Green Synthesis of Zinc Oxide Nanoparticles from Althaea officinalis Flower Extract Coated with Chitosan for Potential Healing Effects on Diabetic Wounds by Inhibiting TNF-α and IL-6/IL-1ß Signaling Pathways.

Background: Diabetes Mellitus is a multisystem chronic pandemic, wound inflammation, and healing are still major issues for diabetic patients who may suffer from ulcers, gangrene, and other wounds from uncontrolled chronic hyperglycemia. Marshmallows or Althaea officinalis (A.O.) contain bioactive compounds such as flavonoids and phenolics that support wound healing via antioxidant, anti-inflammatory, and antibacterial properties. Our study aimed to develop a combination of eco-friendly formulations of green synthesis of ZnO-NPs by Althaea officinalis extract and further incorporate them into 2% chitosan (CS) gel. Method and Results: First, develop eco-friendly green Zinc Oxide Nanoparticles (ZnO-NPs) and incorporate them into a 2% chitosan (CS) gel. In-vitro study performed by UV-visible spectrum analysis showed a sharp peak at 390 nm, and Energy-dispersive X-ray (EDX) spectrometry showed a peak of zinc and oxygen. Besides, Fourier transforms infrared (FTIR) was used to qualitatively validate biosynthesized ZnO-NPs, and transmission electron microscope (TEM) showed spherical nanoparticles with mean sizes of 76 nm and Zeta potential +30mV. The antibacterial potential of A.O.-ZnO-NPs-Cs was examined by the diffusion agar method against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Based on the zone of inhibition and minimal inhibitory indices (MIC). In addition, an in-silico study investigated the binding affinity of A.O. major components to the expected biological targets that may aid wound healing. Althaea Officinalis, A.O-ZnO-NPs group showed reduced downregulation of IL-6, IL-1ß, and TNF-α and increased IL-10 levels compared to the control group signaling pathway expression levels confirming the improved anti-inflammatory effect of the self-assembly method. In-vivo study and histopathological analysis revealed the superiority of the nanoparticles in reducing signs of inflammation and wound incision in rat models. Conclusion: These biocompatible green zinc oxide nanoparticles, by using Althaea Officinalis chitosan gel ensure an excellent new therapeutic approach for quickening diabetic wound healing.

Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery of Cyclosporine and Dithranol: In-Vitro, Ex-Vivo, and in-Vivo Studies.

Purpose: Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential. Methods: Firstly, we developed a niosomal drug delivery system based on ceramide IIIB to form Cerosomes. Cerosomes were prepared from a mixture of Ceramide, hyaluronic acid, and edge activator using a thin-film hydration technique. To co-deliver CsA and DTH topically for the treatment of psoriasis. These two hydrophobic drugs encapsulated into our synthesized positively charged particle cerosomes. Results:  Cerosomes had an average particle size of (222.36 nm± 0.36), polydispersity index of (0.415±0.04), Entrapment Efficiency of (96.91%± 0.56), and zeta potential of (29.36±0.38mV) for selected formula. In vitro, In silico, in vivo, permeation, and histopathology experiments have shown that cerosomes enhanced the skin penetration of both hydrophobic drugs by 66.7% compared to the CsA/DTH solution. Imiquimod (IMQ) induced psoriatic mice model was topically treated with our CsA/DTH cerosomes. We found that our formulation enhances the skin penetration of both drugs and reduces psoriasis area and severity index (PASI score) by 2.73 times and 42.85%, respectively, compared to the CsA/DTH solution. Moreover, it reduces the levels of proinflammatory cytokines, TNF-α, IL-10, and IL-6 compared to CsA/DTH solution administration. Conclusion: The Cerosomes nano-vesicle-containing CsA/DTH represents a more promising topical treatment for psoriasis, giving new hope to individuals with psoriasis, compared to commercial and other conventional alternatives.

An empirical predictive model for determining the aqueous solubility of BCS class IV drugs in amorphous solid dispersions.

CONTEXT: Determining solubility of drugs is laborious and time-consuming process that may not yield meaningful results. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. OBJECTIVE: This study aimed to develop a predictive model to estimate the solubility of a compound from the ASDs in polymer matrices. METHODS: ASDs of model drugs (acetazolamide, chlorothiazide, furosemide, hydrochlorothiazide, sulfamethoxazole) with model polymers (PVP, PVPVA, HPMC E5, Soluplus) and a surfactant (TPGS) were prepared using hotmelt process. The prepared ASDs were characterized using DSC, FTIR, and XRD. The aqueous solubility of the model drugs was determined using shake-flask method. Multiple linear regression was used to develop a predictive model to determine aqueous solubility using the molecular descriptors of the drug and polymer as predictor variables. The model was validated using Leave-One-Out Cross-Validation. RESULTS: The ASDs' drug components were identified as amorphous via DSC and XRD Studies. There were no significant chemical interactions between the model drugs and the polymers based on FTIR studies. The ASDs showed a significant (p < 0.05) improvement in solubility, ranging from a 3-fold to 118-fold, compared with the pure drug. The developed empirical model predicted the solubility of the model drugs from the ASDs containing model polymer matrices with an accuracy greater than 80%. CONCLUSION: The developed empirical model demonstrated robustness and predicted the aqueous solubility of model drugs from the ASDs of model polymer matrices with an accuracy greater than 80%.

Evaluation of ceftriaxone pharmacokinetics in hospitalized Egyptian pediatric patients.

This study aimed to evaluate ceftriaxone pharmacokinetics that affects the achievement of targets in the treatment of critically ill children (meningitis, pneumonia, urinary tract infection, peritonitis, and infective endocarditis( who were admitted to Zagazig University Pediatric hospital in Egypt to monitor for the drug adverse effects.Blood samples were obtained from 24 hospitalized pediatric patients (ages ranging from 2.5 months to 12 years) after administering the calculated dose of ceftriaxone via intravenous bolus route. Then, ceftriaxone plasma concentrations were measured using a validated HPLC method with ultraviolet detection. The pharmacokinetic analysis was conducted using Phoenix Winnonlin Program® software.Data for total and free ceftriaxone best fitted on a one-compartment model with the first-order elimination process. Clearance of ceftriaxone is reduced for patients with reduced kidney function and increased with those with augmented renal clearance. The volume of distribution and the free fraction are increased in these patients, especially those with hypoalbuminemia with a shorter half-life time were detected. A slight increase in total bilirubin and liver enzymes has been observed after treatment with ceftriaxone in these patients.   Conclusion: In most critically ill pediatric patients, the current ceftriaxone treatment regimen (50 to 100 mg/kg) offers adequate pathogenic coverage. The clearance of free ceftriaxone in all patients correlates well with their renal function (eGFR), with r2 = 0.7252. During therapy with ceftriaxone at all doses ranging from 50 to 100 mg/kg, a rise in total bilirubin was observed in these patients. Moreover, liver enzymes (ALT and AST) increased moderately (p 0.0001). So, it is recommended to monitor total bilirubin and liver enzymes during the treatment with ceftriaxone, especially for a long duration (more than 5 days) or use another agent in patients with high baseline values. What is Known: • The dosing regimen of ceftriaxone (50 to 100 mg/kg) provided optimum therapeutic outcomes. • Some studies show data for total and free Ceftriaxone best fitted on a one-compartment model while other studies show data for total and free Ceftriaxone best fitted on a two-compartment model. What is New: • Up to my knowledge this is the first study ,considering individual pharmacokinetic analysis, conducted on hospitalized Egyptian pediatric population most of them with reduced kidney function with ages ranging from 2.5 months to 12 years. Data for total and free Ceftriaxone best fitted on a one-compartment model with linear clearance of the free ceftriaxone. • In all patients, total bilirubin and liver function tests were mildly increased, making them at risk for cholestasis or ceftriaxone-induced cholestatic hepatitis.

A comparative study on micelles, liposomes and solid lipid nanoparticles for paclitaxel delivery.

The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles, liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles, liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation, thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties, paclitaxel loading efficiency, in vitro release behavior, stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm), liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p < 0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy.

The deleterious effect of xylene-induced ear edema in rats: Protective role of dexketoprofen trometamol transdermal invasomes via inhibiting the oxidative stress/NF-κB/COX-2 pathway.

Pain and inflammation could have a negative impact on a patient's quality of life and performance, causing them to sleep less. Dexketoprofen trometamol (DKT) is a water-soluble, nonselective NSAIDs. Because DKT is quickly eliminated in the urine after oral delivery, its efficacy is limited and must be taken repeatedly throughout the day. The main ambition of this work is to develop and characterize the potential of invasomes to enhance the transdermal transport of DKT to achieve efficient anti-inflammatory and pain management. The optimum formulation (C1) showed the least %RE (53.29 ± 2.68 %), the highest %EE (86.51 ± 1.05 %), and spherical nanosized vesicles (211.9 ± 0.57 nm) with (PDI) of 0.353 ± 0.01 and (ZP) of -19.15 ± 2.45 mV. DKT flux and deposition in stratum corneum, epidermal, and dermal skin layers were significantly augmented by 2.6 and 3.51 folds, respectively, from the optimum invasomal gel formulation (C1-G) compared to DKT conventional gel (DKT-G). The anti-inflammatory activity of C1-G was evaluated using a model of xylene-induced ear edema in rats. Xylene exposure upregulated the ear expression of COX-2 level and MPO activity. Xylene also significantly increased the ear NF-κB p65, TNF-α, IL-Iß, and MDA levels. Furthermore, xylene induced oxidative stress, as evidenced by a significant decrease in ear GSH and serum TAC levels. These impacts were drastically improved by applying C1-G compared to rats that received DKT-G and plain invasomal gel formulation (plain C1-G). The histopathological findings imparted substantiation to the biochemical and molecular investigations. Thereby, C1-G could be a promising transdermal drug delivery system to improve the anti-inflammatory and pain management of DKT.

Fabrication of nanostructured lipid carriers ocugel for enhancing Loratadine used in treatment of COVID-19 related symptoms: statistical optimization, in-vitro, ex-vivo, and in-vivo studies evaluation.

Loratadine (LORA), is a topical antihistamine utilized in the treatment of ocular symptoms of COVID-19. The study aimed to develop a Loratadine Nanostructured Lipid Carriers Ocugel (LORA-NLCs Ocugel), enhance its solubility, trans-corneal penetrability, and bioavailability. full-factorial design was established with 24 trials to investigate the impact of several variables upon NLCs properties. LORA-NLCs were fabricated by using hot melt emulsification combined with high-speed stirring and ultrasonication methods. All obtained formulae were assessed in terms of percent of entrapment efficiency (EE%), size of the particle (PS), zeta potential (ZP), as well as in-vitro release. Via using Design Expert® software the optimum formula was selected, characterized using FTIR, Raman spectroscopy, and stability studies. Gel-based of optimized LORA-NLCs was prepared using 4% HPMC k100m which was further evaluated in terms of physicochemical properties, Ex-vivo, and In-vivo studies. The optimized LORA-NLCs, comprising Compritol 888 ATO®, Labrasol®, and Span® 60 showed EE% of 95.78 ± 0.67%, PS of 156.11 ± 0.54 nm, ZP of -40.10 ± 0.55 Mv, and Qh6% of 99.67 ± 1.09%, respectively. Additionally, it illustrated a spherical morphology and compatibility of LORA with other excipients. Consequently, gel-based on optimized LORA-NLCs showed pH (7.11 ± 0.52), drug content (98.62%± 1.31%), viscosity 2736 cp, and Q12% (90.49 ± 1.32%). LORA-NLCs and LORA-NLCs Ocugel exhibited higher ex-vivo trans-corneal penetrability compared with the aqueous drug dispersion. Confocal laser scanning showed valuable penetration of fluoro-labeled optimized formula and LORA-NLCs Ocugel through corneal. The optimized formula was subjected to an ocular irritation test (Draize Test) that showed the absence of any signs of inflammation in rabbits, and histological analysis showed no effect or damage to rabbit eyeballs. Cmax and the AUC0-24 were higher in LORA-NLCs Ocugel compared with pure Lora dispersion-loaded gel The research findings confirmed that NLCs could enhance solubility, trans-corneal penetrability, and the bioavailability of LORA.

