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The application of ketoconazole (KET) in ocular drug delivery is restricted by its poor aqueous solubility though its broad-spectrum antifungal activity. The aim of this study is to develop an ion-sensitive in situ gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), then KET-HPβCD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The in vitro drug release and antifungal activities investigations demonstrated that the KET-IC-ISG formulation increased drug release and anti-fungal activities compared to pure KET. The ex vivo rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (Papp of (6.34 ± 0.21) × 10−4 cm/h) than pure KET (Papp of (3.09 ± 0.09) × 10−4 cm/h). The cytotoxicity assay and the ocular irritation study in rabbits confirmed the KET-IC-ISG safety and well tolerance. The ocular pharmacokinetics of KET in rabbits was investigated and the results showed that the KET-IC-ISG increased its bioavailability in cornea by 47-fold. In conclusion, the KET-IC-ISG system promoted the precorneal retention, the ocular drug bioavailability and the developed formulation is a potential strategy to treat mycotic keratitis. [ABSTRACT FROM AUTHOR]

Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products. [ABSTRACT FROM AUTHOR]

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems. [ABSTRACT FROM AUTHOR]

Based on the administration convenience, transmucosal buccal drug delivery allows special strength points over peroral routes for systemic delivery. It could achieve local or systemic effect and boost drugs' bioavailability for agents with first pass metabolism. The current study aimed to manufacture and optimize a lavender oil-based nanoemulsion loaded with zaleplon and incorporate it into fast-disintegrating tablets to promote its dissolution and oral bioavailability via oral mucosa. Zaleplon-loaded nanoemulsions were devised with various levels of lavender oil (10% to 25%), the surfactant Sorbeth-20 (35% to 65%), and the co-surfactant HCO-60 (20% to 40%); the extreme vertices mixture statistical design was adopted. The droplet size and drug-loading efficiency were the evaluated. The optimal formulation was transformed into self-nanoemulsified lyophilized tablets (ZP-LV-SNELTs), which were tested for their uniformity of content, friability, and disintegration time with in-vitro release. Finally, the pharmacokinetic parameters of the ZP-LV-SNELTs were determined and compared with those of marketed formulations. The optimal nanoemulsion had a droplet size of 87 nm and drug-loading capacity of 185 mg/mL. ZP-LV-SNELTs exhibited acceptable friability and weight uniformity and a short disintegration time. The in-vitro release of ZP-LV-SNELTs was 17 times faster than that of the marketed tablet. Moreover, the optimal ZP-LV-SNELTs increased the bioavailability of zaleplon in rabbits by 1.6-fold compared with the commercial tablets. Hence, this investigation revealed that ZP-LV-SNELTs delivered zaleplon with enhanced solubility, a fast release, and boosted bioavailability thru oral mucosa which provided a favorable route for drug administration which is suggested to be clinically investigated in future studies. [ABSTRACT FROM AUTHOR]

The eye is an invulnerable organ with intrinsic anatomical and physiological barriers, hindering the development of a pioneer ocular formulation. The aim of this work was to develop an efficient ocular delivery system that can augment the ocular bioavailability of the antifungal drug, terconazole. Mesoporous silica microparticles, Syloid® 244 FP were utilized as the carrier system for terconazole. Preliminary studies were carried out using different drug:Syloid® weight ratios. The optimum weight ratio was mixed with various concentrations (30 and 60%w/w) of poly (lactic-co-glycolic acid) (PLGA), ester or acid-capped and with different monomers-ratio (50:50 and 75:25) using the nano-spray dryer. Results revealed the superiority of drug:Syloid® weight ratio of 1:2 in terms of yield percentage (Y%), SPAN and drug content percentage (DC%). Furthermore, incorporation of PLGA with lower glycolic acid monomer-ratio significantly increased Y%. In contrast, increasing the glycolic acid monomer-ratio resulted in higher DC% and release efficiency percentage (RE%). Additionally, doubling PLGA concentration significantly reduced Y%, DC%, drug loading percentage (DL%) and RE%. Applying desirability function in terms of increasing DC%, DL% besides RE% and decreasing SPAN, the selected formulation was chosen for DSC, XRD and SEM investigations. Results confirmed the successful loading of amorphized terconazole on PLGA-modified Syloid® microparticles. Moreover, pharmacokinetic studies for the chosen formulation on male Albino rabbits' eyes revealed a 2, 6.7 and 25.3-fold increase in mean residence time, Cmax and AUC0-24-values, respectively, compared to the drug suspension. PLGA-modified Syloid® microparticles represent a potential option to augment the bioavailability of ocular drugs. [ABSTRACT FROM AUTHOR]

