Showing papers in "Aaps Pharmscitech in 2017"
TL;DR: It is concluded from the outcomes of the investigational works that such composite can be considered as a tissue engineered construct for skin wound healing.
Abstract: In this study, biodegradable poly(e-caprolactone) (PCL) nanofibers (PCL-NF), collagen-coated PCL nanofibers (Col-c-PCL), and titanium dioxide-incorporated PCL (TiO2-i-PCL) nanofibers were prepared by electrospinning technique to study the surface and structural compatibility of these scaffolds for skin tisuue engineering. Collagen coating over the PCL nanofibers was done by electrospinning process. Morphology of PCL nanofibers in electrospinning was investigated at different voltages and at different concentrations of PCL. The morphology, interaction between different materials, surface property, and presence of TiO2 were studied by scanning electron microscopy (SEM), Fourier transform IR spectroscopy (FTIR), contact angle measurement, energy dispersion X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS). MTT assay and cell adhesion study were done to check biocompatibilty of these scaffolds. SEM study confirmed the formation of nanofibers without beads. FTIR proved presence of collagen on PCL scaffold, and contact angle study showed increment of hydrophilicity of Col-c-PCL and TiO2-i-PCL due to collagen coating and incorporation of TiO2, respectively. EDX and XPS studies revealed distribution of entrapped TiO2 at molecular level. MTT assay and cell adhesion study using L929 fibroblast cell line proved viability of cells with attachment of fibroblasts over the scaffold. Thus, in a nutshell, we can conclude from the outcomes of our investigational works that such composite can be considered as a tissue engineered construct for skin wound healing.
139 citations
TL;DR: It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity.
Abstract: Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2–4% w/v and 0–40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 μg cm−2 drug retention in the skin, 44.312 μg cm−2 h−1 drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.
113 citations
TL;DR: It is indicated that the liposomal formulation significantly improved the solubility and oral bioavailability of naringenin, thus leading to wider clinical applications, and isopropyl myristate was very predominant in the liver.
Abstract: This study was aimed at preparing orally administered naringenin-loaded liposome for pharmacokinetic and tissue distribution studies in animal models. The liposomal system, consisting of phospholipid, cholesterol, sodium cholate, and isopropyl myristate, was prepared using the thin-film hydration method. Physicochemical characterization of naringenin-loaded liposome such as particle size, zeta potential, and encapsulation efficiency produced 70.53 ± 1.71 nm, -37.4 ± 7.3 mV, and 72.2 ± 0.8%, respectively. The in vitro release profile of naringenin from the formulation in three different media (HCl solution, pH 1.2; acetate buffer solution, pH 4.5; phosphate buffer solution, pH 6.8) was significantly higher than the free drug. The in vivo studies also revealed an increase in AUC of the naringenin-loaded liposome from 16648.48 to 223754.0 ng·mL-1 h as compared with the free naringenin. Thus, approximately 13.44-fold increase in relative bioavailability was observed in mice after oral administration. The tissue distribution further showed that the formulation was very predominant in the liver. These findings therefore indicated that the liposomal formulation significantly improved the solubility and oral bioavailability of naringenin, thus leading to wider clinical applications.
105 citations
TL;DR: The buccal epithelium is a promising route for biologics administration, which is reflected in clinical trials currently in progress, looking forward to register and commercialize the first biologic product formulated as a buCCal film.
Abstract: The main route of administration for drug products is the oral route, yet biologics are initially developed as injectables due to their limited stability through the gastrointestinal tract and solubility issues. In order to avoid injections, a myriad of investigations on alternative administration routes that can bypass enzymatic degradation and the first-pass effect are found in the literature. As an alternative site for biologics absorption, the buccal route presents with a number of advantages. The buccal mucosa is a barrier, providing protection to underlying tissue, but is more permeable than other alternative routes such as the skin. Buccal films are polymeric matrices designed to be mucoadhesive properties and usually formulated with permeability enhancers to improve bioavailability. Conventionally, buccal films for biologics are manufactured by solvent casting, yet recent developments have shown the potential of hot melt extrusion, and most recently ink jet printing as promising strategies. This review aims at depicting the field of biologics-loaded mucoadhesive films as buccal drug delivery systems. In light of the literature available, the buccal epithelium is a promising route for biologics administration, which is reflected in clinical trials currently in progress, looking forward to register and commercialize the first biologic product formulated as a buccal film.
