Alenka Zvonar

Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs

Abstract Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self- -nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemulsion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions.

Temperature-Sensitive Microemulsion Gel: An Effective Topical Delivery System for Simultaneous Delivery of Vitamins C and E

Microemulsions (ME)—nanostructured systems composed of water, oil, and surfactants—have frequently been used in attempts to increase cutaneous drug delivery. The primary objective addressed in this work has been the development of temperature-sensitive microemulsion gel (called gel-like ME), as an effective and safe delivery system suitable for simultaneous topical application of a hydrophilic vitamin C and a lipophilic vitamin E. By changing water content of liquid o/w ME (o/w ME), a gel-like ME with temperature-sensitive rheological properties was formed. The temperature-driven changes in its microstructure were confirmed by rotational rheometry, viscosity measurements, and droplet size determination. The release studies have shown that the vitamins’ release at skin temperature from gel-like ME were comparable to those from o/w ME and were much faster and more complete than from o/w ME conventionally thickened with polymer (o/w ME carbomer). According to effectiveness in skin delivery of both vitamins, o/w ME was found the most appropriate, followed by gel-like ME and by o/w ME carbomer, indicating that no simple correlation between vitamins release and skin absorption could be found. The cytotoxicity studies revealed good cell viability after exposure to ME and confirmed all tested microemulsions as nonirritant.

A Self-Microemulsifying Drug Delivery System to Overcome Intestinal Resveratrol Toxicity and Presystemic Metabolism

A mixed lipid-mixed surfactant self-microemulsifying drug delivery system (SMEDDS) was developed to exploit the health benefits of resveratrol, a Biopharmaceutical Classification System Class 2 natural polyphenol, subject to extensive intestinal presystemic metabolism. SMEDDS with a mixed lipid phase (castor oil/Capmul MCM 1:1) and a mixed surfactant phase (Kolliphor EL/Kolliphor RH 40 1:1) was developed and evaluated for its self-emulsifying properties and in vitro dispersion. The impact of SMEDDS on the permeability properties of resveratrol and its metabolite fluxes through the rat intestine and Caco-2 cells was monitored. The inhibitory effect of selected SMEDDS components on the efflux transporters multidrug resistance-associated protein and P-gp as well as cytotoxicity was assessed on Caco-2 cells. The formulation allowed for high resveratrol loading (122.5 mg/g SMEDDS), excellent self-emulsifying properties, and very rapid release. When formulated in SMEDDS, resveratrol metabolite efflux significantly declined. The formulation (SMEDDS without incorporated resveratrol) and its individual components did not compromise in vitro cell vitality and integrity. Mixed lipid-mixed surfactant SMEDDS is a prospective formulation to improve resveratrol biopharmaceutical, pharmacokinetic, and toxicological properties, leading the way to resveratrol use not only as a supplement but also as a pharmacological drug.

Mixed lipid phase SMEDDS as an innovative approach to enhance resveratrol solubility

Abstract Context: Despite its promising therapeutic activities, clinical use of resveratrol (RSV) is compromised with unfavorable biopharmaceutical properties, namely low water solubility. Objective: This work deals with improving RSV solubility and release rate through its incorporation in innovative mixed lipid phase self-microemulsifying drug delivery systems (SMEDDS). Methods: (Pseudo)ternary diagrams were constructed for different oils and surfactant mixtures. Selected systems were further evaluated for RSV solubility, self-emulsification ability, accelerated stability, dynamic viscosity, compatibility with hard gelatin capsules and in vitro dissolution of RSV. Results: Lipid phase composed of diverse lipid species, castor oil (long-chained triglyceride) and Capmul MCM (mixture of medium chain mono and diglycerides) allowed formulation of mixed lipid SMEDDS with lower surfactants content (60% Cremophor EL/RH 40/RH 60). Mixed lipid phase SMEDDS showed best self-emulsifying ability with regard to self-emulsifying time as well as droplet size and monodispersity of microemulsions obtained upon SMEDDS dilution with aqueous phase. Overall, incorporation of RSV in SMEDDS resulted in improved solubility (over 23-fold) and dissolution rate compared to crystalline RSV. All SMEDDS formulations were adequately viscous for filling into hard gelatin capsules (>150 mPaċs for empty SMEDDS; >400 mPaċs for RSV-loaded SMEDDS) and no leaking was observed during three months of storage. Conclusion: The presented work indicates the promising potential of mixed lipid SMEDDS formulations for future development of SMEDDS with lower surfactant content and no added cosolvents for incorporation of RSV and other poorly soluble drugs.

High celecoxib-loaded nanoparticles prepared by a vibrating nozzle device.

