Hany M. Ibrahim

Silymarin loaded liposomes for hepatic targeting: In vitro evaluation and HepG2 drug uptake

Silymarin has hepatoprotective properties and is used in treatment of various liver diseases, but its bioavailability from oral products is very poor. In order to overcome its poor oral bioavailability we have prepared silymarin loaded hepatic targeting liposomes suitable for parenteral administration. The liposomal formulations were composed of hydrogenated soy phosphatidylcholine and cholesterol with or without distearoylphosphoethanolamine-(polyethyleneglycol)-2000 and various amounts of β-sitosterol β-D-glucoside (Sito-G) as the hepatic targeting moiety. Increasing the amount of Sito-G in the liposomes gradually decreased drug encapsulation efficiencies from ∼70% to ∼60%; still showing promising drug encapsulation efficiencies. Addition of Sito-G to non-PEGylated liposomes clearly affected their drug release profiles and plasma protein interactions, whereas no effect on these was seen for the PEGylated liposomes. Non-PEGylated liposomes with 0.17 M ratio of Sito-G exhibited the highest cellular drug uptake of 37.5% for all of the studied liposome formulations. The highest cellular drug uptake in the case of PEGylated liposomes was 18%, which was achieved with 0.17 and 0.33 M ratio of added Sito-G. The liposome formulations with the highest drug delivery efficacy in this study showed hemolytic activities around 12.7% and were stable for at least 2 months upon storage in 20 mM HEPES buffer (pH 7.4) containing 1.5% Polysorbate 80 at 4 °C and room temperature. These results suggest that the Sito-G containing liposomes prepared in this work have hepatic targeting capability and that they are promising candidates for delivering silymarin to the liver.

Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol

The objective of this study is to formulate injectable, biodegradable sustained release in situ implant (ISI), and in situ microparticle (ISM) formulations of haloperidol. Factors affecting the in vitro drug release, pharmacokinetics, and stability of the formulations were investigated. The concentration of the polymer, poly(lactide-co-glycolide) acid (PLGA), and the type of solvents showed a pronounced effect on the in vitro drug release from the ISI and ISM formulations. The ISM formulation [20% PLGA in N-methyl-2-pyrrolidone (NMP)-peanut oil, 1:4] showed reduced maximum plasma concentration (60 versus 44 ng/mL) and longer release (30 days, plasma concentration of 8 ng/mL versus 20 days, plasma concentration of 6 ng/mL) compared with the ISI formulation (20% PLGA in NMP) after intramuscular injection in rats. The delivery of haloperidol can be extended further by changing the concentration, molecular weight, and lactide-to-glycolide ratio of the PLGA. These formulations can be easily administered by both intramuscular and subcutaneous injections. The shelf lives of both systems were found to be 2 years when stored at 4°C. Haloperidol can be formulated as an injectable ISI or ISM systems suitable for 1 month or longer release.

In vitro release, rheological, and stability studies of mefenamic acid coprecipitates in topical formulations

A suitable topical formulation of mefenamic acid was developed in order to eliminate the gastrointestinal disorders associated with its oral administration. Drug coprecipitates prepared with different polymers at various drug-to-polymer ratios improved drug solubility and dissolution compared to pure drug and physical mixtures. PVP polymers (ratio 1:4) produced the best results. Aqueous ionic cream, ointments of absorption and water soluble bases and gels of methylcellulose, carboxymethylcellulose sodium, HPMC, Carbopol® 934 and 940, and Pluronic® F127 bases containing 1–10% drug as coprecipitates of PVP polymers (1:4) were prepared. The highest drug release was achieved at 1% drug concentration from water soluble base and methylcellulose among cream/ointment and gel bases, respectively. Gels, in general yielded better release than creams/ointments. All tested medicated creams/ointments exhibited plastic flow while all gels conformed to pseudoplasticity. Most of them showed thixotropy, a desired property of topical preparations. Stability studies revealed that HPMC and methylcellulose had the smallest changes in drug content, viscosity, and pH among the formulations. Considering drug release, rheological properties, and stability, methylcellulose gel containing 1% drug as coprecipitates of PVP K90 was the best among the studied formulations, was promising for improving bioavailability of mefenamic acid and can be used in future studies.

Development of meloxicam in situ implant formulation by quality by design principle

Abstract Objective: The focus of this study was to develop and optimize in situ implant formulation of meloxicam by quality by design (QbD) principle for long-term management of musculoskeletal inflammatory disorders. Methods: The formulation was optimized by Box–Behnken design with polylactide-co-glycolide (PLGA) level (X1), N-methyl pyrrolidone level (X2) and PLGA intrinsic viscosity (X3) as the independent variables and initial burst release of drug (Y1), cumulative release (Y2), and dissolution efficiency (Y3) as the dependent variables. The formulation was physicochemically characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD). Pharmacokinetic studies of the optimized formulation were performed on Sprague--Dawley rats. Results: Y1 was significantly affected by X2 and X3. Y2 was affected by X1 and X3 while Y3 was affected by all three independent variables employed in the formulations. Responses for the optimized formulation were in close agreement with the values predicted by the model. SEM photomicrographs indicated uniform gel formulation. No chemical interaction between the components of formulation was observed by FT-IR and meloxicam was found to be present in the amorphous form in the gel matrix as revealed by PXRD. The maximum plasma concentration (Cmax), time to achieve Cmax and area under plasma concentration curve were significantly different from those of the solution formulation used as the control. Plasma concentration of meloxicam was maintained above its IC50 concentration required for COX-2 inhibition for 23 days. Conclusion: Meloxicam in situ implant may provide long-term management of inflammatory conditions with improved patient compliance and better therapeutic index.

Mucoadhesive controlled release microcapsules of indomethacin: Optimization and stability study

The aim of this project was to develop and optimize indomethacin microcapsules composed of multiple mucoadhesive polymers for high drug entrapment, good mucoadhesiveness and drug release in a controlled fashion over a longer period of time. Microcapsules containing sodium alginate, sodium carboxymethylcellulose, methylcellulose, Carbopol® 934 and hydroxypropyl methylcellulose were prepared by orifice-ionic gelation method. The effects of composition of microcapsules on drug entrapment efficacy, drug release and mucoadhesive character were determined by mixture statistical design. Most formulations exhibited good mucoadhesive property in everted intestinal sac test. Drug entrapment efficiency (68–94%) was dependent on the type of polymers. Drug release (92–100%) extended over 12 h. The optimized formulation resulted in drug entrapment efficiency of 89.3%, drug release of 94.8% and mucoadhesiveness of 30.4%. All formulations were stable for more than 1.5 years. The optimized mucoadhesive microcapsules are promising for controlled delivery of indomethacin with twice a day oral administration.

Peptide–Micelle Hybrids Containing Fasudil for Targeted Delivery to the Pulmonary Arteries and Arterioles to Treat Pulmonary Arterial Hypertension

This study investigates the respirability and efficacy of peptide-micelle hybrid nanoparticles as carriers for inhalational therapy of pulmonary arterial hypertension (PAH). CARSKNKDC (CAR), a cell-penetrating and lung-homing peptide, conjugated polyethylene glycol-distearoyl-phosphoethanolamine micelles containing fasudil, an investigational anti-PAH drug, were prepared by solvent evaporation method and characterized for various physicochemical properties. The pharmacokinetics and pharmacological efficacy of hybrid particles containing fasudil were evaluated in healthy rats and monocrotaline-induced PAH rats. CAR micelles containing fasudil had an entrapment efficiency of approximately 58%, showed controlled release of the drug, and were monodispersed with an average size of approximately 14 nm. Nuclear magnetic resonance scan confirmed the drugs presence in the core of peptide-micelle hybrid particles. Compared with plain micelles, CAR peptide increased the cellular uptake by approximately 1.7-fold and extended the drug half-life by approximately fivefold. The formulations were more prone to accumulate in the pulmonary vasculature than in the peripheral blood, which is evident from the ratio of the extent of reduction of pulmonary and systemic arterial pressures. On the whole, this study demonstrates that peptide-polymer hybrid micelles can serve as inhalational carriers for PAH therapy.

Atorvastatin-loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks

Abstract Atorvastatin (AT) is a widely used lipid-regulating drug to reduce cholesterol and triglycerides. Its poor aqueous solubility and hepatic metabolism require development of drug delivery systems able to improve its solubility and bypass hepatic effect. For this purpose, atorvastatin nanostructured lipid carriers (AT-NLCs) were prepared and characterized. AT-NLCs were prepared by emulsification using high-speed homogenization followed by ultrasonication. The prepared NLCs showed particle size between 162.5 ± 12 and 865.55 ± 28 nm while zeta potential values varied between −34 ± 0.29 and −23 ± 0.36 mV. They also showed high encapsulation efficiency (>87%) and amorphous state of the drug in lipid matrix. Pharmacokinetic parameters of optimized formulation (NLC-1; composed of 2% Gelucire® 43/01, 8% Capryol® PGMC, 2% Pluronic®F68 and 0.5% lecithin) revealed 3.6- and 2.1-fold increase in bioavailability as compared to atorvastatin suspension and commercial product (Lipitor®), respectively. Administration of NLC-1 led to significant reduction (p < .05) in the rats’ serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and significant increase in high-density lipoprotein (HDL). This improvement was confirmed histologically by minimizing the associated hepatic steatosis. These investigations demonstrated the superiority of NLCs for improvement of oral bioavailability and in vivo performance of AT.