86 citations
TL;DR: The stability studies indicated that all CUR-loaded micelles were stable for at least 90 days, and the colon targeted, pH-sensitive NSCS micells may have potential to be a prospective candidate for curcumin delivery to the colon.
Abstract: pH-sensitive N-naphthyl-N,O-succinyl chitosan (NSCS) and N-octyl-N,O-succinyl chitosan (OSCS) polymeric micelles carriers have been developed to incorporate curcumin (CUR) for colon-targeted drug delivery. The physical entrapment methods (dialysis, cosolvent evaporation, dropping, and O/W emulsion) were applied. The CUR-loaded micelles prepared by the dialysis method presented the highest loading capacity. Increasing initial amount of CUR from 5 to 40 wt% to polymer resulted in the increase in loading capacity of the polymeric micelles. Among the hydrophobic cores, there were no significant differences in the loading capacity of CUR-loaded micelles. The particle sizes of all CUR-loaded micelles were in the range of 120–338 nm. The morphology of the micelles changed after being contacted with medium with different pH values, confirming the pH-responsive properties of the micelles. The release characteristics of curcumin from all CUR-loaded micelles were pH-dependent. The percent cumulative release of curcumin from all CUR-loaded micelles in simulated gastric fluid (SGF) was limited to about 20%. However, the release amount was significantly increased after contacted with simulated intestinal fluid (SIF) (50–55%) and simulated colonic fluid (SCF) (60–70%). The released amount in SIF and SCF was significantly greater than the release of CUR from CUR powder. CUR-loaded NSCS exhibited the highest anti-cancer activity against HT-29 colorectal cancer cells. The stability studies indicated that all CUR-loaded micelles were stable for at least 90 days. Therefore, the colon targeted, pH-sensitive NSCS micelles may have potential to be a prospective candidate for curcumin delivery to the colon.
76 citations
TL;DR: Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and production scale, as well as important differences between the two most common types of temperature-measuring instruments.
Abstract: Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and production scale. With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature-measuring instruments—thermocouples and resistance temperature detectors (RTD). Two types of pressure transducers are discussed—thermal conductivity-type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity-type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed. Developing technology for process monitoring worthy of further investigation is also briefly reviewed, including wireless product temperature monitoring, tunable diode laser absorption spectroscopy at manufacturing scale, heat flux measurement, and mass spectrometry as process monitoring tools.
72 citations
TL;DR: The state of the art, the crucial aspects which should be taken into account, and the still-open questions, in order to make 3D printing a suitable manufacturing route for pediatric drugs are discussed.
Abstract: The first medicine manufactured by three-dimensional (3D) printing was recently approved by the Food and Drug Administration (FDA). The advantages of printing as a manufacturing route enabling more flexibility regarding the dose, and enlarging individual treatment options, have been demonstrated. There is a particular need for flexible drug delivery solutions when it comes to children. Printing as a new pharmaceutical manufacturing technology brings manufacturing closer to the patient and can easily be adjusted to the required dosing scheme, offering more flexibility for treatments. Printing of medicine may therefore become the manufacturing route of choice to provide tailored and potentially on-demand treatments for patients with individual needs. This paper intends to summarize and discuss the state of the art, the crucial aspects which should be taken into account, and the still-open questions, in order to make 3D printing a suitable manufacturing route for pediatric drugs.
69 citations
TL;DR: It is suggested that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.
Abstract: Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of −6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8∼39.7 to 21.4∼32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.
68 citations
TL;DR: Inorganic materials, especially those possessing significant porosity, are emerging as good candidates for the delivery of a range of drugs, providing several advantages in formulation and engineering and their utilisation in drug dosage form development is discussed.
