Current Drug Delivery - Volume 11, Issue 1, 2014

The present investigation was carried out to formulate and optimize the bioerodable insert of Azithromycin in order to prolong the release time and improve the ocular availability in ophthalmic infections. A modified solvent casting method was used for the preparation of azithromycin insert in which hydroxyl propyl methyl cellulose (HPMC) and Eudragit RL100 were used as drug reservoir and rate controlling membrane respectively. Thereafter the, formulations were evaluated for the uniformity of thickness and weight, surface pH, folding endurance, percentage moisture loss, percentage moisture absorption, drug content, in-vitro release, kinetics studies (zero order, first order, Higuchi and Korsmeyer - Peppas model) and stability studies. The Formulation H8 (amongst the range of H1-H10), comprising of 1.5% HPMC and 3% Eudragit RL100, was found to be optimized formulation on the basis of uniformity of thickness (0.26±0.004 mm) and weight (24.9±0.27 mg), surface pH (7.1±0.063), folding endurance (18.3±0.81), percentage moisture loss (7.49±0.30%), percentage moisture absorption (5.7%), drug content (1.98 mg), in-vitro release (99%), AUC for in vitro and in vivo release is 38828.33 and 39783.33 g min/ml respectively and higher than pure drug (1190 g min/ml), (Shelf life- 622 days) and further better occular tolerablity found. The formulation H8 showed a steady and controlled release of the drug over a 12 hour period with non-Fickian diffusion release mechanism, compared to a normal release period of 2-3 hours. The optimized insert showed promising results and can be used to treat a wide range of ocular infections.

Liquisolid technique has been widely used to enhance the dissolution of poorly water soluble drugs. The present investigation is on formulation of liquisolid tablets of fenofibrate, a lipid lowering agent. Liquisolid formulation was prepared by applying central composite design (CCD) to optimize various formulation parameters. Amounts of PEG 600 (X1), Avicel PH 102 (X2), and Aerosil 200 (X3) were selected as independent variables while the angle of repose, hardness, disintegration time, and T90% (time required to release 90% drug) of liquisolid tablets were selected as dependent variables. Optimization of formulation was done by multiple linear regression analysis. The results indicated amounts of PEG 600 and Aviel PH 102 show greater effect on dependant variables. In vitro dissolution of fenofibrate in liquisolid formulations was enhanced compared to the pure form. To conclude, Liquisolid technique is a promising strategy in improving dissolution of poorly water soluble fenofibrate.

Cataracts in Small Animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cataractous LECs during cells’ lifespan. Loss of functional telomere length below a critical threshold in LECs of canines during the effect of UV and chronic oxidative stress or metabolic failure, can activate programs leading to LEC senescence or death. Telomerase is induced in LECs of canines at critical stages of cataractogenesis initiation and exposure to oxidative stress through the involvement of catalytically active prooxidant transition metal (iron) ions. This work documents that transition metal ions (such as, ferrous ions- catalytic oxidants) might induce premature senescence in LECs of canines, telomere shortening with increased telomerase activity as adaptive response to UV light, oxidative and metabolic stresses. The therapeutic treatment with 1% N-acetylcarnosine (NAC) prodrug delivery is beneficial for prevention and dissolution of ripe cataracts in canines. This biological activity is based on the findings of ferroxidase activity pertinent to the dipeptide carnosine released ophthalmically from NAC prodrug of L-carnosine, stabilizing properties of carnosine on biological membranes based on the ability of the imidazole-containing dipeptides to interact with lipid peroxidation products and reactive oxygen species (ROS), to prevent membrane damage and delute the associated with membrane fragements protein aggregates. The advent of therapeutic treatment of cataracts in canines with N-acetylcarnosine lubricant eye drops through targeting the prevention of loss of functional telomere length below a critical threshold and “flirting” with an indirect effect with telomerase expression in LECs of canines during the effects of UV, chronic oxidative stress increases the successful rate of cataract management challenges in home veterinary care.

There are no reports about the pharmaceutical applications of hupu gum (HG). Hence the present study was undertaken to test its suitability in the dissolution enhancement of poorly water soluble drug. Rofecoxib (RFB) was taken as model drug. For comparison solid mixtures were prepared with carriers such as poly vinyl pyrrolidone (PVP), sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading (KT) and solvent evaporation (SE) techniques were used to prepare the solid mixtures, using all the carriers in different carrier and drug ratios. The solid mixtures were characterized by powder X-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FTIR). There was a significant improvement in the dissolution rate of solid mixtures of HG, when compared with the solid mixtures of other carriers. There was an increase in dissolution rate with increase in concentration of HG upto 1:1 ratio of carrier and drug. No drug-carrier interaction was found by FTIR studies. XRD studies indicated reduction in crystallinity of the drug with increase in HG concentration. Hence HG could be a useful carrier for the dissolution enhancement of poorly water soluble drugs.

