R. Tawashi

Solid lipid nanoparticles as drug carriers I. Incorporation and retention of the lipophilic prodrug 3'-azido-3'-deoxythymidine palmitate

Abstract Solid lipid nanoparticles (SLN) were prepared with trilaurin (TL) as the SLN solid core and dipalmitoylphosphatidylcholine (DPPC) or a mixture of DPPC and dimyristoylphosphatidylglycerol (DMPG) to produce neutral and negatively charged SLNs. The ester prodrug of 3′-azido-3′-deoxythimidine (Zidovudine®, AZT) with palmitic acid, AZT palmitate (AZT-P), was synthesized and its incorporation and retention in SLNs determined. The incorporation of hydrophilic AZT in SLNs was minimal; however the incorporation of AZT-P increased with increasing phospholipid (PL) content and was independent of the amount of TL used. The incorporation of AZT-P was greater in negatively charged SLNs than in neutral SLNs. The in vitro release of AZT-P from different SLNs formulation was studied at 37°C using a bulk-equilibrium reverse dialysis sac technique. Increased drug release was observed in SLNs formulated with PLs having a transition temperature below 37°C. The results obtained indicate that the highly packed TL core of the SLN is not compatible with lipophilic molecules such as AZT-P. The incorporation and subsequent retention of AZT-P appears to be dependent on the PL coating on the SLNs surface and is independent of the TL solid core.

Evidence for Phospholipid Bilayer Formation in Solid Lipid Nanoparticles Formulated with Phospholipid and Triglyceride

AbstractPurpose. Solid lipid nanoparticles (SLN) are comprised of a high-melting point triglyceride (TG) core with a phospholipid (PL) coating. This study has investigated the possible formation of multiple PL bilayers on the TG core of SLNs as a function of increasing the PL:TG molar ratio. Methods. Trilaurin (TL) was used as the SLN core. Dipalmitoylphosphatidylcholine (DPPC) or a mixture of DPPC and dimyristoylphosphatidylglycerol (DMPG) were used to produce neutral and negatively charged SLNs. The volume of aqueous phase associated with the PL was determined using calcein and 6-carboxyfluorescein (6-CF) as hydrophilic markers incorporated during the preparation of the SLNs. Results. The diameter of the SLNs decreased as the molar ratio of PL to TL was increased, until a PL:TL ratio of 0.15 was reached. After this point the diameter was not affected by further increases in the molar ratio. The experimental amount of PL required to prepare SLNs was significantly higher than the theoretical amount required to form a single monolayer on the surface. The aqueous volume associated with the PL was increased with increasing PL:TL molar ratios. Conclusions. The results obtained suggest that the formation of multiple PL bilayers is probable in SLNs prepared with a high molar ratio of PL to TL. The volume of the aqueous phase between the PL-bilayers, estimated from the amount of the hydrosoluble markers trapped in this phase, provides an indication of the relative number of bilayers at different PL:TL ratios

Solid lipid nanoparticles as drug carriers: II. Plasma stability and biodistribution of solid lipid nanoparticles containing the lipophilic prodrug 3′-azido-3′-deoxythymidine palmitate in mice

Abstract Solid lipid nanoparticles (SLNs) were prepared using trilaurin as the SLNs solid core and a mixture of neutral and negatively charged phospholipid. To produce SLNs with a poly(ethylene glycol) (PEG) coating, PEG was incorporated in SLNs using dipalmitoylphosphatidylethanolamine- N -[poly(ethylene glycol) 2000 ] (PE-PEG). 3′-azido-3′-deoxythymydine palmitate (AZT-P) with [ 3 H]-AZT-P as tracer were synthesized and incorporated in SLNs. Their subsequent retention in SLNs with and without PEG was determined after incubation in 50% bovine plasma. Biodistribution studies were performed in mice using free AZT-P, AZT-P incorporated in SLNs or AZT-P incorporated in PE-PEG coated SLNs (SLN-PE-PEG). The presence of PE-PEG significantly reduced the SLN zeta potential from −22 to −5 mV. Although AZT-P was rapidly released from SLNs during incubation in bovine plasma, the release rate was significantly slower in SLN-PE-PEG. AZT-P was rapidly removed from blood following i.v. injection in mice. The decrease in AZT-P blood level was biphasic and rapid, and the major excretory route of AZT-P was the kidney. Higher levels were observed after i.v. injection of AZT-P incorporated in SLNs. This effect was further increased using SLN-PE-PEG. Both SLN and SLN-PE-PEG incorporation of AZT-P significantly decreased the urinary excretion of AZT-P and increased the localization of AZT-P in the liver. The results obtained in this study indicate that using SLNs as a drug carrier increases the bioavailibility of incorporated AZT-P, and that the pharmacokinetic behaviour of the incorporated drug can be modified by changing the surface characteristics of SLNs by using the amphiphilic solvation enhancer PE-PEG.