Abstract: Innovative methods and materials have been developed to overcome limitations associated with current drug delivery systems. Significant developments have led to the use of a variety of materials (as excipients) such as inorganic and metallic structures, marking a transition from conventional polymers. Inorganic materials, especially those possessing significant porosity, are emerging as good candidates for the delivery of a range of drugs (antibiotics, anticancer and anti-inflammatories), providing several advantages in formulation and engineering (encapsulation of drug in amorphous form, controlled delivery and improved targeting). This review focuses on key selected developments in porous drug delivery systems. The review provides a short broad overview of porous polymeric materials for drug delivery before focusing on porous inorganic materials (e.g. Santa Barbara Amorphous (SBA) and Mobil Composition of Matter (MCM)) and their utilisation in drug dosage form development. Methods for their preparation and drug loading thereafter are detailed. Several examples of porous inorganic materials, drugs used and outcomes are discussed providing the reader with an understanding of advances in the field and realistic opportunities.
67 citations
TL;DR: Various aspects related to pharmacy preparations, clinical application, and preparation of ODFs for pediatric patients are highlighted and discussed.
Abstract: Children frequently receive medicines that are designed for adults. The dose of commercially available products is adapted, mostly based on the child's bodyweight, thereby neglecting differences in pharmacokinetic and pharmacodynamics parameters. If commercial products are unsuitable for administration to children or are unavailable, extemporaneous pharmacy preparations are a good alternative. For this particular population, orodispersible films (ODFs) can be a highly attractive dosage form for the oral administration of drugs. ODFs are relatively easy to prepare in a hospital setting, create dose flexibility, and may suit an individual approach, especially for patients having difficulties in swallowing tablets or being fluid restricted. In this article, various aspects related to pharmacy preparations, clinical application, and preparation of ODFs for pediatric patients are highlighted and discussed.
67 citations
TL;DR: Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion and may be a promising strategy for brain-targeted delivery of quetiapine fumarate.
Abstract: To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter Tmax compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.
TL;DR: An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation, confirming that spanlastics exhibit promising results for the trans-ungual delivery of TBH.
Abstract: Treating a nail infection like onychomycosis is challenging as the human nail plate acts as a formidable barrier against all drug permeation. Available oral and topical treatments have several setbacks. Terbinafine hydrochloride (TBH), belonging to the allylamine class, is mainly used for treatment of onychomycosis. This study aims to formulate TBH in a nanobased spanlastic vesicular carrier that enables and enhances the drug delivery through the nail. The nanovesicles were formulated by ethanol injection method, using either Span® 60 or Span® 65, together with Tween 80 or sodium deoxycholate as an edge activator. A full factorial design was implemented to study the effect of different formulation and process variables on the prepared TBH-loaded spanlastic nanovesicles. TBH entrapment efficiency percentages, particle size diameter, percentage drug released after 2 h and 8 h were selected as dependent variables. Optimization was performed using Design-Expert® software to obtain an optimized formulation with high entrapment efficiency (62.35 ± 8.91%), average particle size of 438.45 ± 70.5 nm, and 29.57 ± 0.93 and 59.53 ± 1.73% TBH released after 2 and 8 h, respectively. The optimized formula was evaluated using differential scanning calorimetry and X-ray diffraction and was also morphologically examined using transmission electron microscopy. An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation. In conclusion, the results confirmed that spanlastics exhibit promising results for the trans-ungual delivery of TBH.
TL;DR: Development of these drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.
Abstract: The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.
TL;DR: Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of crystalline state to amorphous state, and FTIR study of SLNs showed no change in the spectrum of quERCetin, which indicates that the lipid and chitosan were not incompatible with quercets.
Abstract: The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion containing quercetin. SLN was prepared by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of crystalline state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amount was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amount. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distilled water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.
TL;DR: It is suggested that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis by finding them to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness.
Abstract: In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.