Role of physicochemical properties of some grades of hydroxypropyl methylcellulose on in vitro mucoadhesion.

Relationships between physicochemical properties of hydroxypropyl methylcellulose (HPMC) compacts and their in vitro mucoadhesive performances were investigated in this study. Some commercial grades of HPMC (K3, E3, E5, E50, K4M, E4M and K15M) were prepared into compacts, and their surface hydrophilicity and hydration behavior were characterized. The in vitro mucoadhesive performance was determined by the tensile strength between the compacts and different regions of mucosal membrane (buccal, sublingual, stomach, and intestine). Positive correlations were found between: (1) viscosity of HPMC compacts and contact angle in different simulated body fluids; (2) viscosity of HPMC compacts and in vitro mucoadhesive force; (3) contact angle and in vitro mucoadhesive force. The hydration increased with an increase in viscosity of HPMC compacts. The polar lipid content in mucosa was found to be an important factor affecting the mucoadhesion. Lower polar lipid amount in the mucosal membrane promoted the rate of mucoadhesive force with the increasing viscosity of HPMC. The mucoadhesive mechanism of various grades of HPMC compacts were studied using the thermodynamic analysis of Lifschitz-van der Waals (LW) interaction and Lewis acid-base (AB) interactions. The total free energy of adhesion (ΔGTOT) provided a prediction of an overall tendency of mucoadhesion, and deviated from the measured mucoadhesive force.

Promising Swellable Floating Bupropion Tablets: Formulation, in vitro/in vivo Evaluation and Comparative Pharmacokinetic Study in Human Volunteers.

PURPOSE: Bupropion is an antidepressant drug that facilitates weight loss. It is a highly water-soluble drug that needs multiple dosing, so it is considered a potential candidate for oral controlled-release dosage form. The aim of this research was to formulate and evaluate satiety-inducing swellable floating bupropion tablets by direct compression targeting depression associated with eating disorders. Various combinations of natural and semi-synthetic hydrogels were selected to achieve maximum swelling and remaining buoyant in the stomach. This synergistically enhances weight loss by increasing satiety. METHODS: An I-optimal mixture design was conducted to establish the optimal quantitative composition of tablets. Friability, floating lag time, swelling index after 4 and 8 hours, along with the percent of bupropion released at 1 and 8 hours were selected as dependent variables. The optimized formulation was characterized by physicochemical properties, thermal stability, and chemical interaction. In vivo radiographic evaluation of gastric residence besides, the oral bioavailability relative to marketed Wellbutrin® sustained-release tablets were investigated using human volunteers. RESULTS: The optimized formulation (73.3 mg xanthan, 120 mg glucomannan, 8.4 mg tamarind kernel powder, 78.3 mg HPMC K15M) was achieved with the overall desirability equals 0.782. In vivo radiographic study showed that formulation was retained for >8 hours in the stomach. Compared with the marketed BUP tablets, the Cmax was almost the same with a significant increase (p =0.004) for Tmax. CONCLUSION: Using combinations of these hydrogels would be promising gastroretentive delivery systems in the control of bupropion rate release with enhanced floating and swelling features.

Design and preparation of nanostructures based on Krafft point of nonionic amphiphiles for delivery of poorly water-soluble compounds.

Micellar solubilization can effectively dissolve low water-soluble compounds in aqueous environment, however, the micellar systems are not able to withstand dilution and maintain solubilization of poorly water-soluble drugs below critical micelle concentration. To overcome the drawbacks of conventional micellar solubilization, nonionic polyoxyethylated surfactants with Krafft points at or higher than body temperature were chosen to create novel micelle-based nanostructures as a delivery vehicle for poorly water-soluble compounds. A technique "thermo-spray process" was developed for the preparation of the nanostructures-containing formulation, in which the drug-containing micelle solution was first prepared and maintained at the elevated temperature above the Krafft point of the surfactant, then spray dried to solidify the obtained micelle-like nanostructure at room temperature. Lactose was used as an excipient to embed the nanostructures in the thermo-spray products. Water insoluble spherical nanoparticles with size range from 80 to 250 nm were obtained after reconstitution of the product at the temperature lower than Krafft point. When paclitaxel was used as model drug, the micelle-like nanostructures exhibited similar drug entrapment efficiency, solubility enhancement and drug release facilitation as conventional micelles, but provided lower critical micellar concentration at body temperature, and good encapsulation stability upon storage and dilution. These findings indicated that the developed thermo-spray product can serve as a promising delivery platform for drugs with low aqueous solubility.

