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.

Supramolecular Arrangement of Doxycycline with Sulfobutylether-ß-Cyclodextrin: Impact on Nanostructuration with Chitosan, Drug Degradation and Antimicrobial Potency.

Doxycycline (DX) is a well-established and broad-spectrum antimicrobial drug. However, DX has drawbacks, such as physicochemical instability in aqueous media and bacterial resistance. The inclusion of drugs in cyclodextrin complexes and their loading into nanocarriers can overcome these limitations. Thus, we studied the DX/sulfobutylether-ß-CD (SBE-ß-CD) inclusion complex for the first time and used it to reticulate chitosan. The resulting particles were evaluated by their physicochemical characteristics and antibacterial activity. DX/SBE-ß-CD complexes were characterized by nuclear magnetic resonance, infrared spectroscopy, thermal analysis, X-ray diffraction, and scanning electron microscopy (SEM), whereas DX-loaded nanoparticles were characterized by dynamic light scattering, SEM, and drug content. The partial inclusion of the DX molecule in CD happened in a 1:1 proportion and brought increased stability to solid DX upon thermal degradation. Chitosan-complex nanoparticles measured approximately 200 nm, with a narrow polydispersity and particles with sufficient drug encapsulation for microbiological studies. Both formulations preserved the antimicrobial activity of DX against Staphylococcus aureus, whereas DX/SBE-ß-CD inclusion complexes were also active against Klebsiella pneumoniae, indicating the potential use of these formulations as drug delivery systems to treat local infections.

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.

pH-temperature dual-sensitive nucleolipid-containing stealth liposomes anchored with PEGylated AuNPs for triggering delivery of doxorubicin.

Liposomes (Lip) are useful nanocarriers for drug delivery and cancer nanomedicine because of their ability to efficiently encapsulate drugs with different physical and chemical properties. The pH gradient between normal and tumoral tissues, and their rapid metabolism that induces hyperthermia encourage the development of pH- and thermo-sensitive Lip for delivering anticancer drugs. Nucleolipids have been studied as scaffolding material to prepare Lip, mainly for cancer therapy. Herein, we report for the first time the use of 1,2-dipalmitoyl-sn-glycero-3-(cytidine diphosphate) (DG-CDP) to develop pH/thermo-sensitive nucleolipid-containing stealth Lip stabilized by combination with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol, anchored with NH2-PEGylated gold nanoparticles (PEG-AuNPs, 15 nm) for triggering delivery of doxorubicin (Dox). The optimal composition of DPPC, DG-CDP and cholesterol (94:3:3) was established by Langmuir isotherms. Unloaded and Dox-loaded Lip and AuNPs-Lip exhibited nano-scale sizes (415-650 nm), acceptable polydispersity indexes (<0.33), spherical shapes, and negative Z-potential (-23 to -6.6 mV) due to the phosphate groups of DG-CDP, which allowed the anchoring with positively charged AuNPs. High EE% were achieved (>78%) and although efficient control in the Dox release towards different receptor media was observed, the release of Dox from PEG-AuNPs-Lip-Dox was significantly triggered at acidic pH and hyperthermia conditions, demonstrating its responsiveness to both stimuli. Dox-loaded Lip showed high cytotoxic activity against MDA-MB-231 breast cancer cells and SK-OV-3 ovarian cancer cells, suggesting that Dox was released from these nanocarriers over time. Overall, the liposomal formulations showed promising properties as stimuli-responsive nanocarriers for cancer nanomedicine, with prospects for hyperthermia therapy.

Amino acids and its pharmaceutical applications: A mini review.

Amino acids are natural compounds that can be safely used in pharmaceutical applications. Considering the great interest in the amino acids used in the pharmaceutical industry, this article presents an overview of investigations reported in recent years. In this regard, the first sections begin with an introductory description of the properties, classification and safety of amino acids, while in the other sections the most common methods for the preparation of amino acids formulations and their application on solubilization, permeation and stabilization of several active pharmaceutical ingredients are described. Furthermore, available data about the multicomponent systems approach is included. Lastly, the impact of amino acids formulations on therapeutic efficacy is explored. The advantages illustrated suggest that amino acids are capable of improving the biopharmaceutical properties of drugs.

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.

Cholesterol Levels Affect the Performance of AuNPs-Decorated Thermo-Sensitive Liposomes as Nanocarriers for Controlled Doxorubicin Delivery.

