Current Drug Delivery - Volume 10, Issue 4, 2013

Microbubbles are small spherical gas filled bubbles in the size range of 1-10 microns. Their external coat is made of polymers or phospholipids. In combination with ultrasound, they have been explored as contrast agents for ultrasound and also carriers for drug and gene delivery. In response to ultrasound of lower mechanical index, microbubbles oscillate and vibrate to give a distinct signal in ultrasound imaging. At a higher mechanical index, these microbubbles rupture and break to deliver the drugs or genes enclosed in them or attached to their surface. The behaviour of microbubbles in response to ultrasound is a characteristic of the properties of microbubbles like its shell composition, shell thickness and the density and compressibility of the enclosed gas. Microbubbles have various applications in diagnostic imaging like echocardiography, and imaging of cancer cells, inflammed cells etc. They are also used as a medium for drug and gene delivery. Microbubbles can be further modified by binding specific ligands to their surface which specifically attach to certain cells so that selective action of the microbubbles can be seen at that location of cells.

The aim of the present work was to develop and evaluate stomach-specific controlled release, gastroretentable mucoadhesive patch of lercanidipine HCl. This drug is essentially soluble in gastric pH range of 1- 4 and have a partition coefficient (log p-value) of 6.1; according to this concept, it has been decided to formulate the gastroretentive bioadhesive patch. The patch system consisted of a drug release rate controlling film, using the combination of Eudragit RSPO and RLPO; mucoadhesive film by using the combination of various hydrophilic polymers. Bilayered patch were made by using the selected batch of two films using the layering method and evaluated for the various parameters like in vitro swelling study, ex vivo mucoadhesive strength. Film was folded into a hard gelatin capsule, evaluated for in vitro drug release in pH 1.2 containing 0.2% (w/v) sodium lauryl sulphate (SLS), and in vivo bioavailability in rabbits. Patches could control the drug release up to 12 h, having mucoadhesion strength in the range of 4.05±0.4 N to 4.52±0.12 N. In vivo bioavailability results indicate that the gastroretentive patch system provides a novel way to retain the drug matrix for the longer period of time in a stomach, enhance drug absorption and thereby offer a promising strategy for gastroretentive mucoadhesive drug delivery for the lercanidipine HCl.

Poor bioavailability and therapeutic response of conventional therapy due to many pre-corneal constraints necessitate the development of novel controlled and sustained ocular drug delivery to become a standard one in modern pharmaceutical era. This investigation aimed to study the drug release kinetics of betaxolol hydrochloride from a hydrophobic matrix system of PMMA cast with incorporating different proportions of polyethylene oxide (PEO) and evaluate its ability to improve ocular bioavailability and duration of action for the drug. Matrix type ocular inserts were prepared by the film casting technique and characterized in vitro by drug release studies using a flow through apparatus that simulated the eye conditions. All the formulations were subjected to physicochemical evaluation. Rabbit model with steroid induced glaucoma was used to establish in vivo efficacy of inserts. Polymer composition and concentration significantly affected the drug release based on change in diffusional path length and formation of gelaneous pores by polymer erosion. Formulations released the drug by non-fickian diffusion including anomalous transport (0.51). It was also observed that increasing the proportion of PEO in to PMMA does not affect the blend miscibility. IVIVC suggested no significant difference (P< 0.001) between in vitro and in vivo release of drug from inserts. In vivo IOP lowering activity was better for optimized insert F8 (for 24 h) as compared to eye drops (10 h). This ocular insert could be a promising once-a-day sustained release formulation for treating glaucoma.

This study investigated the utility of a 32 factorial design and optimization process for nanoparticle suspension prepared by two different polymers Eudragit® RS 100 and Eudragit® RL 100 respectively. Total 18 formulations (9 formulations with each polymer) were prepared by solvent displacement technique. In these designs, two factors namely polymer weight (X1) and Aq. phase volume (X2) were evaluated each at three levels and experimental trials were performed at all nine possible combinations. Polymer weight (X1) and aqueous phase volume (X2) were selected as independent variables and particle size (Y1), % entrapment (Y2), drug release at 12th hrs. (Y3) are chosen as depended variables. In case of 32 factorial design, a full-model polynomial equation was established by subjecting the transformed values of independent variables to multiple regression analysis, and contour plots were drawn using the equation. The derived polynomial equations for particle size and % drug entrapment were verified by check point formulation. The result showed a wide variation in the responses for both of the polymer. For RS 100 polymer, particle size was 112-350 nm, entrapment: 26-72%, drug release was 42- 89% at 12th hrs. and for RL 100 polymer, particle size was 114-390 nm, entrapment: 30-72%, drug release was 50-90% at 12th hrs. The application of factorial design yielded a statistically systematic approach for the formulation and optimization of nanoparticles with desired particle size and high entrapment efficiency and release profile. The results of the optimized formulations showed particle size 225 nm, 63% drug entrapment and 83% drug release for RS 100 polymer and particle size was 148 nm, drug entrapment was 57%, drug release was 80% for RL 100 polymer.

