This study involves adaptation of bulk or sequential technique to load multiple flavonoids in a single phytosome, which can be termed as "flavonosome". Three widely established and therapeutically valuable flavonoids, such as quercetin (Q), kaempferol (K), and apigenin (A), were quantified in the ethyl acetate fraction of Moringa oleifera leaves extract and were commercially obtained and incorporated in a single flavonosome (QKA-phosphatidylcholine) through four different methods of synthesis - bulk (M1) and serialized (M2) co-sonication and bulk (M3) and sequential (M4) co-loading. The study also established an optimal formulation method based on screening the synthesized flavonosomes with respect to their size, charge, polydispersity index, morphology, drug-carrier interaction, antioxidant potential through in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics, and cytotoxicity evaluation against human hepatoma cell line (HepaRG). Furthermore, entrapment and loading efficiency of flavonoids in the optimal flavonosome have been identified. Among the four synthesis methods, sequential loading technique has been optimized as the best method for the synthesis of QKA-phosphatidylcholine flavonosome, which revealed an average diameter of 375.93±33.61 nm, with a zeta potential of -39.07±3.55 mV, and the entrapment efficiency was >98% for all the flavonoids, whereas the drug-loading capacity of Q, K, and A was 31.63%±0.17%, 34.51%±2.07%, and 31.79%±0.01%, respectively. The in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics of the flavonoids indirectly depicts the release kinetic behavior of the flavonoids from the carrier. The QKA-loaded flavonosome had no indication of toxicity toward human hepatoma cell line as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide result, wherein even at the higher concentration of 200 µg/mL, the flavonosomes exert >85% of cell viability. These results suggest that sequential loading technique may be a promising nanodrug delivery system for loading multiflavonoids in a single entity with sustained activity as an antioxidant, hepatoprotective, and hepatosupplement candidate.
Fungi are a rich source of secondary metabolites with several pharmacological activities such as antifungal, antioxidant, antibacterial and anticancer to name a few. Due to the large number of diverse structured chemical compounds they produce, fungi from the phyla Ascomycota, Basidiomycota and Muccoromycota have been intensively studied for isolation of bioactive compounds. Basidiomycetes-derived secondary metabolites are known as a promising source of antibacterial compounds with activity against Gram-positive bacteria. The continued emergence of antimicrobial resistance (AMR) poses a major challenge to patient health as it leads to higher morbidity and mortality, higher hospital-stay duration and substantial economic burden in global healthcare sector. One of the key culprits for AMR crisis is Staphylococcus aureus causing community-acquired infections as the pathogen develops resistance towards multiple antibiotics. The recent emergence of community strains of S. aureus harbouring methicillin-resistant (MRSA), vancomycin-intermediate (VISA) and vancomycin-resistant (VRSA) genes associated with increased virulence is challenging. Despite the few significant developments in antibiotic research, successful MRSA therapeutic options are still needed to reduce the use of scanty and expensive second-line treatments. This paper provides an overview of findings from various studies on antibacterial secondary metabolites from basidiomycetes, with a special focus on antistaphylococcal activity.
This research aims to formulate and to optimize a nanoemulsion-based formulation containing fullerene, an antioxidant, stabilized by a low amount of mixed surfactants using high shear and the ultrasonic emulsification method for transdermal delivery. Process parameters optimization of fullerene nanoemulsions was done by employing response surface methodology, which involved statistical multivariate analysis. Optimization of independent variables was investigated using experimental design based on Box-Behnken design and central composite rotatable design. An investigation on the effect of the homogenization rate (4,000-5,000 rpm), sonication amplitude (20%-60%), and sonication time (30-150 seconds) on the particle size, ζ-potential, and viscosity of the colloidal systems was conducted. Under the optimum conditions, the central composite rotatable design model suggested the response variables for particle size, ζ-potential, and viscosity of the fullerene nanoemulsion were 152.5 nm, -52.6 mV, and 44.6 pascal seconds, respectively. In contrast, the Box-Behnken design model proposed that preparation under the optimum condition would produce nanoemulsion with particle size, ζ-potential, and viscosity of 148.5 nm, -55.2 mV, and 39.9 pascal seconds, respectively. The suggested process parameters to obtain optimum formulation by both models yielded actual response values similar to the predicted values with residual standard error of <2%. The optimum formulation showed more elastic and solid-like characteristics due to the existence of a large linear viscoelastic region.
Phosphate-free spray dried detergent powders (SDDP) comprising binary anionic surfactants of palm C16 methyl ester sulfonate (C16MES) and linear alkyl benzene sulfonic acid (LABSA) were produced using a 5 kg/h-capacity co-current pilot spray dryer (CSD). Six phosphate-free detergent (PFD) formulations comprising C16MES/LABSA in various ratios under pH 7-8 were studied. Three PFD formulations having C16MES/LABSA in respective ratios of 0:100 (control), 20:80 and 40:60 ratios were selected for further evaluation based on their optimum detergent slurry concentrations. The resulting SDDP from these formulations were analysed for its detergency stability (over nine months of storage period) and particle characteristics. C16MES/LABSA of 40:60 ratio was selected as the ideal PFD formulation since its resulting SDDP has consistent detergency stability (variation of 2.3% in detergency/active over nine months storage period), excellent bulk density (0.37 kg/L), fine particle size at 50% cumulative volume percentage (D50 of 60.48 μm), high coefficient of particle size uniformity (D60/D10 of 3.86) and large spread of equivalent particle diameters. In terms of surface morphology, the SDDP of the ideal formulation were found to have regular hollow particles with smooth spherical surfaces. Although SDDP of the ideal formulation have excellent characteristics, but in terms of flowability, these powders were classified as slightly less free flowing (Hausner ratio of 1.27 and Carr's index of 21.3).
We aimed to investigate the effects that natural lipids, theobroma oil (TO) and beeswax (BW), might have on the physical properties of formulated nanoparticles and also the degree of expulsion of encapsulated amphotericin B (AmB) from the nanoparticles during storage. Lecithin and sodium cholate were used as emulsifiers whilst oleic acid (OA) was used to study the influence of the state of orderliness/disorderliness within the matrices of the nanoparticles on the degree of AmB expulsion during storage. BW was found to effect larger z-average diameter compared with TO. Lecithin was found to augment the stability of the nanoparticles imparted by BW and TO during storage. An encapsulation efficiency (%EE) of 59% was recorded when TO was the sole lipid as against 42% from BW. In combination however, the %EE dropped to 39%. When used as sole lipid, TO or BW formed nanoparticles with comparatively higher enthalpies, 21.1 and 23.3 J/g respectively, which subsequently caused significantly higher degree of AmB expulsion, 81 and 83% respectively, whilst only 11.8% was expelled from a binary TO/BW mixture. A tertiary TO/BW/OA mixture registered the lowest enthalpy at 8.07 J/g and expelled 12.6% of AmB but encapsulated only 22% of AmB. In conclusion, nanoparticles made from equal concentrations of TO and BW produced the most desirable properties and worthy of further investigations.
Response surface methodology was employed to study the effect of formulation composition variables, water content (60%-80%, w/w) and oil and surfactant (O/S) ratio (0.17-1.33), as well as high-shear emulsification conditions, mixing rate (300-3,000 rpm) and mixing time (5-30 minutes) on the properties of sodium diclofenac-loaded palm kernel oil esters-nanoemulsions. The two response variables were droplet size and viscosity. Optimization of the conditions according to the four variables was performed for preparation of the nanoemulsions with the minimum values of particle size and viscosity. The results showed that the experimental data could be sufficiently fitted into a third-order polynomial model with multiple regression coefficients (R(2) ) of 0.938 and 0.994 for the particle size and viscosity, respectively. Water content, O/S ratio and mixing time, quadrics of all independent variables, interaction between O/S ratio and mixing rate and between mixing time and rate, as well as cubic term of water content had a significant effect (P<0.05) on the particle size of nanoemulsions. The linear effect of all independent variables, quadrics of water content and O/S ratio, interaction of water content and O/S ratio, as well as cubic term of water content and O/S ratio had significant effects (P<0.05) on the viscosity of all nanoemulsions. The optimum conditions for preparation of sodium diclofenac nanoemulsions were predicted to be: 71.36% water content; 0.69 O/S ratio; 950 rpm mixing rate, and 5 minute mixing time. The optimized formulation showed good storage stability in different temperatures.