Intra-articular (IA) injection is grasping much interest due to the poor drug bioavailability at the targeted site of action which minimizes the effect of the orally administered moiety. Based on the integral role of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of Rheumatoid Arthritis (RA), much effort is exerted to develop novel localized drug delivery systems to increase their bioavailability and minimize their side effects. Artificial intelligence (AI) is acquiring an increasing role in the design of experiments being an effective tool for saving both time and resources. Hence, the aim of this work was to develop, characterize and optimize targeted in-situ forming nano particles (ISNs) for IA delivery of piroxicam using DesignVR Expert as an AI-based application where a 33 full factorial experimental design was adopted. Morphological investigation, injectability, rheological studies, Fourier Transform Infrared Radiation (FTIR) as well as biological, histopathological, and biochemical examinations were performed to evaluate the optimized-ISNs. The optimized formulation, exhibiting a nano-sized particle size with a dense core, showed significant improvement in the histopathological findings compared to both the oral solution and the placebo. Additionally, the once-a-week IA administration of the optimized-ISNs proved a significant reduction in the protein expression of both STAT-3 and RANKL and the levels of anti-CCP and MCP-1 by almost 54 and 73%, respectively, coupled with a marked decline in the content of IL-17, MMP-3, NF-jB and TNF-a as compared to the positive control. In conclusion, the use of ISNs for intra-articular injection has demonstrated their effectiveness in piroxicam delivery for RA treatment. [ABSTRACT FROM AUTHOR]

Novel intra-articular nanoreservoirs were implemented employing different cartilage targeting approaches to improve cartilage bioavailability of a chondroprotective drug, cassic acid (CA), for effective amelioration of cartilage deterioration off-targeting CA gastrointestinal disorders. Herein, we compared active cartilage-targeting approach via chondroitin sulfate (CHS) functionalization versus passive targeting using positively charged nanoparticles to target negatively charged cartilage matrix. Firstly, CA integrated nanoreservoirs (CA-NRs) were fabricated based on ionic conjugation between CA and cationic hydrophobic surface modifier octadecylamine (ODA) and were further functionalized with CHS to develop CHS-CA-NRs. Confocal laser microscope was used to visualize the accumulation of nanoparticles into the cartilage tissue. Both targeting approaches promoted CA local cartilage availability and prolonged its residence time. Compared to passive targeted CA-NRs, active targeted CHS-CA-NRs showed higher fluorescence signals in proximity to and inside chondrocytes which lasted for up to 21 days. In MIA-osteoarthritic rats, CHS-CA-NRs showed superior antiosteoarthritic activity, exhibiting highest cartilage repair compared to CA-NRs. Additionally, CHS-CA-NRs significantly inhibited OA inflammatory cytokine, degradation enzyme and oxidative stress and improved cartilage matrix biosynthesis. Conclusively, CHS-CA-NRs improved OA repair showing a superior efficacy for articular cartilage targeting with CHS which could be a potential advance for OA therapy. [ABSTRACT FROM AUTHOR]

Pulmonary inhalation administration is an ideal approach to locally treat lung disease and to achieve systemic administration for other diseases. However, the complex nature of the structural characteristics of the lungs often results in the difficulty in the development of lung inhalation preparations. Nanocrystals technology provides a potential formulation strategy for the pulmonary delivery of poorly soluble drugs, owing to the decreased particle size of drug, which is a potential approach to overcome the physiological barrier existing in the lungs and significantly increased bioavailability of drugs. The pulmonary inhalation administration has attracted considerable attentions in recent years. This review discusses the barriers for pulmonary drug delivery and the recent advance of the nanocrystals in pulmonary inhalation delivery. The presence of nanocrystals opens up new prospects for the development of novel pulmonary delivery system. The particle size control, physical instability, potential cytotoxicity, and clearance mechanism of inhaled nanocrystals based formulations are the major considerations in formulation development. [ABSTRACT FROM AUTHOR]

Controlled drug delivery systems are of utmost importance for the improvement of drug bioavailability while limiting the side effects. For the improvement of their performances, drug release modeling is a significant tool for the further optimization of the drug delivery systems to cross the barrier to practical application. We report here on the modeling of the diclofenac sodium salt (DCF) release from a hydrogel matrix based on PEGylated chitosan in the context of Multifractal Theory of Motion, by means of a fundamental spinor set given by 2-2 matrices with real elements, which can describe the drug-release dynamics at global and local scales. The drug delivery systems were prepared by in situ hydrogenation of PEGylated chitosan with citral in the presence of the DCF, by varying the hydrophilic/hydrophobic ratio of the components. They demonstrated a good dispersion of the drug into the matrix by forming matrix-drug entities which enabled a prolonged drug delivery behavior correlated with the hydrophilicity degree of the matrix. The application of the Multifractal Theory of Motion fitted very well on these findings, the fractality degree accurately describing the changes in hydrophilicity of the polymer. The validation of the model on this series of formulations encourages its further use for other systems, as an easy tool for estimating the drug release toward the design improvement. The present paper is a continuation of the work 'A theoretical mathematical model for assessing diclofenac release from chitosan-based formulations,' published in Drug Delivery Journal, 27(1), 2020, that focused on the consequences induced by the invariance groups of Multifractal Diffusion Equations in correlation with the drug release dynamics. [ABSTRACT FROM AUTHOR]