Stimulus-responsive liposomes (L) for triggering drug release to the target site are particularly useful in cancer therapy. This research was focused on the evaluation of the effects of cholesterol levels in the performance of gold nanoparticles (AuNPs)-functionalized L for controlled doxorubicin (D) delivery. Their interfacial and morphological properties, drug release behavior against temperature changes and cytotoxic activity against breast and ovarian cancer cells were studied. Langmuir isotherms were performed to identify the most stable combination of lipid components. Two mole fractions of cholesterol (3.35 mol% and 40 mol%, L1 and L2 series, respectively) were evaluated. Thin-film hydration and transmembrane pH-gradient methods were used for preparing the L and for D loading, respectively. The cationic surface of L allowed the anchoring of negatively charged AuNPs by electrostatic interactions, even inducing a shift in the zeta potential of the L2 series. L exhibited nanometric sizes and spherical shape. The higher the proportion of cholesterol, the higher the drug loading. D was released in a controlled manner by diffusion-controlled mechanisms, and the proportions of cholesterol and temperature of release media influenced its release profiles. D-encapsulated L preserved its antiproliferative activity against cancer cells. The developed liposomal formulations exhibit promising properties for cancer treatment and potential for hyperthermia therapy.

Development of self-microemulsifying lipid-based formulations of trans-resveratrol by systematically constructing lipid-surfactant-water phase diagrams using long-chain lipids.

The aim of this work was to develop self-microemulsifying lipid-based formulations of trans-resveratrol in cod liver oil, a long chain lipid, to increase its solubility, dissolution rate and oral bioavailability. Ternary phase diagrams of cod liver oil with surfactant and water as well as pseudo-ternary phase diagrams of the same by mixing cod liver oil (triglyceride) with glycerol monooleate (monoglyeride) were constructed to identify regions where microemulsions were formed. Kolliphor RH 40, Tween 80 and their 1:1-mixtures were evaluated as surfactants. No organic cosolvents were added. It was observed that cod liver oil alone did not form microemulsion with any of the surfactants used, and a 1:1 mixture of cod liver oil and glycerol monooleate was necessary to enable the formation of microemulsion. Among the surfactants, Kolliphor RH 40 provided the maximum microemulsification effect. Several formulations containing 6:4, 1:1, and 4:6 w/w ratios of lipid to surfactant using the 1:1 mixture of cod liver oil and glycerol monooleate as lipid components and Kolliphor RH 40 or its mixture with Tween 80 as surfactants were identified, and trans-resveratrol solubility in these formulations were determined. Drug concentrations used in the formulations were 80% of saturation solubility, and no organic cosolvents were used in any formulations to increase drug solubility or enable emulsification. In vitro dispersion testing in 250 mL of 0.01 N HCl (pH 2) according to the USP method 2 at 50 RPM showed that the formulations rapidly dispersed in aqueous media forming microemulsions and there was no drug precipitation.

Overcoming Biological Barriers With Block Copolymers-Based Self-Assembled Nanocarriers. Recent Advances in Delivery of Anticancer Therapeutics.

Cancer is one of the most common life-threatening illness and it is the world's second largest cause of death. Chemotherapeutic anticancer drugs have many disadvantages, which led to the need to develop novel strategies to overcome these shortcomings. Moreover, tumors are heterogenous in nature and there are various biological barriers that assist in treatment reisistance. In this sense, nanotechnology has provided new strategies for delivery of anticancer therapeutics. Recently, delivery platforms for overcoming biological barriers raised by tumor cells and tumor-bearing hosts have been reported. Among them, amphiphilic block copolymers (ABC)-based self-assembled nanocarriers have attracted researchers worldwide owing to their unique properties. In this work, we addressed different biological barriers for effective cancer treatment along with several strategies to overcome them by using ABC-based self-assembled nanostructures, with special emphasis in those that have the ability to act as responsive nanocarriers to internal or external environmental clues to trigger release of the payload. These nanocarriers have shown promising properties to revolutionize cancer treatment and diagnosis, but there are still challenges for their successful translation to clinical applications.

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.

Development of solid self-emulsifying drug delivery systems (SEDDS) to improve the solubility of resveratrol.

