Mathematically, the human alimentary tract organs were simplified in the model structure as separate compartments with
pathways of transfer that are kinetically homogenous and equally distributed. The development of gastro-compartment
model follows the first order kinetics of differential equations to describe cadmium absorption, distribution and elimination
in the human digestive system. With the aid of in vitro DIN assay, an artificial gastric and gastrointestinal fluid were
prepared using water leach purification (WLP) residue as a sample that contained toxic metals cadmium. The Simulation,
Analysis and Modelling II (SAAM II) V2.1 software is employed to design models easily, simulate experiments quickly and
analyze data accurately. Based on the experimental inputs and fractional transfer rates parameter incorporated to the
gastro-compartment model, the concentration of cadmium against time profile curves were plotted as the model output.
The curve presented concentration of cadmium in both gastric and gastrointestinal fluid where initially absorption phase
(first hour) occurred followed by the distribution phase (second to third hours) and elimination process (third to fifth
hours). The concentration of cadmium obtained from the simulated model structures was in good agreement with the
fitted model predicted measurements as statistical t-test conducted showed the values were not significantly different.
Therefore, modeling approach with SAAM II software gave realistic and better estimation of cadmium dissolution into
the human gastrointestinal tract.
The present work investigates the formulation and biopharmaceutical estimation of gastric floating drug delivery system (GFDDS) of propranolol HCl using semi-synthetic polymer carboxymethyl ethyl cellulose (CMEC) and a synthetic polymer polyethylene oxide (PEO). A central composite design was applied for optimization of polymer quantity (CMEC or PEO) and sodium bicarbonate concentration as independent variables. The dependent variables evaluated were: % of drug release at 1 hr (D1hr), % drug release at 3 hr (D3hr) and time taken for 95% of drug release (t95). Numerical optimization and graphical optimization were conducted to optimize the response variables. All observed responses of statistically optimized formulations were in high treaty with predicted values. Accelerated stability studies were conducted on the optimized formulations at 40 ± 2°C/75% ± 5% RH and confirm that formulations were stable. Optimized formulations were evaluated for in vivo buoyancy characterization in human volunteers and were found buoyant in gastric fluid. Gastric residence time was enhanced in the fed but not the fasted state. The optimized formulations and marketed formulation were administered to healthy human volunteers and evaluated for pharmacokinetic parameters. Mean residence time (MRT) was prolonged and AUC levels were increased for both optimized floating tablets when compared with marketed product. High relative bioavailability obtained with optimized gastric floating tablets compared to commercial formulation, indicated the improvement of bioavailability.
A quantitative structure-human intestinal absorption relationship was developed using artificial neural network (ANN) modeling. A set of 86 drug compounds and their experimentally-derived intestinal absorption values used in this study was gathered from the literature and a total of 57 global molecular descriptors, including constitutional, topological, chemical, geometrical and quantum chemical descriptors, calculated for each compound. A supervised network with radial basis transfer function was used to correlate calculated molecular descriptors with experimentally-derived measures of human intestinal absorption. A genetic algorithm was then used to select important molecular descriptors. Intestinal absorption values (IA%) were used as the ANN's output and calculated molecular descriptors as the inputs. The best genetic neural network (GNN) model with 15 input descriptors was chosen, and the significance of the selected descriptors for intestinal absorption examined. Results obtained with the model that was developed indicate that lipophilicity, conformational stability and inter-molecular interactions (polarity, and hydrogen bonding) have the largest impact on intestinal absorption.
A sequential algorithm is developed for the non-linear dual-sorption model developed by Chandrasekaran et al. [1,2] which monitors pharmacokinetic profiles in percutaneous drug absorption. In the experimental study of percutaneous absorption, it is often observed that the lag-time decreases with the increase in the donor concentration when two or more donor concentrations of the same compound are used. The dual-sorption model has sometimes been employed to explain such experimental results. In this paper, it is shown that another feature observed after vehicle removal may also characterize the dual-sorption model. Soon after vehicle removal, the plots of the drug flux versus time become straight lines on a semilogarithmic scale as in the linear model, but the half-life is prolonged thereafter when the dual-sorption model prevails. The initial half-life after vehicle removal with a low donor concentration is longer than that with a higher donor concentration. These features, if observed in experiments, may be used as evidence to confirm that the dual-sorption model gives an explanation to the non-linear kinetic behaviour of a permeant.
