergo rapid absorption which is independent of the lipid digestion process.

Drug encapsulation efficiency Drug content of all the formulations was high at 95.2397.95 % and there was no significant difference in drug content among the various formulations (Table 4). Table 4. Drug loading of various SNEDDS
Formulation F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 % Drug content 97.95 96.42 97.73 96.97 97.40 95.99 96.02 96.21 95.23

CONCLUSION

SNEDDS is one of the most promising approaches towards overcoming the formulation difficulties and improving the oral bioavailability of hydrophobic/lipophilic drugs. In the present study SNEDDS of CNZ could be successfully developed and assessed for its in vitro performance. After preliminary screening, the formulations were prepared with different ratios of oleic acid as oil, Tween 80 as surfactant and Capmul MCM C-8 as cosurfactant. The SNEDDS was made by simple mixing method. An optimal formulation of SNEDDS is said to be one which forms nanoemulsions with a small droplet size on dilution with water. In terms of droplet size and drug release, F-1 formulation showed promising results. Zeta potential of F1 formulation was 52.2 mV which indicates good stability and high degree of repulsion between adjacent, similarly charged globules in dispersion. Polydispersity index of formulations F-1 to F-5 were below 0.3 signifying good uniformity in the droplet size distribution after dilution with water. Among the various formulations, F-1 showed highest drug release. It can be concluded that SNEDDS formed from oleic acid, tween 80 and Capmul MCM C-8 and (mix) surfactant co-surfactant ratio (2:1) and (mix)-oil ratio (6:1) is a promising approach to improve the solubility, dissolution rate and bioavailability of CNZ.

Stability studies The stability studies indicated that all the formulations were stable at 4C with no visible changes in color and precipitation. F-8 and F-9 showed a slight color change after storage at 25C after 20 days. Some samples (F-6, F7, F-8, F-9) stored at 45C showed minor changes in color and precipitation after storage for 20 days. In-vitro release study The release profile of CNZ was investigated in 0.1N HCl and Phosphate buffer (pH 6.8) to investigate the effect of pH on the drug release. Dissolution profiles of the various formulations are presented in Figure 3. Figure 3. Cumulative % drug release from the various SNEDDS

ACKNOWLEDGMENT

The authors are thankful to Director, University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur for providing the infrastructural facilities to carry out this work. Thanks are also due, to Hikal Ltd., Bangalore, India for kindly supplying Cinnarizine and to Abitec Corporation, Janesville, WI for kindly donating Capmul MCM C8 and Acconon MC8-2.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. Pharmacie Globale (IJCP), Vol. 02, Issue 09

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