Optimization of Cyclodextrin-Assisted Extraction of Phenolics from Helichrysum italicum for Preparation of Extracts with Anti-Elastase and Anti-Collagenase Properties.

Helichrysum italicum is a plant traditionally used for skin-related disorders that is becoming an increasingly popular ingredient in cosmetic products. In this work, a "green" ultrasound-assisted extraction method for H. italicum phenolics was developed using skin-friendly cyclodextrins (CDs). Extraction conditions needed for the greatest yield of target compounds (total phenolics, phenolic acids, and flavonoids) were calculated. The composition of the extracts was determined using LC-MS and spectrophotometric methods. Among the tested CDs, 2-hydroxylpropyl-beta-CD (HP-ß-CD) was the best suited for extraction of target phenolics and used to prepare two optimized extracts, OPT 1 (the extract with the highest phenolic acid content) and OPT 2 (the extract with the highest total phenol and flavonoid content). The extracts were prepared at 80 °C, using 0.089 g of plant material/g solvent (0.6 mmol of HP-ß-CD), with or without addition of 1.95% (w/w) lactic acid. The main metabolite in both extracts was 3,5-O-dicaffeoylquinic acid. It was found that the addition of lactic acid greatly contributes to the extraction of arzanol, a well-known anti-inflammatory agent. IC50 values of the anti-elastase (22.360 ± 0.125 µL extract/mL and 20.067 ± 0.975 for OPT-1 and OPT-2, respectively) and anti-collagenase (12.035 ± 1.029 µL extract/mL and 14.392 ± 0.705 µL extract/mL for OPT-1 and OPT-2, respectively) activities of the extracts surpassed those of the applied positive controls, namely ursolic and gallic acids. This activity deems the prepared extracts promising ingredients for natural cosmetics, appropriate for direct use in cosmetic products, removing the need for the evaporation of conventional solvents.

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products.

Praziquantel (PZQ) is a biopharmaceutical classification system (BCS) class II anthelmintic drug characterized by poor solubility and a bitter taste, both of which can be addressed by inclusion complexation with cyclodextrins (CD). In this work, a comprehensive investigation of praziquantel/cyclodextrin (PZQ/CD) complexes was conducted by means of UV-vis spectroscopy, spectrofluorimetry, NMR spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS), and molecular modeling. Phase solubility studies revealed that among four CDs tested, the randomly methylated ß-CD (RMßCD) and the sulfobutylether sodium salt ß-CD (SBEßCD) resulted in the highest increase in PZQ solubility (approximately 16-fold). The formation of 1:1 inclusion complexes was confirmed by HRMS, NMR, and molecular modeling. Both cyclohexane and the central pyrazino ring, as well as an aromatic part of PZQ are included in the CD central cavity through several different binding modes, which exist simultaneously. Furthermore, the influence of CDs on PZQ stability was investigated in solution (HCl, NaOH, H2O2) and in the solid state (accelerated degradation, photostability) by ultra-high-performance liquid chromatography-diode array detection-tandem mass spectrometry (UPLC-DAD/MS). CD complexation promoted new degradation pathways of the drug. In addition to three already known PZQ degradants, seven new degradation products were identified (m/z 148, 215, 217, 301, 327, 343, and 378) and their structures were proposed based on HRMS/MS data. Solid complexes were prepared by mechanochemical activation, a solvent-free and ecologically acceptable method.

Lipid Nanoparticle Technology for Delivering Biologically Active Fatty Acids and Monoglycerides.

There is enormous interest in utilizing biologically active fatty acids and monoglycerides to treat phospholipid membrane-related medical diseases, especially with the global health importance of membrane-enveloped viruses and bacteria. However, it is difficult to practically deliver lipophilic fatty acids and monoglycerides for therapeutic applications, which has led to the emergence of lipid nanoparticle platforms that support molecular encapsulation and functional presentation. Herein, we introduce various classes of lipid nanoparticle technology and critically examine the latest progress in utilizing lipid nanoparticles to deliver fatty acids and monoglycerides in order to treat medical diseases related to infectious pathogens, cancer, and inflammation. Particular emphasis is placed on understanding how nanoparticle structure is related to biological function in terms of mechanism, potency, selectivity, and targeting. We also discuss translational opportunities and regulatory needs for utilizing lipid nanoparticles to deliver fatty acids and monoglycerides, including unmet clinical opportunities.