In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium

Abstract The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7 ± 12.9 to 423 ± 15.9 nm while zeta potential values varied from −21.7 ± 0.90 to −22.7 ± 0.85 mV. The loading capacity varied from 17.9 ± 1.21 to 34.1 ± 1.16%. DSC, FT–IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p < .05) in total cholesterol, triglyceride, LDL-C and increased level of beneficial HDL-C along with improvement in the associated liver steatosis as confirmed through photomicrographs of liver sections. In this study, we confirmed that complexation of AC with NS would be a viable approach for improving oral bioavailability and in vivo performance of AC.

Optimization and evaluation of lyophilized fenofibrate nanoparticles with enhanced oral bioavailability and efficacy

Abstract The objective of this study was to enhance physiochemical properties as well as oral bioavailability of the poorly water soluble drug fenofibrate (FB), through preparation of amorphous solid dispersions (ASDs). ASDs were prepared via freeze drying using polyvinylpyrrolidone (PVP) K30 and poloxamer 188 as hydrophilic carriers. Formulations were optimized by 32 full factorial design (FFD) with PVP-K30 level (X1) and poloxamer 188 level (X2) as independent variables and particle size (Y1), zeta potential (Y2), drug content (Y3) and dissolution rate (T90, [Y4]) as dependent variables. Optimized FB nanoparticles were physicochemically evaluated and formulated into lyophilized sublingual tablets. Pharmacokinetic, pharmacodynamics and histological finding of optimized formulation were performed on rabbits. Y1 and Y4 were significantly affected by independent variables while Y2 and Y3 were not affected. Physicochemical characterization showed the drug was in amorphous state, nanometer range and pharmacophore of FB was preserved. Administration of optimized FB tablets to rabbits with fatty liver led to significant reduction (p < 0.001) in serum lipids. Moreover, histological analysis of liver specimens confirmed the improved efficacy in animals with fatty liver. In this study, we confirmed that ASDs of FB had beneficial effects on managing fatty liver and serum lipids level in hyperlipidemic rabbits.

Mucoadhesive self-emulsifying delivery systems for ocular administration of econazole

AIM Development of mucoadhesive self-emulsifying drug delivery systems (SEDDS) providing a prolonged ocular residence time for poorly soluble active pharmaceutical ingredient. METHODS l-Cysteine was covalently linked to 6-mercaptonicotinamide. The obtained ligand, Cysteine-6-mercaptonicotinamide (Cys-6-MNA) was attached to Eudragit® L100-55 via a carbodiimide mediated amide bond formation. The resulting entirely S-protected thiolated Eudragit® L100-55 was characterized regarding the degree of modification as well as stability toward oxidation in the presence of strong oxidizing agent (H2O2). The S-protected thiolated Eudragit® L100-55 was incorporated into SEDDS via hydrophobic ion pairing with benzalkonium chloride (BAK) in a concentration of 2% (m/m). S-protected thiolated Eudragit® L100-55-BAK ion pair SEDDS (S-protected thiolated EU-BAK SEDDS) were characterized regarding their physicochemical and mucoadhesive properties. Econazole nitrate (EN) was incorporated into SEDDS in concentration of 1% (m/m) and in vitro drug release was assessed. Furthermore, toxicity study was performed on procine corneas via resazurin assay. RESULTS The entirely S-protected thiolated Eudragit® L100-55 exhibited 282 ± 78.25 µmol of MNA per gram of polymer. Ellmans test confirmed no free thiol groups and stability study showed no significant increase in dynamic viscosity overtime. The droplet size of developed SEDDS in simulated lacrimal fluid was below 100 nm with polydispersity index below 0.3. S-protected thiolated EU-BAK SEDDS exhibited 2.5-fold higher mucoadhesive properties than blank SEDDS on ocular mucosa. S-protected thiolated EU-BAK SEDDS showed sustained EN release over period of 8 h and no pronounced corneal toxicity in 0.5% (m/v) concentration. CONCLUSION Accordingly, these mucoadhesive SEDDS can be considered as promising ocular delivery system for EN.