Current Drug Delivery - Volume 7, Issue 1, 2010

Introduction and Aim: We report the 2-year efficacy and tolerability of intravesical botulinum A toxin (BoNT/A) injections in patients with painful bladder syndrome (PBS) associated with increased urinary frequency refractory to conventional treatments. Materials and Methods: Thirteen women were prospectively included in the study. The preliminary assessment included voiding diary, urodynamics, urinary tract ultrasound and the visual analog scale (VAS) for pain quantification. All patients received multiple injections of 200 U commercially available BoNT/A diluted in 20 ml 0.9% NaCl, under cystoscopic guidance. Clinical evaluation, urodynamics, urinary tract ultrasound and VAS were repeated at least two times per year throughout the follow-up. Results: A total of 58 injections were administered with a mean of 4.8 ± 0.8 injections per patient. The mean interval between two consecutive injections was 5.25 ± 0.75 months. At 1 and 4 mo follow up ten patients reported a subjective improvement. Mean VAS scores, mean daytime and night-time urinary frequency decreased significantly. Nine patients at 1 month and seven at the 4-month check-up complained of dysuria. The three non-responders to the first intravesical treatment session underwent another three months later with satisfactory results. At 1 and 2 years follow up the beneficial effects persisted in all patients. We did not observe any systemic side effects during the observation time. Conclusions: Intravesically injected BoNT/A is effective and safe in the medium-term management of patients with PBS. As the beneficial effect decreased progressively within a few months after treatment, repeat injections of the neurotoxin were needed over time.

Dissolution testing with subsequent analysis is considered as an imperative tool for quality evaluation of the combination rifampicin-isoniazid (RIF-INH) combination. Partial least squares (PLS) regression has been successfully undertaken to select suitable predictor variables and to identify outliers for the generation of equations for RIF and INH determination in fixed-dose combinations (FDCs). The aim of this investigation was to ascertain the applicability of the described technique in testing a novel oral FDC anti-TB drug delivery system and currently available two-drug FDCs, in comparison to the United States Pharmacopeial method for analysis of RIF and INH Capsules with chromatographic determination of INH and colorimetric RIF determination. Regression equations generated employing the statistical coefficients satisfactorily predicted RIF release at each sampling point (R2≥ 0.9350). There was an acceptable degree of correlation between the drug release data, as predicted by regressional analysis of UV spectrophotometric data, and chromatographic and colorimetric determination of INH (R2=0.9793 and R2=0.9739) and RIF (R2= 0.9976 and R2=0.9996) for the two-drug FDC and the novel oral anti-TB drug delivery system, respectively. Regressional analysis of UV spectrophotometric data for simultaneous RIF and INH prediction thus provides a simplified methodology for use in diverse research settings for the assurance of RIF bioavailability from FDC formulations, specifically modified-release forms.

Polyphosphazene polyelectrolytes are synthetic, biodegradable polymers that have shown great potential in vaccine and drug delivery applications. Numerous investigations in laboratory animals have revealed that polyphosphazenes are also potent immunological adjuvants that can dramatically enhance the magnitude, quality and duration of immune responses to a variety of bacterial and viral vaccine antigens. Evidence is accumulating that these polymers have potent adjuvant activity in large animals as well. Interestingly, polyphosphazenes can be combined with novel immune modulatory agents resulting in even more potent immune activity and protection against experimental infection. While most reports are on the activity of polyphosphazenes in aqueous formulations, these polymers can also be easily made into microparticles, making them especially attractive for mucosal delivery. The mechanisms which mediate the adjuvant activity of polyphosphazenes are not fully understood, but there is evidence to suggest that activation of innate immunity may be involved. Further research and development of polyphosphazene adjuvants is warranted to fully explore their potential in the delivery of vaccines and immunotherapeutic agents.

Fast disintegrating films of levocetirizine dihydrochloride useful for the treatment of acute allergic rhinitis and chronic urticaria have been developed by using the taste masking ability of cyclodextrins. The fast disintegrating films were prepared by solvent casting method. The films contained water-soluble polymers such as Kollicoat IR or pullulan, aspartame and sucralose as sweeteners and pre-gelatinized starch as disintegrant. Levocetirizine dihydrochloride was incorporated into these films by in-situ complex formation with hydroxy propyl β-cyclodextrin. The optimized films were evaluated for weight variation, film thickness, folding endurance, tackiness, tensile strength, assay, content uniformity, in vitro disintegration and dissolution, in vivo disintegration and taste masking ability by human gustatory sensation test. Results revealed that the organoleptic properties of levocetirizine dihydrochloride were improved by complexation with hydroxy propyl β-cyclodextrin and the complex could be successfully formulated into a fast disintegrating film.