Drug delivery research has resulted in the availability of several enabling technologies for formulating poorly water-soluble compounds. In this study the vibrating nozzle device, originally used for encapsulation of drugs, cells and microorganisms, has been used to formulate nanoparticles (NP) with high loading capacity. Celecoxib was incorporated in NP of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) and the influence of polymers, initial drug : polymer ratio and stabilizer concentration on NP size and surface properties, entrapment efficiency, drug loading and in vitro release profile were investigated. NP were in the size range of 230–270 nm, with a polydispersity index less than 0.25 and a spherical shape. The highest celecoxib loading (13% w/w) was obtained at initial ratio celecoxib : Resomer RG 502 (PLA/PGA = 50/50) of 1 : 5 and 0.1% w/w polyvinyl alcohol concentration. Thermal analysis and X-ray diffraction suggested that celecoxib was amorphous or molecularly dispersed in the polymeric matrix. The release profile exhibited an initial burst followed by sustained release. The freeze-dried NP could be completely dispersed on addition of lyoprotectants. The production of NP by the vibrating nozzle device is highly reproducible, time saving, can be performed under aseptic conditions and offers the possibility of scale-up.

Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen

Abstract Context: Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement. Objective: The aim of this work was to develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire® 44/14 to improve the solubility and dissolution rate of naproxen. Material and methods: Various oils and co-surfactants in combination with Gelucire® 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained. Results: The selected formulation of SMEDDS was comprised of Miglyol 812®, Peceol™, Gelucire® 44/14, and Solutol® HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen. Conclusion: This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms.

Characterization of naproxen-loaded solid SMEDDSs prepared by spray drying: the effect of the polysaccharide carrier and naproxen concentration.

The purpose of this study was to prepare solid SMEDDS (sSMEDDS) particles produced by spray-drying using maltodextrin (MD), hypromellose (HPMC), and a combination of the two as a solid carrier. Naproxen (NPX) as the model drug was dissolved (at 6% concentration) or partially suspended (at 18% concentration) in a liquid SMEDDS composed of Miglyol(®) 812, Peceol™, Gelucire(®) 44/14, and Solutol(®) HS 15. Among the sSMEDDSs tested, the MD-based sSMEDDSs (with a granular, smooth-surfaced, microspherical appearance) preserved the self-microemulsifying properties of liquid SMEDDSs and exhibited dissolution profiles similar to those of liquid SMEDDSs, irrespective of the concentration of NPX. In contrast, HPMC-based sSMEDDSs (irregular-shaped microparticles) exhibited slightly prolonged release times due to the polymeric nature of the carrier. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Raman mapping analysis confirmed molecularly dissolved NPX (at 6% of drug loading), whereas at 18% NPX loading drug is partially molecularly dissolved and partially in the crystalline state.

Microencapsulation of self-microemulsifying systems: Optimization of shell-formation phase and hardening process

The preparation of microcapsules with a self-microemulsifying system (SMES) core using a vibrating nozzle technology was improved with regard to process reproducibility and core phase retention. The microcapsule shell was optimized for composition of the alginate-pectin (A/P) ratio and hydrophilic filling agent content. The best-shaped microcapsules with highest encapsulation efficiency for furosemide-loaded SMES were obtained from the shell-formation phase with an A/P ratio of 25:75, containing 10% lactose, which was hardened through a one-step process. Fluid-bed dried microcapsules were examined for their release characteristics and swelling behavior of the polymeric matrix. Incorporation of hydrophilic filling agents in the shell-formation phase was shown to be successful in limiting the leakage of the core phase during the microcapsule production and drying processes. Moreover, the addition of different fillers also allows the drug release profile from Ca-alginate/pectinate microcapsules with a self-microemulsifying core to be modified.

The reflection of the texture of swollen polymer matrix on the release of incorporated substance

Abstract Our aim was to investigate the texture of hydrated biopolymer matrices that are now being considered in the design of pharmaceutical controlled-release dosage forms, in order to determine their influence on the release of an active compound. Prolonged release of pentoxifylline, a highly soluble drug, is needed for once-daily administration to achieve its therapeutic effect. For this purpose, pentoxifylline was incorporated in a polymer matrix made of a combination of xanthan and locust bean gum (XLBG), both of which are of biotechnological origin. Different methods were used to investigate the interplay of the XLBG gel structure characteristics in the absence and presence of 200 mM CaCl2 on pentoxifylline release: drug-release studies, determination of swelling, erosion, and viscoelasticity of the gel, as well as its texture analysis and microscopic imaging. From the results obtained, the following conclusions can be drawn: the pentoxifylline release from XLBG matrices in water was prolonged for 24 h whereas from the control lactose formulation was completed within 30 min. The presence of Ca2+ ions in water resulted in faster pentoxifylline release, in spite of less swelling and erosion. However, the rheology, texture analysis and scanning electron microscopy revealed that in the presence of the Ca2+ ions the gel layer of the XLBG was more cohesive and thinner, as the attraction for water molecules was lower due to the condensation of counter-ions on the xanthan carboxylic-moieties, and consequently greater interpolymer interactions. Therefore, relatively larger amounts of free water molecules were available within the XLBG hydrogel in the presence of Ca2+, allowing faster drug dissolution and diffusion. Here, the presence of Ca2+ ions had a completely opposite effect on XLBG gel structure and drug release in comparison with other more investigated matrix polymers like alginate or non-ionic cellulose ethers. A firm matrix structure that is accompanied by low swelling and erosion cannot guarantee a more prolonged drug release.