Effective loading of incompatible drugs into nanosized vesicles: a strategy to allow concurrent administration of furosemide and midazolam in simulated clinical settings.

The current study aims to assess the use of nanocarriers to limit drug incompatibilities in clinical settings, and thus eliminating serious clinical consequences (e.g., catheter obstruction and embolism), and enhancing in vivo bioavailability and efficacy. As a proof-of-concept, the impact of loading well-documented physically incompatible drugs (i.e., furosemide and midazolam) into nanosized vesicles on in vitro stability and in vivo bioavailability of the two drugs was investigated. Furosemide and midazolam were loaded into nanosized spherical vesicles at high entrapment efficiency (ca. 62-69%). The drug-loaded vesicles demonstrated a sustained drug release patterns, high physical stability and negligible hemolytic activity. Physical incompatibility was assessed by exploiting microscopic technique coupled with image processing and analysis, dynamic light scattering and laser Doppler anemometry. Incorporation of drugs separately inside the nanosized vesicles dramatically decreased size and number of the precipitated particles. In vivo, the niosomal drug mixture demonstrated a significant improvement in pharmacokinetic profiles of furosemide and midazolam compared to the mixed free drug solutions, as evidenced by their longer circulation half-lives and higher area under the plasma-concentration time curves of both drugs. Nanocarriers could provide an auspicious strategy for circumventing drug incompatibilities, thus reducing adverse reactions, hospitalization period and improving therapeutic outcomes.

Methods for preparation of nanostructured lipid carriers.

Construction of nanocarriers of different structures and properties have shown great promise as delivery systems for a wide range of drugs to improve therapeutic effects and reduce side effects. Nanostructured lipid carriers (NLCs) have been introduced as a new generation of solid lipid nanoparticles (SLNs) to overcome several of the limitations associated with the SLNs. NLCs consist of a blend of solid and liquid lipids which result in a partially crystallized lipid system that enables higher drug loading efficiency compared to SLNs. Owing to their biocompatibility, low toxicity, ease of preparation and scaling-up, and high stability, NLCs have been exploited in numerous pharmaceutical applications. Different methods for fabrication of NLCs have been described in the literature. In this article, procedures involved in emulsification-solvent evaporation method, one of the commonly utilized methods for preparation of NLCs, are described in detail. Critical aspects that should be considered throughout preparation process are also highlighted to allow for consistent and reproducible construction of NLCs.

Electrospun vancomycin-loaded nanofibers for management of methicillin-resistant Staphylococcus aureus-induced skin infections.

Skin damage exposes the underlying layers to bacterial invasion, leading to skin and soft tissue infections. Several pathogens have developed resistance against conventional topical antimicrobial treatments and rendered them less effective. Recently, several nanomedical strategies have emerged as a potential approach to improve therapeutic outcomes of treating bacterial skin infections. In the current study, nanofibers were utilized for topical delivery of the antimicrobial drug vancomycin and evaluated as a promising tool for treatment of topical skin infections. Vancomycin-loaded nanofibers were prepared via electrospinning technique, and vancomycin-loaded nanofibers of the optimal composition exhibited nanosized uniform smooth fibers (ca. 200 nm diameter), high drug entrapment efficiency and sustained drug release patterns over 48 h. In vitro cytotoxicity assays, using several cell lines, revealed the biocompatibility of the drug-loaded nanofibers. In vitro antibacterial studies showed sustained antibacterial activity of the vancomycin-loaded nanofibers against methicillin-resistant Staphylococcus aureus (MRSA), in comparison to the free drug. The nanofibers were then tested in animal model of superficial MRSA skin infection and demonstrated a superior antibacterial efficiency, as compared to animals treated with the free vancomycin solution. Hence, nanofibers might provide an efficient nanodevice to overcome MRSA-induced skin infections and a promising topical delivery vehicle for antimicrobial drugs.

Nanomedicine: a new paradigm to overcome drug incompatibilities.

OBJECTIVES: Drug incompatibilities may compromise the safety and effectiveness of combined drugs and result in mild-to-serious clinical complications, such as catheter obstruction, loss of drug efficacy, formation of toxic derivatives and embolism. Various preventive strategies have been implemented to overcome drug incompatibilities with limited success. This review presents an innovative approach to prevent drug incompatibilities via isolating the incompatible drugs into nanostructures. KEY FINDINGS: Several examples of incompatible drugs may be loaded separately into nanostructures of various types. Physicochemical characteristics and biocompatibility of the nanomaterials that are being utilized to prevent physicochemical incompatibilities should be carefully considered. CONCLUSIONS: There is a new era of exploiting nanomaterials in overcoming various types of physicochemical incompatibilities, with additional benefits of further improvements in pharmacokinetic profiles and pharmacological actions of the administered drugs.

Nanostructured lipid carriers for improved oral delivery and prolonged antihyperlipidemic effect of simvastatin.

The purpose of the current study is to develop nanostructured lipid carriers (NLCs) for the delivery of the antihyperlipidemic drug simvastatin (SIM) to increase its extremely low oral bioavailability (<5%) and prolong its antihyperlipidemic effect. NLCs were prepared via emulsification-solvent evaporation technique followed by ultrasonication, and the effect of composition of the nanocarriers on the particle size, size distribution, surface charge, entrapment efficiency, drug release kinetics and physical stability was extensively studied. NLCs exhibited nanosized (<200nm) spherical morphologies with narrow size distribution and high drug entrapment efficiency (>75%), sustained drug release pattern, and negative surface charge (zeta potential of -35-40mV) that imparts sufficient electrostatic physical stability. When tested in vivo, SIM-NLCs of the optimal composition demonstrated improved and prolonged reduction in the total cholesterol and non-high density lipoprotein cholesterol levels, as compared to the drug suspension. After oral administration of a single dose of SIM-NLC, 4-fold increase in bioavailability was observed, as compared to the SIM suspension. Hence, NLCs might provide efficient nanodevices for the management of hyperlipidemia and promising drug delivery systems to enhance SIM oral bioavailability.

Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA.

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.