Drug Delivery Letters - Volume 3, Issue 1, 2013

N-triethyl chitosan (TEC) has recently been proven to be an efficient polymer for improving transport of hydrophilic drugs. Thus, in order to evaluate its gene delivery efficiency, TEC is assembled with Enhanced Green fluorescence protein plasmid DNA (pEGFP) at different polymer to plasmid (N/P) ratios to form TEC/pEGFP nanoparticles. Photon correlation spectroscopy is used to evaluate nanoparticles size and zeta potential. The transfection efficiency and cytotoxicity in gene delivery to AsPC-1 cells (human pancreatic cancer cells) are evaluated via fluorescence microscopy, flow cytometry and MTT assay. Also parameters such as cancer cells’ mean fluorescence intensity (MFI) and cell size changes after transfection are assayed. The results indicate that the incorporation of pEGFP in TEC can form charged nanoparticles at N/P ratios from 10 to 40. Increasing the N/P ratio increases transfection efficiency, MFI, cell size and cytotoxicity. At N/P ratio of 10, transfection increased up to 11.12 fold with the least cytotoxicity. Considering that mathematical models can be used to understand and predict consequences associated with nanomedicine, the relation between TEC /pDNA nanoparticles charge ratio, cell transfection and toxicity was evaluated for the first time with interpolation polynomial method.

A total of six formulations (H1A, H1B, H1C, H1D, H1E and H1F) of Levofloxacin-chitosan/hydroxypropyl β-cyclodextrin nanoparticles were prepared by ionic gelation method. The particle size of the prepared nanoparticles varied between 191 and 623 nm and drug content ranged between 59.12 ± 0.22 and 72.89 ± 0.32 %. The drug entrapment efficiency differed between 60.12 ± 1.2 and 75.82 ± 2.2 %. The particles size of nanoparticles increased with increasing concentration of polymer matrix density and this may be due to the increased viscosity of the inner phase and decreased with increasing concentration of hydroxypropyl β-cyclodextrin. The results of drug entrapment efficiency indicated that, the entrapment efficiency increased with increasing concentration of chitosan. The complexation with the cyclodextrin permits a protection for sensitive drug and in vitro release profile observed for these nanoparticles characterized by an erratic drug release in the beginning and followed by a delayed release phase. Of the above six formulations, three formulations H1B, H1E and H1F followed the drug release in a controlled manner. All the selected formulations were best fitted to super case II transport drug release, according to this drug release mechanism could be due to increased plasticization at the relaxing boundary. Scanning electron microscopy indicated that the prepared nanoparticles were discrete, uniform and spherical with a smooth surface. The surface charge indicated that, the formation of nanoparticle depended dramatically on the concentration of free amino groups, which increase the surface charge of the nanoparticles. At the end of the accelerated stability study, the tested formulation showed almost same drug content, in vitro drug release and no color changes from that observed at the opening of the study.

The objective here was to develop gastroretentive tablets of clarithromycin to provide increased residence time in stomach for delivery of antibiotic to treat H. pylori induced gastric ulcers. Hydroxypropylmethylcellulose K4M (HPMC) was used as a mucoadhesive polymer and Avicel PH101 was used as the release modifier. Tablets containing drug, HPMC and Avicel PH101 were prepared using wet granulation technique. The tablets were evaluated for in vitro drug release profile and ex vivo bioadhesion property. A 3^2 factorial design was employed to study the influence of amount of HPMC (X1) and amount of Avicel PH101 (X2) on drug release at the end of 2nd hour (Y1), 6th hour (Y2) and 10th hour (Y3) from the mucoadhesive tablets. Target release profile was generated for a 12 hour dosage regimen and dissolution profile of the best batch was compared using similarity factor f2. Results of multiple regression analysis indicated that HPMC reduced the drug release at all time points while! Avicel PH101 increased the amount of drug release. The dissolution profile of the optimum batch had the similarity factor value of 61 indicating that the release profile was similar to that of target release profile. No significant interaction was found between the drug and the polymer as indicated by DSC and FTIR study. The in vitro drug release followed Korsmeyer and Peppas model kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type (n = 0.837). Gastroretentive tablets for twice a day dosing could be developed for clarithromycin.

Sirolimus has a poor solubility in water ranging from 2-6 μg/mL. The mean bioavailability is approximately 14%. The present study was carried out with a view to enhance the dissolution rate of poorly water-soluble drug sirolimus using Gelucire® as carriers and lactose monohydrate as an adsorbent. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions (SD) to make final product free flowing. Phase solubility study was conducted to evaluate the effect of carriers on aqueous solubility of sirolimus. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). Mathematical modeling of in vitro dissolution data of optimised batch indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as fickian diffusion. All prepared solid dispersions showed dissolution improvement compared to pure drug. Almost similar dissolution profile was obtained as a function of storage time; this can be explained by no change in XRD and DSC patterns after 45 days of storage period.

Mostly anticancer drugs are given as IV infusions, which result in hypertensive reactions due to formulation excipients. Their oral bioavailability is poor or variable due to high liver metabolism, poor aqueous solubility, high Pgp effluxing and macron size. To promote the oral drug delivery of these potential chemotherapeutics, intestinal lymphatic transport has been recognized as a promising route of drug delivery, especially for nanonized cytotoxic drugs because the spread of cancer is much early in lymphatics than the vascular system. A little research has been endeavored to deliver orally, the chemotherapeutics through lymphatic route owing to the complex mechanism involved in their complete absorption. This review will provide insight into the delivery of lipid based nanocarriers through lymphatic transport system for enhancing the oral bioavailability of anticancer moieties.

