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Journal of Microencapsulation Micro and Nano Carriers

ISSN: 0265-2048 (Print) 1464-5246 (Online) Journal homepage: http://www.tandfonline.com/loi/imnc20

Enhanced Oral Delivery of Risperidone through a Novel Self-Nanoemulsifying Powder (SNEP) Formulations: In-Vitro and Ex-Vivo Assessment Srikanth Bandi, Krishna Sanka & Vasudha Bakshi To cite this article: Srikanth Bandi, Krishna Sanka & Vasudha Bakshi (2016): Enhanced Oral Delivery of Risperidone through a Novel Self-Nanoemulsifying Powder (SNEP) Formulations: In-Vitro and Ex-Vivo Assessment, Journal of Microencapsulation, DOI: 10.1080/02652048.2016.1223200 To link to this article: http://dx.doi.org/10.1080/02652048.2016.1223200

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Date: 16 August 2016, At: 01:53

Enhanced Oral Delivery of Risperidone through a Novel Self-Nanoemulsifying Powder (SNEP) Formulations: In-Vitro and Ex-Vivo Assessment Srikanth Bandi, Krishna Sanka, Vasudha Bakshi Department of Pharmaceutics, School of Pharmacy (Formerly Lalitha College of Pharmacy), Anurag Group of Institutions, Hyderabad-500088, AP, INDIA.

Running title: Risperidone Self Nanoemulsifying Powder Formulation

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Key words: Risperidone, Aerosil® 200, Z-average, polydispersity index, SNEL, SNEP.

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Corresponding author

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Krishna Sanka Department of Pharmaceutics, School of Pharmacy (Formerly Lalitha College of Pharmacy), AGI Hyderabad-500088, Telangana State, India [email protected] +91-9701907755

Abstract Context: The oral delivery of risperidone encounters a number of problems such as pH dependent solubility, low bioavailability due its lipophilicity and aqueous insolubility. Objective: To improve solubility, dissolution

and

intestinal

permeation thereby

bioavailability of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations. Materials and Methods: Oleic acid, Tween® 20, PEG 600 and Aerosil® 200 were chosen as oil, surfactant, co-surfactant and carrier, respectively from solubility and emulsification studies. Ternary phase diagram was constructed to determine emulsifying

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region. Results and Discussion: The Z-average and Polydispersity Index of developed formulation was 83.1 nm and 0.306, respectively. Ex vivo permeation studies on isolated rat

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intestine indicated that the amount of risperidone permeated from SNEP formulation was

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increased around 4 and 1.8 fold than that of pure drug and marketed formulation, respectively. Conclusion: This developed SNEP formulations can be regarded as novel and

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commercially feasible alternative to the current risperidone formulations.

Introduction Over the decades, oral drug delivery system had been a very encouraging and most explored field in pharmaceutical technology due to its ease of administration. However, the only limitation is that different drugs display distinct and different delivery profile from one another. One of the key factors for such phenomenon is the drug solubility. The Biopharmaceutics Classification System (BCS) Class II drugs suffer from poor water solubility resulting in a highly variable oral bioavailability. Even though they hold potential pharmacodynamic activity they fail to reach market. Dissolution is the rate limiting step for

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bioavailability of Class II drugs, hence increase in its dissolution rate results in an increase in bioavailability.

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The drug delivery scientists have employed an extensive range of methods to improve the

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dissolution rate of poorly water‐soluble drugs, including formulations containing nanoparticles, liquisolid formulations or self emulsifying drug delivery system (SEDDS), the

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use of surfactants (Balakrishnan et al., 2004; Razvi N et al., 2005; Jamzad and Fassihi, 2006; Sreedher and Aggarwal, 2009; Fatima et al., 2012), lipids (Basavaraj et al., 2011; Maulik et al., 2011), permeation enhancers, formation of salt (Martin et al., 2013), co-crystallization (Vinesha et al., 2013), solid dispersions (Jalalia et al., 2007; Ghareeb et al., 2009; Ahire et al.,

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2010; Samy et al., 2010; Shilpi et al., 2010; Krishnamoorthy et al., 2011; Kulthe et al., 2011), inclusion complexes with cyclodextrins (Moriwaki et al., 2008; Srikanth et al., 2010; Patel et

