Raida Al-Kassas

Development of solid lipid nanoparticles and nanostructured lipid carriers for improving ocular delivery of acyclovir.

The objective of the present investigation was to improve the ocular bioavailability of acyclovir by incorporating it into solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). This required optimization of the process parameters, such as type of lipid, drug to lipid ratios, type and concentration of surfactants, and type and amount of liquid lipids used in the formulations. SLNs and NLCs were prepared by the modified hot oil in water microemuslion method. The prepared nanoparticles were evaluated for their particle size, zeta potential, entrapment efficiency, solid state characteristics, surface morphology, in vitro drug release, and permeation through excised cornea. The prepared nanoparticles were spherical and within the size range suitable for ocular drug delivery (400–777.56 nm). Incorporation of liquid oil in the structure of SLNs resulted in the formation of NLCs with high entrapment efficiency (25–91.64%) compared to SLNs (11.14%). The drug release from SLNs and NLCs was rather a surface-based phenomenon. In comparison to free drug solution, NLCs were capable of having faster permeation through the excised cornea indicating their potential enhanced corneal penetration properties. However, SLNs have reduced the permeation rate significantly. The results of the study suggest that SLNs can be successfully converted to physically superior NLCs, which have the potential to be developed further as ocular drug delivery systems for ACV.

Liposomal drug delivery: a versatile platform for challenging clinical applications.

Liposomes are lipid based vesicular systems that offer novel platform for versatile drug delivery to target cell. Liposomes were first reported by Bangham and his co-workers in 1964 (1). Since then, liposomes have undergone extensive research with the prime aim to optimize encapsulation, stability, circulation time and target specific drug delivery. Manipulation of a liposomes lipid bilayer and surface decoration with selective ligands has transformed conventional liposomes into adaptable and multifunctional liposomes. Development of liposomes with target specificity provide the prospect of safe and effective therapy for challenging clinical applications. Bioresponsive liposomes offer the opportunity to release payload in response to tissue specific microenvironment. Incorporation of novel natural and synthetic materials has extended their application from stable formulations to controlled release targeted drug delivery systems. Integration and optimization of multiple features into one system revolutionized research in the field of cancer, gene therapy, immunotherapy and infectious diseases. After 50 years since the first publication, this review is aimed to highlight next generation of liposomes, their preparation methods and progress in clinical applications.

Conjunctival and corneal tolerability assessment of ocular naltrexone niosomes and their ingredients on the hen's egg chorioallantoic membrane and excised bovine cornea models.

This study aimed at combining the hens egg test-chorioallantoic membrane (HET-CAM), bovine corneal opacity and permeability (BCOP) test and histological examination of excised corneas to evaluate the conjunctival and corneal toxicity of niosomes and their ingredients. Various surfactant/lipid combinations and concentrations (1-10%, w/v) were investigated for the ocular delivery of an ambitious drug (naltrexone hydrochloride) for treatment of diabetic keratopathy. Four niosomal formulations were investigated and found to be non irritant to the 10 days old HET-CAMs (an acceptable conjunctival model). Only one of the tested ingredients (sodium cholate - CH) showed moderate irritation, however such an effect was diminished when incorporated into niosomes. Corneal opacity and fluorescein permeability scores for the test substances correlated well with the HET-CAM test results. Corneal erosion and stromal thickness were found to be in agreement with the HET-CAM and BCOP results, which discriminated well between moderately and mildly irritant test substances. Corneal histological examination revealed toxicity signs included epithelial erosion, stromal condensation and stromal vacuolisation, which allowed better discrimination between strong and moderate irritants. It is concluded that the prepared niosomes possess good ocular tolerability and minimal ocular tissue irritation. They can be further investigated as ocular delivery systems using appropriate animal models.

Niosomes and discomes for ocular delivery of naltrexone hydrochloride: morphological, rheological, spreading properties and photo-protective effects.

Naltrexone hydrochloride (NTX) is a promising treatment for corneal disorders linked to diabetes mellitus (diabetic keratopathy). However, NTX has a major stability problem due to autoxidation, which is likely to hinder its formulation as eye drops for treatment of diabetic keratopathy. In this study, in-house developed NTX non-ionic surfactant vesicles (niosomes and discomes) were evaluated for their spreading, rheological properties and their ability to impede the inevitable autoxidation of NTX in aqueous solutions. The measured contact angles and spreading coefficients for niosomes reflected significantly (P<0.05) better wetting and spreading abilities than the aqueous vehicle. The prepared niosomes were significantly more viscous (P<0.05) than the aqueous solution. The lipid content, size and composition of niosomes are the main factors affecting the viscosity of niosomal dispersions. Exposure of NTX solution to artificial daylight illumination (10,000 lux) can produce extensive degradation of NTX due to oxidation. The prepared formulations were able to significantly (P<0.05) protect the encapsulated NTX from the photo-induced oxidation compared with free NTX solutions. The investigated niosomes lend themselves as a potential ocular delivery modality for NTX.

Transdermal delivery of propranolol hydrochloride through chitosan nanoparticles dispersed in mucoadhesive gel

This study aimed at improving the systemic bioavailability of propranolol-HCl by the design of transdermal drug delivery system based on chitosan nanoparticles dispersed into gels. Chitosan nanoparticles were prepared by ionic gelation technique using tripolyphosphate (TPP) as a cross-linking agent. Characterization of the nanoparticles was focused on particle size, zeta potential, surface texture and morphology, and drug encapsulation efficiency. The prepared freeze dried chitosan nanoparticles were dispersed into gels made of poloxamer and carbopol and the rheological behaviour and the adhesiveness of the gels were investigated. The results showed that smallest propranolol loaded chitosan nanoparticles were achieved with 0.2% chitosan and 0.05% TPP. Nanoparticles were stable in suspension with a zeta potential (ZP) above ±30mV to prevent aggregation of the colloid. Zeta potential was found to increase with increasing chitosan concentration due to its cationic nature. At least 70% of entrapment efficiency and drug loading were achieved for all prepared nanoparticles. When chitosan nanoparticles dispersed into gel consisting of poloxamer and carbopol, the resultant formulation exhibited thixotropic behaviour with a prolonged drug release properties as shown by the permeation studies through pig ear skin. Our study demonstrated that the designed nanoparticles-gel transdermal delivery system has a potential to improve the systemic bioavailability and the therapeutic efficacy of propranolol-HCl.

