Pharmaceutical Nanotechnology - Volume 1, Issue 4, 2013

From the 1950s, Amphotericin B (AmB) in the form of Fungizone® was considered the “gold standard” in antifungal therapy. This was due to its broad-spectrum of activity. In the 1990s, Fungizone® was relegated to a second line treatment option after the commercialization of lipid-based formulations (AmBisome®, Abelcet® and Amphocil®). These new medicines have similar efficacies but more favourable safety profiles. These formulations will be coming off patent over the coming months and so there is an opportunity for generics manufacturers to enter the arena. However, the lack of clear regulatory guidance on how to perform bioequivalence studies with liposomal drugs makes it difficult to ensure that generic parenteral formulations present quality, efficacy and safety profiles similar to the innovator product. To date, AmB therapy relies mostly on parenteral administration although infusion-related side effects and nephrotoxicity can lead to treatment being halted. Non-parenteral AmB administration would potentially lead to safer treatments and expand the benefits of antifungal and antileishmanial therapy with this drug worldwide. Despite real scientific advances in the area over the last ten years, very few delivery systems have progressed from proof-of-concept to clinical trials as oral, topical or pulmonary AmB medicines. Cyclodextrins and nanoparticle based formulations (self-emulsifying systems, cochleates and liposomes) are the most promising delivery systems to date.

With the aim to reduce dosing frequency and to target drugs to cellular compartments actually in need of treatment, the design of drug delivery systems is becoming complementary to new drug discovery. The review highlights various drug/antigen delivery approaches comprising of vesicular and particulate nanocarriers that are associated with spectacular advantages like improved solubility and stability for poorly soluble drugs, good safety profile, versatility for encapsulating nearly all drugs, drug-release modulation, high drug payloads etc. In this review, light is shed on the remarkable potential of nanotechnology to provide more effective therapeutic and prophylactic approaches for the treatment and prevention for HIV/AIDS.

The design of precise and biodegradable gene transfer carriers is one important aim in gene therapy. Here we describe a strategy where we combine sequence-defined oligomers with precise bioreversible coupling to a multivalent dendrimer core. The dendrimer polypropylenimine of generation 2 (PPI G2) was chosen as a core and its eight primary surface amines were modified with 3-nitro-2-pyridinesulfenyl (Npys) modified cysteine. Npys-cysteines react avidly with free thiols forming bioreducible disulfide bonds. By these means, the activated PPI core molecule can be coupled in a directed manner in solution to eight molecules of cysteine-containing sequence-defined oligomers synthesized by solidphase supported synthesis. As proof of concept, oligomers comprising a C-terminal cysteine and one to five succinoyltetraethylene pentamine (Stp) units were conjugated to the dendrimer core. The resulting conjugates were evaluated for plasmid DNA (pDNA) delivery with regard to their biophysical and biological properties. Nanosized polyplexes stable in 90% serum were formed with higher cellular internalization levels of Stp modified conjugates in comparison to unmodified PPI G2. Consistent with protonation capacity at early endosomal pH and endosomal release, enhanced nuclear association of polyplexes and luciferase reporter gene expression was observed, correlating with increasing numbers (≥2) of Stp units per dendrimer arm, revealing PPI-Stp5 conjugate as the most promising conjugate. The new biodegradable conjugates possessed substantially lower cytotoxicity than PPI G2. Intravenous tail-vein injection of PPI-Stp5/pDNA polyplexes as compared with PPI G2 polyplexes revealed superior transgene expression in subcutaneous tumors of mice, but lower gene expression in the lung and liver.

Triamcinolone acetonide niosomes were prepared by thin film hydration technique using surfactants Brij 52, Span 20, cetrimide and cholesterol by 23 factorial design. Niosomes were evaluated for their morphology, vesicle size, in vitro drug release and skin permeation study using human skin. From the factorial design it was found that the cetrimide used in the formulation had greater effect on the entrapment efficiency, in vitro drug release and skin permeability and the particle size was found to be in the range of 50-80 nm. Clinical study was carried out using histamine wheal suppression test for the niosomal formulation and was compared with marketed product on healthy human volunteers with and without iontophoresis. It was found that niosomal formulation with iontophoresis at 15 min has more effect than at 60 min and 120 min when compared to the marketed product.

The objective of the present research was to design and develop microemulsion (ME) based transdermal systems of poorly water soluble drug, Lercanidipine hydrochloride (LDPH) by assimilation of central composite design and principal component analysis (PCA) as two important paradigms of quality by design. LDPH loaded O/W MEs were optimized with amounts of oil (Capryol 90), surfactants mixture (Cremophor EL and Ethanol) and water as independent variables along with cumulative amount of drug permeated in 24 h (Q24), flux (Jss) and lag time (tL) as dependent variables. The optimized batch of LDPH loaded ME was successfully converted into microemulsion based gel (MBG) for increased patient compliance. The results of in vitro skin permeation of the optimized batch of LDPH loaded MBG revealed significant increase in permeability parameters as compared to its convention formulation. The values of Jss for optimized batch of LDPH loaded MBGs (196.47 μg/cm2h) revealed 7.95 cm2 area requirement to obtain the desired input rate of LDPH within 24 h application. All these concluded suitability of experimental design and PCA for design and development of O/W type MEs as carriers for transdermal delivery of poorly water soluble drug, LDPH.

The aim of this research was to formulate the ofloxacin loaded lipospheres as a drug delivery system to improve the oral bioavailability, reduce toxicity and achieve better patient compliance. The ofloxacin loaded lipospheres were formulated by melt dispersion technique using cetyl alcohol; poly vinyl alcohol (0.1%w/v) and pectin (1%w/v) act as lipid carrier, surfactant and co-surfactant respectively. The in vitro release kinetic studies were carried out for lipospheres loaded with ofloxacin and the value of R2 in Higuchi model is greater than 0.99 and release exponent (n), was found to be more than 0.5 that is Non-Fickian type. The in vitro release kinetic followed dissolution and then Korsmeyer–Peppas models. The bioavailability of ofloxacin loaded lipospheres was performed in rabbits after oral administration was studied. The plasma drug concentration was estimated by using a simple, accurate and precise high performance thin layer chromatographic technique. The pharmacokinetics studies demonstrated that the liposphere system enhance the bioavailability of ofloxacin by 2.45 fold after oral administration. Based on these results, we concluded that lipospheres might be a promising lipid based colloidal carrier system to enhance the bioavailability of ofloxacin.