Raid G. Alany

Drug delivery to the posterior segment of the eye

Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants, liposomes and nanoparticles, have been developed to overcome such adverse effects, with some success. The periocular route is a promising alternative, owing to the large surface area and the relatively high permeability of the sclera. Yet, the blood-retinal barrier and efflux transporters hamper the transport of therapeutic entities to the retina. As such, the efficient delivery of drugs to the posterior eye remains a major challenge facing the pharmaceutical scientist. In this review, we discuss the barriers of the posterior eye drug delivery and the various drug-delivery strategies used to overcome these barriers.

Characterizing colloidal structures of pseudoternary phase diagrams formed by oil/water/amphiphile systems

Two pseudoternary phase diagrams were constructed using ethyl oleate, water, and a surfactant blend containing poly (oxyethylene 20) sorbitan monooleate and sorbitan monolaurate with or without the cosurfactant 1-butanol. Two colloidal regions were identified in the cosurfactant-free phase diagram; a microemulsion (ME) and a region containing lamellar liquid crystals (LC). The addition of 1-butanol increased the area in which systems formed microemulsions and eliminated the formation of any liquid crystalline phases. Samples that form the colloidal regions of both systems were investigated by freeze-fracture transmission electron microscopy and by viscosity and conductivity measurements. The three techniques were compared and evaluated as characterisation tools for such colloidal systems and also to identify transitions between the colloidal systems formed. A droplet ME was present at a low water volume fraction (ϕw) in both systems (ϕw <0.15) as revealed by electron microscopy. At higher ϕw values, LC structures were observed in micrographs of samples taken from the cosurfactant-free system while the structure of samples from the cosurfactant-containing system was that of a bicontinuous ME. The viscosity of both systems increased with increasing ϕw to 0.15 and flow was Newtonian. However, formation of LC in the cosurfactant-free system resulted in a dramatic increase in viscosity that was dependent on ϕw and a change to pseudoplastic flow. In contrast, the viscosity of the bicontinuous ME was independent of ϕw. Three different methods were used to estimate the percolation threshold from the conductivity data for the cosurfactant-containing system. The use of nonlinear curve fitting was found to be most useful yielding a value close to 0.15 for the ϕw.

Effects of alcohols and diols on the phase behaviour of quaternary systems

The aim of the current study was to investigate the effect of different co-surfactants on the phase behaviour of the pseudoternary system water:ethyl oleate:nonionic surfactant blend (sorbitan monolaurate/polyoxyethylene 20 sorbitan mono-oleate). Four aliphatic alcohols (1-propanol, 1-butanol, 1-hexanol and 1-octanol) and four 1, 2-alkanediols (1,2-propanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol) were used. The co-surfactant-free system forms two different colloidal structures, a water-in-oil microemulsion (w/o ME) and lamellar liquid crystals (LC) and two coarse dispersions, water-in-oil (w/o EM) and oil-in-water (o/w EM) emulsions. Microemulsion region area (%ME), liquid crystalline region area (%LC), amount of amphiphile blend required to produce a balanced microemulsion (%AMPH) and amount of water solubilised (%W) were used as assessment criteria to evaluate the co-surfactants. Seven calculated physico-chemical descriptors were used to represent the different co-surfactants. 1-butanol, 1,2-hexanediol and 1, 2-octanediol produced balanced MEs capable of solubilising a high percentage of both oil and water. A similarity was observed between the descriptors attributed to 1-butanol and 1,2-hexanediol. The requirements of a co-surfactant molecule to produce a balanced microemulsion were: HLB value 7.0-8.0, a carbon backbone of 4-6 atoms, percentage carbon of 60-65%, percentage oxygen of 20-30%, logP value 0.2-0.9 and log 1/S (S: aqueous solubility) close to zero.

Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1: physicochemical characterisation and in vitro release

Conventional eye drops can result in poor drug bioavailability due to the unique ocular anatomy and physiology. Ion-activated in situ gelling systems are able to crosslink with cations present in the tear fluid, therefore forming a gel on the ocular surface, which results in prolonged corneal contact time. The present study compared a number of anionic polysaccharides (gellan gum, xanthan gum, carrageenan and alginate) to an uncharged (HPMC) and a positively charged (chitosan) polymer system with emphasis on the gelling behaviour, rheological and textural properties, gel microstructure, contact angle and in vitro release characteristics. All systems exhibited physically entangled polymer networks that were able to disentangle upon shear stress and significantly prolonged the in vitro release of a model hydrophilic drug compared to a solution. While systems based on HPMC and chitosan showed no structural changes upon addition of cations, formulations based on gellan gum and carrageenan demonstrated a remarkable increase in viscosity, pseudoplasticity and hardness upon addition of Ca(2+) and K(+) respectively. This renders them favourable for ocular use as they would gel once in contact with the cations of the tear fluid, thus reducing nasolacrimal drainage, but would thin upon shearing, preventing ocular irritation and therefore induced lacrimation.

Design and Evaluation of Controlled-Release Niosomes and Discomes for Naltrexone Hydrochloride Ocular Delivery

This study aimed at preparing and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearyl amine (STA)] and surfactants [poly-24-oxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepared using four different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2%-5% mol/mol additives. Differential scanning calorimetry thermograms revealed that the additives completely abolished gel/liquid transition suggesting that the bilayer membranes could accommodate the additives. The volume diameters D (4, 3) of the prepared niosomes were significantly [p < 0.05, analysis of variance (ANOVA)] dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 ± 1.40 and 5.37 ± 1.40 μ m, respectively. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepared niosomes significantly (p < 0.01, ANOVA) controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepared niosomal formulations were found practically nonirritant when applied onto the surface of a 10-day-old hens chorioallantoic membrane.

Recent advances in non-ionic surfactant vesicles (niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations

Abstract Non-ionic surfactant vesicles, simply known as niosomes are synthetic vesicles with potential technological applications. Niosomes have the same potential advantages of phospholipid vesicles (liposomes) of being able to accommodate both water soluble and lipid soluble drug molecules control their release and as such serve as versatile drug delivery devices of numerous applications. Additionally, niosomes can be considered as more economically, chemically, and occasionally physically stable alternatives to liposomes. Niosomes can be fabricated using simple methods of preparations and from widely used surfactants in pharmaceutical technology. Many reports have discussed niosomes in terms of physicochemical properties and their applications as drug delivery systems. In this report, a brief and simplified summary of different theories of self-assembly will be given. Furthermore manufacturing methods, physical characterization techniques, bilayer membrane additives, unconventional niosomes (discomes, proniosomes, elastic and polyhedral niosomes), their recent applications as drug delivery systems, limitations and directions for future research will be discussed.

Borage oil in the treatment of atopic dermatitis

Nutritional supplementation with omega-6 essential fatty acids (omega-6 EFAs) is of potential interest in the treatment of atopic dermatitis. EFAs play a vital role in skin structure and physiology. EFA deficiency replicates the symptoms of atopic dermatitis, and patients with atopic dermatitis have been reported to have imbalances in EFA levels. Although direct proof is lacking, it has been hypothesized that patients with atopic dermatitis have impaired activity of the delta-6 desaturase enzyme, affecting metabolism of linoleic acid to gamma-linolenic acid (GLA). However, to date, studies of EFA supplementation in atopic dermatitis, most commonly using evening primrose oil, have produced conflicting results. Borage oil is of interest because it contains two to three times more GLA than evening primrose oil. This review identified 12 clinical trials of oral or topical borage oil for treatment of atopic dermatitis and one preventive trial. All studies were controlled and most were randomized and double-blind, but many were small and had other methodological limitations. The results of studies of borage oil for the treatment of atopic dermatitis were highly variable, with the effect reported to be significant in five studies, insignificant in five studies, and mixed in two studies. Borage oil given to at-risk neonates did not prevent development of atopic dermatitis. However, the majority of studies showed at least a small degree of efficacy or were not able to exclude the possibility that the oil produces a small benefit. Overall, the data suggest that nutritional supplementation with borage oil is unlikely to have a major clinical effect but may be useful in some individual patients with less severe atopic dermatitis who are seeking an alternative treatment. Which patients are likely to respond cannot yet be identified. Borage oil is well tolerated in the short term but no long-term tolerability data are available.

