Essay: Ondansetron hydrochloride (OND)

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Ondansetron hydrochloride (OND) is an anti-emetic drug commonly used for management of postoperative and chemotherapeutic-induced nausea and vomiting. It suffers from low absolute bioavailability (60%) and rapid elimination (t1/2; 3-4 h). The current work aimed to develop OND-loaded bilosomes as a promising transdermal delivery system capable of surmount drug limitations. The variables influencing the development of OND-loaded bilosomes (18 systems) via the thin film hydration technique were investigated, including; surfactant type (Span® 60 or Span® 80), surfactant: cholesterol molar ratio (7:0, 7:1 or 7:3) and sodium deoxycholate (SDC) concentration (0, 2.5 or 5%, w/v). The systems were characterized for particle size, polydispersity index, zeta potential, drug entrapment efficiency (EE %) and in-vitro permeation. Based on factorial analysis (32.21) and calculations of desirability values, 6 systems were further subjected to ex-vivo permeation through excised rat skin, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) and transmission electron microscopy (TEM). Histopathological examination and in-vivo permeation studies in rats were conducted on the best achieved system (B6) in comparison to drug solution. Higher desirability values were achieved with Span® 60-based bilosomes, Surfactant: cholesterol molar ratio of 7:1 and SDC concentration of 2.5%, w/v with respect to small vesicle size, polydespersity index and high zeta potential, EE% and cumulative drug permeation. TEM micrographs showed spherical shaped vesicles. OND was dispersed in amorphous state as revealed from DSC and PXRD studies. No marked effect was observed in rat skin following application of B6 system while higher ex-vivo and in-vivo cumulative permeation profiles were revealed.


Ondansetron- Bilosomes- Transdermal- Sodium deoxycholate- Permeation.


Cancer treatment is commonly followed by nausea and emesis, which is called by Chemotherapy-induced nausea and vomiting (CINV) and may affect the quality of patient life, discontinuance or decreasing the dose of chemotherapy. Around 70 % of patients, subjected to chemotherapy, suffer from emesis within or after 24 hours of administration, and 30% of patients suffer from anticipatory emesis (1).

CINV can be managed by number of drugs including; Dopamine antagonists, steroids or 5-HT3 receptor antagonists (2). 5-HT3 receptor antagonists showed superiority over other drugs in the prohibition and curing of CINV (3).

Ondansetron (OND) is commonly used for management of emesis after operations, radiotherapy or even chemotherapy. It is available in number of dosage forms; intravenous or intramuscular injections, tablets, oral solution, orally disintegrating tablets and suppositories (4).

Ondansetron suffers from low bioavailability (about 60%) as a result of first-pass metabolism effect which results and rapid elimination (t1/2; 3-5 h). Moreover, frequent dosing and invasive dosage forms of ondansetron decrease patient compliance, hence, comes the importance of developing a more safe, effective and convenient OND delivery system for cancer patients who receive chemotherapy (4). Therefore, transdermal delivery may represent a good tool to increase convenience administration to the patient (5). Moreover, physicochemical properties of Ondansetron hydrochloride (Mw: 365.15; logP: 2.07; logD (pH5.5): 0.19) increase chances of the transdermal delivery of its molecules(6).

Treatment of the intercellular lipid barrier of stratum corneum (SC) by colloidal vesicles makes it more loose and permeable (7). Lipid components of these vesicles enhance penetration and drug permeation by fluidization effect of the SC layer (8).

Many vesicular carriers such as liposomes (9), niosomes (10), transferosomes (11) and ethosomes (12) have been tried for their transdermal delivery to avoid the problems associating administering drugs by oral dosage forms. Bilosomes vesicles have same composition of niosomes with the addition of bile salts and were first reported by Conacher et al. (13). Bilosomes were previously studied as gastro-intestinal resistant vesicular carriers for vaccines to promote their oral delivery (14–16). They were also studied for transdermal drug delivery of tenoxicam by Al-mahallawi et al. (17).

The aim of this study was to develop OND-loaded bilosomal systems in comparison to niosomes in an attempt to promote transdermal delivery of OND, thereby, increasing its bioavailability. A full 32.21 factorial design was used to determine the effect of different formulation variables and to calculate highest desirability values for the best achieved bilosomal systems in comparison to OND-loaded niosomes. In-vitro permeation through cellulose membrane was conducted and desirability of all the prepared systems was determined to select systems for further analysis. Ex-vivo, In-vivo histopathological and permeation studies were accomplished for further assessment.

