Volume 57 (2007): Issue 3 (September 2007)

In addition to several well-known drug delivery strategies developed to facilitate effective chemotherapy with anticancer agents, some new approaches have been recently established, based on specific effects arising from the applications of ultrasound, magnetic and electric fields on drug delivery systems. This paper gives an overview of newly developed methods of drug delivery to tumors and of the related anticancer therapies based on the combined use of different physical methods and specific drug carriers. The conventional strategies and new approaches have been put into perspective to revisit the existing and to propose new directions to overcome the threatening problem of cancer diseases.

A 3² factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X₁) and proportion of stearic acid in the wax (X₂) on geometric mean diameter (d_g), percent encapsulation efficiency (% EE), release at the end of 12 h (rel₁₂) and time taken for 50% of drug release (t₅₀), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of d_g, % EE, rel₁₂ and t₅₀ values for the optimized formulation were found to be 57.54 ± 1.38 μm, 86.28 ± 1.32%, 77.23 ± 2.78% and 5.60 ± 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats.

The purpose of this study was to obtain an amorphous system with minimum unit operations that will prevent recrystallization of amorphous drugs since preparation, during processing (compression) and further storage. Amorphous celecoxib, solid dispersion (SD) of celecoxib with polyvinyl pyrrollidone (PVP) and co-precipitate with PVP and carrageenan (CAR) in different ratios were prepared by the spray drying technique and compressed into tablets. Saturation solubility and dissolution studies were performed to differentiate performance after processing. Differential scanning calorimetry and X-ray powder difraction revealed the amorphous form of celecoxib, whereas infrared spectroscopy revealed hydrogen bonding between celecoxib and PVP. The dissolution profile of the solid dispersion and co-precipitate improved compared to celecoxib and amorphous celecoxib. Amorphous celecoxib was not stable on storage whereas the solid dispersion and co-precipitate powders were stable for 3 months. Tablets of the solid dispersion of celecoxib with PVP and physical mixture with PVP and carrageenan showed better resistance to recrystallization than amorphous celecoxib during compression but recrystallized on storage. However, tablets of co-precipitate with PVP and carageenan showed no evidence of crystallinity during stability studies with comparable dissolution profiles. This extraordinary stability of spray-dried co-precipitate tablets may be attributed to the cushioning action provided by the viscoelastic polymer CAR and hydrogen bonding interaction between celecoxib and PVP. The present study demonstrates the synergistic effect of combining two types of stabilizers, PVP and CAR, on the stability of amorphous drug during compression and storage as compared to their effect when used alone.

The purpose of this study is to develop novel intestinal-specific drug delivery systems with pH sensitive swelling and drug release properties. Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate) and a methacrylic derivative of N-(4-hydroxyphenyl)-2-(4-methoxyphenyl) acetamide in the presence of ethylene glycol dimethacrylate as crosslinking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1.2) and intestinal fluids (SIF, pH 7.0). The dynamic swelling behavior of these hydrogels was investigated to determine the mechanism of water transport through these hydrogels. The mechanism of water transport through the gels was significantly affected by the pH of the swelling medium and became more relaxation-controlled in a swelling medium of pH 7.0. The swelling and hydrolytic behaviors of hydrogels were dependent on the content of methacrylic acid (MAA) groups and caused a decrease and increase in gel swelling in SGF and SIF, respectively. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of N-(4-hydroxyphenyl)-2-(4-methoxyphenyl) acetamide.

The aim of the present study was to investigate the potential of nanoemulsion formulations for transdermal delivery of celecoxib (CXB). The in vitro skin permeation profile of optimized formulations was compared with CXB gel and nanoemulsion gel. Significant increase in the steady state flux (J_ss), permeability coefficient (K_p) and enhancement ratio (E_r) was observed in nanoemulsion formulations T1 and T2 (p < 0.05). The highest value of these permeability parameters was obtained in formulation T2, which consisted of 2% (m/m) of CXB, 10% (m/m) of oil phase (Sefsol 218 and Triacetin), 50% (m/m) of surfactant mixture (Tween-80 and Transcutol-P) and 40% (m/m) water. The anti-inflammatory effects of formulation T2 showed a significant increase (p < 0.05) in inhibition after 24 h compared to CXB gel and nanoemulsion gel on carrageenan-induced paw edema in rats. These results suggested that nanoemulsions are potential vehicles for improved transdermal delivery of CXB.