TL;DR: The study underlined the suitability of the HME process to obtain a solid dispersion of protein inside a polymeric matrix providing sustained protein release, however, the incomplete protein release and the impact by storage conditions require thorough characterization and understanding of erosion and release mechanisms.
Abstract: The design of biodegradable implants for sustained release of proteins is a complex challenge optimizing protein polymer interaction in combination with a mini-scale process which is predictive for production The process of hot melt extrusion (HME) was therefore conducted on 5- and 9-mm mini-scale twin screw extruders Poly(lactic-co-glycolic acid) (PLGA) implants were characterized for their erosion properties and the in vitro release of the embedded protein (bovine serum albumin, BSA) The release of acidic monomers as well as other parameters (pH value, mass loss) during 16 weeks indicated a delayed onset of matrix erosion in week 3 BSA-loaded implants released 170% glycolic and 59% lactic acid after a 2-week lag time Following a low burst release (37% BSA), sustained protein release started in week 4 Storage under stress conditions (30°C, 75% rH) revealed a shift of erosion onset of 1 week (BSA-loaded implants: 269% glycolic and 93% lactic acid) Coherent with the changed erosion profiles, an influence on the protein release was observed Confocal laser scanning and Raman microscopy showed a homogenous protein distribution throughout the matrix after extrusion and during release studies Raman spectra indicated a conformational change of the protein structure which could be one reason for incomplete protein release The study underlined the suitability of the HME process to obtain a solid dispersion of protein inside a polymeric matrix providing sustained protein release However, the incomplete protein release and the impact by storage conditions require thorough characterization and understanding of erosion and release mechanisms
TL;DR: The challenges and achievements of the European Union to realize “better” medicines for children are described, with a focus on paediatric drug development and formulation design.
Abstract: The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.
TL;DR: Overall results confirmed nanosuspensions as promising approach for NRG delivery with high absorption in gastrointestinal tract, improved dissolution and oral bioavailability.
Abstract: The clinical potential of naringenin (NRG) is compromised due to its poor aqueous solubility and low oral bioavailability The study is aimed at addressing these issues by means of naringenin nanosuspensions (NRG-NS) formulated using polyvinylpyrrolidone (PVP K-90) as stabiliser via antisolvent sonoprecipitation method Optimisation of sonication time, drug concentration and stabilisers was done based on particle size Characterisation of pure NRG and NRG-NS was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), x-ray powder diffractometry (XRD) and Fourier transform infrared spectroscopy (FTIR) In vitro dissolution, intestinal absorption by non-everted rat intestinal sac model and in situ single pass intestinal perfusion techniques were performed for further investigation Nanosuspensions prepared using PVP K-90 lead to minimum particle size (117 ± 5 nm) with zeta potential of -146 ± 56 mV The particle size was affected by increasing sonication time, concentration of stabiliser and drug Nanosizing process converted the crystalline drug into amorphous form as predicted from DSC and XRD patterns FTIR demonstrated the formation of hydrogen bonds between drug and polymer NRG-NS displayed a higher dissolution amount (91 ± 44% during 60 min) compared to NRG powder (42 ± 041%) The apparent and effective permeability of NRG-NS was increased as compared to the pure NRG The in vivo pharmacokinetics demonstrated that the C max and AUC0-24 h values of NRG-NS were approximately 2- and 18-fold superior than the pure drug Hence, overall results confirmed nanosuspensions as promising approach for NRG delivery with high absorption in gastrointestinal tract, improved dissolution and oral bioavailability
TL;DR: In order to improve oral absorption of insulin, Eudragit S100® (ES)-coated chitosan nanoparticles loading insulin and a trans-activating transcriptional peptide (Tat) were employed as the vehicle and provided an exploratory means for the improvement of oral absorption.