Cyclodextrin-based Pickering emulsions: functional properties and drug delivery applications.

Cyclodextrins (CDs) are biocompatible, cyclic oligosaccharides that are widely used in various industrial applications and have intriguing interfacial science properties. While CD molecules typically have low surface activity, they are capable of stabilizing emulsions by inclusion complexation of oil-phase components at the oil/water interface, which results in Pickering emulsion formation. Such surfactant-free formulations have gained considerable attention in recent years, owing to their enhanced physical stability, improved tolerability, and superior environmental compatibility compared to conventional, surfactant-based emulsions. In this review, we critically describe the latest insights into the molecular mechanisms involved in CD stabilization of Pickering emulsions, including covering practical aspects such as methods to prepare CD-based Pickering emulsions, lipid encapsulation, and relevant stability issues. In addition, the rheological and textural features of CD-based Pickering emulsions are discussed and particular attention is focused on promising examples for drug delivery, cosmetic, and nutraceutical applications. The functionality of currently developed CD-based Pickering emulsions is also summarised, including examples such as antifungal uses, and we close by discussing emerging possibilities to utilize the molecular encapsulation of CD-based emulsions for translational medicine applications in the antiviral and antibacterial spaces.

Comparison of Maceration and Ultrasonication for Green Extraction of Phenolic Acids from Echinacea purpurea Aerial Parts.

Echinacea purpurea is used in herbal medicinal products for the prevention and treatment of the common cold, as well as for skin disorders and minor wounds. In this study, the efficiency of traditional maceration using water and ethanol was compared with the maceration using mixtures of water and glycerol, a non-toxic, biodegradable solvent from renewable sources. It was found that the glycerol-water mixtures were as effective as ethanol/water mixtures for the extraction of caffeic acid derivatives. All the prepared extracts demonstrated notable antiradical properties. Furthermore, an efficient ultrasound-assisted extraction using glycerol-water mixtures was developed using six independent variables. Their levels needed for the maximum extraction of caffeic acid derivatives were as follows: glycerol 90% (m/m), temperature 70 °C, ultrasound power 72 W, time 40 min, and ascorbic acid 0 mg/mL. Under the optimized conditions, ultrasound-assisted extraction was superior to maceration. It achieved significantly higher yields of phenolic acids in shorter extraction time. The presence of zinc in plant material may contribute to the beneficial effects of E. purpurea preparations. Since glycerol is a non-toxic solvent with humectant properties, the prepared extracts can be directly used for the preparation of cosmetics or oral pharmaceutical formulations without the need for solvent removal.

Co-grinding with surfactants as a new approach to enhance in vitro dissolution of praziquantel.

This paper evaluates the process of co-grinding with a surfactant as a new approach to enhance physicochemical and biopharmaceutical properties of praziquantel (PZQ), a poorly soluble drug that is essential for the treatment of schistosomiasis, a neglected tropical disease. Surfactants used in this study were poloxamer F-127 and sucrose stearate (C-1816), selected based on their well-documented biocompatibility and solubilizing activity. A series of products were prepared by mechanochemical activation using vibrational ball-mill at different drug to surfactant ratio and milling times. The obtained products were characterised in terms of drug recovery, solubility and in vitro dissolution rates. The obtained results were correlated to solid-state properties of the products analysed by differential scanning calorimetry, powder X-ray diffraction and particle size analysis. Results of UPLC-MS analysis and 1H-NMR spectroscopy showed that the used surfactants and applied grinding procedures caused no chemical degradation of the PZQ. The physicochemical properties, solubility and the in vitro dissolution enhancement of the co-ground products were related to the drug to surfactant ratio and the grinding protocol applied. The highest enhancement of the in vitro dissolution rate was achieved at the drug to surfactant ratio of 10:3 and 10:2 for F-127 and C-1816, respectively with the milling time of 30 min. The MTT assay on Caco-2 cell line demonstrated the biocompatibility of both co-ground products. Furthermore, the surfactants used did not change intrinsically high intestinal permeability of PZQ (Papp ∼ 4.00 × 10-5 cm s-1). The presented results confirmed that the co-grinding with surfactant is a promising new approach in enhancing in vitro dissolution of poorly soluble drugs like PZQ.

Development, characterisation and nasal deposition of melatonin-loaded pectin/hypromellose microspheres.

In this study, we present the development of spray-dried pectin/hypromellose microspheres as efficient melatonin carrier for targeted nasal delivery. Different pectin to hypromellose weight ratios in the spray-dried feed were employed (i.e. 1:0, 3:1, 1:1 and 1:3) in order to optimise microsphere physicochemical properties influencing overall powder behaviour prior, during and upon nasal delivery. All microspheres assured complete melatonin entrapment and increased dissolution rate in relation to pure melatonin powder. Among all combinations tested, combining pectin with hypromellose at 1:3 wt ratio resulted in the microspheres with the highest potential for melatonin nasal delivery as they assured highest swelling ability and most prominent mucoadhesive properties. Studies on deposition profile revealed adequate turbinate and olfactory deposition of microsphere/lactose monohydrate powder blend administered nasally using MIAT® device, complementing findings relevant for their therapeutic potential. In conclusion, developed microspheres bear the potential to ensure prolonged melatonin retention at the nasal mucosa, improved bioavailability and advanced therapeutic outcome.

Preparation of in situ hydrogels loaded with azelaic acid nanocrystals and their dermal application performance study.

Azelaic acid (AZA) is a dicarboxylic acid that is topically used in the treatment of acne and rosacea since it possesses antibacterial and keratolytic activity. The primary objective of this study was to develop an AZA nanocrystal suspension. It is expected that improved solubility and dissolution rate will result in advanced biopharmaceutical properties, primarily the dermal bioavailability. Furthermore, a topical nanocrystal AZA-loaded hydrogels composed of Pluronic® F127 and hyaluronic acid mixture that are able to deliver AZA into the stratum corneum and deeper skin layers were considered. This study was conducted in order to: 1) determine the effect of non-ionic Polysorbate 60 on the stabilization and particle size of the AZA nanocrystals, as well as the effect of Pluronic® F127, used as an in situ gelation agent, and hyaluronic acid on the viscoelastic properties and the drug release of composed hydrogels, 2) determine the relationship between the rheological properties of the gels and the penetration of AZA into the stratum corneum. The composed hydrogels revealed pseudoplastic flow behaviour. The increase in Pluronic® F127 concentration induced a domination of elastic over viscous behaviour of the gels. The gel containing 15% of Pluronic® F127, 1% of hyaluronic acid and lyophilised 10% nanocrystal AZA suspension was considered to be an optimal formulation, since it possessed the rheological and drug delivery properties desirable for an in situ gelling platform for dermal application.

Grinding as Solvent-Free Green Chemistry Approach for Cyclodextrin Inclusion Complex Preparation in the Solid State.

Among the different techniques proposed for preparing cyclodextrin inclusion complex in the solid state, mechanochemical activation by grinding appears as a fast, highly efficient, convenient, versatile, sustainable, and eco-friendly solvent-free method. This review is intended to give a systematic overview of the currently available data in this field, highlighting both the advantages as well as the shortcomings of such an approach. The possible mechanisms involved in the inclusion complex formation in the solid state, by grinding, have been illustrated. For each type of applied milling device, the respective process variables have been examined and discussed, together with the characteristics of the obtained products, also in relation with the physicochemical characteristics of both the drug and cyclodextrin subjected to grinding. The critical process parameters were evidenced in order to provide a useful guide for a rational selection of the most suitable conditions for an efficient inclusion complex preparation by grinding, with the final purpose of promoting a wider use of this effective solvent-free cyclodextrin inclusion complex preparation method in the solid state.

Valorization of Olive Pomace-Based Nutraceuticals as Antioxidants in Chemical, Food, and Biological Models.