Formulation, Characterization and Comparative Pharmacokinetic Study of Bupropion Floating Raft System as a Promising Approach for Treating Depression.

The aim of this study was to formulate, evaluate, and compare satiety-enhancing floating raft system (FRS) of bupropion as gastroretentive drug delivery systems (GRDDS) using in-situ gelling pectin and alginate. Bupropion was considered as a good candidate for such systems due to high water solubility that requires frequent dosing. Pectin and alginate could prolong satiety sensation augmenting weight loss of bupropion. A 24 full factorial design was tailored to inspect the effect of the response variables (gel-forming polymer type, calcium carbonate percentage, glyceride lipid type and percentage). Gelation lag time, floating lag time, as well as drug released percent after 1 and 8 h were selected as dependent variables. The optimal system was investigated for compatibility and bioavailability study in healthy human volunteers relative to marketed Wellbutrin® sustained release tablets. The optimal FRS (3% alginate, 2% precirol®, and 2% CaCO3) was selected. This system had an optimum viscosity that will allow a rapid sol-gel transformation in the stomach, excellent floating behavior, and controlled release profile with a comparable bioavailability. The optimal FRS would be a novel liquid GRDDS in controlling bupropion rate release especially for depression associated with eating disorders or dysphagia improving patient compliance and drug efficacy.

Development, Implementation and Assessment of a Comprehensive Strategic Plan in a School of Pharmacy.

Objective. To develop, implement and assess a strategic plan and its process within a school of pharmacy. Methods. The process for developing the strategic plan included five phases: designing and scanning by a planning committee; divergent thinking with input from key internal and external stakeholders who shared their vision for the school; convergent planning in which faculty members helped to prioritize the clusters, goals, and metrics that had been identified; refining ideas into strategies; and assessment, during which metrics were aligned with assessment plans and data were collected and analyzed. Results. The completed strategic plan had five broad strategies, 20 specific goals, and 90 associated metrics. The plan was implemented with engagement by all major stakeholders in the program. Reallocation of existing resources and generation of new resources were key in making progress. The assessment, which was conducted three years after implementation of the strategic plan, found that each strategy had affected the school's mission to provide an exemplary educational experience for students and to advance the institution. Conclusion. The strategic plan provided direction and focus to meet the challenges of continuing to advance the school. The keys for success in strategic planning are having a well-defined process, involving all faculty members and other key stakeholders, implementing the plan, and routinely assessing progress in meeting the strategic goals.

A Rational Approach for Creating Peptides Mimicking Antibody Binding.

This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR. The designed peptide, Pep11, bound to EGFR with KD of 252 nM. Cytotoxicity of Monomethyl Auristatin E (MMAE)-EGFR-Pep11 peptide-drug conjugate was more than 2,000 fold higher against EGFR overexpressing cell lines A431, MDA MB 468 than control HEK 293 cells which lack EGFR overexpression. MMAE-EGFR-Pep11 conjugate also showed more than 90-fold lower cytotoxicity towards non-EGFR overexpressing HEK 293 cells when compared with cytotoxicity of MMAE itself. In conclusion, a method that can rationally design peptides using knob-socket model is presented. This method was successfully applied to create peptides based on the antigen-antibody interaction to mimic the specificity, affinity and functionality of antibody.

Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa.

Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of ß-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of ß-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility.

In Vitro and In Vivo Efficacy of Self-Assembling RGD Peptide Amphiphiles for Targeted Delivery of Paclitaxel.