Aims: The mechanisms behind cellular anthracycline uptake are not completely understood. Knowledge about uptake mechanisms could be used to increase the selectivity of the drugs. We compared the uptake patterns of, daunorubicin (DNR), doxorubicin (DOX), epirubicin (EPI), idarubicin (IDA), and pirarubicin (PIRA) by cultured leukemic cells and investigated possible involvement of specific carriers. Methods: HL-60 cells were incubated with anthracyclines for 1 hour in the absence or presence of transport inhibitors, suramin, or nucleosides and cellular drug uptake was determined. Cell survival was also determined. MCF-7 breast cancer cells were used as a negative control for concentrative nucleoside transporters (CNTs). Anthracycline concentration was determined with HPLC and fluorometric detection and apoptosis was determined with propidium iodide and flow cytometry. Results: DNR, IDA, and PIRA had higher uptake than DOX and EPI with a prominent increase in uptake at concentrations > 1 µM. Uptake of all anthracyclines was greatly reduced at 0°C. Suramin, a purinergic-2-receptor inhibitor, strongly inhibited the uptake of all anthracyclines except PIRA and increased cell survival. Dipyridamole, an equilibrative NT (ENT) inhibitor, significantly inhibited the uptake of DNR only. The addition of nucleosides significantly inhibited the uptake of DNR, IDA, and PIRA but not in MCF-7 cells lacking functional CNTs. Conclusion: Our results suggest different uptake mechanisms for the anthracyclines studied. We found evidence for carrier mediated uptake mechanisms, supporting involvement of NTs in transmembrane transport of DNR, IDA, and PIRA. The results also showed a strong inhibition of suramin on anthracycline uptake by so far unknown mechanisms.

The work was aim to design and characterize the sustained release mucoadhesive microspheres of Tolterodine tartrate prepared by non-aqueous solvent evaporation technique using ethyl cellulose based selected mucoadhesive polymers. Selected microspheres formulations of were found to be discrete, spherical and free flowing from the preliminary formulations. The microspheres exhibit good mucoadhesive property in in-vitro wash off test and showed high drug entrapment efficiency. Tolterodine tartrate release from these microspheres was slowed, extended and depended on the concentration of ethyl cellulose and type of mucoadhesive polymer used. In vitro drug release studies suggested that formulation F6c showed consistent drug release for up to 24 h time period. Among all the formulations, F6c containing ethyl cellulose with chitosan showed the reproducible results with best mucoadhesive profile and good surface morphology. The correlation value (r2) indicated that the drug release followed Higuchi model. Analysis of variance (ANOVA) showed significant difference in the release of drug from all formulations at P < 0.05 level. Accelerated stability study of optimized formulation (F6c) up to 3 month showed there was no change in drug content and release characteristics during storage.

The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

This study presents development and evaluation of novel sustained release system of diclofenac sodium (DS) prepared by solid dispersion (SD) technique using Eudragit E 100 (EE 100) and/or Eudragit S 100 (ES 100) as carriers. Compatibility of the drug and its crystalline nature in the SD were examined using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The drug was relatively stable, amorphous in the SD. The greater amount of EE100 or ES 100 in the SD slowed down the release rates with smaller dissolution efficiency and hence the mean dissolution time was enhanced. Moreover, combined carriers of EE 100-ES 100 exhibited more dissolution retarding effect than any of the carriers. The release of drug followed anomalous transport in artificial intestinal juice (pH 6.8).

Objective: Present work focuses on the use of mimosa seed gum to develop a drug delivery system making combined use of floating and pulsatile principles, for the chrono-prevention of nocturnal acid breakthrough. Methodology: The desired aim was achieved by fabricating a floating delivery system bearing time – lagged coating of Mimosa pudica seed polymer for the programmed release of Famotidine. Response Surface Methodology was the statistical tool that was employed for experiment designing, mathematical model generation and optimization study. A 32 full factorial design was used in designing the experiment.% weight ratio of mimosa gum to hydroxy propyl methyl cellulose in the coating combination and the coating weight were the independent variables, whereas the lag time and the cumulative % drug release in 360 minutes were the observed responses. Key findings: Results revealed that both the coating composition and the coating weight significantly affected the release of drug from the dosage form. Conclusion: The optimized formulation prepared according to the computer generated software, Design-Expert® deciphered response which were in close proximity with the experimental responses, thus confirming the robustness as well as accuracy of the predicted model for the utilization of natural polymer like mimosa seed gum for the chronotherapeutic treatment of nocturnal acid breakthrough.

Microsponge is a microscopic sphere capable of absorbing skin secretions, therefore reducing the oiliness of the skin. Microsponge having particle size of 10-25 microns in diameter, have wide range of entrapment of various ingredients in a single microsponges system and release them at desired rates. Conventional topical preparations have various disadvantages due to irritancy, odour, greasiness and patient compliance. In many topical dosage forms fail to reach the systemic circulation in sufficient amounts in few cases. These problems overcome by the usage of formulation as microsponge in the areas of research. Drug release in microsponge is done by the external stimuli like pH, temperature and rubbing. It has several advantageous over the other topical preparations in being non-allergenic, non-toxic, non-irritant and non- mutagenic. These microsponges are used in the sun screens, creams, ointments, over-the-counter skin care preparations, recently nanosponge were reported in literature used in delivery of drug by the use of cyclodextrins to enhance the solubility of poorly water soluble drugs, which are meant for topical application.

Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported.

The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and 1H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA.