Cyclodextrins and Their Derivatives as Drug Stability Modifiers.

Cyclodextrins (CDs) are cyclic oligosaccharides that contain a relatively hydrophobic central cavity and a hydrophilic outer surface. They are widely used to form non-covalent inclusion complexes with many substances. Although such inclusion complexes typically exhibit higher aqueous solubility and chemical stability than pure drugs, it has been shown that CDs can promote the degradation of some drugs. This property of stabilizing certain drugs while destabilizing others can be explained by the type of CD used and the structure of the inclusion complex formed. In addition, the ability to form complexes of CDs can be improved through the addition of suitable auxiliary substances, forming multicomponent complexes. Therefore, it is important to evaluate the effect that binary and multicomponent complexes have on the chemical and physical stability of complexed drugs. The objective of this review is to summarize the studies on the stabilizing and destabilizing effects of complexes with CDs on drugs that exhibit stability problems.

Optimization of the Extraction Conditions of Bioactive Compounds from Ocimum basilicum Leaves Using Ultrasound-Assisted Extraction via a Sonotrode.

Sweet basil (Ocimum basilicum) leaves are rich in bioactive compounds that present therapeutic benefits for human health. Ultrasonic-assisted extraction (UAE) is frequently used to obtain phenolic compounds from plants/herbal sources. However, few works have developed multi-variable studies to find the optimal conditions to extract the maximum amount of compounds, especially when applied to UAE via a sonotrode. The purpose of this work was to perform a multi-variable study by employing a Box-Behnken design to collect the highest active compound content from Ocimum basilicum leaves. The efficacy of the design was endorsed by ANOVA. The studied parameters for UAE via a sonotrode were the ethanol/water ratio, amplitude, and time. The analyzed responses were the rosmarinic acid, the sum of phenolic acids, and the sum of phenolic compounds content. The optimal conditions were found to be 50% ethanol/water, 50% amplitude, and 5 min. Twenty bioactive compounds were identified by HPLC-ESI-TOF-MS when the extract was collected by applying the optimal conditions. Ocimum basilicum may be appreciated as a valuable source of important bioactive substances for pharmaceutical use.

Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution.

In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using ß-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing ß-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott's method and statistical studies. The structure of the binary systems with ß-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect ß-cyclodextrin and N-acetylcysteine on the polymorph's chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the ß-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution.

Development and Characterization of Pharmaceutical Systems Containing Rifampicin.

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was evaluated by phase-solubility studies. The mechanism of interaction was established through proton nuclear magnetic resonance spectroscopy and molecular modeling. Physicochemical characterization was investigated using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. The dissolution properties, antimicrobial activity (antibacterial, antibiofilm, and antileishmanial), and stability of the different samples were studied. The results obtained in this investigation demonstrate that multicomponent complexes can improve the water solubility and dissolution rate of rifampicin, as well as its antibacterial and antileishmanial action, and present suitable stability. In conclusion, rifampicin complexed with γ-cyclodextrin and arginine is an attractive approach for developing pharmaceutical dosage forms of rifampicin with increased antimicrobial activities.

Sulfobutylether-ß-cyclodextrin: A functional biopolymer for drug delivery applications.

Sulfobutylether ß-cyclodextrin (SBE-ß-CD) is a polyanionic cyclic oligosaccharide that contains glucopyranose units forming a torus ring-like structure. SBE-ß-CD is gifted with many favorable properties viz. relatively high solubility (>50 folds compared to ß-CD), improved stability, and biocompatibility that praised SBE-ß-CD as a smart polymer for drug delivery applications. Commercially, SBE-ß-CD is popular by its brand name Captisol®. The present review discusses the structure, properties, and preparation methods of SBE-ß-CD-based inclusion complexes (ICs). Furthermore, we discuss here the preparation and applications of SBE-ß-CD ICs-based nanoparticulate drug delivery systems, which combines the merits of both, ICs (enhanced solubility) and nanoparticles (NPs, targeted therapy). Patents on and FDA-approved Captisol®-enabled products are tabulated in the benefit of readers. The toxicological aspects and current clinical status of SBE-ß-CD or SBE-ß-CD-based products are briefly explained in the present review. In our opinion, the present review would be a pathfinder to allow dissemination of information on SBE-ß-CD.

Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications.

Cyclodextrins (CDs) are naturally available water-soluble cyclic oligosaccharides widely used as carriers in the pharmaceutical industry for their ability to modulate several properties of drugs through the formation of drug-CD complexes. The addition of an auxiliary substance when forming multicomponent complexes is an adequate strategy to enhance complexation efficiency and to facilitate the therapeutic applicability of different drugs. This review discusses multicomponent complexation using amino acids; organic acids and bases; and water-soluble polymers as auxiliary excipients. Special attention is given to improved properties by including information on the solubility, dissolution, permeation, stability and bioavailability of several relevant drugs. In addition, the use of multicomponent CD complexes to enhance therapeutic drug effects is summarized.

Simultaneous improvement of ketoconazole solubility, antifungal and antibiofilm activity by multicomponent complexation.

Background: A novel multicomponent complex (MC) of ketoconazole (KET) with ß-cyclodextrin (ß-CD) and N-acetylcysteine (NAC) was developed with the purpose of improving the solubility as well as the antifungal and antibiofilm activity of KET against Candida albicans. Results & methodology: The interactions among the components were studied using nuclear magnetic resonance, thermal analysis, powder x-ray diffraction, infrared spectroscopy and scanning electron microscopy. Phase-solubility studies demonstrated a considerable increase in the solubility of the MC. An enhancement in antibiofilm and antifungal activity of MC was determined against C. albicans by XTT assay and microbiological studies. Conclusion: This MC, with improvements in the drug pharmaceutical performance, might have an important potential in the development of new pharmaceutical formulations of KET.

Improved Activity of Rifampicin Against Biofilms of Staphylococcus aureus by Multicomponent Complexation.

The aim of this study was to evaluate a multicomponent complex (MC) between rifampicin (RIF), ß-cyclodextrin (ß-CD), and selected amino acids to enhance the solubility and antibiofilm activity of RIF. After performing phase-solubility studies that demonstrated a considerable increase in the solubility of RIF for the MC, the corresponding solid system was prepared by a freeze-drying method. Characterization of the MC was performed by Fourier transform-infrared spectroscopy, thermal analysis, powder X-ray diffraction, and scanning electron microscopy. Structural analyses evidenced molecular interactions between the components, resulting in a MC with amorphous solid features. Structural studies involving both experimental (i.e., 1H NMR) and theoretical (i.e., molecular modeling) methodologies demonstrated the inclusion of the RIF piperazine ring in the ß-CD cavity. The bioactivity of the MC measured against biofilms of Staphylococcus aureus showed a significant reduction in the metabolic activity of the bacterium. Overall, the studied MC exhibited promising properties for the development of pharmaceutical formulations to treat bacterial infections.

Exploring solid forms of oxytetracycline hydrochloride.

Oxytetracycline hydrochloride, an antibiotic of the tetracycline family, is a polymorphic drug that evidences erratic absorption in oral administration. Additionally, poor solid state characterization of the polymorphs and diversity in the existing nomenclature impede the correct identification of the raw materials. In this work, oxytetracycline hydrochloride solid forms were prepared from isopropyl alcohol, ethanol and methanol through different crystallization techniques, and then their physicochemical and microbiological properties were evaluated. A combination of advanced techniques such as solid state nuclear magnetic resonance, powder X-ray diffraction, infrared spectroscopy, thermal analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy were used in the characterization of solid samples giving clear evidence of the existence of three stable and one metastable solid forms of the oxytetracycline hydrochloride. Solubility was determined in aqueous solution, simulated gastric fluid, and simulated intestinal fluid. In addition, microbiological studies were performed. The polymorphs showed similar antimicrobial activity against Escherichia coli and Staphylococcus aureus. Therefore, these solid forms of oxytetracycline hydrochloride constitute promising candidates to encourage studies for repositioning old and known antibiotic drugs in the developing strategies for new therapeutic alternatives.

Evaluating ternary systems with oligosaccharides as a strategy to improve the biopharmaceutical properties of furosemide.