Abstract: In order to improve oral absorption of insulin, especially the absorption at the colon, Eudragit S100® (ES)-coated chitosan nanoparticles loading insulin and a trans-activating transcriptional peptide (Tat) were employed as the vehicle. In vitro releases of insulin and Tat from ES-coated chitosan nanoparticles had a pH-dependant characteristic. A small amount of the contents was released from the coated nanoparticles at pH 1.2 simulated gastric fluid, while a fairly fast and complete release was observed in pH 7.4 medium. Caco-2 cell was used as the model of cellular transport and uptake studies. The results showed that the cellular transport and uptake of insulin for ES-coated chitosan nanoparticles co-loading insulin and Tat (ES-Tat-cNPs) were about 3-fold and 4-fold higher than those for the nanoparticles loading only insulin (ES-cNPs), respectively. The evaluations in vivo of ES-Tat-cNPs were conducted on diabetic rats and normal minipigs, respectively. The experimental results on rats revealed that the pharmacodynamical bioavailability of ES-Tat-cNPs had 2.16-fold increase compared with ES-cNPs. After oral administration of nanoparticle suspensions to the minipigs, insulin bioavailability of ES-Tat-cNPs was 1.73-fold higher than that of ES-cNPs, and the main absorption site of insulin was probably located in the colon for the two nanoparticles. In summary, this report provided an exploratory means for the improvement of oral absorption of insulin.
TL;DR: Both DSC and powder XRD studies indicated that curcumin as well as resveratrol were present in a non-crystalline state, in the nanoparticles, which indicated that the drug-loaded nanoparticles exhibit cytotoxic effects on DU145 cells.
Abstract: Curcumin and resveratrol are naturally occurring polyphenolic compounds having anti-cancer potential. However, their poor aqueous solubility and bioavailability limit their clinical use. Entrapment of hydrophobic drugs into hydrophilic nanoparticles such as calcium alginate presents a means to deliver these drugs to their target site. Curcumin and resveratrol-loaded calcium alginate nanoparticles were prepared by emulsification and cross-linking process. The nanoparticles were characterized for particle size, zeta potential, moisture content, physical state of the drugs, physical stability, and entrapment efficiency. An UPLC method was developed and validated for the simultaneous analysis of curcumin and resveratrol. Alginate nanoformulation was tested for in vitro efficacy on DU145 prostate cancer cells. The particle size of the nanosuspension and freeze-dried nanoparticles was found to be 12.53 ± 1.06 and 60.23 ± 15 nm, respectively. Both DSC and powder XRD studies indicated that curcumin as well as resveratrol were present in a non-crystalline state, in the nanoparticles. The entrapment efficiency for curcumin and resveratrol was found to be 49.3 ± 4.3 and 70.99 ± 6.1%, respectively. Resveratrol showed a higher percentage of release than curcumin (87.6 ± 7.9 versus 16.3 ± 3.1%) in 24 h. Curcumin was found to be taken up by the cells from solution as well as the nanoparticles. Resveratrol had a poor cellular uptake. The drug-loaded nanoparticles exhibit cytotoxic effects on DU145 cells. At high concentration, drug solution exhibited greater toxicity than nanoparticles. The alginate nanoformulation was found to be safe for intravenous administration.
TL;DR: The results obtained in this study can be useful for various applications in different fields, including pharmaceutical, cosmetics, and drug delivery in biomedical and tissue engineering.
Abstract: Niosomal vesicle, as a unique novel drug delivery system, is synthesized by non-ionic surfactants. Both hydrophilic and lipophilic drugs and also biomacromolecular agents, such as peptides and proteins can be encapsulated in this vesicular particle. Regarding polypeptide-based component loading, and delivery potential of the niosome, some valuable studies have been conducted in recent years. However, exploring the full potential of this approach requires fine tuned optimization and characterization approaches. Therefore, this study was conducted to achieve the following two goals. First, formulation and optimization of bovine serum albumin (BSA) load and release behavior as a function of cholesterol (CH) to sorbitan monostearate (Span 60) molar ratio. Second, investigating a cost- and time-effective polypeptide detecting method via methyl orange (MO) dye. To this aim, BSA-loaded niosomes were prepared by reversed-phase evaporation technique. The effect of CH to Sorbitan monostearate (Span 60) molar ratio on noisome entrapment efficiency (EE%) and release profile of BSA was studied using a ultraviolet (UV) spectrophotometer technique (NanoDrop 2000/2000c).Niosome with a 60% CH content showed the highest BSA EE% and release behavior. Then, BSA was dyed using MO in an acidic solution and used in BSA-niosome formulation. The MO-colored protein, loaded into the vesicles, was successfully assessed by an inverted light microscope, in order to observe the protein location in the vesicle. The results obtained in this study can be useful for various applications in different fields, including pharmaceutical, cosmetics, and drug delivery in biomedical and tissue engineering.