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.
Capillary electrophoresis coupled with a capacitively coupled contactless conductivity detector (CE-C(4)D) has been employed for the determination of the β-blocker drugs (atenolol and amiloride) in pharmaceutical formulations. 150 mM acetic acid was used as background electrolyte. The influence of several factors (detector excitation voltage and frequency, buffer concentration, applied voltage, capillary temperature, and injection time) was studied. Non-UV absorbing L-valine was used as an internal standard; the analytes were all separated in less than 7 min. The separation was carried out in normal polarity mode at 28 °C, 25 kV, and using hydrodynamic injection (25 s). The separation was effected in a bare fused-silica capillary 75 μm × 52 cm. The CE-C(4)D method was validated with respect to linearity, limit of detection and quantification, accuracy, precision, and selectivity. Calibration curves were linear over the range 5-250 μg mL(-1) for the studied analytes. The relative standard deviations of intra- and inter-day precisions of migration times and corrected peak areas were less than 6.0%. The method showed good precision and accuracy and was successfully applied to the simultaneous determination of the β-blocker drugs in different pharmaceutical tablets.
The aim of the present study is to formulate and investigate the potential of nanoemulsion formulation for topical delivery of ketoprofen. In this study, Palm Oil Esters (POEs) a newly introduced oil by Universiti Putra Malaysia researchers was chosen for the oil phase of the nanoemulsion, because the oil was reported to be a good vehicle for pharmaceutical use. Oil-in-water nanoemulsion was prepared by spontaneous emulsification method. The droplets size was studied by laser scattering spectroscopy (Nanophox) and Transmission Electron Microscopy (TEM). Franz diffusion cells were used, to determine the drug release and drug transferred through methyl acetate cellulose membrane (artificial membrane). The results of droplets size analysis shows the droplets are in the range of nanoemulsion which is below than 500 nm. The in vitro release profile shows a sufficient percentage of drugs released through the methyl acetate cellulose membrane. This initial study showed that the nanoemulsion formulated using POEs has great potential for topical delivery of ketoprofen.
A capillary electrophoresis (CE) method has been developed that allows the separation and estimation of primaquine enantiomers using hydroxypropyl-gamma-cyclodextrin (HP-gamma -CD) as a chiral selector. The influence of chemical and instrumental parameters on the separation, such as type and concentration of CD, buffer concentration, buffer pH, applied voltage, capillary temperature, and injection time, were investigated. Good separation of the racemic mixture of primaquine was achieved using a fused-silica capillary (52.5 cm effective length x 50 microm id) and a background electrolyte composed of tris-phosphate buffer solution (50 mM, pH 2.5) containing 15 mM HP-gamma-CD as a chiral selector. The recommended applied voltage, capillary temperature, and injection time were 15 kV, 25 degrees C, and 6 s, respectively. Within-day and interday reproducibility of peak area and migration time gave relative standard deviation values ranging from 1.05-3.30%. Good recoveries (range of 96.8-104.9%) were obtained from the determination of placebos that were spiked with 0.25-1.00 mg/L primaquine. The proposed CE method was successfully applied to the assay of primaquine diphosphate in pharmaceutical formulations (tablets).
Prevention of cardiovascular disease by modifying its major risk factors, including serum cholesterol levels, is an important strategy. Regular intake of garlic has been suggested, but its impact on cholesterol levels has been inconsistent.
The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r2 value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.
Response surface methodology (RSM) was utilized to investigate the influence of the main emulsion composition; mixture of palm and medium-chain triglyceride (MCT) oil (6%-12% w/w), lecithin (1%-3% w/w), and Cremophor EL (0.5%-1.5% w/w) as well as the preparation method; addition rate (2-20 mL/min), on the physicochemical properties of palm-based nanoemulsions. The response variables were the three main emulsion properties; particle size, zeta potential and polydispersity index. Optimization of the four independent variables was carried out to obtain an optimum level palm-based nanoemulsion with desirable characteristics. The response surface analysis showed that the variation in the three responses could be depicted as a quadratic function of the main composition of the emulsion and the preparation method. The experimental data could be fitted sufficiently well into a second-order polynomial model. The optimized formulation was stable for six months at 4 °C.
Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.