Novel ternary systems with ß-cyclodextrin or maltodextrin and triethanolamine as the third component were developed with the aim of improving the oral bioavailability of furosemide. These new solids were characterized by solid-state nuclear magnetic resonance, Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The solubility, dissolution and stability (chemical and physical) were studied. Among the most important results, it was observed that both ternary systems showed an important enhancement in the solubility of the drug. In particular, the system obtained by combination of ß-cyclodextrin and TEA exhibited improvement in the dissolution profiles and photo-stability of furosemide compared with the binary system previously reported. Moreover, this system constitutes an interesting therapeutic alternative as it did not produce cellular toxicity compared with free furosemide. In conclusion, the results obtained revealed that this ternary system establishes a promising approach for oral delivery of the drug.

Effect of Complexes and Microemulsions on the Permeability of Drugs: Determination Using a New Biomimetic Artificial Membrane.

The aim of this work was to predict the permeability of two model drugs, sulfamerazine (SMR) and indomethacin (INM), and to determine the effect on their apparent permeabilities by complexation with cyclodextrins and/or meglumine or incorporation in microemulsions. Permeation experiments were performed using two-chamber diffusion cells with a new composition of bio-mimetic membrane composed of 80% of Lipoid® S100 and 20% of cholesterol in n-octanol 10% w/w solution, at 37 ± 0.5°C and 14,000 rpm. The predictive capacity of the permeability of passive diffusion absorbed compounds was evaluated using 20 drug standards and showed an exponential correlation between the apparent permeability coefficients (Papp) and the fraction absorbed percentages in humans (Fa%), with an R2 value of 0.67942 and a constant value of - 4.1 ± 0.8. SMR and INM were classified as Class II and I, respectively, according to the Biopharmaceutical Classification System. These drugs were complexed and incorporated in microemulsions. The Fa% from all the drug products was higher than 90%. SMR in the complexes and both drugs in microemulsions were classified as highly soluble. Thus, SMR and INM incorporated in these pharmaceutical products could be classified as Class I.

Improving Properties of Albendazole Desmotropes by Supramolecular Systems with Maltodextrin and Glutamic Acid.

Albendazole, an effective broad-spectrum anthelmintic agent, showed unpredictable therapeutic response caused by poor water solubility and slow dissolution rate. Then, novel binary and multicomponent supramolecular systems of two different solid forms of albendazole (I and II) with maltodextrin alone or with glutamic acid were studied as an alternative to improve the oral bioavailability of albendazole. The interactions and effects on the properties of albendazole were studied in solution and solid state. The solid systems were characterized using Raman and Fourier transform-infrared spectroscopy, thermal analysis, powder X-ray diffraction, and scanning electron microscopy. The solubility measurements, performed in aqueous and simulated gastric fluid, showed that albendazole (form II) was the most soluble form, while its supramolecular systems showed the highest solubility in simulated gastric fluid. On the other hand, the dissolution profiles of binary and multicomponent systems in simulated gastric fluid displayed pronounced increments of the dissolved drug and a faster dissolution rate compared to those of free albendazole forms. Thus, these supramolecular structures constitute an interesting alternative to improve the physicochemical properties of albendazole, with potential application for the preparation of pharmaceutical oral formulations.

Artificial Lipid Membrane Permeability Method for Predicting Intestinal Drug Transport: Probing the Determining Step in the Oral Absorption of Sulfadiazine; Influence of the Formation of Binary and Ternary Complexes with Cyclodextrins.

We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5 donor/pH 7.4 receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (Papp) and the oral dose fraction absorbed in humans (fa) of 16 drugs with different absorption properties. The Papp values correlated well with the absorption rates under the two conditions, and the method showed high predictability and good reproducibility. On the other hand, with this method, we successfully predicted the transport characteristics of oral sulfadiazine (SDZ). Also, the tradeoff between the increase in the solubility of SDZ by its complex formation with cyclodextrins and/or aminoacids and its oral permeability was assessed. Results suggest that SDZ is transported through the gastrointestinal epithelium by passive diffusion in a pH-dependent manner. These results support the classification of SDZ as a high/low borderline permeability compound and are in agreement with the Biopharmaceutics Classification Systems (BCS). This conclusion is consistent with the in vivo pharmacokinetic properties of SDZ.