Indomethacin is a widely used non-steroidal anti-inflammatory drug (NSAID) and extensively employed for treatment of arthritis. Delayed action (at the morning or night) is needed for arthritic patients. To improve the patient compliance, in this study we aimed to delay the drug release by designing multi-particulates system in the form of microspheres, which would efficiently release the drug into the colon and replace the conventional therapy. The aim of the present work was to elucidate the effect of formulation variables e.g., amount of eudragit polymer (X1), surfactant concentration (X2) and agitation speed (X3) on in-vitro release profiles (Y1-Y3), drug entrapment efficiency (Y4) and particle size (Y5) of multi-particulates system of indomethacin. Experiments were designed according to a three levels face centered central composite design. Microspheres were formulated with the combination of ethyl cellulose (EC) and Eudragit RS 100/Eudragit S100; by using a novel quasi emulsion solvent diffusion technique. Developed formulations were characterized and evaluated on the basis of FTIR, thermal, particle size, SEM, XRD analysis and drug release kinetics studies. The formulation variables were optimized by response surface methodology (RSM). It was found that in-vitro release (Y1-Y3) was decreased significantly (p<0.05) with increase in amount of eudragit polymer but increased significantly (p<0.05) with increase in surfactant concentration and stirring speed. It was observed that the drug release data of the selected formulation was similar to the predicted release pattern. FTIR study indicated that no prominent chemical interaction or changes took place between the drug and excipients of prepared formulations. DSC and XRD studies indicated that drug was present in the amorphous state and may have been homogenously dispersed into the polymers matrix. Therefore this approach suggested that the combination of EC and Eudragit S100 microspheres may be useful in a better way, for the delivery of maximum amount of indomethacin in intact form to the colon.

As skin is one of the crucial and important organs of the human body, delivering the drug across it requires an effective development in the field of research. Topical drug delivery system is specifically designed with the objective to accomplish the delivery of therapeutically active drugs across the skin. Though skin is considered to be a multifunctional organ of a human body, it has the limitation of lesser permeability across the stratum corneum. As this layer constitutes an effective barrier for the drugs, various carrier systems have been developed to overcome this barrier. Vesicular carriers are one of the recently invented carriers. Liposomes, niosomes, transferosomes and ethosomes constitute the major part of these vesicles that have been sufficiently employed for the treatment of variety of topical skin diseases. In the past few years various research reports on the development of topical carrier systems showed that these carriers have emerged as a novel vesicular carrier. These are considered to be effective enough for the enhanced and safe delivery of both hydrophilic and lipophilic drugs. The present review focuses on the topical delivery via these vesicles, emphasizing on various aspects of all these carriers.

Biodegradable spray-dried chitosan microparticles loaded with clindamycin phosphate (CDP) were formulated to deliver drugs locally into the periodontal pocket. The effects of spray dryer conditions, drug/polymer ratio, and added amounts of glutaraldehyde (GA) solution on the characterization of microparticles were investigated by determining process yield, encapsulation efficiency, particle size and size distribution, surface morphology, drug release, release kinetics, thermal analysis, and antimicrobial efficacy of formulations. Burst release was obtained for all formulations due to the water solubility of the drug, but the increased amount of chitosan decreased the drug release rates. Microparticles with a more wrinkled surface were obtained by increasing the amount of the drug. Incorporation efficiencies higher than 80% were obtained for all preparation conditions. The addition of GA caused higher viscosity of the chitosan solution, leading to larger particles with more spherical and smooth surface characteristics. However, the increased GA amount did not significantly influence the drug release. The data obtained from in vitro release experiments were best fitted to the Weibull and Higuchi models. The amorphous nature of the drug-loaded microparticles was detected by differential scanning calorimetric (DSC) thermographs. A delayed drug release of more than one week could be obtained by loading the drug into the chitosan microparticles. Antimicrobial efficacy studies reflected a positive drug release profile. These results indicate that spray-dried clindamycin-loaded microparticles with sustained antimicrobial efficacy appear to be a promising periodontal therapy for drug delivery into the periodontal pocket.