Two formulations of lambda-cyhalothrin (EC-Emulsion concentrate and MC-Microencapsulated) were impregnated into bednets made of polyethylene and polyester. The nets were treated at a dosage of 15 mg/m2. For bioassay of insecticidal efficacy, female Anopheles maculatus and Aedes aegypti were exposed to the nets for two minutes and mortality was scored 24 hours later. The nets were also tested after repeated washings with water and with soap and water. Microencapsulated (2.5CS) formulation was more effective than emulsion concentrate (2.5EC) formulation on both net materials--polyethylene and polyester. Repeated washing with water and soap reduces the efficacy of all bednet treatment combinations. Microencapsulated formulation on polyethylene gave best results; it could sustain up to five washes with water and two with soap and water.
To investigate and compare the effect of three analytical methods, hydrogen bromide titrimetry (HBr titrimetry), infrared spectroscopy (IR spectroscopy), and first derivative UV-spectrophotometry (FDUV-spectrophotometry) in the determination of degree of deacetylation (DD) of chitosan.
The aims of the present research were to mask the intensely bitter taste of sumatriptan succinate and to formulate orally disintegrating tablets (ODTs) of the taste masked drug. Taste masking was performed by coating sumatriptan succinate with Eudragit EPO using spray drying technique. The resultant microspheres were evaluated for thermal analysis, yield, particle size, entrapment efficiency and in vitro taste masking. The tablets were formulated by mixing the taste masked microspheres with different types and concentrations of superdisintegrants and compressed using direct compression method followed by sublimation technique. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. All the tablet formulations disintegrated in vitro within 37-410 s. The optimized formulation containing 5% Kollidon CL-SF released more than 90% of the drug within 15 min and the release was comparable to that of commercial product (Suminat®). In human volunteers, the optimized formulation was found to have a pleasant taste and mouth feel and disintegrated in the oral cavity within 41 s. The optimized formulation was found to be stable and bioequivalent with Suminat®.
Conventional melt pelletization and granulation processes produce round and dense, and irregularly shaped but porous agglomerates respectively. This study aimed to design centrifugal air-assisted melt agglomeration technology for manufacture of spherical and yet porous "granulets" for ease of downstream manufacturing and enhancing drug release. A bladeless agglomerator, which utilized shear-free air stream to mass the powder mixture of lactose filler, polyethylene glycol binder and poorly water-soluble tolbutamide drug into "granulets", was developed. The inclination angle and number of vane, air-impermeable surface area of air guide, processing temperature, binder content and molecular weight were investigated with reference to "granulet" size, shape, texture and drug release properties. Unlike fluid-bed melt agglomeration with vertical processing air flow, the air stream in the present technology moved centrifugally to roll the processing mass into spherical but porous "granulets" with a drug release propensity higher than physical powder mixture, unprocessed drug and dense pellets prepared using high shear mixer. The fast-release attribute of "granulets" was ascribed to porous matrix formed with a high level of polyethylene glycol as solubilizer. The agglomeration and drug release outcomes of centrifugal air-assisted technology are unmet by the existing high shear and fluid-bed melt agglomeration techniques.
The human small intestine, with its enormous absorptive surface area, is invariably the principal site of drug absorption. Hence, the residence time of a dosage form in this part of the gut can have a great influence on the absorption of the contained drug. Various methods have been employed to monitor the gastrointestinal transit of pharmaceutical dosage forms, but the use of gamma-scintigraphy has superceded all the other methods. However, careful consideration of the time interval for image acquisition and proper analysis of the scintigraphic data are important for obtaining reliable results. Most studies reported the mean small intestinal transit time of various dosage forms to be about 3-4h, being closely similar to that of food and water. The value does not appear to be influenced by their physical state nor the presence of food, but the timing of food intake following administration of the dosage forms can influence the small intestinal transit time. While the mean small intestinal transit time is quite consistent among dosage forms and studies, individual values can vary widely. There are differing opinions regarding the effect of density and size of dosage forms on their small intestinal transit properties. Some common excipients employed in pharmaceutical formulations can affect the small intestinal transit and drug absorption. There is currently a lack of studies regarding the effects of excipients, as well as the timing of food intake on the small intestinal transit of dosage forms and drug absorption.