Materials and methods


Ondansetron hydrochloride (OND) and Emerest® ampoules (Ondansetron hydrochloride 2mg/mL) were generously donated by Global Napi Pharmaceuticals (Cairo, Egypt). Ondansetron, olmesartan (internal standard), span® 60, span® 80, sodium deoxycholate (SDC) and cellulose acetate dialysis tubing (M.wt cut-off 12,000-14,000) were purchased from Sigma Aldrich (St. Louis, MO). Cholesterol (CHL) NF was purchased from Parchem Industries (New rochelle, NY). Sodium lauryl sulfate, sodium chloride, potassium chloride, potassium dihydrogen orthophosphate-1-hydrate, disodium hydrogen orthophosphate-1-hydrate, and absolute ethyl alcohol were purchased from El Nasr Chemicals (Abuzabal, Egypt).

Preparation of OND-loaded niosomes and bilosomes

The thin-film hydration method was applied for preparation of OND-loaded niosomes and bilosomes using a surfactant, CHL and SDC (18). The investigated variables included; surfactant type (Span® 60 or Span® 80), surfactant: CHL molar ratio (7:0, 7:1, and 7:3) and SDC concentration (0, 2.5, and 5%, w/v). To prepare OND-loaded niosomes, OND (20 mg), the surfactant (Span® 60 or Span® 80) and CHL (if present) were added to ethyl alcohol (25 mL) (19) in a round bottom flask and dissolved via utilizing ultrasonic bath sonicator (ElmaS30H; Wetzikon, Switzerland) for 10 minutes (40 ºC). Rotary evaporator (Büchi® Rotavapor®; Flawil, Switzerland) was used for evaporation of the organic solvent under reduced pressure (60 ºC, 150 rpm, 5 minutes), till formation of the desired film on the inner wall of the flask. Distilled water (10 mL) was then added for hydration of the produced film under normal pressure at 700 rpm for 45 to confirm complete hydration and formation of OND-loaded niosomes. With respect to OND-loaded bilosomes, the same technique was employed except for incorporating SDC in the hydrating aqueous phase. To obtain uniform particle size dispersions, the developed systems were sonicated for 10 minutes (25 ºC). The prepared niosomes and bilosomal systems were then placed at 4 ºC until use.

Characterization of OND-loaded niosomes and bilosomes

Evaluation of polydispersity index (PDI), particle size (PS), and zeta potential (ZP).

The average PS of each dispersion was measured by photon correlation spectroscopy (PCS) which depends on analyzing the changes in scattered light intensity due to the random motion of particles (20), each dispersion was diluted (10 times) with deionized water before being analyzed. Measurements were carried out, in triplicate, at 90º to the incident beam using a Zetasizer (Malvern; Worcester-shire, UK) at 25±0.5 ºC. The zeta potential of each dispersion was measured in triplicate, at the same temperature, based on electrophoretic light scattering technology via laser Doppler Anemometer attached to Zetasizer. Lower PDI values reveals uniform and better distri
bution for particle size.

Determination of OND entrapment efficiency percentage (EE %).

The percentage of OND entrapped in each prepared system was determined, in triplicate, by determining the free (non-entrapped) OND. One mL of the dispersion was centrifuged via a cooling centrifuge (Sigma Laborzentrifugen GmbH; Osterode am Harz, Germany) at 4 ºC and 15,000 rpm for 1 hour. The supernatant was separated, diluted, and the concentration of OND was calculated after measuring the UV absorbance at λ max 303 nm using a spectrophotometer (UV-1800 Shimadzu; Kyoto, Japan). OND EE% was calculated as following:

OND EE%=[(total amount of OND- amount of free OND)/(total amount of OND)]×100

Transmission electron microscopy (TEM)

The morphological characteristics of representative OND-loaded bilosomal system was observed using TEM (H-7500, Hitachi; Tokyo, Japan). The selected bilosomal system dispersion was diluted, then, one drop of the dispersion was placed on copper grid, stained with phosphotungstic acid 1%, w/v and then air-dried for 10 minutes at 25 ºC prior to TEM examination.

