Novel polyglycerol-dioleate based cubosomal dispersion with tailored physical characteristics for controlled delivery of ondansetron.

In this study different amphiphilic lipids viz. glycerylmonooleate (GMO), Glycerylmonolinoleate (GML), Plurol® (polyglycerol 3-dioleate), Soya phosphatidylcholine (Soya PC), Dipalmitoyl-phosphatidylcholine (DPPC) and Dipalmitoyl- phosphatidylglycerol (DPPG) were screened for their ability to form cubosomes and the formed particles were optimized for controlled delivery using ondansetron as a model drug. Polarized optical microscopy and high resolution transmission electron microscopy were performed to investigate the morphology of the prepared particles. A full factorial study was developed to optimize formulation composition and process conditions. Atomic force microscopy and in vitro drug release studies were done on selected formulae. Results showed that GMO, Plurol and GML were able to form cubosomes while DPPC was able to form spherical nanoparticles. There was a negative correlation between homogenization speed and PS, PDI and EE%. Furthermore, there was a significant positive correlation between Lipid: Polymer ratio and PS as well as PDI values, while there was a slight negative correlation between it and EE% in all nanoparticles except for those based on DPPC, which showed significant increase in EE% upon increase in the lipid:polymer ratio. Additionally, cumulative percent release of ondansetron from the particles shows that their design was efficiently tailored throughout this study to afford sustained drug release with diffusion pattern. T80 reached 19.3h in case of Plurol. Further confirmation studies on cubic structure formation were done on selected GMO and Plurol-based nanoparticles using scanning electron microscopy and x-ray powder diffraction. Results showed that Plurol was able to form cubic nanostrucures resembling those formed by GMO. Finally, Plurol (polyglyceroldioleate) showed to be a promising amphiphilic lipid that is capable of forming cubic nanostructures like GMO opening a new era for polyglycerols to take a step as a self assembling lipid resembling the unsaturated monoglycerols (UMGs).

Physically cross-linked polyvinyl alcohol for the topical delivery of fluconazole.

The aim of this study was to develop fluconazole in an ultrapure polyvinyl alcohol (PVA) hydrogel able to deliver the drug in a sustained release pattern for local treatment of skin fungal infections. The topical fluconazole hydrogels were prepared using PVA hydrogels physically cross-linked by freeze-thaw technique. Polyethylene glycol (PEG) was added as a hydrophilic excipient as a release enhancer of fluconazole. The effects of PVA molecular weight, PEG molecular weight, and PEG concentration were studied using a 2 x 4 x 2 factorially designed experiment. The selected fluconazole hydrogel proved to be physically stable over a period of 6 months and to be effective in the topical treatment of cutaneous candidiasis. Therefore, it could be concluded that the formula composed of 10% PVA 205000 and 1.5% PEG 4000 and 2% fluconazole and prepared by three cycles of freezing, and thawing is very promising in the local treatment of skin fungal infection as an alternative to the systemic use of fluconazole.

Rapid-onset intranasal delivery of metoclopramide hydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetized rats.

Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications and to circumvent their first-pass elimination when taken orally. Metoclopramide (MCP) is a potent antiemetic, effective even for preventing emesis induced by cancer chemotherapy. The feasibility of developing an efficacious intranasal formulation of metoclopramide has been undertaken in this study. The nasal absorption of MCP was studied in anesthetized rats over 60min using the in vivo in situ technique. The influence of several formulation variables, vis., pH and the addition of preservative, viscosity and absorption enhancing agents on the nasal MCP absorption was examined. The data obtained showed that MCP was well absorbed nasally where almost 90% of the drug was absorbed after 60min from the rat nasal cavity. The MCP absorption was pH-dependant such that the apparent first-order rate constant of absorption (K(app)) was almost tripled when the pH of the solution was increased from 5 to 8. However, deviation from the classical pH-partition theory was observed pointing to the role of aqueous pore pathway in MCP nasal absorption. The K(app) was significantly increased (P<0.05) by incorporation of 0.01% of the preservative benzalkonium chloride. Conversely, increasing the solution viscosity by the use of hydroxylpropyl methylcellulose adversely affected the rate of absorption. The use of enhancers namely sodium deoxycholate, sodium cholate, chitosan low and high molecular weight, protamine sulphate and poly-l-arginine resulted in significant increase in MCP absorption. The highest promoting effect was observed with the bile salt sodium deoxycholate where about 92% of the drug was absorbed in 25min from the rat nasal cavity and the K(app) showed more than two-fold increase as compared to control (from 0.0452 to 0.1017min(-1)).

Rapid-onset intranasal delivery of metoclopramide hydrochloride Part II: Safety of various absorption enhancers and pharmacokinetic evaluation.

In the present study, several nasal absorption enhancers, used in metoclopramide hydrochloride (MCP HCl) nasal solutions, have been screened for their possible damaging effect in the in vitro human erythrocytes lysis experiment. Moreover, the in vivo leaching of biological markers from the rat nasal epithelium was used as a quantitative assessment for possible nasal mucosal irritation whereby the extent of release of total protein and lactate dehydrogenase (LDH) in the nasal lavage fluid was determined. Results showed that insignificant hemolysis from normal saline (P<0.05) occurred with the enhancer protamine sulphate while poly-l-arginine and sodium cholate demonstrated very low (<15%) hemolysis and caused insignificant protein and LDH release from the rat nasal mucosa. Conversely, sodium deoxycholate and chitosan polymers (either of low or high molecular weight) showed high (>60%) hemolysis in vitro and the release of the biological markers in vivo was significantly higher (P<0.05) than the control solution (no enhancer). A significant correlation (P<0.05) existed between the enhancement effect of MCP HCl nasal absorption and the amounts of protein (r=0.85) and LDH (r=0.88). Furthermore, the pharmacokinetics of MCP HCl was determined after intravenous (IV), per-oral and intranasal administration of 10mg drug dose in rabbits. The application of a nasal spray (NS) solution containing 0.5% sodium cholate resulted in a significant improvement (P<0.05) in both the rate and extent of absorption of MCP HCl where the T(max) achieved was 23.3min as compared to 50min in case of the oral solution while the area under the serum concentration-time curve (AUC(0-infinity)) were 506.1, 434.9 and 278.7microg/mlmin for IV, NS and oral solutions, respectively. These values corresponded to absolute bioavailabilities of 87.21 and 55.61% for the NS and oral solutions, respectively. It could thus be concluded that NS of MCP HCl represents a viable approach to achieving rapid and high systemic drug absorption during the emergency treatment of severe emesis.