Studies on Almond Gum and Gelucire-Based Pellets Prepared by Extrusion and Spheronization for Sustained Release.

Objectives: The aim of the investigation was to prepare sustained release (SR) pellets of diltiazem hydrochloride employing almond gum and gelucire. The study was performed to explore the suitability of almond gum in the preparation of pellets of diltiazem hydrochloride without the use of microcrystalline cellulose and role and effectiveness of hydrophobic gelucire (43/01) in controlling the drug release. Materials and Methods: Pellets were prepared by extrusion-spheronization of the blend previously obtained by incorporation of the drug in a mixture of melted gelucire 43/01 and almond gum. A 32 factorial design was employed to study the effect of two independent variables, almond gum and gelucire, on the size, friability and drug release from pellets. Scanning electron microscopy, differential scanning calorimetry and infrared spectroscopy were performed to characterize pellets. Results: Free flowing spherical pellets could be prepared. The 32 factorial study revealed that as the proportion of almond gum increased, the size of pellets increased, while increasing gelucire had opposite effect. The yield of pellets prepared in different formulations is in the range of 86 to 92%. The size of the pellets varied from 1128 to 1458 µ. Higher amounts of gelucire resulted in pellets with greater friability, whereas increasing the amount of almond gum yielded pellets with low friability. The pellets exhibited SR of diltiazem and the presence of gelucire in the matrix of the pellets had an enhanced sustaining effect on release. Conclusion: Dispersion of the drug in gelucire before it was converted to pellets resulted in extended release of drug. The drug release rate changed with changes in the proportion of pellet composition. The results of the study suggest that employing gelucire (43/01) in the preparation of pellets is a useful approach in the design of SR products of highly water-soluble drug such as diltiazem hydrochloride.

Fabrication of Alginate-Based O/W Nanoemulsions for Transdermal Drug Delivery of Lidocaine: Influence of the Oil Phase and Surfactant.

Transdermal drug delivery of lidocaine is a good choice for local anesthetic delivery. Microemulsions have shown great effectiveness for the transdermal transport of lidocaine. Oil-in-water nanoemulsions are particularly suitable for encapsulation of lipophilic molecules because of their ability to form stable and transparent delivery systems with good skin permeation. However, fabrication of nanoemulsions containing lidocaine to provide an extended local anesthetic effect is challenging. Hence, the aim of this study was to address this issue by employing alginate-based o/w nanocarriers using nanoemulsion template that is prepared by combined approaches of ultrasound and phase inversion temperature (PIT). In this study, the influence of system composition such as oil type, oil and surfactant concentration on the particle size, in vitro release and skin permeation of lidocaine nanoemulsions was investigated. Structural characterization of lidocaine nanoemulsions as a function of water dilution was done using DSC. Nanoemulsions with small droplet diameters (d < 150 nm) were obtained as demonstrated by dynamic light scattering (DLS) and cryo-TEM. These nanoemulsions were also able to release 90% of their content within 24-h through PDMS and pig skin and able to the drug release over a 48-h. This extended-release profile is highly favorable in transdermal drug delivery and shows the great potential of this nanoemulsion as delivery system.

Development and evaluation of a cream containing solid lipid nanoparticles loaded with Vitamin E.

Solid lipid nanoparticles (SLNs) have several potential applications in the topical drug delivery. The current project aimed to prepare and characterize SLNs loaded with vitamin E for topical administration and incorporating the prepared SLNs in a cream base. Further, the permeation of prepared SLNs was studied through a synthetic membrane and the release profiles were compared with vitamin E cream. The prepared SLNs were subjected to stability studies at two different temperatures. Hot homogenization followed by dilution technique was used for the preparation of SLNs. In this project, PDMS membrane was used to mimic the skin for permeation studies. From the results of this study, it can be concluded that prepared SLNs had enhanced the permeation of vitamin E as compared to vitamin E cream.

Studies on the Effect of Oil and Surfactant on the Formation of Alginate-Based O/W Lidocaine Nanocarriers Using Nanoemulsion Template.