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al., 2011; Chaturvedi et al., 2011; Sucheta et al., 2011; Mehta et al., 2012; ) and modified cyclodextrins, nanosuspensions and colloidal vesicles like liposomes (Yaping et al., 2009), niosomes and stable amorphous form of the drug (Gursoy et al., 2003; Gursoy and Benita, 2004; Tamilvanan and Benita, 2004; Ichikawa et al., 2007). Aditionally, several strategies have been reported for the better oral delivery of the drugs, including microspheres (Sullad et al., 2014; Phadke et al., 2015), coated microspheres (Kajjari et al., 2013; Angadi et al., 2012;

Angadi et al., 2013; Kajjari et al., 2014; Phadke et al., 2014), nanoparticles (Agnihotri, et al., 2004), ultra small nanoparticles (Chaturvedi et al., 2013a), polymeric hydrogels (Chaturvedi et al., 2013b; Chaturvedi et al., 2015) In recent years, however, much attention has been focused on lipid based formulations with particular emphasis on self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of poorly water soluble drugs (Woo et al., 2008; Balakrishnan et al., 2009; Cui et al., 2009). SNEDDS is oral lipid dosage form. It is a mixture of oil, surfactant and co-surfactants that have the capacity to form fine oil in water emulsions upon gentle

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agitation following dilution with the aqueous phase. SNEDDS are thermodynamically stable systems with the droplet size usually <100 nm. SNEDDS have been widely studied to

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increase the bioavailability of hydrophobic drugs (Constantinides, 1995; Gao et al., 1998;

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Lawrence and Rees 2000; Kawakami et al., 2002; Araya et al., 2006; Ghosh et al., 2006). The hydrophobic drugs are easily dissolved in the oil phase. The mechanisms for the enhance in

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the bioavailability are improvement of drug solubilization, protection against enzymatic degradation, the increased specific surface area of the droplets that led to wide distribution of the drug in the gastro intestinal tract and surfactant induced permeability changes (Ke et al., 2005).

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One of the most accepted and commercially feasible formulation strategies for resolving the solubility and bioavailability problems is SNEDDS. This has been shown to be reasonably

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successful in enhancing the oral availability of poorly water-soluble drugs (Gursoy et al., 2004; Sanka et al., 2016). However, SNEDDS are generally prepared as liquids that create some disadvantages, for instance, high manufacturing costs, stumpy stability and limited drug loading. More significantly, the large amount (around 50%) of surfactants in the formulations can lead gastrointestinal irritation.

To tackle these problems, Self nanoemulsifying powder (SNEP) formulations have been studied as alternative strategies. Such systems require the solidification of self-emulsifying liquid (SNEL) ingredients into powders to create various solid dosage forms Self nanoemulsifying tablets (Nazzal et al., 2002; Attama et al., 2003), Self nanoemulsifying pellets (Franceschinisa et al., 2005; Abdalla et al., 2007), self nanoemulsifying powder filled capsules (Lip et al., 2014)). Thus, SNEP combine the advantages of SNEL (improved solubility and bioavailability) with those of solid dosage forms (low manufacturing cost, ease of process control, elevated stability and reproducibility, improved patient compliance).

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The current investigation deals with ‘risperidone’ a benzisoxazole derivative psychotropic agent, which is a selective monoaminergic antagonist. It is approved by the United States

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Food and Drug Administration (USFDA) for treatment of schizophrenia, bipolar disorder and

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irritability in children and adolescents ages. It is practically insoluble in water and exhibits a pH dependent solubility. The daily dose of risperidone varies between 0.25 mg and 16 mg

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and frequently prescribed dose is 2 mg for the adult. Therefore, for the present study, 2 mg dose was selected for the development of nanoemulsion formulation. The aim of the study was to enhance the solubility of risperidone in water and thereby bioavailability by

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formulating it as a self nanoemulsifying powder (SNEP) formulation.

Materials and Methods Materials Risperidone was generously provided by Dr. Reddy’s Laboratories, Hyderabad, India. Isopropyl myristate (IPM) was procured from Sisco Research Laboratories Pvt. Ltd., Mumbai, India. Triacetin, Myglyol® 812, Tween® 80, Tween® 20, PEG 300, PEG 400, PEG 600, Propylene glycol, Span® 80, Span® 20, Oleic acid, Arachis oil, Sesame oil, Sotton seed oil and Soya oil were procured from SD fine chemicals Ltd, Mumbai, India. Both methanol and acetonitrile, HPLC grade were obtained from Merck specialties Pvt. Ltd., Mumbai, India.