It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer's disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD. [ABSTRACT FROM AUTHOR]

For weakly basic drugs, the sharp decrease of drug solubility and the following drug precipitation after drugs transferring from the gastric fluid to the intestinal fluid in the gastrointestinal (GI) tract is a main reason for the poor oral bioavailability of drugs. Here, an anticoagulant dabigatran etexilate (DE) was used as a model drug, and a composite nanocarrier system of DE was developed to improve the drug dissolution by decreasing the drug leakage in the stomach and inhibiting the drug precipitation in the intestinal tract. With the encapsulation of drugs in nanocarriers, the precipitation percentage of DE in composite nanocarriers was 22.25 ± 3.88% in simulated intestinal fluid, which was far below that of the commercial formulation. Moreover, the relative bioavailability of DE-loaded composite nanocarriers (456.58%) was greatly enhanced and the peak of its activated partial thromboplastin time was also significantly prolonged (p <.01) compared with the commercial formulation, indicating that the anticoagulant effect of DE was effectively improved. Therefore, the designed composite nanocarrier system of DE presents great potentials in improving the therapeutic efficiency and expanding the clinical applications of poorly water-soluble weakly basic drugs. [ABSTRACT FROM AUTHOR]

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy. [ABSTRACT FROM AUTHOR]

Objectives: Ginsenosides Rb1 (Rb1) could form micelles in aqueous solutions. Self-assembled Rb1 micelles could potentially be utilized as ocular drug delivery system, and it was postulated that the encapsulation of a medicine within Rb1 micelles might strengthen the drug's therapeutic action and reduce side effects. Methods: Diclofenac-loaded Rb1 micelles (Rb1-Dic micelles) were formulated, optimized, and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vivo corneal permeation, and in vivo anti-inflammatory efficacy. Results: Rb1 self-assembled into micelles with ultra-small particle size (<8 nm) in a homogeneous distribution state (polydispersity index [PDI] < 0.3). Diclofenac was highly encapsulated into the micelles according to the weight ratios of Rb1 to diclofenac. The ophthalmic solution of Rb1-Dic micelle was simple to prepare. Rb1 had good cellular tolerance, and it also improved the cellular tolerance of the encapsulated diclofenac. Rb1-Dic micelles also showed non-irritants to the rabbit eyes. The use of Rb1 micelles significantly improved the in vivo corneal permeation as well as the anti-inflammatory efficacy of diclofenac when compared to commercial diclofenac eye drops. Conclusion: Rb1 micelle formulations have great potential as a novel ocular drug delivery system to improve the bioavailability of drugs such as diclofenac. [ABSTRACT FROM AUTHOR]

Context: Increased use of organophosphate insecticides (OPI) and possibility of terror groups using stocks of nerve agents underscore the need to develop effective and safe antidotes. While intramuscular administration of antidotes like atropine sulphate (AS) has certain lacunae, intravenous route may not be always feasible in emergency field conditions. Objective: Objective was (a) to develop a novel inhalable submicronic-AS respiratory fluid as potential antidote for OPI poisoning, (b)in-vitroandin-vivoevaluation in terms of respiratory fraction, and (c) clinical study to assess drug bioavailability in blood and atropinization pattern post-inhalation. Methods: Formulation was optimized on the basis of particle size of aerosolized droplets andin-vitronebulization rate. Anderson cascade impaction (ACI) studies were carried out to validate the advantage of test formulation in terms of respirable fraction. Six healthy volunteers were inhaled the test formulation and blood bioavailability and atropinization were noted serially. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized ASin-vivo. Results: The formulation was optimized using 30% ethanol–saline with particle size in the range of 350–500 nm.In-vitroACI data showed high respirable fraction (82.6 ± 3.1%) for the test formulation.In-vivoscintigraphy suggested whole lung deposition of 80.2 ± 6.8% of the total inhaled dose. Early blood bioavailability and atropinization pattern confirmed that therapeutic concentration of the drug in blood was reached within 5 min. Conclusions: 3% submicronic-AS respiratory fluid might be used as potential prophylactic/therapeutic option against OPI poisoning with several advantages over intramuscular injection, including early blood bioavailability and atropinization. [ABSTRACT FROM AUTHOR]