Characterization of systems with amino-acids and oligosaccharides as modifiers of biopharmaceutical properties of furosemide.

Furosemide is the most commonly prescribed diuretic drug in spite of its suboptimal biopharmaceutical properties. In this work, the addition of different amino-acids was studied with the aim of selecting an enhancer of the furosemide solubility. The best results were obtained with arginine. Also, binary (furosemide:arginine) and ternary (furosemide:arginine:ß-cyclodextrin and furosemide:arginine:maltodextrin) systems were prepared by the kneading method and they were compared with their corresponding physical mixtures. These new systems were characterized by Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. In addition, dissolution studies were performed in simulated gastric fluid. The best results in relation to improving biopharmaceutical properties were obtained with a binary combination of furosemide and arginine, demonstrating that this system could result in a suitable candidate for the development of a promising pharmaceutical formulation of the drug.

Preparation of Chloramphenicol/Amino Acid Combinations Exhibiting Enhanced Dissolution Rates and Reduced Drug-Induced Oxidative Stress.

Chloramphenicol is an old antibiotic agent that is re-emerging as a valuable alternative for the treatment of multidrug-resistant pathogens. However, it exhibits suboptimal biopharmaceutical properties and toxicity profiles. In this work, chloramphenicol was combined with essential amino acids (arginine, cysteine, glycine, and leucine) with the aim of improving its dissolution rate and reduce its toxicity towards leukocytes. The chloramphenicol/amino acid solid samples were prepared by freeze-drying method and characterized in the solid state by using Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance. The dissolution properties, antimicrobial activity, reactive oxygen species production, and stability of the different samples were studied. The dissolution rate of all combinations was significantly increased in comparison to that of the pure active pharmaceutical ingredient. Additionally, oxidative stress production in human leukocytes caused by chloramphenicol was decreased in the chloramphenicol/amino acid combinations, while the antimicrobial activity of the antibiotic was maintained. The CAP:Leu binary combination resulted in the most outstanding solid system makes it suitable candidate for the development of pharmaceutical formulations of this antimicrobial agent with an improved safety profile.

Toward novel antiparasitic formulations: Complexes of Albendazole desmotropes and ß-cyclodextrin.

Novel complexes of two different solid forms of Albendazol and ß-cyclodextrin were investigated in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. The interaction between each form of Albendazol and ß-cyclodextrin was studied in solution and solid state, in order to investigate their effect on the solubility and dissolution rate of Albendazol solid forms. The solid supramolecular systems were characterized using a variety of techniques including natural-abundance 13C cross-polarization magic-angle-spinning nuclear magnetic resonance, powder X-ray diffraction, Fourier transform-infrared spectroscopy and scanning electron microscopy. The results obtained showed the highest increment of solubility and dissolution rate, in simulated gastric fluid, for the Albendazole II:ß-cyclodextrin systems. Thus, these new complexes constitute an interesting alternative for improving the oral bioavailability of Albendazol.

Enhanced inhibition of bacterial biofilm formation and reduced leukocyte toxicity by chloramphenicol:ß-cyclodextrin:N-acetylcysteine complex.

The purpose of this study was to improve the physicochemical and biological properties of chloramphenicol (CP) by multicomponent complexation with ß-cyclodextrin (ß-CD) and N-acetylcysteine (NAC). The present work describes the ability of solid multicomponent complex (MC) to decrease biomass and cellular activity of Staphylococcus by crystal violet and XTT assay, and leukocyte toxicity, measuring the increase of reactive oxygen species by chemiluminescence, and using 123-dihydrorhodamine. In addition, MC was prepared by the freeze-drying or physical mixture methods, and then characterized by scanning electron microscopy and powder X-ray diffraction. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the MC and its association binding constants, respectively. The results obtained allowed us to conclude that MC formation is an effective pharmaceutical strategy that can reduce CP toxicity against leukocytes, while enhancing its solubility and antibiofilm activity.

Supramolecular aggregates of oligosaccharides with co-solvents in ternary systems for the solubilizing approach of triamcinolone.