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Brij® 30 was purchased from Sigma Life Sciences, Bangalore, India. Castor oil was procured from Jatin Chemicals, Hyderabad, India. High Performance Liquid Chromatography (HPLC)

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grade water was freshly prepared from SG-Lobostar (3TWF-UV, Labindia, Mumbai, India)

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water purification system. All other materials were of analytical grade. Methods

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HPLC operating conditions for risperidone analysis

HPLC (Shimadzu, Tokyo, Japan) equipped with a Chemisil® ODS C18 column (5 µm, 250 mm x 4.6 mm ID) and a PDA detector (Model SPD M20A) was used in this analysis. The mobile phase was composed of methanol and 0.2% ortho phosphoric acid in water in the

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volume ratio of 80:20. The eluent was monitored at 235 nm with a flow rate of 0.6 ml/min. And the retention time of risperidone was 3.695 min. The calibration curve was constructed

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over a range of 500 to 10,000 ng/ml in methanol (R2= 0.996). (Sanka et al., 2014) Selection of oil

Various commonly used both synthetic and natural oils were screened for their capability to dissolve the maximum amount of risperidone. An excess amount of risperidone was added to each of the 1.5 ml Eppendorf tubes containing 1 ml of different oils (Arachis oil, Myglyol® 812, Sesame oil, Cotton seed oil, Oleic acid, Soya oil, Castor oil, Isopropyl Myristate and

Triacetin) investigated in the study. The mixtures were vortexed on a cyclomixer (REMI CM 101DX, REMI equipment, Mumbai, India) for 5 min to ease proper mixing and solubilization of risperidone in different oils. The mixtures were then allowed to equilibrate at 25 ± 1.0 ºC temperature by keeping in an orbital shaking incubator (CL 24, REMI Electrotech Ltd., Chennai, India) for 48 h (Wang et al., 2009). The samples were then centrifuged at 5000 rpm for 20 min to remove the undissolved drug using micro centrifuge (RM 12C, REMI equipment, Chennai, India). Aliquots of supernatant, usually 0.1 ml, were suitably diluted with methanol after filtration through a 0.45µm syringe filter. The risperidone dissolved in

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different oils was quantified using RP-HPLC method described in methods section 2.2.1 (Shweta et al., 2011). The solubility of risperidone was determined in different oils,

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replicated for three times in each oil and the data was represented as mean ± SD.

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Selection of surfactant

The solubility of risperidone was determined in Tween® 80, Tween® 20, Span® 80, Span® 20

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and Brij® 30 by following the similar procedure as explained under the selection of oil by substituting oils with the surfactants. Thereafter, the surfactants were selected based on their ability to emulsify the selected oil phase. To verify the emulsification ability, 20 µl of surfactant was added to 20 µl of the selected oily phase, mixed thoroughly. From this mixture

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25 µl was transferred and diluted to 25 ml with distilled water in a volumetric flask. The ease of formation of emulsions was monitored by the number inversions of volumetric flask that

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are required to produce a uniform emulsion. The emulsions were kept aside for 2 h and their transmittance was measured at 638.2 nm using UV–visible spectrophotometer (UV-3200, Shimadzu, Japan) using distilled water as the blank (Date and Nagarsenker, 2007; Shweta et al., 2011). The total process was repeated for three times and the results were represented as mean ± SD.

Selection of co-surfactant The solubility of risperidone was also determined in various co-surfactants (PEG 200, PEG 300, PEG 400, PEG 600 and Propylene Glycol) by following the same procedure as described under the selection of oil by substituting oils with co-surfactants. Co-surfactants were screened based on their efficacy to improve the nanoemulsification ability of the selected surfactants. For this, 40 µl of surfactant was mixed with 20 µl of the co-surfactant (surfactant: co-surfactant = 2:1). The selected oil (60 µl) was added to this mixture (oil: Smix =

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1:1) and the mixture was heated in a water bath to allow proper mixing. Then 25 µl of this mixture was transferred to volumetric flask and diluted it to 25 ml with distilled water and the

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ease of formation of emulsions was monitored by the number of inversions necessary to

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produce uniform emulsion. The emulsions were kept aside for 2 h. Then the transmittances of emulsions were measured at 638.2 nm using UV–visible spectrophotometer using distilled

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water as the blank (Shweta et al., 2011). The total process was repeated for three times and the results were represented as mean ± SD. Construction of ternary phase diagrams

Oleic acid, Tween® 20 and PEG 600 were selected as oil, surfactant and co-surfactant

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respectively from solubility studies and screening. The selected surfactant and co-surfactants were mixed in four different weight ratios (1:1, 2:1, 3:1 and 4:1 respectively) to prepare Smix.

