Current Drug Delivery - Volume 4, Issue 2, 2007

Proteins administered orally must pass through the gastric environment in order to reach their site of absorption in the intestine. How to protect these exogenously administered proteins from the damaging effects of gastric acid and pepsin proteolytic activity, which often induce irreversible structural and functional alterations to the molecules, is an intriguing challenge. Another problem is the physical and chemical instability of proteins during some technological processes, which often involve the use of organic solvents or high temperatures. In this study we investigated the use of alginate microparticles containing one of two enzymes, an enteric polymer and a lyoprotectant for the intestinal delivery of proteins. The two enzymes tested in this protein delivery system were lactate dehydrogenase and alpha-amylase: the former was chosen because of its sensitivity to denaturation, the latter for its relevance in nutrition and medicine. A sodium alginate aqueous solution containing the enteric polymer, a lyoprotectant and the enzyme was either extruded or sprayed into a calcium chloride solution, with the resultant formation of beads and microspheres which were freeze-dried. About 90% of the enzyme activity was maintained during the process of loading the proteins into the microparticles and the subsequent freeze-drying process. The stability of the encapsulated enzyme in an acid medium and the enzymatic activity in an intestinal environment were then investigated by a dissolution test. This consisted of exposing the microparticles to simulated gastric fluid (pH 1.2) for 2 hours and to simulated intestinal fluid (pH 7.5±0.1) for 1 hour. The morphology of the microparticles did not change in the acid environment, whereas they completely dissolved within 3 min in the simulated intestinal fluid. Residual enzymatic activity after the test remained satisfactory for both enzymes. In conclusion, these microparticle systems offer promise for applications in human and veterinary medicine as well as in human and animal nutrition.

The interaction of a series of amphiphilic 2-alkyl aminoacids (lipoamino acids, LAAs) with different cell cultures and biomembrane models was investigated. LAAs can be useful promoieties to modify the physico-chemical properties of many drugs, and in particular their lipophilicity. Tests were performed in vitro on mammalian cells (murine astrocytes) and human red blood cells (haemolysis), and in vivo on rabbit eye as alternative models to assess the tolerability or the potential damaging effects of these compounds on different biological systems. The mode of interaction of LAAs with pure phospholipid multilamellar liposomes, taken as a biomembrane model, was also analysed by differential scanning calorimetry experiments. Different tolerability/toxicity patterns were obtained in the various models; in particular, the most lipophilic terms of the series, methyl 2-aminohexadecanoate (LAA16), displayed haemolytic activity and toxicity for mouse astrocyte cultures. A specific assay confirmed that LAA16 acted at level of cell membranes, while neither any damaging effects on nucleus or apoptotic induction were observed. The shorter-chain LAAs and the tetradecyl homologue (LAA14) showed the best compatibility with the various cell models.

Microsponges are polymeric delivery systems consisting of porous microspheres having a size range in between 5 to 300 μm depending upon the degree of smoothness or after feel required for the end formulations. Microsponge Delivery System MDS is a unique technology for controlled delivery of drug. The present review introduces Microsponge technology along with its synthesis, characterization, programmable parameters and release mechanism of MDS. Wide ranges of applications are also suggested to develop drug or cosmetic products with enhanced safety and efficacy. MDS can provide increased efficacy for topically active agents with enhanced safety, extended product stability and improved aesthetic properties in an efficient and novel manner.

The effects of the formulation and particle composition of gadolinium (Gd)-containing lipid nanoemulsion (Gd-nanoLE) on the biodistribution of Gd after its intravenous (IV) injection in D1-179 melanoma-bearing hamsters were evaluated for its application in cancer neutron-capture therapy. Gd-nanoLEs whose particles had an oily core (soybean oil, ethyl oleate, lipiodol, or triolein) and a surface layer of hydrogenated phosphatidylcholine, gadolinium-diethylenetriaminepentaacetic acid-distearylamide, and a cosurfactant (Myrj 53, Brij 700, or HCO-60) were prepared by a thinlayer hydration-sonication method. Biodistribution data revealed that Brij 700 and HCO-60 prolonged the retention of Gd in the blood and enhanced its accumulation in tumors. Among the core components employed, soybean oil yielded the highest Gd concentration in the blood and tumor and the lowest in the liver and spleen. Gd-nanoLEs with a Gd content of 1.5-4.5 mg/ml could be formulated by using HCO-60 and soybean oil at a constant oil-to-water ratio, and by enriching Gd in the surface layer with the particle size maintained below 100 nm. When each Gd-nanoLE was IV injected once or twice at a 24-h interval, the Gd concentration in the tumor correlated well with the total dose of Gd, and it reached a maximum of 189 μg/g wet tumor. This maximum Gd level was greater than the limit required for significantly suppressing tumor growth in neutron-capture therapy.