A nanoemulsion drug delivery system was developed to increase the oral bioavailability of mebudipine as a calcium channel blocker with very low bioavailability profile. The impact of nano-formulation on the pharmacokinetic parameters of mebudipine in rats was investigated. Nanoemulsion formulations containing ethyl oleate, Tween 80, Span 80, polyethylene glycol 400, ethanol and deionized water were prepared using probe sonicator. The optimum formulation was evaluated for physicochemical properties, such as particle size, morphology and stability. The particle size of optimum formulation was 22.8 ± 4.0 nm. Based on the results of this study, the relative bioavailability of mebudipine nanoemulsion was enhanced by about 2.6-, 2.0- and 1.9-fold, respectively, compared with suspension, ethyl oleate solution and micellar solution. In conclusion, nanoemulsion is an interesting option for the delivery of poorly water soluble molecules, such as mebudipine. [ABSTRACT FROM PUBLISHER]

Biodegradable polymer nanoparticle drug carriers are an attractive strategy for oral delivery of peptide and protein drugs. However, their ability to cross the intestinal epithelium membrane is largely limited. Therefore, in the present study, cell-penetrating peptides (R8, Tat, penetratin) and a secretion peptide (Sec) with N-terminal stearylation were introduced to modify nanoparticles (NPs) on the surface to improve oral bioavailability of peptide and protein drugs.In vitrostudies conducted in Caco-2 cells showed the value of the apparent permeability coefficient (Papp) of the nanoparticles co-modified with Sec and penetratin (Sec-Pen-NPs) was about two-times greater than that of the nanoparticles modified with only penetratin (Pen-NPs), while the increase of transcellular transport of nanoparticles modified together with Sec and R8 (Sec-R8-NPs), or Sec and Tat (Sec-Tat-NPs), was not significant compared with nanoparticles modified with only R8 (R8-NPs) or Tat (Tat-NPs). Using insulin as the model drug,in vivostudies performed on rats indicated that compared to Pen-NPs, the relative bioavailability of insulin for Sec-Pen-NPs was 1.71-times increased after ileal segments administration, and stronger hypoglycemic effects was also observed. Therefore, the nanoparticles co-modified with penetratin and Sec could act as attractive carriers for oral delivery of insulin. [ABSTRACT FROM PUBLISHER]

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm withn = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to develop Carvedilol nanostructured lipid carriers (CAR-NLCs) using stearic acid and oleic acid as lipid, and to estimate the potential as oral delivery system for poorly water soluble drug. The particle-size analysis revealed that all the developed formulations were within the nanometer range. The EE and loading were found to be between 69.45–88.56% and 9.58–12.56%, respectively. The CAR–NLCopt showed spherical morphology with smooth surface under transmission electron microscope (TEM). The crystallization of the drug in NLC was investigated by powder X-ray diffraction and differential scanning calorimetry (DSC) and revealed that the drug was in an amorphous state in the NLC matrix. Theex vivogut permeation study showed many folds increment in the permeation of CAR-NLCs compared to Carvedilol suspension (CAR-S). The oral bioavailability study of CAR was carried out using Wistar rats and relative bioavailability of CAR–NLCopt was found to be 3.95 fold increased in comparison with CAR-S.In vivoantihypertensive study in Wistar rats showed significant reduction in mean systolic BP by CAR-NLCopt vis-à-vis CAR-S (p < 0.05) owing to the drug absorption through lymphatic pathways. In conclusion, the NLC formulation remarkably improved the oral bioavailability of CAR and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs. The promising findings in this investigation suggest the practicability of these systems for the enhancement of bioavailability of CAR. [ABSTRACT FROM PUBLISHER]

Context: Applicability of natural polymers in pharmaceutical drug delivery. Objective: The objective of the present investigation was to evaluate the applicability of badam gum (BG) obtained fromTerminalia catappaLINN, belongs to the family combretaceae as a buccoadhesive polymer using metoprolol succinate as a model drug. Methods: Tablets were prepared by wet granulation technique. Compression coating technique was employed for the preparation of unidirectional release buccal tablets using cellulose acetate as an impermeable backing layer. Results: Muco/buccoadhesive properties of the BG were increased with the increase in the concentration of polymer which was evident form the detachment force measurement,ex vivoresidence time, and swelling studies. MBG 2 was found to be the optimized formulation based on drug dissolution studies and bioadhesion studies. FTIR and DSC studies performed on the optimized formulation indicated no drug–polymer interaction. MBG 2 was found to be stable after accelerated stability testing for 6 months as per ICH guidelines. Pharmacokinetic studies of the optimized formulation were performed in six healthy human volunteers in comparison with that of the commercial extended release oral tablet GUDPRESS XL-25 by estimating pharmacokinetic parameters and mean residence time (MRT). It was found that there is a significant increase in the bioavailability of metoprolol succinate from BG formulation which was evident from the high AUC and MRT values compared with the commercial formulation. Conclusion: The above results clearly indicated that badam gum can be used as a mucoadhesive polymer for buccal drug delivery. [ABSTRACT FROM AUTHOR]