Gout is a painful disease of joints generated because of the deposition of urate crystals within the joints. Uricase is an enzyme capable of degrading less water soluble urate crystals into a compound allantoin, which is more water soluble and hence is easily excreted. Uricase being proteinaceous is degraded by the protein digestive enzymes of gastro intestinal tract (GIT) when administered orally. Colonic part of GIT lacks protein digestive enzymes and thus provides suitable conditions for the absorption of uricase. Colon consists of several microbial flora which secrete enzymes capable of degradation of alginates and pectin which are not digested by upper GI tract. Eudragit S-100 (pH sensitive polymer) coated alginate - pectinate microbeads were found to be effective for delivery of uricase directly to the colonic site. Sodium taurocholate, a bile salt, was found to be suitable for the effective absorption of uricase from colonic site into the systemic circulation.

Herein reported is a novel and versatile method to prepare drug-carrying polymeric nanoparticles of less than 50 nm in mean diameter and very narrow polydispersity. The process starts with the preparation of ultrafine poly(methyl methacrylate) nanoparticles by a technique termed as semicontinuous heterophase polymerization. Then, the obtained polymeric nanoparticles are loaded with hydrophobic drugs, where Ibuprofen being used as a model compound, by addition of an organic solution of the drug in a water immiscible low boiling point solvent; diffusion of the solution into the polymer nanoparticles allowed loading contents up to 18% IB/dry basis nanoparticles by weight. Analyzed by scanningtransmission electron microscopy, the prepared nanoparticles showed number-average diameters around 18 nm with 1.06- 1.07 polydispersity determined as the ratio weight-average to number-average diameter. Ibuprofen-loaded polymeric nanoparticles with sizes significantly smaller than those obtained by the typical methods reported in the specialized literature can conveniently be prepared by this method, which also permits the use of diverse monomers to synthesize a variety of different polymeric nanoparticles. It is expected that the ease of production, control of size and polydispersity and drug loading will help the polymeric nanoparticles thus prepared emerge as useful drug carriers in the present arsenal for disease control.

A preconcentrate containing Carbamazepine (CBZ) was designed, with the objective to improve its oral bioavailability, which on dilution with aqueous vehicles in vitro/in vivo would yield CBZ nanosuspension in situ. When preconcentrate containing hydrophilic stabilizer alone was diluted with aqueous medium, CBZ precipitated as needle shaped crystals within few minutes, due to Ostwald ripening and probably, due to conversion to dihydrate polymorph. Combination of lipophilic stabilizers and hydrophilic stabilizers imparted adequate colloidal stability to CBZ nanosuspension. Preconcentrate containing a mix of different stabilizers which could yield nanosuspension in situ was optimized with respect to colloidal stability and mean particle size. Preconcentrate containing Tween 80 (31.4% w/v) as hydrophilic stabilizer and Labrafil M1944 CS (20.9 %w/v) as lipophilic stabilizer yielded mean particle size and polydispersity index of 192.7±5.65 nm and 0.35±0.02, respectively, on dilution with aqueous medium in situ. This optimized formula of nanoprecipitating preconcentrate (NPP) yielded CBZ nanosuspension in situ on dilution with aqueous media. The size of CBZ NPP dispersed in water was confirmed with TEM studies, which also provided information on surface morphology of CBZ nanosuspension. The CBZ NPP preconcentrate was converted to free flowing granules (NPPG 1) by adsorption on to Aerosil R 974, for ease of handling. Amorphous state of CBZ in NPPG 1 system as indicated by XRD studies coupled with greater surface area of nanosized CBZ particles could have resulted in improved dissolution velocity of CBZ as compared to CBZ suspension, as observed during in vitro dissolution testing. Anti-epileptic studies in mice demonstrated CBZ NPP superior to plain CBZ suspension in delaying onset of seizures and in reducing mortality.

Indian Propolis, a resin-like substance obtained from plants and modified by bees is a blend of various natural components and a potential candidate for topical application for chemoprevention of skin cancer. In the present study, the potential role of propolis loaded ethosomal transgel for the chemoprevention of skin cancer was investigated. Ethosomal vesicular systems were optimized by varying the proportions of lecithin and ethanol taking vesicle size, polydispersity index (PDI) and entrapment efficiency as dependent variables. The vesicles were found to be unilamellar spherical shaped entities with size varying from 100 nm to 300 nm and entrapment efficiency in a range of 48% to 84%. The permeation and extent of penetration of the optimized formulation were evaluated by Franz diffusion cell and Confocal scanning laser microscopy (CSLM) respectively. It showed a sustained mode of release and remarkable penetration capacity of vesicles (133µm) as compared to hydroethanolic solution of the drug. Histopathological evaluation of the formulation treated skin revealed the interaction of vesicles with the skin which was further supported by FTIR analysis reflecting the mechanism of vesicle permeation via skin. Propolis loaded ethosomal vesicles were then incorporated into carbopol gel and characterized using a texture profile analyzer. The optimized gel so obtained was then finally evaluated for its chemo preventive activity by exposing Swiss albino mice to UVB radiation. The study indicated the possible use of propolis for the prevention of skin cancer through a deep-rooted delivery via ethosomal system eventually circumventing the problem of poor penetrability of topical preparations.