Waste remaining after the production of olive oil (olive pomace) is known to contain significant amounts of phenolic compounds that exert different types of biological activities, primarily acting as antioxidants. In this work, a sustainable approach that combines ultrasound-assisted extraction with food-grade solvents and encapsulation with different types of cyclodextrins was used to prepare olive pomace-based polyphenol rich extracts that were tested as antioxidants in various chemical, food, and biological model systems. Encapsulation with cyclodextrins had a significant positive impact on the chemical composition of obtained extracts and it positively affected their antioxidant activity. Observed effects can be explained by an increased content of polyphenols in the formulations, specific physical properties of encapsulated compounds improving their antioxidant activity in complex food/physiological environment, and enhanced interaction with natural substrates. Depending on the applied model, the tested samples showed significant antioxidant protection in the concentration range 0.1⁻3%. Among the investigated cyclodextrins, hydroxypropyl-ß-cyclodextrin and randomly methylated-ß-cyclodextrin encapsulated extracts showed particularly good antioxidant activity and were especially potent in oil-in-water emulsion systems (1242 mg/g and 1422 mg/g of Trolox equivalents, respectively), showing significantly higher antioxidant activity than Trolox (reference antioxidant). In other models, they provided antioxidant protection comparable to commonly used synthetic antioxidants at concentration levels of 2⁻3%.

Cyclodextrin encapsulation of daidzein and genistein by grinding: implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts.

This work aimed to investigate the potential effect of cyclodextrin encapsulation on intrinsic ability of daidzein (DAD) and genistein (GEN) to inhibit the glycosaminoglycan (GAG) synthesis in fibroblasts originating from patients with mucopolysaccharidosis (MPS), type II and III. DAD or GEN encapsulation with either 2-hydroxypropyl-ß-cyclodextrin or sulphobuthylether-ß-cyclodextrin were achieved by neat grinding and were characterised by thermal analysis, X-ray powder diffraction, scanning electron microscopy and solubility testing which confirmed the complexes formation with increased solubility with respect to starting compounds. Both isoflavones, as well as their co-ground cyclodextrin complexes reduced GAG levels in the fibroblasts of MPS II and MPS III patients from 54.8-77.5%, in a dose dependent manner, without any significant cytotoxic effect. Cyclodextrin encapsulation did not change the intrinsically high effect of both DAD and GEN on the GAG level reduction in the treated cells, thus could be considered as a part of combination therapies of MPS.

An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems.

In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration.

Membrane of Candida albicans as a target of berberine.

BACKGROUND: We investigated the mechanisms of anti-Candida action of isoquinoline alkaloid berberine, active constituent of medically important plants of Barberry species. METHODS: The effects on membrane, morphological transition, synthesis of ergosterol and the consequent changes in membrane permeability have been studied. Polarization and lipid peroxidation level of the membrane following berberine treatment have been addressed. RESULTS: Minimal inhibitory concentration (MIC) of berberine against C. albicans was 17.75 µg/mL. Cytotoxic effect of berberine was concentration dependent, and in sub-MIC concentrations inhibit morphological transition of C. albicans cells to its filamentous form. Results showed that berberine affects synthesis of membrane ergosterol dose-dependently and induces increased membrane permeability causing loss of intracellular material to the outer space (DNA/protein leakage). Berberine also caused membrane depolarization and lipid peroxidation of membrane constituents indicating its direct effect on the membrane. Moreover, ROS levels were also increased following berberine treatment indicating further the possibility of membrane damage. CONCLUSION: Based on the obtained results it seems that berberine achieves its anti-Candida activity by affecting the cell membrane.

Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding.

Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl-ß-cyclodextrin (HPßCD) and randomly methylated ß-cyclodextrin (MEßCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPßCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPßCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPßCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (Papp(PZQ)=(3.72±0.33)×10-5cms-1 and Papp(PZQ/HPßCD)=(3.65±0.21)×10-5cms-1; p>0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug.

The Influence of Extraction Parameters on Antimicrobial Activity of Propolis Extracts.