TL;DR: This review analyzes the impact of manufacturing methods on those properties of amorphous solid dispersions and describes the mechanism of Manufacturing methods and the thermodynamic theories that relate to amorphously formulations.
Abstract: The use of amorphous solid dispersions to improve the bioavailability of active ingredients from the BCS II and IV classifications continues to gain interest in the pharmaceutical industry. Over the last decade, methods for generating amorphous solid dispersions have been well established in commercially available products and in the literature. However, the amorphous solid dispersions manufactured by different technologies differ in many aspects, primarily chemical stability, physical stability, and performance, both in vitro and in vivo. This review analyzes the impact of manufacturing methods on those properties of amorphous solid dispersions. For example, the chemical stability of drugs and polymers can be influenced by differences in the level of thermal exposure during fusion-based and solvent-based processes. The physical stability of amorphous content varies according to the thermal history, particle morphology, and nucleation process of amorphous solid dispersions produced by different methods. The in vitro and in vivo performance of amorphous formulations are also affected by differences in particle morphology and in the molecular interactions caused by the manufacturing method. Additionally, we describe the mechanism of manufacturing methods and the thermodynamic theories that relate to amorphous formulations.
TL;DR: The properties of a mucoadhesive chitosan-pectinate nanoparticulate formulation able to retain its integrity in the milieu of the upper gastrointestinal tract and subsequently, mucoedhere and release curcumin in colon conditions strongly indicates that the system has the potential to be applied as a colon-targeted muco adhesionCurcumin delivery system for the possible treatment of colon cancer.
Abstract: In the present study, we report the properties of a mucoadhesive chitosan-pectinate nanoparticulate formulation able to retain its integrity in the milieu of the upper gastrointestinal tract and subsequently, mucoadhere and release curcumin in colon conditions. Using this system, we aimed to deliver curcumin to the colon for the possible management of colorectal cancer. The delivery system comprised of a chitosan-pectinate composite nanopolymeric with a z-average of 206.0 nm (±6.6 nm) and zeta potential of +32.8 mV (±0.5 mV) and encapsulation efficiency of 64%. The nanoparticles mucoadhesiveness was higher at alkaline pH compared to acidic pH. Furthermore, more than 80% release of curcumin was achieved in pectinase-enriched medium (pH 6.4) as opposed to negligible release in acidic and enzyme-restricted media at pH 6.8. SEM images of the nanoparticles after exposure to the various media indicate a retained matrix in acid media as opposed to a distorted/fragmented matrix in pectinase-enriched medium. The data strongly indicates that the system has the potential to be applied as a colon-targeted mucoadhesive curcumin delivery system for the possible treatment of colon cancer.
TL;DR: With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.
Abstract: Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.
TL;DR: The in vivo pharmacodynamic study suggested TM-GC-NPs had a better intraocular pressure (IOP) lowering efficacy and a prolonged working time compared to commercial TM eye drops (P ≤ 0.05) and the optimization could be prepared successfully promising their use as an ocular delivery system.