Delivery of therapeutic proteins/ peptides has received a considerable amount of attention over the last 10 years, but there are number of limitations to oral delivery of proteins. The barriers to peptide bioavailability after oral administration are intestinal membrane permeability, size, intestinal and hepatic metabolism and lastly solubility. A number of approaches have been used to overcome these limitations. Poor membrane permeabilities of hydrophilic peptides might be overcome by structurally modifying the compound, thus increasing their membrane partition characteristics and their affinity for carrier proteins. Another approach is site specific delivery of the peptides to the most permeable part of the intestine. Metabolism (hepatic and intestinal) of peptides might be controlled by co-administration of competitive enzyme inhibitors, structural modifications and administration of the compound as well as absorbed prodrug that is converted into therapeutically active agent after its absorption. Various delivery systems like prolease technology, nano- particulate and microparticulate delivery system, mucoadhesive delivery of peptides and microspheres have been developed for the delivery of proteins and peptides. Non-conventional delivery systems for proteins are biodegradable and non-biodegradable systems. Besides these, some other approaches for protein and peptide delivery are vector mediated delivery of proteins using adenovirus, macroflux transdermal patches, pulmonary delivery of proteins, delivery of proteins and peptides across blood brain barrier.

Polymethylmethacrylate (PMMA) microspheres of ethylhexyl methoxycinnamate (EHM) were prepared by emulsion solvent evaporation method to improve its photostability and effectiveness as sunscreening agent. Process parameters like stirring speed and aqueous polyvinyl alcohol (PVA) concentration were analyzed in order to optimize the formulations. Shape and surface morphology of the microspheres were examined using scanning electron microscopy. Particle size of the microspheres was determined using laser diffraction particle size analyzer. The PMMA microspheres of EHM were incorporated in water-removable cream base. The in vitro drug release of EHM in pH 7.4 was performed using dialysis membrane. Thin layer chromatography was performed to determine photostability of EHM inside the microspheres. The formulations were evaluated for sun protection factor (SPF) and minimum erythema dose (MED) in albino rats. Cream base formulation containing microspheres prepared using EHM: PMMA in ratio of 1:3 (C3) showed slowest drug (EHM) release and those prepared with EHM: PMMA in ratio of 1:1 showed fastest release. The cream base formulations containing EHM loaded microspheres had shown better SPF (more than 16.0) as compared to formulation Cd that contained 3% free EHM as sunscreen agent and showed SPF 4.66. These studies revealed that the incorporation of EHM loaded PMMA microspheres into cream base had greatly increased the efficacy of sunscreen formulation approximately four times. Further, photostability was also shown to be improved in PMMA microspheres.

RNA interference (RNAi) has emerged as a potential therapeutic approach for neurodegenerative diseases, particularly those associated with autosomal dominant patterns of inheritance. In proof of concept experiments, several groups have demonstrated efficacy of using viral vectors expressing short hairpin RNA (shRNA) directed against therapeutically relevant genes in mouse models of neurodegenerative diseases, including spinocerebellar ataxia, Amyotrophic Lateral Sclerosis, Huntington 's Disease and amyloidosis (a pathological aspect of Alzheimer's Disease). Although viralbased RNAi has limitations that most likely will preclude its usage in humans, a few recent developments underscore the potential of non-viral-based delivery of relevant RNAi as therapeutics for neurodegenerative diseases. Here, I will review the recent literature on effectiveness of RNAi as a therapeutic strategy in mouse models of neurodegenerative diseases.

In spite of conventional treatment modalities which include surgery, chemotherapy, and radiotherapy, the survival rates for patients with malignant gliomas remain disappointing. Successful treatment has been limited by difficulties in delivering therapeutic agents to the central nervous system (CNS). Specifically, drug penetration of the blood brain barrier (BBB) poses a unique and challenging problem in glioma therapy. Recently, however, promising techniques have emerged to circumvent this problem. One such advancement is convection-enhanced delivery (CED). This method was originally introduced and refined in the early 1990s by researchers at the National Institute of Health (NIH) and involves drug infusion under high pressure using intracranial catheters. CED allows for delivery of high concentrations of therapeutic agents directly into brain tumors and surrounding parenchyma. This method eludes the BBB and allows the use of regional drug therapy, while at the same time limiting systemic toxicity. In the present article, we review both the preclinical and clinical studies concerning CED. We also discuss future directions and the potential impact of this modality on the treatment of malignant gliomas.