Malaria intervention policies and pharmaceutical nanotechnology as a potential tool for malaria management

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV

Isolation and characterization of degradation products of moxidectin using LC, LTQ FT-MS, H/D exchange and NMR

AbstractThis study aimed to evaluate the degradation profile and pathways, and identify unknown impurities of moxidectin under stress conditions. During the experiments, moxidectin samples were stressed using acid, alkali, heat and oxidation, and chromatographic profiles were compared with known impurities given in European Pharmacopeia (EP) monograph. Moxidectin has shown good stability under heat, while reaction with alkali produced 2-epi and ∆2,3 isomers (impurities D and E in EP) by characteristic reactions of the oxahydrindene (hexahydrobenzofuran) portion of the macrocyclic lactone. Two new, previously unreported, unknown degradation products, i.e. impurity 1 and impurity 2, detected after acid hydrolysis of moxidectin (impurity 2 was also observed to a lesser extent after oxidation), were isolated from sample matrices and identified using liquid chromatography, NMR, high-resolution FT-ICR MS, and hydrogen/deuterium exchange studies. FTMS analysis showed accurate mass of molecular ion peaks for moxidectin at m/z 640.38412, impurity 1 at m/z 656.37952 and impurity 2 at m/z 611.35684, giving rise to daughter ions traceable up to the seventh levels of MSn experiments and supporting the proposed structures. Both unknown impurities along with moxidectin were fully characterized by 1H, 13C, 1D HMBC and 2D (NOESY, COSY and HSQC) NMR experiments. The interpretation of experimental data positively identified impurity 1 as 3,4-epoxy-moxidectin and impurity 2 as 23-keto-nemadectin. The identification of new impurities and correlation of their chromatographic profiles with the EP method is very useful to establish the stability profile of moxidectin and its preparations, as well as add value to the forthcoming moxidectin finished product European Pharmacopeia monographs. FigureAcid catalyzed degradation of moxidectin into 23-keto-moxidectin and 3,4-epoxy-moxidectin

Ocular delivery systems for topical application of anti-infective agents

Abstract For the treatment of anterior eye segment infections using anti-infective agents, topical ocular application is the most convenient route of administration. However, topical delivery of anti-infective agents is associated with a number of problems and challenges owing to the unique structure of the eye and the physicochemical properties of these compounds. Topical ocular drug delivery systems can be classified into two forms: conventional and non-conventional. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation resulting in low ocular bioavailability. Recently, attention has been focused on improving topical ocular delivery of anti-infective agents using advanced drug delivery systems. This review will focus on the challenges of efficient topical ocular delivery of anti-infective agents and will discuss the various types of delivery systems used to improve the treatment anterior segment infections.

Preformulation characteristics of the opioid growth factor antagonist-naltrexone hydrochloride: stability and lipophilicity studies

In the last twenty years mesoporous materials (e.g., silica, silicon, and to a lesser extent titanium) have been extensively investigated as possible carriers for controlled drug delivery purposes. The great benefits of these materials are their high surface areas and pore volumes with tunable pore sizes and easily functionalized pore surface properties, which allow high drug payloads and from very rapid to slow release kinetics for controlled drug release formulations. The present review focuses on recent research on the exploitation of mesoporous silica and silicon based materials for controlled drug release applications. In particular, fabrication processes of these materials, drug loading and drug release profiles and mechanisms, as well as further functionalization of the porous surface structures of the materials are surveyed. Several examples of drug delivery formulations, together with drug release mechanisms, such as sustained release and stimuli-responsive controlled-release, are also presented herein.

Separation and identification of degradation products in eprinomectin formulation using LC, LTQ FT-MS, H/D exchange, and NMR

The aim of this study was to evaluate the suitability of the compendial active pharmaceutical ingredient (API) method for the analysis of finished products and characterization of degradation products in eprinomectin (EPM) samples. Heat stressed sample tests revealed a limitation of the API method in distinguishing an impurity merging with the principal analyte peak. A new selective, specific and sensitive method was therefore developed for the determination of EPM in formulations that separates its degradation products currently undetectable with the official method. The determination was carried out by reversed-phase HPLC using an isocratic solvent elution. The method was validated and found to be precise, accurate and specific; the detector response was linear over 50-150 μg/ml (EPM) and 0.1-3 μg/ml (degradation product) range of concentrations. Two major degradation products detected with the new method were isolated from sample matrices and characterized using LC-PDA, high resolution FT-ICR MS, NMR and hydrogen/deuterium exchange (HX-MS) studies. FTMS analysis showed accurate mass of molecular ion peaks for EPM and its two degradation products at m/z 914.52505 (mass error ≤ 1 ppm) with almost identical fragmentation patterns. Given the isomeric nature of the compounds, all three were further evaluated by ¹H, ¹³C, 1D NOESY and 2D (COSY) NMR experiments. The interpretation of experimental data positively identified Unknown 1 as the 2-epimer of EPM and Unknown 2 as the structural isomer Δ2,3-EPM containing a conjugated enoate. The new HPLC method and identification exercise is useful for analysis of EPM and its degradation products.