Oral delivery of 5-fluorouracil (5-FU) is difficult due to its serious adverse effects and extremely low bioavailability. Therefore, the aim of present investigation was to develop and evaluate low HLB surfactant nanoemulsion of 5-FU for topical chemoprevention of skin cancer. Low HLB surfactant nanoemulsions were prepared by oil phase titration method. Thermodynamically stable nanoemulsions were characterized in terms of droplet size distribution, zeta potential, viscosity and refractive index. Selected formulations and control were subjected to in vitro skin permeation studies through rat skin using Franz diffusion cells. Optimized formulation F9 was subjected to stability and in vitro cytotoxic studies on melanoma cell lines. Enhancement ratio was found to be 22.33 in formulation F9 compared with control and other formulations. The values of steady state flux and permeability coefficient for formulation F9 were found to be 206.40 ± 14.56 µg cm−2 h−1 and 2.064 × 10−2 ± 0.050 × 10−2 cm h−1, respectively. Optimized formulation F9 was found to be physical stable. In vitro cytotoxicity studies on SK-MEL-5 cancer cells indicated that 5-FU in optimized nanoemulsion is much more efficacious than free 5-FU. From these results, it can be concluded that the developed nanoemulsion might be a promising vehicle for chemoprevention of skin cancer. [ABSTRACT FROM AUTHOR]

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article. [ABSTRACT FROM AUTHOR]

There is lot of confusion in the literatures regarding the method of production of nanoemulsion. According to some authors, only the methods using high energy like high-pressure microfluidizer or high-frequency ultra-sonic devices can produce actual nanoemulsions. In contrast to this concept, one research group reported for the first time the preparation of nanoemulsion by a low-energy method. Later on many authors reported about the low-energy emulsification method. The purpose of this work is to formulate, evaluate and compare nanoemulsions prepared using high-energy as well as low-energy method. Nanoemulsions formulated were based on the phase inversion composition technique (low energy method) and were selected from the ternary phase diagram based on the criterion of their being a minimum concentration of Smix used in the formulation. For high-pressure homogenization method (high energy method) Design-Expert software was used, and the desirability function was probed to acquire an optimized formulation. No significant difference ( p > 0.05) was observed in the globule size of formulations made by each method, but the value of poly-dispersibility index between the two methods was found to be extremely significant ( p < 0.001). A very significant difference ( p < 0.001) was observed in the drug release from formulations made by each method. More than 60% of the drug was released from all the formulations in the initial 2 h of the dissolution study. [ABSTRACT FROM AUTHOR]

Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50 nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher ( p < 0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC0-24) of NRG from SNEDDS formulation revealed a significant increase ( p < 0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS. [ABSTRACT FROM AUTHOR]

