Pharmaceutical Nanotechnology (v.2, #2)

Editorial: by Ijeoma F. Uchegbu (57-57).

Nanocarbon Materials for Photodynamic Therapy and Photothermal Therapy by Qian Li, Hong Ruan, Hongguang Li (58-64).
Photodynamic therapy (PDT) and photothermal therapy (PTT) are two kinds of methodologies that can be appliedto the treatment of cancer. They own some advantages over the existing strategies including chemo- and radiotherapybut at the same time, are also facing big challenges. During the past decades, great efforts have been devoted toovercome the bottlenecks and to push these two newly-emerging methodologies to practical applications. One of the bigachievements is the utilization of nanocarbon materials in PDT and PTT. Nanocarbon materials include zero-dimensionalfullerene, one-dimensional carbon nanotubes (CNTs), and two-dimensional graphene. Upon illumination, fullerene cangenerate reactive oxygen species (ROS) through both Type I and Type II photochemistry, which allows it a good candidatefor PDT. CNTs and graphene generate significant amount of heat upon excitation with near-infrared light, whichmakes them suitable for PTT. In this review, recent developments of the application of nanocarbon materials in PDT andPTT are briefly summarized and discussed.

The Oral and Intranasal Delivery of Propofol Using Chitosan Amphiphile Nanoparticles by Ijeoma F. Uchegbu, Marie-Christine Jones, Federica Corrente, Lisa Godfrey, Davide Laghezza, Maria Carafa, Per Holm, Andreas G. Schatzlein (65-74).
The intravenous anaesthetic propofol acts on gamma amino butyric acid A (GABAA) receptors in the brain.Propofol is often used as a procedural sedative and is also effective (at sub-anaesthetic doses) against intractable migraineand non-migraine headaches. However intravenous propofol is associated with pain on injection and with peripherallymediated hypotension. Here we introduce N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan(GCPQ) - propofol nanoparticles and demonstrate, for the first time, that propofol nanoparticles are centrally active viathe oral and the intranasal routes. Utilising these routes would abolish the pain on injection and, with respect to the nasalroute, reduce peripheral exposure. The nanoparticles are 40-500 nm in size and stable for 21 days at room temperature.Brain drug exposure with orally administered GCPQ-propofol nanoparticles (350 mg kg-1 propofol) was not significantlydifferent from a comparable oral dose of Diprivan. However there was less inter-individual variability with the GCPQformulation (brain concentration coefficient of variation at the 5 minute peak time point = 1.24 and 0.72 for the Diprivanand GCPQ nanoparticle formulations respectively). Furthermore there was increased inter-individual variability in thepharmacodynamic response to oral Diprivan when compared to oral GCPQ-propofol, as measured by the loss of rightingreflex (LORR) time. The LORR time after oral doses of 250 mg kg-1 and 350 mg kg-1 propofol as Diprivan was 15.7±24.6minutes and 47.2±35.70 minutes respectively while the LORR time after oral 250 mg kg-1 and 350 mg kg-1 GCPQpropofolwas 0 minutes and 52.7±22.9 minutes respectively. These data have implications for the safety of oral Diprivan.Via the intranasal route, the LORR time with Diprivan (4mg kg-1 propofol) was not significantly different from that of intranasalsaline, while the intranasal administration of GCPQ-propofol formulations (4 mg kg-1 and 8 mg kg-1 propofol)produced significantly higher LORR times than when saline was administered. In summary, these animal data demonstratethat GCPQ-propofol nanoparticles may provide an effective method of administering non-parenteral propofol forpotential use in non-anaesthetic settings.

Cefuroxime axetil is a Class IV drug as per the Biopharmaceutical Classification System. It is a prodrug ofCefuroxime which is practically insoluble in water with a log P of 3.8. The absolute bioavailability of cefuroxime axetil,determined after intravenous injection of 1 g of cefuroxime and oral administration of 1 g of cefuroxime axetil (uncoatedtablet), is 32-35% (range 23-44%). The present investigation was aimed at preparation of nanosuspension of Cefuroximeaxetil for improving its solubility and thereby its bioavailability. Cefuroxime axetil nanosuspensions were prepared by themedia milling technique using zirconium oxide beads and characterized by particle size, saturation solubility, differentialscanning calorimetry, scanning electron microscopy and transmission electron microscopy. The nanosuspensions wereevaluated for in vivo diffusion studies, ex vivo intestinal permeability studies and in vivo bioavailability studies. The particlesize of the drug was drastically reduced to 221.2±0.26 nm from 5 µm after nanosizing. Saturation solubility achievedwas 2387±3.35 µg/ml which was 16 times more than the bulk drug. DSC thermograms confirmed the non interference ofexcipients on the drug particles. In vivo diffusion studies showed 94.17±5.689% drug release from nanosuspension asagainst 62.34±1.139% release from plain Cefuroxime axetil suspension in 24 hours. Similarly, for ex vivo studies,57.52±1.159% was released from plain Cefuroxime Axetil suspension in comparison to 85.58±3.12% for nanosuspensionin 24 hours. In vivo studies in rats demonstrated a two times increase in oral bioavailability from the nanosuspension incomparison to marketed formulation. Therefore, nanosuspension which exhibited improved solubility, dissolution andabsorption could be a better option as a delivery system compared to the present oral suspension formulation.

