Pharmaceutical Nanotechnology (v.1, #4)

Editorial by Ijeoma Uchegbu (249-249).

Amphotericin B Formulations - The Possibility of Generic Competition by Dolores R. Serrano, Maria P. Ballesteros, Andreas G. Schätzlein, Juan J. Torrado, Ijeoma F. Uchegbu (250-258).
From the 1950s, Amphotericin B (AmB) in the form of Fungizone® was considered the “gold standard” in antifungaltherapy. This was due to its broad-spectrum of activity. In the 1990s, Fungizone® was relegated to a second linetreatment option after the commercialization of lipid-based formulations (AmBisome®, Abelcet® and Amphocil®). Thesenew medicines have similar efficacies but more favourable safety profiles. These formulations will be coming off patentover the coming months and so there is an opportunity for generics manufacturers to enter the arena. However, the lack ofclear regulatory guidance on how to perform bioequivalence studies with liposomal drugs makes it difficult to ensure thatgeneric 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 leadto treatment being halted. Non-parenteral AmB administration would potentially lead to safer treatments and expand thebenefits of antifungal and antileishmanial therapy with this drug worldwide. Despite real scientific advances in the areaover the last ten years, very few delivery systems have progressed from proof-of-concept to clinical trials as oral, topicalor pulmonary AmB medicines. Cyclodextrins and nanoparticle based formulations (self-emulsifying systems, cochleatesand liposomes) are the most promising delivery systems to date.

Nanocarrier based Antiretroviral Drug Delivery Approaches by Sakshi Taneja, Kapil Khatri (259-268).
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 variousdrug/antigen delivery approaches comprising of vesicular and particulate nanocarriers that are associated with spectacularadvantages like improved solubility and stability for poorly soluble drugs, good safety profile, versatility for encapsulatingnearly all drugs, drug-release modulation, high drug payloads etc. In this review, light is shed on the remarkablepotential of nanotechnology to provide more effective therapeutic and prophylactic approaches for the treatment andprevention for HIV/AIDS.

Gene Transfer with Sequence-Defined Oligo(ethanamino)amides Bioreducibly Attached to a Propylenimine Dendrimer Core by Petra Kos, Claudia Scholz, Eveline E. Salcher, Annika Herrmann, Ernst Wagner (269-281).
The design of precise and biodegradable gene transfer carriers is one important aim in gene therapy. Here wedescribe a strategy where we combine sequence-defined oligomers with precise bioreversible coupling to a multivalentdendrimer core. The dendrimer polypropylenimine of generation 2 (PPI G2) was chosen as a core and its eight primarysurface amines were modified with 3-nitro-2-pyridinesulfenyl (Npys) modified cysteine. Npys-cysteines react avidly withfree thiols forming bioreducible disulfide bonds. By these means, the activated PPI core molecule can be coupled in a directedmanner in solution to eight molecules of cysteine-containing sequence-defined oligomers synthesized by solidphasesupported synthesis. As proof of concept, oligomers comprising a C-terminal cysteine and one to five succinoyltetraethylenepentamine (Stp) units were conjugated to the dendrimer core. The resulting conjugates were evaluated forplasmid DNA (pDNA) delivery with regard to their biophysical and biological properties. Nanosized polyplexes stable in90% serum were formed with higher cellular internalization levels of Stp modified conjugates in comparison to unmodifiedPPI G2. Consistent with protonation capacity at early endosomal pH and endosomal release, enhanced nuclear associationof polyplexes and luciferase reporter gene expression was observed, correlating with increasing numbers (≥ 2) ofStp units per dendrimer arm, revealing PPI-Stp5 conjugate as the most promising conjugate. The new biodegradable conjugatespossessed substantially lower cytotoxicity than PPI G2. Intravenous tail-vein injection of PPI-Stp5/pDNA polyplexesas compared with PPI G2 polyplexes revealed superior transgene expression in subcutaneous tumors of mice, butlower gene expression in the lung and liver.

Formulation and Clinical Evaluation of Triamcinolone Acetonide Niosomes: Effect of Iontophoresis on the Permeation Across Skin by Veintramuthu Sankar, Elizabeth Babu, Karthik Siram, Shalini D. Penmetsa, Balakumar Kabila, Chakravarthi R. Srinavas, Reena Rai (282-289).
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 thecetrimide used in the formulation had greater effect on the entrapment efficiency, in vitro drug release and skin permeabilityand the particle size was found to be in the range of 50-80 nm. Clinical study was carried out using histamine whealsuppression test for the niosomal formulation and was compared with marketed product on healthy human volunteers withand without iontophoresis. It was found that niosomal formulation with iontophoresis at 15 min has more effect than at 60min and 120 min when compared to the marketed product.

The objective of the present research was to design and develop microemulsion (ME) based transdermal systemsof poorly water soluble drug, Lercanidipine hydrochloride (LDPH) by assimilation of central composite design andprincipal component analysis (PCA) as two important paradigms of quality by design. LDPH loaded O/W MEs were optimizedwith amounts of oil (Capryol 90), surfactants mixture (Cremophor EL and Ethanol) and water as independentvariables 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 increasedpatient compliance. The results of in vitro skin permeation of the optimized batch of LDPH loaded MBG revealedsignificant increase in permeability parameters as compared to its convention formulation. The values of Jss for optimizedbatch of LDPH loaded MBGs (196.47 μg/cm2h) revealed 7.95 cm2 area requirement to obtain the desired input rate ofLDPH within 24 h application. All these concluded suitability of experimental design and PCA for design and developmentof O/W type MEs as carriers for transdermal delivery of poorly water soluble drug, LDPH.

Formulation of Ofloxacin Loaded Lipospheres with Improved Oral Bioavailability by Satheesh Babu Natarajan, Prabakaran Laksmanan (306-315).
The aim of this research was to formulate the ofloxacin loaded lipospheres as a drug delivery system to improvethe oral bioavailability, reduce toxicity and achieve better patient compliance. The ofloxacin loaded liposphereswere formulated by melt dispersion technique using cetyl alcohol; poly vinyl alcohol (0.1%w/v) and pectin (1%w/v) act aslipid carrier, surfactant and co-surfactant respectively. The in vitro release kinetic studies were carried out for lipospheresloaded with ofloxacin and the value of R2 in Higuchi model is greater than 0.99 and release exponent (n), was found to bemore than 0.5 that is Non-Fickian type. The in vitro release kinetic followed dissolution and then Korsmeyer-Peppasmodels. 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 layerchromatographic technique. The pharmacokinetics studies demonstrated that the liposphere system enhance the bioavailabilityof ofloxacin by 2.45 fold after oral administration. Based on these results, we concluded that lipospheres might be apromising lipid based colloidal carrier system to enhance the bioavailability of ofloxacin.