Polyphenolic bioflavonoid, Rutin possesses wide range of pharmacological activities. However, it shows poor bioavailability when administered orally. The aim of this study was to formulate and compare the potential of nanoemulsions for the solubility enhancement of rutin (RU) by using different techniques. RU-loaded nanoemulsions were prepared by spontaneous emulsification method and high-pressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 andtranscutol P as oil phase, surfactant and co-surfactant, respectively. The prepared formulations were compared for various parameters like droplet size, percentage transmittance, zeta potential, viscosity, refractive index and in vitro release. The HPH nanoemulsions showed smaller droplet size and increased in vitro release when compared to nanoemulsions prepared by spontaneous emulsification method. The optimized formulation showed spherical globules with average globule diameter of 18 nm and zeta potential of −41 mV. Cumulative percentage drug released obtained for RU, PF6 (spontaneous emulsification formulation F6) and HF6 (HPH formulation F6) were 41.5 ± 0.04%, 49.5 ± 0.06% and 94.8 ± 0.03%, respectively, after 6 h. The permeability of RU from HF6 was found to be ≈4.6 times higher than RU suspension during ex vivo everted gut sac studies. Antioxidant activity was determined by using DPPH assay and reducing power assay method. Results showed a high scavenging efficiency toward DPPH radicals by HF6. Anti-inflammatory effect of RU as determined by carrageenan-induced rat paw edema method was found to be higher (75.2 ± 4.8%) when compared to RU suspension (46.56 ± 3.5%). It can be inferred that TPGS-loaded nanoemulsion of RU serve as an effective tool in increasing solubility and permeability of RU. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop self-emulsifying drug delivery system (SEDDS) to improve solubility and enhance the oral absorption of the poorly water-soluble drug, nevirapine. This lipid-based formulation may help to target the drug to lymphoid organs where HIV-1 virus resides mainly. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SEDDS were investigated in detail. Two SEDDS (F1 and F2) were prepared and characterized by morphological observation, droplet size and zeta potential determination, cloud point measurement and in vitro diffusion study. The influence of droplet size on the absorption from formulations with varying concentration of oil and surfactant was also evaluated from two self-emulsifying formulations. Oral bioavailability of nevirapine SEDDS was checked by using rat model. Results of diffusion rate and oral bioavailability of nevirapine SEDDS were compared with marketed suspension. The absorption of nevirapine from F1 and F2 showed 1.92 and 1.98-fold increase ( p < 0.05) in relative bioavailability, respectively, compared with that of the suspension. There was no statistical significant difference ( p < 0.05) between F1 and F2 in their AUC and Cmax. This indicated that there was apparent poor correlation between the droplet size and in vivo absorption. However, nevirapine in SEDDS showed higher ex vivo stomach and intestinal permeability and in vivo absorption than the marketed suspension, suggesting that the SEDDS may be a useful delivery system for targeting nevirapine to lymphoid organs. [ABSTRACT FROM AUTHOR]

The aim of this research was to increase the oral bioavailability of puerarin by N-trimethyl chitosan-modified microemulsions (TMC-MEs) loaded with puerarin. Different concentrations of TMC-modified microemulsions were prepared in our study, and then evaluated for particle size, zeta potential, morphological observation and changes of the microenvironment polarity of inner oil core. It was shown that the zeta potential of the microemulsion was increased with the increasing concentration of TMC, and the peak value was achieved when the concentration of TMC was 3.0 mg/mL. The enhancement of the ratio of I1/ I3 (the ratio between the first band and the third band of the emission fluorescence spectrum of pyrene, I1 = 373 nm, I3 = 384 nm) indicated that polarity of the inner core of TMC-MEs was increased with the addition of the modifier. Pharmacokinetic studies demonstrated that after oral administration of puerarin N-trimethyl chitosan (TMC)-modified microemulsions (PUE-TMEs) and puerarin microemulsions (PUE-MEs) to rats at a dose of 100 mg/kg, relative bioavailability was enhanced about 6.8- and 1.2-fold, respectively, compared to puerarin suspension (PUE-SUS) as control. It indicated that the TMC-MEs could be used as an effective formulation for enhancing the oral bioavailability of puerarin. [ABSTRACT FROM AUTHOR]

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir-hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir-hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30 min with greater dissolution efficiency (90.05 ± 2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ∼160%; p < 0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses. [ABSTRACT FROM AUTHOR]

The aims of the present study were to prepare new dual-mode floating gastroretentive tablets (DF-GRT) containing itraconazole (ITR) and to evaluate influence of the dosage forms on pharmacokinetic parameters of ITR. The solubility of ITR was enhanced around 200 times (from 1.54 to 248.38 µg/mL) by preparing solid dispersion (SD) with hydroxypropylmethyl cellulose. Buoyancy of DF-GRT containing ITR-SD was established by both camphor sublimation and gas generation. Camphor sublimation decreased density of DF-GRT by making pores in tablet matrix, which led to elimination of lag time for floating. Carbon dioxide generated by sodium bicarbonate and citric acid helped to maintain buoyancy of DF-GRT. Therefore DF-GRT floated on the medium without lag time until disintegrated entirely during in vitro release study. They released 89.11% of the drug at 2 h. Residual camphor was <0.5 wt% after sublimation. The pharmacokinetics of DF-GRT was evaluated in six miniature pigs and compared to immediate release tablets (IRT). Mean AUC ratio of GRT/IRT was 1.36 but there was no statistical difference between AUC values. However delayed tmax, increased MRT and equivalent Cmax of DF-GRT supposed it could be a promising tool for gastroretentive drug delivery system containing ITR. [ABSTRACT FROM AUTHOR]