PURPOSE: The objective of this work was to compare the efficacy of self-assembling cyclic and linear RGD peptide amphiphiles as carriers for delivering paclitaxel to αvß3 integrin overexpressing tumors. METHODS: Linear (C18-ADA5-RGD) and cyclic (C18-ADA5-cRGDfK) peptide amphiphiles were synthesized and characterized for CMC, aggregation number and micelle stability using fluorescence spectroscopy methods. Size and morphology of micelles was studied using TEM. Fluorescence polarization and confocal microscopy assays were established to compare binding and internalization of micelles. The targeting efficacy was studied in A2058 cells using cytotoxicity assay as well as in vivo in melanoma xenograft mouse model. RESULTS: The linear and cyclic RGD amphiphiles exhibited CMC of 25 and 8 µM, respectively, formed nano-sized spherical micelles and showed competitive binding to αvß3 integrin protein. FITC-loaded RGD micelles rapidly internalized into A2058 melanoma cells. Paclitaxel-loaded RGD micelles exhibited higher cytotoxicity compared with free drug in A2058 cells in vitro as well as in vivo. CONCLUSION: Cyclic RGD micelles exhibited better targeting efficacy but were less effective compared to linear RGD micelles as drug delivery vehicle due to lower drug solubilization capacity and lesser kinetic stability. Results from the study proved the effectiveness of self-assembling low molecular weight RGD amphiphiles as carriers for targeted delivery of paclitaxel.

Expression of P-glycoprotein and CYP3A4 along the porcine oral-gastrointestinal tract: implications on oral mucosal drug delivery.

OBJECTIVES: To characterize the expression of Pgp and CYP3A4 along the oral-gastrointestinal (GI) tract for understanding the potential roles of CY3A4 and Pgp in oral mucosal drug delivery. DESIGN: Porcine buccal mucosa, sublingual mucosa, esophagus and jejunum, ileum and colon tissues were used for studying the mRNA and protein expression of CYP3A4 and Pgp. mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and western blot, respectively. The expression levels of CYP3A4 and Pgp in different segments of oral-GI tract were compared. RESULTS: Levels of Pgp mRNA were significantly lower (14-40 times lower) in buccal and sublingual mucosa than that in intestine. In contrast, higher levels of CYP3A4 mRNA were observed in the oral mucosa as compared to that in intestine, but the difference was not statistically different. The levels of Pgp protein along the oral-GI tract followed the order: sublingual ∼buccal ∼esophagus < jejunum ∼ileum ∼ colon while the expression of CYP3A4 protein in the oral mucosa was similar to that in intestine. CONCLUSION: Expression of Pgp in oral mucosa is lower than that in intestine, while the expression of CYP3A4 in oral mucosa is similar to that in intestine. Because of lower Pgp in oral mucosa, oral mucosal drug delivery can be used as an alternative strategy to avoid the coordination of Pgp and CYP3A4 metabolism in drug absorption. However, CYP3A4-dependent metabolism may play a role in oral mucosal drug delivery as in per oral-GI absorption.

Binding and uptake of novel RGD micelles to the αvß3 integrin receptor for targeted drug delivery.

PURPOSE: To understand the binding and internalization of novel RGD micelles in tumor cells that overexpress the αvß3 integrin receptor. METHODS: Peptide amphiphiles containing a C16 or C18 fatty-acid chain with one or two ADA units linked to an RGD motif were prepared, characterized, and assessed for their binding specificity to the αvß3 receptor. The internalization of the amphiphiles was evaluated by confocal microscopy and cytotoxicity studies in A2058 cells that overexpress the αvß3 integrin receptor. RESULTS: The CMC and size and of RGD micelles ranged from 9 to 30 µM and 130 to 300 nm, respectively. Micelles showed good in vitro stability by retaining their micellar integrity and good specificity by binding to the αvß3 integrin receptor in an RGD-dependent manner. Confocal studies showed higher intracellular fluorescence when FITC was delivered through the micelles compared with its free form and showed significantly higher FITC uptake at 37 °C versus 4 °C (p < 0.05). The lower IC50 values were obtained when paclitaxel was delivered to A2058 cells via the RGD-loaded carriers (3.6-4.87 nM) compared with unencapsulated drug (7.86 nM), further demonstrated micelle specificity to the αvß3 receptor. CONCLUSION: RGD micelles bound specifically to the αvß3 receptor and their uptake was mediated by an endocytic process.