This review highlights in vitro drug dissolution/permeation methods available for topical and transdermal nanocarriers that have been designed to modulate the propensity of drug release, drug penetration into skin, and permeation into systemic circulation. Presently, a few of USFDA-approved in vitro dissolution/permeation methods are available for skin product testing with no specific application to nanocarriers. Researchers are largely utilizing the in-house dissolution/permeation testing methods of nanocarriers. These drug release and permeation methods are pending to be standardized. Their biorelevance with reference to in vivo plasma concentration-time profiles requires further exploration to enable translation of in vitro data for in vivo or clinical performance prediction.
The Nanoemulgel drug delivery system is a formulation related intervention to improve the systemic delivery and therapeutic profile of lipophilic drugs. Nanoemulgel is an amalgamated formulation of two different systems in which nanoemulsion containing drug is incorporated into a gel base. The fusion of the two systems makes this formulation advantageous in several ways. Lipophilic drugs can be easily incorporated and the skin permeability of the incorporated drugs can be enhanced in several folds due to the finely distributed droplets of nanoemulsion phase. As a result, the pharmacokinetic and pharmacodynamic profiles of the lipophilic drugs are improved significantly. An increasing trend in topical nanoemulgel use in recent years has been noticed because of the better acceptability of the preparation to the patients due to their noninvasive delivery, avoidance of gastrointestinal side effects, easier applicability and good therapeutic and safety profile. Despite of having few limitations, nanoemulgel formulation can be considered as a potential and promising candidates for topical delivery of lipophilic drugs in the future. The aim of this review is to evaluate and report the current potential and future scope of nanoemulgel formulation for becoming an effective delivery system for poorly water soluble drugs. In this review, we have summarized and discussed the outcome of different studies on permeability, pharmacokinetic, pharmacodynamic and safety profile of the drugs delivered topically through nanoemulgel. Rationality of use along with the major challenges to overcome for nanoemulgel formulation has been discussed.
Dissolved oil palm empty fruit bunch (EFB) cellulose in NaOH/urea solvent was mixed with sodium carboxymethylcellulose (NaCMC) to form a green regenerated superabsorbent hydrogel. The effect of concentration of epichlorohydrin (ECH) as the crosslinker on the formation, physical, and chemical properties of hydrogel was studied. Rapid formation and higher gel content of hydrogel were observed at 10% concentration of ECH. The superabsorbent hydrogel was successfully fabricated in this study with the swelling ability >100,000%. Hydrogel with higher concentration of ECH showed opposite trend by having higher superabsorbent property than that of lower concentration. The covalent bond of COC was observed with Attenuated total reflectance fourier transform infrared (ATR-FT-IR) spectroscopy to confirm the occurrence of crosslinking. The physical and chemical properties of hydrogel were affected by swelling phenomenon. Hydrogel with higher degree of swelling exhibited lower moisture retention and higher transparency. Moreover, the weight of the superabsorbent hydrogel increased with the decrement of pH value of external media (distilled water). This study provided substantial information on the effect of different percentage of ECH as crosslinker on hydrogel basic properties. Furthermore, this study affords correlation of many essential driving forces that affected hydrogel superabsorbent property.
The interaction of a dipole antenna with a human eye model in the presence of a metamaterial is investigated in this paper. The finite difference time domain (FDTD) method with convolutional perfectly matched layer (CPML) formulation have been used. A three-dimensional anatomical model of the human eye with resolution of 1.25 mm × 1.25 mm × 1.25 mm was used in this study. The dipole antenna was driven by modulated Gaussian pulse and the numerical study is performed with dipole operating at 900 MHz. The analysis has been done by varying the size and value of electric permittivity of the metamaterial. By normalizing the peak SAR (1 g and 10 g) to 1 W for all examined cases, we observed how the SAR values are not affected by the different permittivity values with the size of the metamaterial kept fixed.
Drug delivery through the skin improves solubility, bioavailability, and unwanted systemic side effects of the drug. The selection of a suitable carrier is a challenging process. The conventional lipid vesicles have some limitations. They deliver the drug in the stratum corneum and have poor colloidal stability. Here comes the need for ultra-deformable lipid vesicles to provide the drug beyond the stratum corneum. Transethosomes are novel ultra-deformable vesicles that can deliver drugs into deeper tissues. The composition of transethosomes includes phospholipid, ethanol and surfactants. Each ingredient has a pivotal role in the properties of the carrier. This review covers the design, preparation method, characterisation, and characteristics of the novel vesicle. Also, we cover the impact of surfactants on vesicular properties and the skin permeation behaviour of novel vesicles.