The aim of the present study was to formulate and evaluate buccoadhesive gels of model drug, glibenclamide indented as an alternate route of drug delivery to have enhanced bioavailability. The buccoadhesive gels were prepared by solution polymerization technique containing Hydroxy Propyl Methyl Cellulose (HPMC, E15 LV) and Carbopol (CP, 934P). An apparatus, simulating the in-vivo conditions of the mouth was designed in order to assess in-vitro release kinetics of the prepared gels. The gels were also evaluated for buccoadhesive strength, hydration, and swelling index, and viscosity. In-vivo evaluation for pharmacodynamic and pharmacokinetic properties of the optimized gel was done in rabbits. The drug release of buccoadhesive gels through rabbit buccal mucosa increased significantly ( p < 0.05) by the use of penetration enhancers. The release kinetics followed Higuchi model with release mechanism being Fickian diffusion. In-vivo results of the optimized gel (2% CP: 2% HPMC) revealed that the gel successfully prevented severe hypoglycemia, showed sustained action, and enhanced relative bioavailability with and without penetration enhancers as compared to the marketed formulation. The buccoadhesive gels could possibly be a means for alternative dosage form in avoiding first pass metabolism and ensuring enhanced bioavailability for glibenclamide. [ABSTRACT FROM AUTHOR]

This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by 1H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three differents approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300°C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential complexing agents for hydrophobic drugs and, in particular, for fenretinide, to increase drug solubility, bioavailability, and thus therapeutic efficacy. [ABSTRACT FROM AUTHOR]

To investigate the effect of RMP-7 and its derivative on drug transport across blood brain barrier (BBB), RMP-7 and DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)]-hydroxy succinamide, PEG M 3400] were conjugated under mild conditions and the reaction ratio was determined using MALDI–TOF-MS (matrix-assisted laser desorption-ionization time-of-flight mass spectrometry). An endothelial cell monolayer in vitro BBB model was established and used to determine the bioactivity of RMP-7 and its derivative“opening BBB.”Horse radish peroxide (HRP), liposome (HRP-L-PEG), and Evens blue (EB) liposome (EB-L-PEG) were prepared using the reverse-phase evaporation method. HRP-L-PEG-RMP-7 and EB-L-PEG-RMP-7 were obtained by inserting DSPE-PEG-RMP-7 into the surface of liposome. The bioactivity of RMP-7 and DSPE-PEG-RMP-7 opening BBB were evaluated to determine their effect on the permeation ratio of HRP and HRP liposome across the in vitro BBB model. To evaluate the in vivo bioactivity of RMP-7 and DSPE-PEG-RMP-7 on EB transport across BBB into the brain, the indicated compounds were administered to rats. Then, brain slices were analyzed using confocal laser scanning microcopy and the EB concentration in the brain, liver, spleen, lung, and kidney was determined using the formamide–extraction–ultraviolet-spectrophotometric method. The results demonstrated that RMP-7 was conjugated with DSPE-PEG-NHS at the molecular ratio of 1:1 and the product is DSPE-PEG-RMP-7. Compared with adding HRP alone, RMP-7 and DSPE-PEG-RMP-7 improved 2- to 3-fold the transport of HRP in the in vitro BBB model. The in vivo experiments showed that DSPE-PEG-RMP-7 was better at facilitating EB transport into brain than RMP-7. The reason may be that DSPE-PEG-RMP-7 can“open BBB”as soon as the EB-L-PEG-RMP-7 reaches BBB. [ABSTRACT FROM AUTHOR]

The influence of ultrasound on percutaneous absorption of ketorolac tromethamine was studied in vitro across rat skin. Sonication was carried out with a continuous mode, at an intensity of 1-3 W/cm 2 and a frequency of 1 MHz for 30 min. A significant increase in permeation of ketorolac through rat skin was observed with the applied sonication at 3 W/cm 2 when compared with permeation at 1 and 2 W/cm 2 . Enhanced ketorolac penetration at 3 W/cm 2 can be explained by the mechanical and/or thermal action of ultrasound waves. The distance of the ultrasound probe from the skin surface did not influence the flux of the drug. Pretreatment of skin by 5% d-limonene in ethanol for 2 hr followed by sonication at 3 W/cm 2 (30 min) significantly enhanced the permeation of ketorolac when compared with passive flux with or without enhancer pretreatment. [ABSTRACT FROM AUTHOR]