The application of various nanocarrier systems was widely explored in the field of pharmaceuticals to achieve better drug encapsulation and delivery. The aim of this study was to encapsulate lidocaine in alginate-based o/w nanocarriers based on the type of oil (i.e., solid or liquid), using a nanoemulsion template prepared by ultrasound-assisted phase inversion temperature (PIT) approach. The nanoemulsion template was initially prepared by dissolving lidocaine in the oil phase and surfactant and alginate in the aqueous phase, and keeping the PIT at around 85 °C, accompanied by gradual water dilution at 25 °C, to initiate the formation of nanoparticles (o/w) with the aid of low frequency ultrasound. The composition and concentration of the oil phase had a major impact on the particle size and led to an increase in the size of the droplet. The lipids that showed a higher drug solubility also showed higher particle size. On the other hand, increasing the concentration of surfactant decreases the size of the droplet before the concentration of the surfactant exceeds the limit, after which the size of the particle increases due to the aggregates that could be produced from the excess surfactant. The method used produced nanoemulsions that maintained nano-sized droplets < 50 nm, over long-term storage. Our findings are important for the design of nanocarrier systems for the encapsulation of lipophilic molecules.

Physicochemical characteristics and in vitro permeation of loratadine solid lipid nanoparticles for transdermal delivery.

Aim: To prepare loratadine-loaded solid lipid nanoparticles (SLNs) using a modified two-step ultrasound-assisted phase inversion temperature (PIT) process. Results/methodology: Loratadine was dissolved in beeswax and Tween 80 was dissolved in water. The two phases were mixed together to prepare a water-in-oil emulsion preconcentrate (w/o) at a PIT of 85°C, followed by gradual water addition at 25°C to trigger nanoparticles formation (o/w). Kinetic stability was investigated. No change in the size was observed within 6 months. Fourier-transform infrared spectroscopy demonstrated stability of the emulsions via molecular structure of water at the interface of the o/w nanoemulsions. SLNs enhanced the in vitro skin permeation of loratadine. Conclusion: Stable SLNs were successfully prepared by ultrasound-assisted PIT.

Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuberculosis Drugs-Induced Liver Injury.

The purpose of this study is to analyze the polyphenolic rich extract of Crocus sativus L. petals (CSP) in modulating liver oxidative stress and inflammatory response status against rifampicin isoniazid (INH-RIF) drug-induced liver injury. The INH-RIF was administered for 14 days with varying doses in Wistar rats, while silymarin was administered as standard dose. We report the defensive impacts of CSP against INH-RIF induced liver oxidative stress and proinflammatory cytokine. The CSP treatment at both doses significantly controlled all modulating biochemical hepatic injury indicators and resulted in the attenuation of arbitral INH-RIF damage. The components present in CSP identified by LC-ESI-Q-TOF-MS were found to be flavonoids and fatty acids. It can be inferred that CSP possesses a hepatoprotective capacity against INH-RIF-mediated hepatic injury, which may prove to be a medically beneficial natural product for the management of drug-induced liver injury.

Formation of stable nanoemulsions by ultrasound-assisted two-step emulsification process for topical drug delivery: Effect of oil phase composition and surfactant concentration and loratadine as ripening inhibitor.