Polar lipids and various surfactants exhibit rich phase behavior depending on the composition of the lipids and the physicochemical conditions. Lamellar (Lα), hexagonal (Inverted [HII]) and normal or inverted cubic (bicontinuous or micellar) structures are some of the most common lyotropic liquid crystalline phases. Hexosomes are the reverse hexagonal phases comprised of hexagonally close-packed infinite water layers covered by surfactants monolayer. Hexosomes (dispersed HII phases) due to their special structural properties have potential to be used as alternative delivery vehicle for pharmaceuticals. Biologically active molecules can either be accommodated within the aqueous domains or can be directly coupled to the lipid hydrophobic moieties oriented radially outwards from the centre of the water rods. Due to these special properties of hexosomes, they are used to improve solubility of poorly water soluble drugs and to transport therapeutic peptides and proteins by oral, transdermal, and parenteral routes. This article includes various methods of preparation of hexosomes and their application in drug delivery through various routes.

Gellan gum has been reported to have wide pharmaceutical applications such as tablet binder, disintegrant, gelling agent and as a controlled release polymer. Multiparticulate delivery systems spread out more uniformly in the gastrointestinal tract and reduce the local irritation. The purpose of this study is to explore possible applicability of gellan macro beads as an oral controlled release system of a sparingly soluble drug, amoxicillin. Gellan gum beads were prepared by ionotropic gelation with calcium ions. The effect of drug loading, stirring time, polymer concentration, electrolyte (CaCl2) concentration, curing time etc. influencing the preparation of the gellan gum macro beads and the drug release from gellan gum beads were investigated in this study. Optimal preparation conditions allowed very high incorporation efficiency for amoxicillin (91%) The release kinetics of amoxicillin from gellan beads followed the diffusion model for an inert porous matrix in the order: 0.1 N HCl > phosphate buffer > distilled water. Change in curing time did not significantly affect the release rate constant, but drug concentration, polymer concentration and electrolyte concentration significantly affect the release rate of amoxicillin from the beads. The gellan macro beads may be suitable for gastro retentive controlled delivery of amoxicillin.

Repaglinide solid lipid nanoparticles (RG-SLN) were fabricated using stearic acid as lipid. Pluronic F68 (PLF68) and soya lecithin were used as a stabilizer. SLNs were prepared by modified solvent injection and ultrasonication methods. SLNs prepared with modified solvent injection method have larger particle size (360±2.5nm) than prepared with ultrasonication method (281± 5.3nm). The zeta potential of the prepared formulations by these two methods varied from - 23.10 ± 1.23 to -26.01 ± 0.89 mV. The maximum entrapment efficiency (62.14 ± 1.29%) was obtained in modified solvent injection method. The total drug content was nearly same (98% ) in both the methods. In vitro release studies were performed in phosphate buffer (pH 6.8) with 0.5% sodium lauryl sulphate (SLS) using dialysis bag diffusion technique. The cumulative drug release was 30% and 50% within 2 hrs in modified solvent injection and ultrasonication method, respectively. This indicates that RG-SLN prepared from modified injection method released the drug more slowly than SLNs prepared with ultrasonication method. Differential scanning calorimetry indicates that repaglinide (RG) entrapped in the solid lipid nanoparticles (SLN) exist in an amorphous or molecular state. Repaglinide loaded solid lipid nanoparticles prepared with both methods were of spherical shape as observed by transmission electron microscopy (TEM). These results suggest that modified solvent injection method is more suitable for preparation of repaglinide SLNs using stearic acid.

Etoposide is one of the most commonly used drugs in chemotherapy of acute lymphocytic leukemia and acute myelogenous leukaemia. Etoposide has variable oral bioavailability ranging from 24-74% and has terminal half life of 1.5 hours by intravenous route. The conventional parenteral therapy causes inconvenience and pain to the patients as it has to be given through a continuous IV infusion over 24-34 h. The present investigation was aimed at developing etoposide loaded biodegradable nanoparticles which would be a sustained release formulation and replace the conventional therapy of continuous intravenous administration. Nanoparticles were prepared by emulsion solvent evaporation method using high pressure homogenization. The process parameters like homogenization cycles (four) and homogenization pressure (10000 psi) were first optimized using a 32 factorial design based on response Y1(mean particle size of 98±1nm). Then a 32 factorial design was carried out to study the effect of two independent variables, ratio of drug and polymer (X1) and surfactant concentration (X2) on the two responses to obtain their optimized values, percentage entrapment efficiency (Y2, 83.12±8.3%) and mean particle size (Y3, 105±5.4 nm) for Etoposide loaded PLGA Nanoparticles. Contour plots and response surface plots showed visual representation of relationship between the experimental responses and the set of input variables. The adequacy of the regression model was verified by a check point analysis. The zeta potential values ranged between -23.0 to -34.2 mV, indicating stability. Sucrose was used as cryoprotectant during lyophilization. DSC and XRD studies indicated that etoposide was present in the amorphous phase and may have been homogeneously dispersed in the PLGA matrix. The electron micrographs showed spherical, discrete and homogenous particles. Drug release study showed that etoposide loaded PLGA nanoparticles sustained release up to 72h. The release from the nanoparticles followed first order kinetics and mechanism of drug release was Fickian. Stability studies indicated that it was best to store nanoparticle formulations in the freeze dried state at 2-8 C where they remained stable in terms of both size and drug content upto three months.