The aim of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2% w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing 4% w/w of limonene as a penetration enhancer. The permeability flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer (9 to 28%). The effect of pressure-sensitive adhesives such as TACKWHITE A 4MED® on the permeability of nimodipine through EVA membrane 2825 (28% w/w vinyl acetate) or membrane/rat skin composite also was studied. The permeability flux of nimodipine from the chosen EVA 2825 (with 28% vinyl acetate content) was 159.72 ± 1.96 μg/cm 2 /hr, and this flux further decreased to 141.85 ± 1.54 μg/cm 2 /hr on application of pressure-sensitive adhesive (TACKWHITE A 4MED®). However, the transdermal permeability flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED®/rat skin composite was found to be 126.59 ± 2.72 μg/cm 2 /hr, which is 1.3-fold greater than the required flux. Thus, a new transdermal therapeutic system for nimodipine was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED® and 2% w/w HPMC gel as reservoir containing 4% w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nimodipine, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 20 hr with improved bioavailability in comparison with the immediate release tablet dosage form. [ABSTRACT FROM AUTHOR]

Liposomes are colloidal carriers that form when certain (phospho)lipid molecules are hydrated in an aqueous media with some energy input. The ideal liposome formulation with optimum stability will improve drug delivery by decreasing the required dose and increasing the efficacy of the entrapped drug at the target organ or tissue. The most important parameter of interest in this article was to compare the efficacy of three different liposomes formulated with DSPC, DMPC, and DPPC, all saturated neutral phospholipids with different acyl chain lengths and transition temperatures. DMPC has a phase transition temperature (Tc) below 37°C, whereas the other two phospholipids possess Tcs above the physiological temperature. These lipids were then added to a cholesterol concentration of 21% to optimize the stability of the vesicles. The liposomes were prepared by a sonication and incubated in phosphate buffered saline (PBS) at 4°C and 37°C. The encapsulation efficiency, initial size, and drug retention of the vesicles were tested over a 48-hr period employing radiolabeled inulin as a model drug. The phase transition temperature of liposomes, which depends on the Tc of the constituent lipids, was an important factor in liposome stability. Of all the liposomes tested, the greatest encapsulation efficiency was found for the DSPC liposomes (2.95%) that also had the greatest drug retention over 48 hr at both 4°C (87.1 ± 6.8%) and 37°C (85.2 ± 10.1%), none of these values being significantly different from time zero. The lowest drug retention was found for DMPC liposomes for which a significant difference in drug retention was seen after only 15 min at both 4°C (47.3 ± 6.9%) and 37°C (53.8 ± 4.3%). The DPPC liposomes showed a significant difference in drug retention after 3 hr at 4°C (62.1 ± 8.2%) and after 24 hr at 37°C (60.8 ± 8.9%). Following the initial drop at certain time intervals a plateau was reached for all of the liposome formulations after which no significant difference in drug retention was observed. In conclusion, liposomes with higher transition temperatures appear to be more stable in PBS either at 4°C or 37°C, indicating that the increase in acyl chain length (and therefore transition temperature) is directly proportional to stability. [ABSTRACT FROM AUTHOR]

Drug release from hydrophilic matrix tablets can be strongly influenced by the proportion of matrix forming polymer and the dimensions and geometry of the tablets. A complete two-factor, three-level factorial design, followed by multiple regression analysis and response surface methodology, was applied to investigate the influence of polymer level and tablet size on drug release kinetics from hydrophilic matrix tablets prepared with Carbopol 971P and Carbopol 71G. Tablet diameter, radius-to-height ratio, tablet surface area, and surface-area-to-volume ratio were evaluated as independent variables in terms of their applicability to characterize tablet size and geometry. The results indicate that it may be possible to control the rate of drug release by modifying the proportion of carbomer in tablets and tablet dimensions. The practical benefit of these simulations is to optimize the geometry and dimensions of a controlled release device and reduce the number of experiments involved in the development of new controlled release dosage forms. [ABSTRACT FROM AUTHOR]

The significance of monitoring transepithelial electrical resistance (TEER) value during the study on drug absorption through Caco-2 monolayers in Transwells was re-evaluated. TEER value was monitored before, during, and after the absorption of Streptokinase (45 KD). Four enhancers--disodium ethylenediaminetetracetate (disodium EDTA), sodium cholate (NaC), sodium taurocholate (NaTC), and sodium caprate along with α-hemolysin (a cell membrane pore-forming toxin)--were used to signify the outcome of this study. Modified trypan blue exclusion technique was used to examine the Caco-2 cell viability throughout the absorption studies. The enhancers at the used concentration exhibited toxic effect on the Caco-2 cells as evident from the trypan blue exclusion studies. This toxic effect was not reflected by the TEER profile because TEER value dropped after the addition of the absorption enhancers. But it came back to its initial value after the cell culture media was replaced by enhancer-free media. This toxic effect was confirmed by the antiproliferation studies on the four enhancers and α-hemolysin against Caco-2 cells. Therefore, we concluded that the measurement of TEER is not a reliable method to determine the absorption enhancers toxicity or integrity of the Caco-2 monolayers in the Transwells. [ABSTRACT FROM AUTHOR]