Abstract: This study was conducted to develop timolol maleate (TM)-loaded galactosylated chitosan (GC) nanoparticles (NPs) (TM-GC-NPs) followed by optimization via a four-level and three-factor Box-Behnken statistical experimental design. The optimized nanoparticles showed a particle size of 213.3 ± 6.83 nm with entrapment efficiency of 38.58 ± 1.31% and drug loading of 17.72 ± 0.28%. The NPs were characterized with respect to zeta potential, pH, surface morphology, and differential scanning calorimetry (DSC). The determination of the oil-water partition coefficient demonstrated that the TM-GC-NPs had a high liposolubility at pH 6 as compared to timolol-loaded chitosan nanoparticles (TM-CS-NPs) and commercial TM eye drops. The in vitro release study indicated that TM-GC-NPs had a sustained release effect compared with the commercial TM eye drops. Ocular tolerance was studied by the hen's egg chorioallantoic membrane (HET-CAM) assay and the formulation was non-irritant and could be used for ophthalmic drug delivery. The in vitro transcorneal permeation study and confocal microscopy showed enhanced penetration, and retention in the cornea was achieved with TM-GC-NPs compared with the TM-CS-NPs and TM eye drops. Preocular retention study indicated that the retention of TM-GC-NPs was significantly longer than that of TM eye drops. The in vivo pharmacodynamic study suggested TM-GC-NPs had a better intraocular pressure (IOP) lowering efficacy and a prolonged working time compared to commercial TM eye drops (P ≤ 0.05). The optimized TM-GC-NPs could be prepared successfully promising their use as an ocular delivery system.
TL;DR: The overall results support that PLGA nanoparticles, applied as a subconjunctival injection, can be considered as a promising carrier for ocular brinzolamide delivery with targeting delivery of the drug to the eye tissues.
Abstract: Nanoparticles fabricated from the biodegradable and biocompatible polymer, polylactic-co-glycolic acid (PLGA), could be a promising system for targeting ocular drug delivery. The objective of this work was to investigate the possibility of encapsulating brinzolamide in PLGA nanoparticles in order to be applied as a subconjunctival injection that could represent a starting point for developing new therapeutic strategies against increase in ocular pressure. The brinzolamide-loaded PLGA nanoparticles were fabricated using emulsion-diffusion-evaporation method with varying concentrations of Tween 80 or poloxamer 188 (Plx) in aqueous and organic phases. The nanoparticles were characterized in terms of particle size and size distribution, entrapment efficiency and in-vitro drug release pattern as well as DSC and X-ray analysis. Nanoparticles prepared using Tween 80 in the aqueous phase showed higher encapsulation efficiency and smaller particle size-values compared to those prepared using Plx. Furthermore, the addition of Plx 188 or Brij 97 to the organic phase in the formulation containing Tween 80 in the aqueous phase led to an increase in the particle diameter-values of the obtained nanoparticles. The nanoparticles had the capacity to release the brinzolamide in a biphasic release profile. The nanoparticles were spherical in shape and the drug was entraped in the nanoparticles in an amorphous form. Selected nanoparticles, injected subconjunctivally in normotensive Albino rabbits, were able to reduce the IOP for up to 10 days. Nanoparticles loaded with brinzolamide with lower particle size were able to reduce the IOP for longer period compared to those with higher particle size. Histopathological studies for the anterior cross sections of the rabbits’ eyes revealed that the tested nanoparticles were compatible with the ocular tissue. The overall results support that PLGA nanoparticles, applied as subconjunctival injection, can be considered as a promising carrier for ocular brinzolamide delivery with targeting delivery of the drug to the eye tissues.
TL;DR: This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler and demonstrated that co-suspension delivery technology overcomes well-known sources of variability in MDI drug delivery.