Comparison of nanomilling and coprecipitation on the enhancement of in vitro dissolution rate of poorly water-soluble model drug aripiprazole.

The aim of this study was to evaluate the effect of coprecipitation and nanomilling on the crystallinity of a model drug, aripiprazole and evaluate the in vitro dissolution rate (IDR). Aripiprazole compositions were prepared by physical mixing, coprecipitation and nanomilling using hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP) K17 and pluronic F127. The particle size, solubility, IDR and drug crystallinity were studied. Aripiprazole pluronic compositions were compressed into tablets and dissolution rate was evaluated. The particle size of nanomilled compositions was significantly smaller than that of the other compositions. The saturation solubility of aripiprazole from nanoparticle (NP) and coprecipitate (CP) from PVP and Pluronic was comparable, however, NP of HPC containing composition showed higher solubility when compared to its CP compositions. The crystallinity of aripiprazole decreased from physical mixtures to coprecipitates and further in NPs. The increased aripiprazole IDR was due to decreased crystallinity from coprecipitate compositions and disruption of crystallinity from nanomilled compositions. Aripiprazole tablets prepared from nanomilled powder dissolved >75% within 10 min compared with 17% and 20% for tablets prepared from physical mixture and coprecipitate powders, respectively. The increase in IDR due to nanomilling was more significant than coprecipitation and NPs retained the IDR after compression into tablets.

In silico model of drug permeability across sublingual mucosa.

The objective of this work was to develop an in silico model to predict the sublingual permeability of a drug based on physicochemical descriptors of a molecule. Fourteen model drugs with diverse physicochemical properties were selected for this study. Molecular volume, molecular weight, logP, logD (pH 6.8), pKa, total polar surface area, hydrogen bond acceptors and donors (HBD), number of rotatable bonds, solubility (pH 6.8), and melting point were used as molecular descriptors. Apparent permeability coefficients (Pe) of drugs across porcine sublingual mucosa were determined experimentally. Multiple linear regression (MLR) was used to develop the model with permeability as the response variable and various descriptors as the predictive variables. Q(2), the cross-validated correlation coefficient, was used to assess the prediction ability of the model. MLR analysis showed that HBD and logD were the significant descriptors (P<0.05, Q(2)=0.88) in the sublingual permeability model. The resulting model is expressed as the following equation:An excellent fit with R(2) of 0.93 was obtained between experimental and predicted permeabilities. The analysis of contributions of molecular descriptors to sublingual permeability revealed the molecular structure basis of permeation across sublingual mucosa. In conclusion, an in silico model was developed to predict sublingual permeability of drugs using known descriptors for evaluating the feasibility of sublingual drug delivery.

Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions.

The aim of this study was to evaluate the effect of the thickness of adsorbed polymer layer (also known as Fixed Aqueous Layer Thickness, FALT) of polymeric stabilizers on zeta potential and stability of nanoparticles in a suspension. Aripiprazole, a poorly water soluble drug was used as a model drug to evaluate rationale for increased FALT and to understand the effect of hydrophilicity and hydrophobicity of polymeric stabilizers on FALT of aripiprazole nanosuspensions. The nanosuspensions were prepared by media milling and Pluronic F68, Pluronic F127, Hydroxypropyl methylcellulose (HPMC) and Hydroxypropyl cellulose (HPC) were used as polymeric stabilizers. The particle size (immediately after preparation and after 1 week of storage at 25°C) and zeta potential of aripiprazole nanosuspensions were determined. For Pluronics, FALT was determined theoretically whereas for HPMC and HPC it was calculated as Debye Huckel parameter from the zeta potential dependence on the ionic strength. An increase in FALT resulted in reduced zeta potential. With an increase in FALT of polymers used, the stability of nanosuspensions showed improvement. Furthermore, a linear correlation was shown to exist between the FALT and length of hydrophilic chains in Pluronics.