Nanoemulsions are very interesting systems as they offer capacity to encapsulate both hydrophilic and lipophilic molecules in a single particle, as well as the controlled release of chemical moieties initially entrapped in the internal droplets. In this study, we propose a new two-step modified ultrasound-assisted phase inversion approaches-phase inversion temperature (PIT) and self-emulsification, to prepare stable o/w nanoemulsions from a fully water-dilutable microemulsion template for the transdermal delivery of loratadine (a hydrophobe and as Ostwald ripening inhibitor). Firstly, the primary water-in-oil microemulsion concentrate (w/o) was formed using loratadine in the oil phase (oleic acid or coconut oil) and Tween 80 in the aqueous phase and by adjusting the PIT around 85 °C followed by stepwise dilution with water at 25 °C to initiate the formation the nanoemulsions (o/w). To assure the long-term stability, a brief application of low frequency ultrasound was employed. Combining the two low energy methods resulted in nanoemulsions prepared by mixing constant surfactant/oil ratios above the PIT with varying water volume fraction (self-emulsification) during the PIT by stepwise dilution. The kinetic stability was evaluated by measuring the droplet size with time by dynamic light scattering (DLS). The droplet size ranged 15-43 nm and did not exceed 100 nm over the period of 6 months indicating the system had high kinetic stability. Cryo-TEM showed that the nanoemulsions droplets were monodispersed and approaching micellar structure and scale. All nanoemulsions had loratadine crystals formed within 20 days after preparation, which tended to sediment during storage. Nanoemulsions improved the in vitro permeation of loratadine through porcine skin up to 20 times compared to the saturated solution.

An investigation and characterization on alginate hydogel dressing loaded with metronidazole prepared by combined inotropic gelation and freeze-thawing cycles for controlled release.

The purpose of this study was to investigate the effect of combined Ca(2+) cross-linking and freeze-thawing cycle method on metronidazole (model drug) drug release and prepare a wound film dressing with improved swelling property. The hydrogel films were prepared with sodium alginate (SA) using the freeze-thawing method alone or in combination with ionotropic gelation with CaCl2. The gel properties such as morphology, swelling, film thickness, and content uniformity and in vitro dissolution profiles using Franz diffusion cell were investigated. The cross-linking process was confirmed by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. In vitro protein adsorption test, in vivo wound-healing test, and histopathology were also performed. The hydrogel (F2) composed of 6% sodium alginate and 1% metronidazole prepared by combined Ca(2+) cross-linking and freeze-thawing cycles showed good swelling. This will help to provide moist environment at the wound site. With the in vivo wound-healing and histological studies, F2 was found to improve the wound-healing effect compared with the hydrogel without the drug, and the conventional product.

Development and validation of HPLC analytical method for nepafenac in ophthalmic dosage form (suspension).

The aim of the present study was to develop and validate an analytical method for the estimation of nepafenac as a raw material as well as in dosage form (suspension) by using reverse phase high performance liquid chromatographic (RP-HPLC). The target was to obtain an easy, rapid, reproducible as well as a rugged method. The HPLC system that was used in the proposed study was LC-20AD liquid chromatograph equipped with SPD-20A UV-VIS detector. The separation was performed on C18 column which was attached with loop 20 ß l. Elution was done at ambient temperature with a mobile phase consisting of acetonitrile: Water (40: 60v/v) at a flow rate of 1ml/min and at a wavelength of 254 nm. The proposed method was validated as per the ICH guidelines. The retention time for nepafenac was 7.49 minutes (% CV=0.0076). The percentage coefficient variation (CV) of six consecutive peak areas of injections was 0.34% with tailing factor 1.76. The peak area responses were linear within the concentration range of 0.078-20.0 ßg/ml (R(2)=0.9993). The sensitivity of the method could be evaluated by limits of detection (LOD) (0.0195 ß g/ml) and limits of quantitation (LOQ) (0.039 ß g/ml). Nepafenac drug is s in its diluent that could see by intra-day (% CV =0.45-1.96) and inter-day variation (%CV=0.173-1.898%). The accuracy and recovery results of 80%, 100% and 120% were 97.40% to 102.10% with % CV of 0.3201% to 1.3496%. The robustness and ruggedness of the method are significantly broader and is reproducible. It could be used as a more convenient, efficient, easy and time saving method for the analysis of drug in raw material as well as in dosage form (ophthalmic suspension).

Use of the skin sandwich technique to probe the role of the hair follicles in sonophoresis.