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The each Smix was mixed with selected oil in seventeen different weight ratios viz. 1:9 to 9:1 (1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 and 2:1). Thus, the total number of final mixtures were seventy eight. These mixtures were mixed using cyclomixer (REMI CM 101DX, REMI equipment, Mumbai, India) for 5-10 min, after which 0.1 ml of homogeneous mixtures formed was transferred to 100 ml glass beakers. To these beakers containing 0.1 ml oil, Smix mixtures, 100 ml of distilled water was added and stirred

for 10 minutes using a magnetic stirrer (100 rpm) at 37⁰ C temperature. Then these solutions were allowed to stand for 2 h and the % transmittance were taken at 638.2 nm using UV visible spectrophotometer using distilled water as blank. The resultant emulsions were checked for clarity, phase separation, coalescence of oil droplets and transmittance. Emulsions showing phase separation, turbidity, coalescence and high transmittance (> 85%) were judged as “unstable” or “bad” emulsions. Emulsions that are not showing any phase separation, turbidity, coalescence and shows high transmittance (> 85%) were judged as “stable” or “good” emulsions. Ternary phase diagram was constructed using oil, Smix ratios

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with which “stable” or “good” emulsions formed upon dilution with distilled water. The nano emulsion region in the ternary phase diagram was shown as the shaded area (Fig. 1) (Ana et

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al., 2012).

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Preparation of SNEL formulation

From the nanoemulsifying region obtained from constructing ternary phase diagram, twelve

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different SNEL formulations were formulated using oil (10%, 17% and 50%) and Smix in the ratios of 1:9, 1:5 and 1:1 as well as the surfactant and co-surfactants in the ratios of 1:1, 2:1, 3:1 and 4:1. The drug loaded SNEL formulations were formulated by dissolving accurately weighed amount of risperidone in the oil phase. The oil phase was added drop wise to Smix.

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The mixture was vortexed until a clear solution was obtained. The final formulation was investigated for signs of turbidity or phase separation after equilibration at ambient

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temperature for 48 h prior to self-emulsification and particle size studies. The compositions of prepared SNEL formulations were represented in table 1. Particle size and Poly dispersity index (PDI) analysis The particle size of the twelve above formulated emulsions were determined by using a Zetasizer (Delsa™ nano C, Beckman coulter, Mumbai, India) photon correlation spectroscopy particle size analyzer at a wavelength of 635 nm at 25 ºC. Aliquots (1 ml) of

each SNEL formulations, serially diluted 100-fold with purified water, were used to measure the particle size and PDI. The values of Z-average diameters were used in the study. Preparation of SNEP formulation Adsorption of SNEL formulations on to the surface of inert solid carriers is the simplest technique to convert SNEL formulations to SNEP formulations. Aerosil® 200 was used as an inert solid carrier in the present study. The dose equivalent, prepared SNEL formulation was transferred to a china dish and Aerosil® 200 was added in increments with vigorous stirring until a free flowing powder was formed. Finally the dose equivalent amount of free flow

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powder was filled in hard gelatin capsules (Size: 1). Characterization of optimized formulations

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In vitro drug release studies

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The release of risperidone from the optimized SNEL and SNEP formulation (both equivalent to 2 mg of risperidone), marketed tablet (2 mg) and pure risperidone (2 mg) was determined

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by using USP II dissolution test apparatus (DS 8000, LAB INDIA, Mumbai, India). The test was performed at 35 ± 0.5 ºC at a paddle speed of 100 rpm using 900 ml of 0.1 N HCl as dissolution medium. At predetermined time intervals (0, 5, 10, 15, 30, 45, 60, 90 and 120 min), an aliquot (2 ml) of the samples was withdrawn and filtered using a nylon syringe

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membrane filter (0.45 µm) and same volume (2 ml) of the fresh dissolution medium was added to the respective dissolution jars to compensate for any loss due to sampling. The

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quantification of the risperidone in the resulting solution was determined using the HPLC method described in section 2.2.1. The dissolution release test for developed formulations and marketed formulation was repeated for six times and the obtained release data was represented as mean ± SD.

Ex vivo permeation studies In this study male Wistar rats weighing between 175 to 230 g were used with prior approval from the Institutional Ethical Committee, School of pharmacy, Anurag group of institutions, Hyderabad, India (CPCSEA Reg.No:1412/A/11/CPCSEA). The animals were housed in separate cages. They were maintained under controlled conditions of temperature and the rats had free access to water and food until they were sacrificed. The rats were sacrificed by excess ether inhalation. The abdomens were opened and small intestines were isolated and

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the peripheral tissues were removed. The entire length of small intestines were placed in krebs- ringer solution before the tissue preparation and continuously aerated. The intestines

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were then flushed with krebs solution to remove the mucous and adhered intestinal contents.

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One end of each intestine segment was ligated with silk thread. SNEP formulation (equivalent to 2 mg of risperidone), was introduced into lumens of three different intestines

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using a syringe and were tightly closed with the threads. The tissues were placed in four different beakers containing 150 ml of HPLC grade water with continuous aeration and maintained at a temperature of 37 ± 0.5˚C. At predetermined time intervals, an aliquot of samples (2 ml) was collected from the four beakers and the medium was replaced with an

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equal volume of fresh medium. The samples were analyzed for risperidone using HPLC method described in section 2.2.1 ( Pradip et al., 2006). The same procedure was repeated

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for pure risperidone, SNEL formulation and crushed marketed tablet formulation for comparison. Permeation experiments for developed and marketed formulations were repeated for six times and the obtained permeation data was represented as mean ± SD. Permeation data analysis The cumulative amount of risperidone drug permeated (Q) was plotted against time. The steady state flux (Jss) was calculated from the slope of the linear portion of the cumulative

amount permeated per unit area vs. Time plot. The permeability coefficient (Kp) of the drug through intestine was calculated by dividing steady state flux (Jss) with initial concentration of risperidone in donor compartment. The enhancement ratio (ER) was calculated by dividing steady state flux (Jss) of the formulation with steady state flux (Jss) of pure drug (Gurrapu et al., 2012; Janga et al., 2012). Solid state characterization of SNEP formulation Fourier transform infrared (FT-IR) spectroscopy Infrared spectra of risperidone, Aerosil® 200 and optimized SNEP formulations were

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obtained by employing a FT-IR spectrophotometer (Bruker, Alpha-T, USA). The samples were prepared by conventional KBr pressed pellet technique. The scanning range was 400-

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4000 cm-1 and the resolution was 4 cm-1.

Morphological analysis of SNEP formulation

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The outer macroscopic structures of pure risperidone, Aerosil® 200 and risperidone SNEP formulation, were examined by using scanning electron microscope (S-3700, Hitachi, Japan). The powders to be analyzed were fixed to a brass specimen club using double sided adhesive tape made electrically conductive by coating in a vacuum (6 Pa) with platinum

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using ion sputter at 15 mA. The SEM photographs were taken at an excitation voltage of 10 kV.

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Differential scanning calorimetry (DSC) The thermal characteristics of pure risperidone powder, Aerosil® 200 and risperidone SNEP formulation were investigated by employing a Differential scanning calorimeter (DSC 60, Shimadzu, Japan), by keeping about 2 mg of each sample individually in a sealed aluminum pan before heating under a nitrogen flow (25 ml/min) and at a heating rate of 10 ºC/min from 0 ºC to 200 ºC.

Powder X-ray diffractometry (PXRD) The assessment of crystallinity of the final SNEP formulation powder, pure risperidone and Aerosil® 200 was conducted by powder X-ray powder diffractometer ((XRD-700, Shimadzu, Japan), at room temperature using monochromatic Cu Kα-radiation at 30 mA and 40kV in the region of 2º ≤ 2θ ≤ 50º with an angular increment of 0.02º /Sec. Results Selection of oil The solubility of risperidone in different oils was given in Table 2. The solubility of

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risperidone in water is 0.0028 mg/ml. The drug was more soluble in all oils compared to its solubility in water. Among these oils, Oleic acid showed higher drug solubility (21.292 ±

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to its good solubilisation capacity for risperidone.

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1.265 mg/ml) compared to remaining oils. Thus, Oleic acid was selected as the oily phase due

Selection of surfactant

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The solubility of risperidone in various surfactants was given in Table 3. Among the tested surfactants in the study, Span® 20 showed the highest drug solubility and the drug solubility in the remaining surfactants were in the order of Span® 80 > Tween® 20 > Brij® 30 > Tween® 80. But the surfactant selection was based on both the drug solubility as well as the capability

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of forming spontaneous fine emulsion. From the screening, Tween® 20 was selected for the study as it showed both the ability to emulsify the selected oil and good solubilization

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capacity for risperidone.