The extraction optimization of the poplar-type propolis was performed in order to improve the isolation of flavonoids as well as the corresponding antimicrobial activity of the products obtained. The efficiency of flavonoids extraction depended upon the type of extraction media used, following the rank. 80% ethanol >40 ethanol>> water, regardless of pH value. Ultrasound assisted extraction was as efficient as the maceration procedure, offering additional benefits such as short duration time and low extraction temperature. The antimicrobial efficiency of extracts prepared with 80 and 40% ethanol against the -tested microbial stains was comparable, regardless of the extraction technique used, while aqueous extracts mainly showed scarce activity. Observed activity against the yeast Candida albicans strongly correlated with flavones and flavonols content in extracts prepared (r²=0.8217), while regression analysis showed that beside flavonoids, some other components which were successfully extracted from the crude propolis contributed to the observed antimicrobial efficiency. against Bacillus subtilis and Staphylococcus aureus.

Therapeutic Potential of Hydroxypropyl-ß-Cyclodextrin-Based Extract of Medicago sativa in the Treatment of Mucopolysaccharidoses.

Mucopolysaccharidoses are inherited metabolic disorders resulting in the dysfunction of enzymes involved in the degradation of glycosaminoglycans, leading to severe clinical symptoms and a significantly shortened life span of patients. Flavonoids are recognized as glycosaminoglycan metabolism modulators, able to correct glycosaminoglycan cell storage. Therefore, the aim of this work was the development of an efficient and eco-friendly extraction process of phytochemicals from Medicago sativa by simultaneous use of ultrasound extraction and hydroxypropyl-ß-cyclodextrin complexation, and investigation of the potential of such an extract as a glycosaminoglycan metabolism modulator. The Box-Behnken design and response surface methodology were used in order to optimize the extraction process, considering hydroxypropyl-ß-cyclodextrin concentration, ultrasonic power, and extraction time as the key parameters. The dependent variables included total phenolicand total flavonoid content, DPPH radical scavenging activity, and Fe2+ chelating activity, due to the importance of oxidative stress in the pathology of mucopolysaccharidoses. The developed technology using hydroxypropyl-ß-cyclodextrin led to more selective flavonoid extraction from M. sativa than obtained either by the use of water or ethanol. The lyophilization of extracts resulted in products with high radical scavenging activity, suitable for further use. The application of 20 mM hydroxypropyl-ß-cyclodextrin solution, 432 W ultrasonic power, and an extraction time of 45 min resulted in an extract with both the highest total flavonoid content and the lowest radical scavenging activity IC50. This extract reduced the levels of glycosaminoglycans in skin fibroblasts of mucopolysaccharidose III patient in a dose-dependent manner. At concentrations of 3 and 6 µg/mL, the observed levels of glycosaminoglycans were reduced by 41.2 and 51.1 %, respectively, clearly demonstrating the validity of the selected approach.

Amidated pectin-based wafers for econazole buccal delivery: formulation optimization and antimicrobial efficacy estimation.

Combinations of low-methoxy amidated pectin (LMAP) and carboxymethylcellulose (CMC) were used to develop a lyophilized wafer formulation, aimed to obtain prolonged residence and controlled release of econazole nitrate (ECN) in the oral cavity. Ternary ECN/sulphobutylether-ß-cyclodextrin/citric acid complex, resulted as the most efficient system against selected Candida strains, was loaded into this formulation. The final product with the desired and predicted quality was developed by an experimental design strategy. The experimental values of mucoadhesion strength (28.37 ± 0.04 mg/cm(2)) and residence time (88.1 ± 0.1 min) obtained for the optimized wafer formulation were very close to the predicted ones, thus demonstrating the actual reliability and usefulness of the assumed model in the preparation of buccal wafers. The optimized formulation provided a constant ECN in situ release of 5mg/h and was efficacious against selected Candida strains in vitro. This clearly proved its potential as a novel effective delivery system for the therapy of oral candidiasis.

Comparative analysis of binary and ternary cyclodextrin complexes with econazole nitrate in solution and in solid state.