Abstract: To ensure consistency of clinical outcomes, orally inhaled therapies must exhibit consistent delivered dose and aerosol properties at the time of manufacturing, throughout storage, and during various patient-use conditions. Achieving consistency across these scenarios has presented a significant challenge, especially for combination products that contain more than one drug. This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI; Bevespi Aerosphere™). GFF MDI, a fixed-dose combination (FDC) of a long-acting muscarinic antagonist, glycopyrrolate (18 μg, equivalent to glycopyrronium 14.4 μg), and a long-acting β2-agonist, formoterol fumarate (9.6 μg; equivalent to formoterol fumarate dihydrate 10 μg), is formulated using innovative co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. In this study, delivered dose uniformity was assessed through the labeled number of doses, and aerosol properties, such as percent fine particle fraction (FPF) and mass median aerodynamic diameter, were determined by cascade impaction. GFF MDI achieved reproducible dose delivery and an FPF greater than 55%, whether formulated and delivered as a monocomponent or dual FDC. The performance of GFF MDI was maintained across various manufacturing batches, under extended storage, and with variations in flow rate. Furthermore, unlike a GFF drug crystal-only suspension, drug delivery remained consistent for GFF MDI when simulated patient-handling errors were applied, such as reduced shake energy and delays between shaking and actuation. These results demonstrate that co-suspension delivery technology overcomes well-known sources of variability in MDI drug delivery.
TL;DR: Solid-state analysis and pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of lor atadine.
Abstract: Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T
g
over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T
g
over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.
TL;DR: The in vitro skin permeation study showed that the essential oil-based microemulsions could enhance the permeation capacity of quercetin by 2.5–3 times compared to the aqueous solution.
Abstract: Quercetin can bring many benefits to skin based on its various bioactivities However, the therapeutic effect of quercetin is limited due to the poor water solubility, pH instability, light instability, and skin permeation The aim of the present work was applying essential oil-based microemulsions to improve the solubility, pH stability, photostability, and skin permeation of quercetin for topical application Peppermint oil (PO-ME), clove oil (CO-ME), and rosemary oil (RMO-ME) were selected as model essential oils Microemulsions composed of Cremophor EL/1,2-propanediol/essential oils (47:23:30, w/w) were selected as model formulations, based on the pseudo-ternary phase diagram and the characterizations In the solubility study, the solubility of quercetin was improved dozens of times by microemulsions Quercetin was found instable under alkaline condition, with 50% degraded in the solution of pH 13 However, PO-ME, CO-ME, and RMO-ME could protect quercetin from the hydroxide ions, with 47, 9, and 12% of quercetin degraded In the photostability study, the essential oil-based microemulsions showed the capability of protecting quercetin from degradation under UV radiation Where more than 67% of quercetin was degraded in aqueous solution, while less than 7% of quercetin degraded in microemulsions At last, the in vitro skin permeation study showed that the essential oil-based microemulsions could enhance the permeation capacity of quercetin by 25-3 times compared to the aqueous solution Hence, the prepared essential oil microemulsions could improve the solubility, pH stability, photostability, and skin permeation of quercetin, which will be beneficial for its topical application
TL;DR: The results suggest that the ODF measles vaccine formulation is a viable dosage form alternative to noninvasive immunization that may increase patient compliance and commercial distribution.
Abstract: The aim of this study is to develop an orally disintegrating film (ODF) containing a microparticulate measles vaccine formulation for buccal delivery. The measles vaccine microparticles were made with biocompatible and biodegradable bovine serum albumin (BSA) and processed by spray drying. These vaccine microparticles were incorporated in the ODF, consisting of Lycoat RS720®, Neosorb P60W® and Tween 80. The yield of the microparticles was approximately 85–95%, w/w. The mean size of the vaccine microparticles was 3.65 ± 1.89 μm and had a slightly negative surface charge of 32.65 ± 2.4 mV. The vaccine particles were nontoxic to normal cells at high concentrations (500 μg/2.5 × 105 cells) of vaccine particles. There was a significant induction of innate immune response by vaccine microparticles which was observed in vitro when compared to blank microparticles (P < 0.05). The vaccine microparticles also significantly increased the antigen presentation and co-stimulatory molecules expression on antigen presenting cells, which is a prerequisite for Th1 and Th2 immune responses. When the ODF vaccine formulation was dosed in juvenile pigs, significantly higher antibody titers were observed after week 2, with a significant increase at week 4 and plateauing through week 6 comparative to naive predose titers. The results suggest that the ODF measles vaccine formulation is a viable dosage form alternative to noninvasive immunization that may increase patient compliance and commercial distribution.