Despite recent success, rapidly disintegrating lyophilized tablets still face problems of low mechanical strength and higher disintegration times resulting in poor patient compliance. The aim of the current work was to carry out a systematic study to understand the factors controlling mechanical properties of these formulations. The work investigated the influence of two bloom strengths of gelatin: low (60 bloom) and high (225 bloom) at different stock solution concentrations (2, 5, 7.5, and 10 %w/w). This was followed by investigation of addition of five saccharides (xylitol, glucose, trehalose, maltotriose and mannitol) at varied concentration range (10-80 %w/w) to decipher their influence on disintegration time, mechanical and thermal properties of the formulation. The results indicated that the disintegration time of the tablets dramatically decreased by decreasing the concentration and bloom strength of gelatin in the stock solution. However the mechanical properties of the tablets were mainly influenced by the concentration of gelatin rather than the bloom strength. The addition of saccharides resulted in enhancement of tablet properties and was concentration dependent. All the saccharides improved the fractubility of the tablets significantly at high concentration (equal or higher than 40% w/w). However, only high concentration (equal or higher than 40% w/w) of trehalose, maltotriose and mannitol significantly enhanced the hardness. Additionally, mannitol crytallised during freeze drying and consequently produced elegant tablets, whilst the other saccarides exhibited lyoprotectant activity as they were able to retain amorphous status. Based on the above findings, an optimized formulation was also successfully developed and characterized to deliver 100 μg dose of Clonidine HCl.

Background. Although the relationship between antidepressant use during pregnancy and its adverse effects has been widely investigated, very few studies have evaluated the impact of antidepressant use during pregnancy on the risk of spontaneous abortion. We present an overview of the evidence relating to the association between antidepressant use during gestation and the risk of spontaneous abortion. Methods. We systematically searched PubMed and the reference lists of all relevant articles, including reviews, published in English or French from 1975 through 2009 for studies that examined the association between adverse pregnancy outcomes and gestational exposure to antidepressants with data on spontaneous abortions. Only etiologic studies were considered. Results. Fifteen studies met inclusion criteria. The majority of these were prospective cohort studies on tricyclics antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) use during pregnancy. Overall, in unadjusted analyses, fluoxetine (OR = 2.0; 95% CI = 1.4 - 3.0) and bupropion (OR = 4.1; 95% CI = 1.5 - 11.1) were significantly associated with the risk of spontaneous abortion. However, in adjusted analyses, only paroxetine (OR = 1.7; 95% CI = 1.3 - 2.3) and venlafaxine (OR = 2.1; 95% CI = 1.3 - 3.3) were significantly associated with the risk of spontaneous abortion. Conclusions. This review suggests that gestational exposure to antidepressants, especially paroxetine and venlafaxine, can lead to spontaneous abortion.

Most of the floating systems have an inherent drawback of high variability in the GI transit time, invariably affecting the bioavailability of drug. An attempt has been made to develop floating drug delivery system for improving the drug bioavailability by prolongation of gastric residence time of famotidine in stomach. The floating microballoons were prepared using polymer Eudragit L-100 by solvent evaporation and diffusion technique. The prepared famotidine loaded microspheres were characterised for drug loading, entrapment, encapsulation efficiency, particle size distribution, surface morphology, differential scanning calorimetry, test for buoyancy, in-vitro release and in-vivo antiulcer studies. The results showed an increased drug loading, encapsulation and entrapment efficiency. The thermogram of the DSC showed that the drug was encapsulated in amorphous form and SEM studies revealed the discrete, spherical shaped spheres with rough surface and presence of holes on floating microspheres due high entrapment of PEG which are responsible for drug release and floating ability. The sizes of spheres were found between 20-120 μm which exhibited prolonged release (Invitro > 8 h) and remained buoyant for > 10 h. The mean particle size increased and the drug release rate decreased at higher Eudragit L-100 polymer concentration. The in-vivo results showed significant antiulcer property of famotidine loaded microspheres when compared to control and standard group of rats by using pyloric ligation method. The mean volume of gastric secretion, mean pH and mean total acid for formulation treated group was calculated as 3.45+0.88 ml, 5.65+ 0.74, and 114.15+1.80 mEq/L respectively.