A comparison is made between atebrin-musonate and quinine bihydrochloride in the treatment of acute malaria. 286 cases of acute malaria due to Malayan strains of P. falciparum, P. vivax, and P. malariae, were treated in alternating sequence with one or other of these drugs. The rates at which the atebrin-musonate and the quinine case groups became trophozoite-free and fever-free are contrasted in a series of graphs. It is shown that there was a tendency for trophozoites to disappear from the peripheral blood and for temperatures to fall to normal somewhat earlier among cases treated with atebrin-musonate. No toxic effects of any importance were observed (but see footnote p. 657). Evidence is recorded which suggests that the minimal effective daily dose for an adult is 0·375 gramme (= atebrin 0·3 gramme). This dose when given either intramuscularly or intravenously on two successive days effected a rapid disappearance of parasites and fever. Intramuscular administration is regarded as the method of choice. It is noted that absorption of the drug from the muscles is very rapid, and that atebrin may be demonstrated in the urine within 10 minutes of an intramuscular injection of 0·3 gramme. A method of testing for the presence of atebrin in the urine which is sensitive to over one in a million is described. It was not possible to obtain precise data regarding the permanency of cure but an analysis of cases returning to hospital within 10 weeks of discharge suggests that relapses after atebrin-musonate treatment are probably fairly common.
Glycols stand out as one of the most commonly employed safe and effective excipients for pharmaceutical and cosmeceutical products. Their widespread adoption can be attributed to their exceptional solvency characteristics and their ability to interact effectively with skin lipids and keratin for permeation enhancement. Notably, propylene glycol enjoys significant popularity in this regard. Ongoing research endeavours have been dedicated to scrutinising the impact of glycols on dermal drug delivery and shedding light on the intricate mechanisms by which glycols enhance skin permeation. This review aims to mitigate the discordance within the existing literature, assemble a holistic understanding of the impact of glycols on the percutaneous absorption of active compounds and furnish the reader with a profound comprehension of the foundational facets pertaining to their skin permeation enhancement mechanisms, while simultaneously delving deeper into the intricacies of these processes.
Over the years, in vitro Franz diffusion experiments have evolved into one of the most important methods for researching transdermal drug administration. Unfortunately, this type of testing often yields permeation data that suffer from poor reproducibility. Moreover, this feature frequently occurs when synthetic membranes are used as barriers, in which case biological tissue-associated variability has been removed as an artefact of total variation. The objective of the current study was to evaluate the influence of a full-validation protocol on the performance of a tailor-made array of Franz diffusion cells (GlaxoSmithKline, Harlow, UK) available in our laboratory. To this end, ibuprofen was used as a model hydrophobic drug while synthetic membranes were used as barriers. The parameters investigated included Franz cell dimensions, stirring conditions, membrane type, membrane treatment, temperature regulation and sampling frequency. It was determined that validation dramatically reduced derived data variability as the coefficient of variation for steady-state ibuprofen permeation from a gel formulation was reduced from 25.7% to 5.3% (n = 6). Thus, validation and refinement of the protocol combined with improved operator training can greatly enhance reproducibility in Franz cell experimentation.
The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.
Transdermal drug delivery is impeded by the natural barrier of epidermis namely stratum corneum. This limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500 Da and melting point of less than 200°C. Nanotechnology has received widespread investigation as nanocarriers are deemed to be able to fluidize the stratum corneum as a function of size, shape, surface charges, and hydrophilicity-hydrophobicity balance, while delivering drugs across the skin barrier. This review provides an overview and update on the latest designs of liposomes, ethosomes, transfersomes, niosomes, magnetosomes, oilin- water nanoemulsions, water-in-oil nanoemulsions, bicontinuous nanoemulsions, covalently crosslinked polysaccharide nanoparticles, ionically crosslinked polysaccharide nanoparticles, polyelectrolyte coacervated nanoparticles and hydrophobically modified polysaccharide nanoparticles with respect to their ability to fuse or fluidize lipid/protein/tight junction regimes of skin, and effect changes in skin permeability and drug flux. Universal relationships of nanocarrier size, zeta potential and chemical composition on transdermal permeation characteristics of drugs will be developed and discussed.
Oil spill constitutes a major source of fresh and seawater pollution as a result of accidental discharge from tankers, marine engines, and underwater pipes. Therefore, the need for cost-effective and environmental friendly sorbent materials for oil spill cleanup cannot be overemphasized. The present work focuses on the preliminary study of empty palm fruit bunch fibre as a promising sorbent material. The morphology of the unmodified empty palm fruit bunch, EPFB fibre, was examined using an optical microcopy, scanning electron microcopy coupled with EDX and X-ray diffraction. The effects of oil volume, fibre weight, and time on oil absorption of EPFB fibre were evaluated with new engine oil from the model oil. The results show that EPFB fibre consists of numerous micro pores, hydrophobic, and partially crystalline and amorphous with approximately 13.5% carbon. The oil absorbency of the fibre increased with the increase in oil volume, immersion time, and fibre weight. However, sorption capacity decreased beyond 3 g in 100 mL. Additionally unmodified EPFB fibre showed optimum oil sorption efficiency of approximately 2.8 g/g within three days of immersion time.