Solid state characterization of OND-loaded bilosomes

The following characterization studies were conducted on representative lyophilized OND-loaded bilosomal system using freeze dryer (Martin Christ Company; Osterode, Germany) under vaccum -0.016 mbar, at -57 ºC for 24 hours.

a) Differential scanning calorimetry (DSC). The thermal characteristics of pure OND hydrochloride, SDC, CHL, Span® 60, physical mixture of OND with other bilosomes’ ingredients and lyophilized OND-loaded bilosomal system were examined using DSC (Shimadzu; Kyoto, Japan). The device was calibrated with purified nitrogen (99.9%). Samples (4 mg) were weighed accurately and placed in standard aluminum pans. Heating temperature range was from 10 ºC to 400 ºC and scanning rate was 10 ºC/min.

b) Powder X-ray diffraction (PXRD). To affirm DSC analysis, the XRD analysis of the same samples were conducted (PertPro®, PANalytical; Arnhem, Netherlands) using Cu Ka radiation ( 50 Kv, 60 mA) in the angular region of 2Ө = 4º-70º (21).

In-vitro drug permeation study

Cellulose acetate dialysis tubing pieces were equilibrated overnight in Sorensens’ Phosphate buffer (pH 7.4) containing Sodium lauryl sulfate (0.4%, w/v) (22). The membrane was mounted on a diffusion cell (Hanson Research Corporation; chatsworth, CA). The membrane surface area available for diffusion was 1.767 cm2. OND-loaded bilosomal system dispersion (0.25 mL) was placed at the donor side, while the receptor side was filled with 7.2 mL of Sorensens’ phosphate buffer (pH 7.4) containing sodium lauryl sulfate (0.4%, w/v) to maintain sink conditions and stirred at 600 rpm (32 ± 0.5 ºC) (23). Samples from the receptor compartment (0.25 mL) were withdrawn at different time intervals till 8 hours, and immediately replaced with fresh buffer solution to keep up constant volume and sink conditions. The obtained samples were then analyzed spectrophotometrically. For comparative studies, the cumulative percentages of OND permeated after 0.5 hour (P0.5h) and 8 hours (P8h) were determined. The results were statistically analyzed at P= 0.05.

Studying the effect of the formulation variables via a 32.21 full factorial design

A full 32.21 factorial design was compiled to estimate and optimize the effect of formulation variables on OND-loaded bilosomal system’s characteristics using the minimum number of experiments (24). Three factors were selected as the independent variables. (i) The surfactant type (X1) was assessed at two levels (Span® 60 or Span® 80), (ii) surfactant: cholesterol molar ratio (X2) was assessed at three levels (7:0, 7:1, 7:3) and (iii) the bile salt concentration (X3) was evaluated at three levels (0, 2.5, 5%, w/v). The ZP (Y1), PS (Y2), PDI (Y3), EE% (Y4), P0.5h (Y5) and P8h (Y6) were specified as the dependent variables. Analysis of the experimental results was performed using Minitab software (ver.17, Minitab Inc.; London, UK).

Optimization of OND-loaded bilosomes

In order to determine best achieved systems, the desirability function was calculated for determination of the optimum levels of studied variables (25). The set criteria was achieving the minimal PS and PDI accomplished with the highest ZP (as an absolute value) and EE% and highest P0.5h and P8h.

Ex-vivo studies

Preparation of skin. Newly born rats (70 ± 20 g) were shaved at the abdominal surface 24 hours before the experiment day to allow healing of any possible inflammations that would happen (22). At the day of the experiment, rats were sacrificed prior to excising the abdominal skin (26). Skin surface was neatly cleaned and subcutaneous tissues adhering fats were removed without harming the epidermal surface. Skin was equilibrated in phosphate buffer saline for 2 hours prior to the experiment.

Ex-vivo permeation study. Permeation of OND, through excised rat skin, from the best achieved bilosomal systems was assessed in comparison to OND-loaded solution (Emerest® ampoules 2mg/mL) (control). The excised skin was mounted on a diffusion cell (dermis facing the receptor compartment and SC fronting the donor compartment) and experiment was completed as previously reported in the in-vitro study.

Data analysis. Plots were constructed using the cumulative amount of OND permeated per unit surface area of skin as a function of time (t, h). Slope of the steady state part of the plot was calculated which represents skin permeation rate at steady state; flux (Jss, µg/cm2/h). The permeability coefficient (Kp, cm/h) was calculated as previously reported (27).

Kp = Jss/C (1)

Where C is the drug concentration at the donor compartment.

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