Nebivolol HCl (NBL) a third generation beta blocker poses lack of oral bioavailability (12%) owing to its lowsolubility and first pass biotransformation in liver. The present research was undertaken to prepare solid Selfnanoemulsifyingdrug delivery system (S-SNEDDS) of NBL which will present NBL at molecular level in nanoemulsionform throughout GIT. Increased solubility along with intestinal lymphatic transport of lipid rich nanoemulsified drug bypassinghepatic first pass may enhance bioavailability. Based on solubilization of the drug and spontaneity of selfemulsification,Peceol as an oily phase, Cremophore RH 40 and Gelucire 50/13 as surfactants and ethanol as cosurfactant/co-solvent were selected as the excipients to produce NBL loaded S-SNEDDS. Total 9 formulations were madewith different ratios of the excipients and the optimized formulation was selected on the basis of solidification ofSNEDDS on refrigeration and maintenance of the solid state. Spherical shaped morphology of oil globules was confirmedby TEM analysis. On dilution S-SNEDDS showed nanoparticles of size 180-190nm with a Polydispersity index 0.4-0.8and Zeta potential -5.17, -7.56mV. The DSC and X-ray diffraction patterns of the S-SNEDDS show the amorphous stateof NBL in the lipid matrix. Developed S-SNEDDS showed pH-independent drug dissolution which in SIF was fourfoldgreater as compared to plain drug. The intestinal permeability by everted sac technique showed threefold increase intransportation of NBL from S-SNEDDS formulation compared to NBL solid suggesting that S-SNEDDS of NBL is anexcellent and practical approach of enhancing the oral bioavailability through improved solubility.

Challenges in Developing a Safe Nanomedicine based on Ocotea Duckei Vattimo to Leishmaniasis Treatment: Methodology, Nanoparticle Development and Cytotoxicity Assays by Fabia C. Rossetti, Sandro S. Leal, Jose M.B. Filho, Eduardo J. Oliveira, Hernane S. Barud, Juliana I. Hori, Franciane Marquele-Oliveira, Andresa A. Berretta (101-114).
Different studies have reported the promising pharmacological activities of yangambin, a lignan from Ocoteaduckei Vattimo, mainly as an anti-leishmanial and antitumor compound. However, this lignan has demonstrated to becommonly isolated only as a mixture of diastereoisomers. In this regard, here it is described for the first time, the separationand quantification of yangambin diastereoisomers through HPLC-DAD. Additionally, it was assessed the loading ofthe Lignan Fraction (LF) from Ocotea duckei, rich in yangambin diastereoisomers, in a nanopharmaceutical formulationfollowed by the assessment of their effects on macrophage citotoxicity. To this, a RP-HPLC-DAD method was developedand validated; biomarkers identity and purity were assessed by UV profile, IR, ESI-IT MS, 13C and 1H NMR and meltingpoint range. Lipid nanoparticles were obtained by the microemulsion method. Cytotoxicity studies were conducted inbone marrow-derived macrophages (BMDMs) from C57BL/6 mice by quantification of propidium iodide (PI) uptake. Theresults showed that this novel, fast and reliable HPLC-DAD methodology allowed the simultaneous separation and quantificationof yangambin and its diastereoisomer, epi-yangambin, in Ocotea duckei extract. Lignan Fraction and LF loadednanoparticles. In addition, the method was validated according to ICH and ANVISA (Brazilian) standards. The LF loadednanoparticles demonstrated to be in nanometer range and the encapsulation efficiency (EE) was 55.72±1.33% for YANand 66.11±9.29% for EPI-YAN. The cytotoxicity studies revealed that in the LF fraction (20 and 40µg/mL), neither YAN(3 and 6µg/mL) nor EPI-YAN (3.5 and 7µg/mL) were toxic to macrophages for up to 18 hours of treatment. These resultsconfirmed the low toxicity of Ocotea duckei lignan rich fraction and its isolated compounds, in mammalian macrophages,enabling them to be used in future biological studies. On the other hand, besides LF loaded nanoparticle presentednanoscale profile, it requires adjustments to safely deliver LF to macrophages.