Molecular descriptors that influence the amount of drugs transfer into human breast milk

Most drugs are excreted into breast milk to some extent and are bioavailable to the infant. The ability to predict the approximate amount of drug that might be present in milk from the drug structure would be very useful in the clinical setting. The aim of this research was to simplify and upgrade the previously developed model for prediction of the milk to plasma (M/P) concentration ratio, given only the molecular structure of the drug. The set of 123 drug compounds, with experimentally derived M/P values taken from the literature, was used to develop, test and validate a predictive model. Each compound was encoded with 71 calculated molecular structure descriptors, including constitutional descriptors, topological descriptors, molecular connectivity, geometrical descriptors, quantum chemical descriptors, physicochemical descriptors and liquid properties. Genetic algorithm was used to select a subset of the descriptors that best describe the drug transfer into breast milk and artificial neural network (ANN) to correlate selected descriptors with the M/P ratio and develop a QSAR. The averaged literature M/P values were used as the ANNs output and calculated molecular descriptors as the inputs. A nine-descriptor nonlinear computational neural network model has been developed for the estimation of M/P ratio values for a data set of 123 drugs. The model included the percent of oxygen, parachor, density, highest occupied molecular orbital energy (HOMO), topological indices (chiV2, chi2 and chi1) and shape indices (kappa3, kappa2), as the inputs had four hidden neurons and one output neuron. The QSPR that was developed indicates that molecular size (parachor, density) shape (topological shape indices, molecular connectivity indices) and electronic properties (HOMO) are the most important for drug transfer into breast milk. Unlike previously reported models, the QSPR model described here does not require experimentally derived parameters and could potentially provide a useful prediction of M/P ratio of new drugs only from a sketch of their structure and this approach might also be useful for drug information service. Regardless of the model or method used to estimate drug transfer into breast milk, these predictions should only be used to assist in the evaluation of risk, in conjunction with assessment of the infants response.

New therapeutic approaches in the treatment of diabetic keratopathy: a review.

The cornea is densely innervated, and the integrity of these nerve fibres is critical in maintaining the refractive and protective functions of the cornea. Many ocular and systemic diseases can adversely affect corneal sensory nerves and consequently impair their function, with vision loss being the inevitable consequence of severe corneal neurotrophic ulceration. However, current standard treatments regimens are often ineffective. Over the past three decades, the role of growth factors in maintaining the normal structure and function of the cornea, and in corneal epithelial healing, has become increasingly evident. Many preclinical and clinical trials have shown that growth factors and cytokines can significantly enhance epithelialization (epithelial proliferation and migration) and consequently accelerate wound healing. More recently, local/topical administration of insulin, naltrexone (opioid antagonist) and nicergoline (ergoline derivatives) were found to improve, and significantly increase, the corneal wound healing rate. This report reviews the major attributes of these growth factors and therapeutic agents that may be used in ameliorating impaired corneal wound healing, and presents a perspective on the potential clinical use of these agents as a new generation of ophthalmic pharmaceuticals for the treatment of diabetic keratopathy.The cornea is densely innervated, and the integrity of these nerve fibres is critical in maintaining the refractive and protective functions of the cornea. Many ocular and systemic diseases can adversely affect corneal sensory nerves and consequently impair their function, with vision loss being the inevitable consequence of severe corneal neurotrophic ulceration. However, current standard treatments regimens are often ineffective. Over the past three decades, the role of growth factors in maintaining the normal structure and function of the cornea, and in corneal epithelial healing, has become increasingly evident. Many preclinical and clinical trials have shown that growth factors and cytokines can significantly enhance epithelialization (epithelial proliferation and migration) and consequently accelerate wound healing. More recently, local/topical administration of insulin, naltrexone (opioid antagonist) and nicergoline (ergoline derivatives) were found to improve, and significantly increase, the corneal wound healing rate. This report reviews the major attributes of these growth factors and therapeutic agents that may be used in ameliorating impaired corneal wound healing, and presents a perspective on the potential clinical use of these agents as a new generation of ophthalmic pharmaceuticals for the treatment of diabetic keratopathy.

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.