A second compound is generally associated with oligosaccharides as a strategy to maximize the solubilizing effect for nonpolar compounds. This study elucidated the role and the mechanism whereby liquid compounds interact in these supramolecular aggregates in the solubilization of triamcinolone. Three different oligosaccharides (beta-cyclodextrin, 2-hydroxipropil-beta-cyclodextrin, and randomly methylated beta-cyclodextrin) and two potent co-solvents (triethanolamine and N-methyl pyrrolidone) were carefully evaluated by using three distinct experimental approaches. Incredibly stable complexes were formed with cyclodextrins (CDs). The structure of the complexes was elucidated by magnetic resonance spectra 2D-ROESY. The interactions of the protons of ring "A" of the drug with H(3) and H(5) protons of the CD cavity observed in the binary complexes remained in both ternary complexes. Unlike the observed ternary associations with triethanolamine, N-methyl pyrrolidone competed with the triamcinolone CD cavity and considerably decreased the stability of the complex and the solubility of the drug. The molecular dynamics (MD) and quantum mechanics:molecular mechanics (QM:MM) calculations supported that triethanolamine stabilized the drug-CD interactions for the conformer identified in the 2D-ROESY experiments, improving the quality and uniformity of the formed complex. The role played by the co-solvent in the ternary complexes depends on its specific ability to interact with the CD cavity in the presence of the drug, which can be predicted in theoretical studies to select the best candidate.

Nanostructured Lipid Carriers as a Strategy to Improve the In Vitro Schistosomiasis Activity of Praziquantel.

Praziquantel (PZQ) is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Currently, due to its efficacy, PZQ is the drug of choice against all species of Schistosoma. Although widely used, PZQ exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water soluble drugs. The aim of this study was to investigate nanostructured lipid carriers as a strategy to improve the efficacy of PZQ in S. mansoni treatment. We prepared NLC2 and NLC4 by adding seventy percent glycerol monostearate (GMS) as the solid lipid, 30% oleic acid (OA) as the liquid lipid and two surfactant systems containing either soybean phosphatidylcholine/poloxamer (PC/P-407) or phosphatidylcholine/Tween 60 (PC/T60), respectively. The carriers were characterized by nuclear magnetic resonance, differential scanning calorimetry, thermogravimetric analysis and Fourier transform-infrared spectroscopy. The safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. The results showed that the encapsulation of PZQ in NLC2 or NLC4 improved the safety profile of the drug. Treatment efficacy was evaluated on the S. mansoni BH strain. PZQ-NLC2 and PZQ-NLC4 demonstrated an improved efficacy in comparison with free PZQ. The results showed that the intestinal transport of free PZQ and PZQ-NLC2 was similar. However, we observed that the concentration of PZQ absorbed was smaller when PZQ was loaded in NLC4. The difference between the amounts of absorbed PZQ could indicate that the presence of T60 in the nanoparticles (NLC4) increased the rigid lipid matrix, prolonging release of the drug. Both systems showed considerable in vitro activity against S. mansoni, suggesting that these systems may be a promising platform for the administration of PZQ for treating schistosomiasis.

Development and Characterization of a Biocompatible Soybean Oil-Based Microemulsion for the Delivery of Poorly Water-Soluble Drugs.

The aim of this work was the development and characterization of a biocompatible microemulsion (ME) containing soybean oil (O), phosphatidylcholine/sodium oleate/Eumulgin®HRE40 as the surfactant mixture (S) and water or buffer solution as the aqueous phase (W), for oral delivery of the poorly water-soluble drugs sulfamerazine (SMR) and indomethacin (INM). A wide range of combinations to obtain clear oil-in-water (o/w) ME was observed from pseudo-ternary phase diagrams, which was greater after the incorporation of both drugs, suggesting that they acted as stabilizers. Drug partition studies indicated a lower affinity of the drugs for the oil domain when they were ionized and with increased temperature, explained by the fact that both drugs were introduced inside the oil domain, determined by nuclear magnetic resonance. High concentrations of SMR and INM were able to be incorporated (22.0 and 62.3 mg/mL, respectively). The ME obtained presented an average droplet size of 100 nm and a negative surface charge. A significant increase in the release of SMR was observed with the ME with the highest percentage of O, because of the solubilizing properties of the ME. Also, a small retention effect was observed for INM, which may be explained by the differences in the partitioning properties of the drugs.