The aim of this work was to investigate in-depth interactions of econazole nitrate (ECN), a very poorly water-soluble antifungal agent, with different ß-cyclodextrin (ßCD) derivatives, and to evaluate the potential synergistic effect of suitable third compounds (l-amino acids, citric acid, hydrophilic polymers). Phase-solubility studies showed the formation of equimolar complexes with all tested CDs, and indicated sulfobutyl-ßCD (SBEßCD) as the best complexing and solubilizing agent for ECN, followed by hydroxypropyl-ßCD (HPßCD). 1D and 2D (1)H NMR studies demonstrated the actual formation of inclusion complexes of 1:1mol:mol stoichiometry, and gave insight about different inclusion modes of ECN molecule into the CD cavity, simultaneously existing in solution. Among the different tested ternary systems, only those with citric acid (CA) enabled a significant increase in complexing and solubilizing ability towards the drug with respect to the binary ones, indicating a synergistic effect between SBEßCD and CA and the formation of highly soluble ternary complexes, which was further supported by NMR studies. Solid equimolar binary and ternary systems of ECN, CDs and CA were prepared by co-grinding in high energy vibrational micro-mills and characterized by differential scanning calorimetry, X-ray powder diffractometry and in vitro dissolution studies. In the case of binary systems, total sample amorphization, indicative of strong solid state interactions and possible inclusion complex formation, was obtained only for co-ground products with HPßCD and SBEßCD, but they both presented a dissolution profile typical of a supersaturated system, with a limited improvement of drug dissolution efficiency (8.3 and 22.13 times, respectively). On the contrary, the ternary ECN/SBEßCD/CA co-ground product presented superior dissolution properties, increasing the ECN dissolution efficiency of 66.62 times, clearly having the best potential for further development of a novel ECN delivery system for efficient delivery of the drug to the oral cavity, thus improving the therapy of oral candidosis.

Development of low methoxy amidated pectin-based mucoadhesive patches for buccal delivery of triclosan: effect of cyclodextrin complexation.

A novel mucoadhesive buccal patch formulation of triclosan (TR), a broad spectrum antibacterial agent, was developed using low methoxy amidated pectin (AMP). The integrity of AMP matrix was improved by addition of 20% (w/w) Carbopol (CAR). The efficiency of ß-cyclodextrin-epichlorohydrin polymer (EPIßCD) and anionic carboxymethylated ß-cyclodextrin-epichlorohydrin polymer (CMEPIßCD) in optimization of TR solubility and release from such a matrix was investigated and confronted to that of parent ß-cyclodextrin (ßCD). Loading of TR/ßCD co-ground complex into AMP/CAR matrix resulted in a biphasic release profile which was sensitive upon the hydration degree of the matrix, due to lower solubilizing efficiency of ßCD, while the drug release from patches loaded with TR/EPIßCD complex was significantly faster with a constant release rate. Microbiological studies evidenced faster onset and more pronounced antibacterial action of TR/EPIßCD loaded patches, clearly demonstrating their good therapeutic potential in eradication of Streptococcus mutans, a cariogenic bacteria, from the oral cavity.

Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state.

The aim of this work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon (ZAL) complexation with parent ß-cyclodextrin (ßCD) and its randomly methylated derivative (RAMEB) in solution and in solid state. The addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (K(ZAL/RAMEB)=156±5M(-1) and K(ZAL/RAMEB/HPMC)=189±8M(-1); p<0.01), while such effect was not observed for ßCD (K(ZAL/ßCD)=112±2M(-1) and K(ZAL/ßCD/HPMC)=119±8M(-1); p>0.05). Although PVP increased the ZAL aqueous solubility from 0.22 to 0.27mg/mL, it did not show any synergistic effects on ZAL solubilization with the cyclodextrins tested. Binary and ternary systems of ZAL with ßCD, RAMEB and HPMC were prepared by spray-drying. Differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy demonstrated a partial ZAL amorphization in spray-dried binary and ternary systems with ßCD, while the drug was completely amorphous in all samples with RAMEB. Furthermore, inclusion complex formation in all systems prepared was confirmed by solid-state NMR spectroscopy. The in vitro dissolution rate followed the rank order ZAL/RAMEB/HPMC>ZAL/RAMEB=ZAL/ßCD/HPMC>ZAL/ßCD≫ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, RAMEB complexes had no positive effect on drug dissolution, because HPMC and RAMEB acted as a binders inside the tablets, prolonging their disintegration. Oppositely, the formulation with mannitol, a soluble excipient, containing a ternary RAMEB system, released the complete drug-dose in only 5min, clearly demonstrating its suitability for the development of immediate-release oral formulation of ZAL.