The human skin sandwich technique was used to explore the effect of brief ultrasound exposure on the transfollicular pathway of absorption. Hydrocortisone was used as a model drug. In order to calculate the permeability coefficient of hydrocortisone, its concentration at saturation in the PBS donor solution was determined. Skin samples were prepared by sandwich technique with total hydration of the epidermal and sandwich membranes. The skin was sonicated for 0 s (control), 30 s or 45 s using a pulsed mode (10% duty cycle) with the spatial and temporal average intensity (SATA) of 3.7 W/cm(2). The transducer was then removed and permeation was allowed to proceed for 52 h. Then the percentage follicular contribution was determined. It was determined that without ultrasound, drug entry into follicles accounted for 46% of total penetration. As the duration of sonication increased, the follicular contribution fell to zero even though total transepidermal flux dramatically increased. This is explained by ultrasound exposure causing sloughing off of the uppermost stratum corneum. This permeabilises the continuous surface but at the same time the disturbed cornceocytes will plug hair follicle orifices.

Design and evaluation of a bioadhesive film for transdermal delivery of propranolol hydrochloride.

The objective of the study was to develop a suitable trans-dermal delivery system for propranolol hydrochloride (PPL) via employing chitosan as a film former. Drug concentration uniformity, thickness, moisture uptake capacity and skin bioadhesion of the films were characterized. The effects of chitosan and PPL concentration and different penetration enhancers on the release and permeation profiles from the films were investigated. Skin irritation of the candidate film was evaluated. Chitosan film (PPL 2 mg cm(-2), chitosan 2%, m/m, cineol 10%, m/m) was found nonirritant and achieved 88.2% release after 8 hours in phosphate buffer. Significant high (p < 0.001) permeation of PPL through rat skin was obtained using this film compared to the film without enhancer (about 8 times enhancement factor), making it a promising trans-dermal delivery system for PPL.

Development of an optimised application protocol for sonophoretic transdermal delivery of a model hydrophilic drug.

It has now been known for over a decade that low frequency ultrasound can be used to effectively enhance transdermal drug penetration - an approach termed sonophoresis. Mechanistically, acoustic cavitation results in the creation of defects in the stratum corneum that allow accelerated absorption of topically applied molecules. The aim of this study was to develop an optimised sonophoresis protocol for studying transdermal drug delivery in vitro. To this end, caffeine was selected as a model hydrophilic drug while porcine skin was used as a model barrier. Following acoustic validation, 20kHz ultrasound was applied for different durations (range: 5 s to 10 min) using three different modes (10%, 33% or 100% duty cycles) and two distinct sonication procedures (either before or concurrent with drug deposition). Each ultrasonic protocol was assessed in terms of its heating and caffeine flux-enhancing effects. It was found that the best regimen was a concurrent 5 min, pulsed (10% duty cycle) beam of SATA intensity 0.37 W/cm(2). A key insight was that in the case of pulsed beams of 10% duty cycle, sonication concurrent with drug deposition was superior to sonication prior to drug deposition and potential mechanisms for this are discussed.

Assessment of drug permeability distributions in two different model skins.

Past in vitro studies with human skin have indicated that drug permeability coefficient (Kp) distributions do not always follow a Gaussian-normal pattern. This has major statistical implications, exemplified by the fact that use of t-tests to evaluate significance is limited to normally distributed populations. Percutaneous absorption research often involves using animal or synthetic skins to simulate less readily available human skin. However, negligible work has been performed on assessing the permeability variabilities of these model membranes. This paper aims to fill this gap. To this end, four studies were undertaken representing two different drugs (caffeine and testosterone) with each drug penetrating through two different model skins (silicone membrane and pig skin). It was determined that in the silicone membrane studies, both compounds' Kp distributions could be fitted to a normal pattern. In contrast, in the pig skin studies, there were notable differences between each drug. While the testosterone Kp values could be fitted to a normal distribution, this was not possible with the caffeine Kp data, which could be fitted to a log-normal distribution. There is some evidence from the literature as well as physicochemical considerations that these outcomes may reflect general trends that are dependent upon both membrane and penetrant properties.