A new, simple and sensitive spectrophotometric method for the determination of some sulfonamide drugs has been developed. The method is based on the diazotization of sulfacetamide, sulfadiazine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfamethoxazole, and their coupling with 8-hydroxyquinoline in alkaline media to yield red coloured products with absorption maxima at 500 nm. Beer's law is obeyed from 0.1--7.0 μg mL^-1. The limits of quantification and limits of detection were 0.11--0.18 and 0.03--0.05 μg mL^-1, respectively. Intraday precision (RSD 0.1--0.5%) and accuracy (recovery 97.3--100.8%) of the developed method were evaluated. No interference was observed from common adjuvants. The method has been successfully applied to the assay of sulpha drug in pharmaceutical formulations.

An asymmetric membrane capsule of cellulose acetate for osmotic delivery of flurbiprofen has been developed and influence of osmogents and solubilizing agent on in vitro drug release were evaluated. The capsule membrane was prepared by the phase inversion technique. To ensure the osmotic delivery of drug, two approaches were adopted: (i) the drug was encapsulated with osmogents like sodium chloride and mannitol to increase the osmotic pressure of the core, and (ii) the drug was encapsulated with sodium lauryl sulfate in the core of the formulation to increase the solubility and thus its osmotic pressure. Scanning electron microscopy of the membrane confirmed its porous, dense asymmetric nature. Dye test revealed in situ pore formation. The in vitro release study showed that as the proportion of osmogent and solubilizing agent was increased the release rate also increased. A good correlation was observed between the zero-order rate constant and the amount of the osmogent and solubilizing agent used.

The binary system of etoricoxib with β-cyklodextrin (β-CD) was prepared by the kneading method. Drug-cyclodextrin interactions in solution were investigated by the phase solubility analysis. Differential scanning calorimetry, infrared spectroscopy, powder X-ray diffractometry and microscopic study were used to characterize the solid state of all binary systems, whereas their dissolution properties were evaluated according to the USP XXIII paddle method. The results indicate partial interaction of the drug with β-CD in the physical mixture and complete interaction in the kneaded complex. The dissolution of etoricoxib was notably increased as compared to pure drug as well as its physical mixture. The complex showed more than 75% drug released in 30 min.

The synthesis of some aliphatic and arylaliphatic amides of caffeine-8-thioglycolic acid was studied. The structures of synthesized compounds were proved by micro-analyses, IR- and ¹H NMR data. Values of acute p.o. and i.p. toxicity in mice show lower toxicity compared to caffeine. Declines in spontaneous locomotor activity support the idea of depressive CNS activity of the compounds. Two compounds exhibited brain antihypoxic activity (5a and 5b against haemic and circulatory hypoxia, respectively).

Flavonoids obtained from Sideritis species (Lamiaceae), S. raeseri and S. scardica, grown in Macedonia were studied. Qualitative and quantitative analyses of the flavonoid aglycones were performed using high-performance liquid chromatography (HPLC) with a UV diode array detector. Extracts were prepared by acid hydrolysis in acetone, re-extraction in ethyl acetate and evaporation to dryness; the residue dissolved in methanol was subjected to HPLC analysis.

Isoscutellarein, chryseriol and apigenin were identified in the extracts. Also, a 4'-methyl ether derivative of isoscutellarein was found, together with hypolaetin and its methyl ether derivative, which were identified according to previously isolated glycosides and literature data. Quantitation was performed using calibration with apigenin.

According to this screening analysis, the samples of the genus Sideritis from Macedonia are rich in polyhydroxy flavones and analogous with the previously studied Mediterranean Sideritis species from the Ibero-North African and Greek Sideritis species with respect to the presence of 8-OH flavones and their derivatives.