Morphic features of solid particles after micronization in the fluid energy mill

Abstract Salbutamol particles were comminuted in a fluid energy mill to particles less than 5 μm. Fourier descriptors extracted from the particle contour clearly indicate that the shape mix of salbutamol particles, changed significantly after micronization. The resulting daughter fragments became more and more simple in shape. The study of the shape features of the original and micronized particles indicate that microgrinding results in particles with smoother boundaries, less elongation and higher degree of roundness.

Morphic features variation of solid particles after size reduction: sonification compared to jet mill grinding

Abstract Fourier descriptors of the contour were used to evaluate the effect of sonification and jet mill grinding on particle shape. While jet mill grinding produced particles with smoother boundary, less elongation and higher degree of roundness, sonification yielded fragments closer in shape to the original crystal. Data obtained suggest that the morphic features of daughter fragments are determined mainly by the mechanism of size reduction and material structure.

Effect of particle morphology on the hiding power of talc powder

Abstract Two samples of talc powder USP—from different sources—showed remarkable difference, over a wide range of concentrations, in their hiding capacities. Particle size, size distribution and surface area were not adequate to account for the difference in physical behavior of the two samples. Morphological characterization based on Fourier shape descriptors of the particle boundary can better explain the difference. The study suggests that in addition to size parameters, the particle shape is equally important in the quality assurance monographs of pharmaceutical solid excipients.

Chemoprophylaxis of schistosomiasis using liposome-encapsulated tartar emetic

In this work, tartar emetic was entrapped in liposomes of l-α-dipalmitoyl-phosphatidyl choline, cholesterol with or without a charge-inducing agent. A dose of drug equivalent to 25 mg/kg b. wt., entrapped in neutral or negatively charged liposomes, was injected 7 days before infection with 150 cercariae of Schistosoma mansoni per mouse. After 3 months, the results obtained indicated a 100% survival compared to 28% for the mice injected with drug free liposomes. A 100% survival was also observed for the mice injected with free tartar emetic. The worm count, conducted for the groups of mice injected with free or liposome encapsulated drug, reveals statistically schistosomicidal activity for the liposome encapsulated drug. The same data reveal that neutral liposomes are more effective than negatively charged ones.

Date Palm Pollen as a Preventative Intervention in Radiation- and Chemotherapy-Induced Oral Mucositis A Pilot Study

Objective. The objective of this study was to explore the effectiveness of date palm pollen (DPP) in the prevention and treatment of oral mucositis induced by radiation and chemotherapy. Methods. Twenty subjects with varying head and neck cancers were enrolled. Ten subjects were treated with DPP administered orally (2 g daily for 42 days) as a swish and swallow suspension, and 10 control subjects received the facility standard of care. Objective oral assessments using the Oral Mucositis Assessment Scale (OMAS) were conducted at baseline and while the subjects were on treatment. Study subjects also evaluated the treatment impact by visual analog scales for severity of mouth pain and ability to swallow. Results. The results obtained demonstrate a statistically significant difference between the mean OMAS score in the DPP treatment group and the control group. Symptoms such as impairment of solid food intake observed with the control group were not observed in the DPP-treated group following the treatment. Reduction of mucositis severity of pain and ability to swallow were statistically significant in the DPP-treated group. Conclusion. DPP treatment reduced the incidence of mouth pain and oral ulcers that often require modifications to soft/liquid diet. The complex mixture of bioactive constituents contained in DPP may have protected the oral mucosa by blocking oxidative free radicals, preventing DNA damage, and neutralizing inflammatory reactions. Further randomized controlled studies are needed to validate DPP efficacy in the broader management of chemotherapy- and radiation-induced mucositis.

Reduced kallikrein excretion by liposome-encapsulated cyclosporin in the rat.

Abstract— Different phospholipids and methods of preparation were used to produce cyclosporin encapsulated in liposomes. The optimal formulation of cyclosporin‐liposome was compared to the oily cyclosporin after intraperitoneal administration of 25 mg kg−1 body weight to rats. Urinary kallikrein excretion was significantly reduced with the liposomal form. The abrupt increase of kallikrein excretion after the tenth day with the control oil preparation suggests that cyclosporin toxicity could be present at the tubular level, and the encapsulation of cyclosporin in liposomes reduces tubular damage.

Effect of fluid viscosity on the size and morphic features of salicylic acid during ball-mill grinding

Abstract The effect of ball milling on the morphic features of salicylic acid crystals was studied in wet and dry grinding. Fourier shape descriptors of individual particles were computed using an image analysis system. Data obtained indicated that the ball milled particles differ significantly from the original crystals with regard to size and shape parameters. The degree of roundness and elongation of the fragments obtained depend on the viscosity of the grinding media.