Intravaginal mucoadhesive microspheres of tenofovir disoproxil fumarate (TDF) has been formulated using chitosan as the matrix-forming mucoadhesive polymer and evaluated. Ionotropic gelation method was used to produce the microspheres. Drug-polymer compatibility, percentage yield, particle size determination by optical microscopy, drug content & encapsulation efficiency, ex vivo mucoadhesion and in vitro release were evaluated. Based on the evaluation studies, F6 was selected as the best formulation and evaluated further for release kinetics and curve fitting analysis. F6 followed Korsmeyer-Peppas and Higuchi models. Accelerated stability study was conducted as per ICH guidelines. Drug content analysis, FTIR, XRD, SEM analysis showed that it remained stable for a period of six months.

Systemic drug delivery is the most prevalent form of the drug administration; but it is not possible to extend this approach to all of diseases. In the traditional approaches of drug delivery, the drug spreads through whole of body and this could cause severe side effects in the healthy parts. In addition, in some parts of our body like the eye, ear and brain, there are biological barriers against drug penetration which made drug delivery to these organs as a challenging work. Micropumps are one of the MEMS based devices with great capabilities in controlled drug administration. The most prevalent application of micropumps in drug delivery is known as continuous subcutaneous insulin infusion (CSII) for diabetic patients; but our study showed that there are some other ongoing investigations to extend application of micropumps in new treatment methods for some incurred diseases.

The objective of this work was to increase the solubility, in vitro skin permeability of lornoxicam from semisolid topical formulations and also to investigate the in vivo potential of nanoemulsion formulation. Optimized lornoxicam loaded nanoemulsion was prepared successfully by spontaneous self-emulsification method and the size of the stable formulations was found within the range of 102 to 200 nm. The stable nanoemulsion formulations characterized for viscosity, droplet size, transmission electron microscopy (TEM) and refractive index. In vitro permeation rate of nanoemulsion and conventional gel of lornoxicam (LX) were determined. Prmeability parameters like steady-state flux (Jss), permeability coefficient (Kgt), and enhancement ratio (Egt) were significantly increased in nanoemulsion NE8 and the nanogel NG8 as compared to conventional gel (LG). In vivo studies revealed a significant increase in anti-inflammatory effects as compared with conventional gel of LX. The anti-inflammatory effects of formulation NG8 showed a significant increase in percent inhibition value when compared with control, this difference was found to be highly significant (p<0.001). This work shows for the first time that lornoxicam can be formulated into nanoemulsions and may show promise in enhancing solubility and permeation.

One of the popular approaches in controlling drug delivery from the polymeric carriers is suitably achieved by the inclusion of crosslinking agents into the formulations at different concentrations. Nevertheless, addition of the chemical crosslinkers such as glutaraldehyde, formaldehyde etc, used in the drug delivery systems causes very serious cytotoxic reactions. These chemical crosslinking agents did not offer any significant advantageous effects when compared to the natural crosslinking agents for instance genipin, which is quite less toxic, biocompatible and offers very stable crosslinked products. Based on the earlier reports the safety of this particular natural crosslinker is very well established, since it has been widely used as a Chinese traditional medicine for long-time, isolated from fruits of the plant Gardenia jasminoides Ellis. This concise article largely portrayed the value of this unique natural crosslinker, utilized in controlling the drug delivery from the various formulations.

In this study, we examined the in-vivo characteristics of a novel microencapsulated thalidomide formulation in a murine model of experimental Crohn's disease. Crohn's disease was induced with a single intra-colonic injection of 120 mg/kg of bodyweight of 2,5,6-trinitrobenzene sulfonic acid (TNBS) dissolved in 30% ethanol in Balb/c mice. Level of tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1β), interleukin 6 (IL-6) and nitric oxide (NO) were measured in tissue homogenate. Moreover, myeloperoxidase (MPO) activity was determined to assess the extent of neutrophil infiltration. Dose response study showed that treating the mice with microencapsulated thalidomide (100 mg/kg of bodyweight) for two weeks significantly decreased the degree of intestinal inflammation related to Crohn’s disease. Higher and lower doses (0, 25, 50 and 200 mg/kg of bodyweight) did not exhibit comparable effects. The present study validates the success of alginate-poly-L-lysine-alginate (APA) microcapsules containing thalidomide in reducing colonic inflammation, and proposes a potential remedy for Crohn’s disease.