The kinetics of topical triamterene penetration were estimated from the time-course measurements of triamterene (in Dyazide) concentrations in the anterior chamber of six rabbits (n=12, left and right eyes). The two-compartment model of Jones and Maurice (1) was fitted to the measurements. We found the apparent elimination rate constant oftriamterene A = 0.33 +/- 0.12 hr(-1), the apparent absorption rate constant of triamterene B = 2.68 +/- 0.55 hr(-1), the cornea-aqueous transfer coefficient in reference to the corneal volume of triamterene kc.ca = 0.28 +/- 0.05 hr(-1), the loss coefficient of triamterene from the anterior chamber ko = 0.43 +/- 0.16 hr(-1) and the amount of triamterene in the cornea at time zero Mo = 483 +/- 125 ng/ml. The mean of ko = 0.43 hr(-1) is significantly lower (p = 0.04% using ZTEST) than the lower limit of aqueous loss coefficient = 0.58 hr(-1) usually found in rabbits (2). We conclude that Dyazide lowers the aqueous flow rate in the positive direction, considering glaucoma treatment. Peak triamterene concentration in the anterior chamber was P = 120 +/- 32 ng/ml. Half-life for elimination from the aqueous humor was T1/2 = 1.84 +/- 0.65 hr (Mean +/- SD).
Inhaled/oral insulin have been investigated as an alternative to injectable insulin, but are met with unsatisfactory outcomes. Transdermal administration bears several advantages unmet by inhalation/oral delivery, but macromolecular drugs permeation is poor. This study explored microwave to elicit transdermal insulin permeation, and compared against conventional permeation enhancers (fatty acids) in vitro/in vivo. The transdermal insulin permeation was promoted by microwave (2450 MHz/1 mW) > oleic acid (monounsaturated) ~ linoleic acid (double unsaturated bonds). The linolenic acid (triple unsaturated bonds) or combination of microwave/fatty acid reduced skin insulin permeation. Transdermal insulin permeation enhancement was attributed to epidermal lipid bilayer fluidization (CH) and corneocyte shrinkage due to keratin condensation (OH/NH, CO), which had aqueous pore enlarged to facilitate insulin transport. Its reduction by linolenic acid, a molecularly larger and rigid fatty acid with higher surface tension, was due to reduced fatty acid permeation into epidermis and minimal skin microstructural changes. The oleic acid, despite favoured skin microstructural changes, did not provide a remarkably high insulin permeation due to it embedded in skin as hydrophobic shield to insulin transport. Microwave penetrates skin volumetrically with no chemical residue retention. It alone promoted insulin absorption and sustained blood glucose level reduction in vivo.
Gentamicin, whether administered either intravenously, incorporated into bone cement or for local intra-operative irrigation, is a commonly used antibiotic in orthopaedic practice. The former two have been well studied, however the literature on the therapeutic efficacy and safety of gentamicin irrigation is sparse. The objective of this study was to assess systemic absorption of gentamicin irrigation in joint replacement surgery. This was a non-randomised, prospective study. Ninety-eight patients (group A) who underwent total joint replacement and 40 patients (group B) who underwent hemi-arthroplasty were treated traoperatively with gentamicin irrigation. Serum gentamicin levels were assayed at 4 hours and 24 hours post-surgery. Sixteen of 98 patients in group A (16%) and 12 out of 40 patients in group B (30%) were found to have serum gentamicin level above 2mcg/ml at 4 hours post-surgery. We conclude that intra-articular gentamicin irrigation is systemically absorbed at substantial levels.
For effective topical and transdermal drug delivery, it is necessary for most actives to penetrate and permeate through the stratum corneum (SC). Extensive investigation of the thermal behaviour of mammalian SC has been performed to understand the barrier function of the skin. However, little attention has been paid to the related experimental variables in thermal analysis of the SC using differential scanning calorimetry that may influence the results obtained from such studies. In this review, we provide a comprehensive overview of the thermal transitions of the SC of both porcine and human skin. More importantly, the selection and impact of the experimental and instrumental parameters used in thermal analysis of the SC are critically evaluated. New opportunities for the use of thermal analysis of mammalian SC in advancing skin research, particularly for elucidation of the actions of excipients employed in topical and transdermal formulations on the skin are also highlighted.