Selection of Co-surfactant The drug risperidone solubility in various co-surfactants was shown in Table 4. The order of drug solubility in co-surfactants was found to be PEG 600 > PEG 200 > Propylene glycol > PEG 400 > PEG 300. From the screening of co-surfactants PEG 600 was selected for the

study as it showed both the ability to improve the nanoemulsification efficiency of the selected surfactant and high drug solubility. Construction of ternary phase diagram The ternary phase diagrams were constructed in the absence of risperidone to optimize concentrations of oil, surfactant and co-surfactant in the SNEL formulations and to identify the self-emulsifying regions. The phase diagram of the system containing Oleic acid, Tween® 20 and PEG 600 as the oil, surfactant and co-surfactant, respectively and was shown in Fig. 1. Emulsion particle size measurement and PDI analysis

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The Z-average size and the PDI values of prepared twelve SNEL formulations were given in Table 5. Based on Z-average and PDI, the final formulation of respiridone loaded SNEL was

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optimized. Among all the formulations, three formulations (F4 (125.4) , F7 (110.1) and F10

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(83.1)) showed Z average of less than 200 nm. As the acceptable value of PDI ranges from 0.3 - 0.7, only two formulations namely F7 and F10 were observed to be within the range.

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The formulations whose PDI value outside the limit, those are considered to be polydisperse. Although, the Z-average value of F7 and F10 was below 200 nm, the Z-average of F10 was significantly (p<0.05) smaller than F7. Hence the F10 formulation was chosen as the optimized SNEL formulation and converted to SNEP formulation for further studies.

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Fourier transform infrared (FT-IR) spectroscopy The comparative FTIR spectra of pure drug, Aerosil® 200 and final SNEP formulation was

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shown in Fig. 2.I The FTIR spectrum of pure risperidone has seven characteristic peaks at 1650 cm-1, 1192 cm-1 , 1650 cm-1, 1309 cm-1, 1536 cm-1, 1413 cm-1 and 1130 cm-1 for C=N stretching vibration, C-N stretching, C=O stretching, C-F stretching, N-O stretching, C=C stretching and C-O functional groups respectively. The FTIR spectrum of final SNEP formulation has seven characteristic peaks at 1646 cm-1, 1163 cm-1, 1646 cm-1, 1373 cm-1, 1535 cm-1, 1430 cm-1 and at 1113 cm-1.

Morphological analysis of SNEP formulation The scanning electron micrographs of pure risperidone drug, Aerosil® 200 and final SNEP formulations were represented in Fig. 2.II. The pure risperidone powder (Fig. 2.II.A) appeared as smooth surfaced rectangular crystals in shape, whereas Aerosil® 200 (Fig. 2.II.B) appeared as rough surfaced porous particles. However, the SNEP formulation (Fig. 2.II.C) prepared with Aerosil® 200 appeared as rough surfaced particles without any crystalline shape, indicating that the SNEL formulation was absorbed or coated inside the pores of Aerosil® 200. Differential scanning calorimetry (DSC)

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The DSC curves of pure risperidone drug, Aerosil® 200 and final SNEP formulations were

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depicted in Fig. 3. The pure risperidone drug showed a sharp endothermic peak at 170.27 ºC

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Powder X-ray diffractometry (PXRD)

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(Fig. 3A) corresponding to its melting point and indicating its crystalline nature.

The powder X-ray diffactometry patterns of pure risperidone, Aerosil® 200 and SNEP formulations were represented in Fig. 4. Pure risperidone had sharp peaks at different diffraction angles, showing a typical crystalline pattern (Fig. 4A). Aerosil® 200 showed no

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intrinsic peaks (Fig. 4B). The SNEP formulation showed no peaks at diffraction angles (Fig. 4C), showing an amorphous pattern.

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In vitro drug release studies

The dissolution rate of the drug from the both SNEL formulation and SNEP formulations was compared with that of pure risperidone and marketed tablet formulations (Fig. 5). The SNEL and SNEP formulations of risperidone were showed 73.44 ± 6.2 and 68.93 ± 3.8 % cumulative drug release within 15 min as a result of the fast, spontaneous emulsion formation and the smallest droplet size, whereas the pure drug showed 15.11 ± 3.6 % and the marketed

tablet (Rispidon-2) showed 52.11 ± 3.6 %. More than 85 % (88.3 ± 4.6 and 85.09 ± 3.7 % for SNEL and SNEP, respectively) drug release was observed within 60 min from both SNEP and SNEL formulation. Complete (more than 90 %) drug release was observed within 90 min from both SNEP and SNEL formulations. The total % cumulative drug release within 90 min of study from pure drug and marketed tablets were found to be only 29.53 ± 4.7 % and 71.02 ± 7.4 %, respectively. Ex vivo permeation studies Therefore, to have an insight on the ability of SNEP formulations for improved absorption,