Aim: A solid self-emulsifying drug delivery systems was developed by using the spray-drying technique, to improve the solubility of resveratrol (RES). Materials & methods: Cod liver oil and three surfactant system were tested: soy phosphatidylcholine (SPC)/Eumulgin® HRE-40 (EU)/Sodium oleate (system A); SPC/Tween®80 (TW) /Sodium oleate (system B) and SPC/EU/TW (system C). Results: The greatest incorporation was obtained with system C (21.26 mg/ml). Solid self-emulsifying drug delivery systems with the highest yield were obtained with colloidal silicon dioxide (CSD) (80.12%), and CSD sodium croscarmelose 9:1 and 5:5. RES dissolution attained 100% at 45 min with CSD:CS 5:5. Discussion: The surface modification to hydrophilic by CSD:sodium croscarmellose reduced the cohesive force among drug particles. Conclusion: The developed systems are a good approximation for the design of strategies that could allow increasing the oral bioavailability of RES.

ß-cyclodextrin complexation as an approach to enhance the biopharmaceutical properties of Norfloxacin B Hydrate.

Binary systems of Norfloxacin B Hydrate with ß-CD were explored by reliable biopharmaceutical studies as potential candidates for the preparation of drug delivery systems. Initially, studies of antimicrobial activity and solubility of the different polymorphic forms of Norfloxacin provided evidence to select Norfloxacin B Hydrate as the optimal solid form of Norfloxacin. Solid binary systems were preparing by kneading, freeze-drying, and physical mixture methods. The influence on the solubility, dissolution rate and chemical stability of Norfloxacin B Hydrate was investigated. These studies showed an increment of solubility and dissolution rate in physiological simulated fluids. However, the solid systems were moderated hygroscopically under accelerated storage conditions, which produces a destabilizing effect that accelerated the chemical reactivity of the drug in such conditions. Therefore, special cares must be considered in the manufacturing process and the packaging selection. Moreover, the experimental results proved that freeze-drying was not an appropriate method for the preparation. In conclusion, the Norfloxacin oral bioavailability can be improved with this binary systems, that could be applied in the production of an alternative pharmaceutical formulation of the drug.

Inclusion complexes of ß-cyclodextrin and polymorphs of mebendazole: Physicochemical characterization.

Mebendazole (MBZ), designated as a WHO essential drug, can exist in diverse solid forms and presents low absorption at the gastrointestinal level. Considering the potential of cyclodextrins to enhance the solubility and permeability of drugs, inclusion complexes of polymorphs A and C of MBZ with ß­cyclodextrin were obtained. The characterization of the complexes in solid state was performed by using a combination of experimental techniques including Fourier transform infrared spectroscopy, powder X-ray diffractometry and solid state nuclear magnetic resonance. Moreover, the effect of the binary complexes on their physical stability was evaluated. In addition, for a complete characterization of polymorphs A and C, one dimensional spectra and correlation nuclear magnetic resonance experiments were employed. Our physical studies showed that the inclusion complexes were new crystalline forms that induced shifts and broadening in the infrared and nuclear spectra. A molecular modelling analysis performed on the inclusion modes, demonstrated that the most favourable structure for the complex was the head down orientation. Moreover, the intermolecular interactions calculated for the complex with the atoms in molecules theory are in good agreement with the spectroscopic results. The inclusion complexes exhibited an increment of solubility in simulated physiological media. Furthermore, it was demonstrated that the complex formation did not affect the physical stability of the polymorphs.

Synthesis and characterization of supramolecular systems containing nifedipine, ß-cyclodextrin and aspartic acid.

The purpose of this work was to characterize complexes of nifedipine with ß-cyclodextrin (ß-CD), with and without auxiliary agents, to improve aqueous solubility and the dissolution profile of nifedipine. Complexes were characterized using infrared spectroscopy, thermoanalytical methods, powder X-Ray diffraction, scanning electron microscopy, phase solubility analysis and dissolution studies. Spatial configurations were determined by NMR and further examined using computational techniques. This investigation showed that the amino acid Asp was the most efficient auxiliary agent for multicomponent complexes. The spatial configurations were consistent with those obtained by molecular modelling; evidencing that nifedipine inserted its aromatic ring into ß-CD, in all complexes, with Asp interacting with the wide hydrophilic rim of ß-CD. The dissolution rates of nifedipine:ß-CD:Asp complexes were significantly increased compared to those of the pure drug or nifedipine:ß-CD. These results indicate that the nifedipine:ß-CD:Asp system is a promising approach for the preparation of optimized formulations of nifedipine.