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ex-vivo permeation study was carried out using isolated rat intestinal segment. The ex-vivo intestinal permeation study results showed the drug diffused at a faster rate from both the

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SNEL formulation and SNEP formulations than from the pure drug and marketed formulation

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(fig. 6). The cumulative amount of risperidone permeated from control was 65.01 ± 12.14µg and it was significantly increased to 142.81 ± 12.32, 257.41 ± 12.65, 314.92 ± 11.45 µg with

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marketed tablet, SNEP formulation and SNEL formulation respectively. The steady state flux (Jss) of pure drug, marketed tablet, SNEP formulation and SNEL formulation were 1.2188 ± 0.0101, 1.7995 ± 0.0211, 6.3681 ± 0.0511and 8.0865 ± 0.0021 µg/cm2/h *10-2, respectively. The permeability co-efficient (kp) of pure drug, marketed tablet, SNEP formulation and

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SNEL formulation were found to be 0.6094 ± 0.0021 , 0.8997± 0.021, 3.1840 ± 0.0051 and 4.0432± 0.1011 cm/h*10-3 respectively, and the enhancement ratio of marketed tablet, SNEP

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formulation and SNEL formulation were 1.48 ± 0.02, 5.23 ± 0. 14and 6.64 ± 0.22 when compared to pure drug (control). Discussion In this study, the SNEP formulations were prepared by using SNEL and Aerosil® 200. The SNEL was composed of Oleic acid, Tween® 20 and PEG 600. From the constructed ternary phase diagram it was observed that incorporation of the co-surfactant, PEG 600, within the

self-emulsifying region increased the spontaneity of the self-emulsifying process. The emulsification efficiency was good when the surfactant/co-surfactant concentration was greater than 75% v/v of the SNEL formulation. In this system, the formulations surrounding the self-emulsifying region in the phase diagram could not form nanoemulsion. It has been reported that the drug added to the SNEL formulation pre concentrate may occasionally have some effect on the self-emulsifying performance (Balakrishnan et al., 2009). However, in this study, no significant differences were observed in the self-emulsifying performance. The self-emulsification efficiency can be estimated by determining the rate of emulsification

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and droplet size distribution. The droplet size of the emulsion is an important factor in selfemulsification performance because it determines the rate and extent of drug release and

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absorption (Constantinides et al., 1994). From the Zetasizer results, it was observed that

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increasing the surfactant concentration in the SNEL formulation decreased the Z-average value of the formed emulsion. The SNEL formulations prepared with 18% co-surfactant (at

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72% surfactant) showed significantly smaller z-average value than that of other. Hence it was chosen as the optimized SNEL formulation for further studies. The IR spectra of both pure drug and final SNEP formulations were almost similar because of the similar functional groups which indicate that there was no interaction between

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risperidone and excipients employed in the formulation. The solid state characterization of SNEP by scanning electron microscopy (SEM), X-ray

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powder diffraction and differential scanning calorimetry (DSC) revealed the absence of crystalline risperidone in the final SNEP. The sharp endothermic peak in DSC of the risperidone was absent in the SNEP formulation (Fig. 3C) which indicates that risperidone might have been in an amorphous state in the SNEP formulation prepared with Aerosil® 200. Like the DSC results, the PXRD results indicate the presence of risperidone in an amorphous state in the optimized SNEP formulation.

The in vitro drug release studies of SNEP formulation revealed that the initial % cumulative risperidone release from porous carrier i.e., Aerosil® 200, was insignificant (p>0.05, Fcalculated (1.69) was less than F critical (7.14) and the number of data included in the study was 6) slower when compared to SNEL formulation (the statistical analysis was performed on cumulative Area Under the time vs % cumulative drug release Curve (AUC) data up to 15th minute). This may be attributed to additional steps involved during dissolution such as disintegration of the solid structure of the SNEP formulation and desorption of the SNEL formulation from the voids of porous carrier.

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The cumulative amount permeated in ex vivo studies across the intestine was found to be higher for both SNEL formulation and SNEP formulation compared to marketed and pure

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drug. The steady state flux was also increased with SNEL formulation and SNEP

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formulations compared to marketed tablet and pure drug. The enhancement ratio value above one indicates improved permeation. In this present study, we noticed an ER more than 1 for

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SNEP formulation and SNEL formulation compared to control. The improvement in the ER may be due to a combination of several reasons: (i) presence of nonionic surfactant due to which the fluidization of the intercellular lipid bilayer taken place; (ii) better membrane contact of non-ionic surfactant and improved partitioning of the drug into the bilayer; (iii)

Conclusion

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direct transfer of nano sized emulsion droplets across the epithelial membrane.

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An optimized SNEP formulation composed of Oleic acid, Tween® 20 and PEG 600 was successfully developed with enhanced dissolution rate and oral delivery. The SNEP formulation readily released the lipid phase containing drug to form fine oil in water type nanoemulsion, with narrow particle size distribution. The solid state characterization results reveal that the native crystalline state of the drug has been transformed into amorphous and molecular state. Further, the ex vivo permeation across the rat intestine, reveals the potential

of SNEP formulations for improved absorption of risperidone across intestinal tract. In conclusion, the SNEP formulation proved to be an efficient carrier system for improved oral delivery of risperidone. Acknowledgements The authors greatly acknowledge the receipt of pure risperidone from Aurobindo Laboratories Ltd, Bangalore, India and are also thankful to Dr. P. Rajeshwar Reddy, Chairman, School of Pharmacy (Anurag Group of Institutions) Hyderabad for providing research facilities.

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Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content

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and writing of the paper

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TABLES

Oil : Smix

Surfactat: Co-surfactant

Oil (% w/w)

Surfactant (% w/w)

F1

1:9

1:1

10

45

Cosurfactant (% w/w) 45

F2

1:5

1:1

17

41.5

41.5

F3

1:1

1:1

50

25

25

F4

1:9

2:1

10

60

30

F5

1:5

2:1

17

55.34

27.66

F6

1:1

2:1

50

33.4

16.6

F7

1:9

3:1

10

67.5

22.5

F8

1:5

3:1

17

62.25

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20.75

F9

1:1

3:1

50

37.5

F10

1:9

4:1

10

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12.5

72

18

F11

1:5

4:1

17

67.2

16.8

F12

1:1

4:1

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Table 1 Formulation table of risperidone SNEL formulation

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40

10

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Formula code

Table 2 Solubility of risperidone in various oils. Vehicle

Solubility mg/ml (n=3)

1

Arachis oil

1.062 ± 0.102

2

Myglyol

0.180 ± 0.031

3

Triacetin

0.941 ± 0.051

4

Iso propyl myristate

0.133 ± 0.022

5

Sesame oil

0.671 ± 0.056

6

Cotton seed oil

0.471 ± 0.071

7

Oleic acid

21.292 ± 1.265

8

Soya oil

0.401 ± 0.011

9

Castor oil

2.773 ± 0.862

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S.NO.

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Table 3 Solubility of risperidone in surfactants Surfactants

Solubility (mg/ml) (n=3)

1

Brij® 30

1.383 ± 0.147

3 4 5

5.085 ± 0.463

Tween® 80

0.994 ± 0.056

Tween® 20

1.573 ± 0.051

Span® 80 Span® 20

7.611 ± 0.547

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Table 4 Solubility of risperidone in Co-surfactants S.NO.

Co-surfactants

Solubility (mg/ml) (n=3)

1

PEG 200

3.28 ± 0.102

2

PEG 300

1.03 ± 0.042

3

PEG 400

1.54 ± 0.019

4

PEG 600

4.73 ± 0.114

5

Propylene glycol

2.24 ± 0.107

Oil : Smix

Z-average value (Droplet size)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

1:9 1:5 1:1 1:9 1:5 1:1 1:9 1:5 1:1 1:9 1:5 1:1

216.5 278.4 623 125.4 234.2 538.8 110.1 221.9 514.6 83.1 214.4 471.4

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Formulation

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Table 5 Droplet size and PDI of SNEL formulations PDI 0.27 0.326 0.403 0.291 0.306 0.359 0.305 0.321 0.349 0.306 0.314 0.346

Figure captions: Fig. 1 Ternary phase diagram for Oleic acid (oil), Tween 20 (Surfactant) and PEG 600 (cosurfactant) indicating the efficient self-emulsifying region (Shaded area). Fig. 2 I) Comparitive FTIR spectra and II) SEM images of A) Pure Drug B) Aerosil® 200 C) SNEP final formulation. Fig. 3 DSC thermograms of A) Pure Drug B) Aerosil® 200 C) SNEP final formulation Fig. 4 Powder X-ray difractograms of A) Pure drug B) Aerosil® 200 C) risperidone SNEP final formulation

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Fig. 5 Percentage Cumulative drug release from SNEL, SNEP, marketed formulation and Pure drug.

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Fig. 6 Amount of drug permeated profile from SNEP, SNEL and marketed formulation and

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pure risperidone through rat intestine.

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