Solubility Of Hydrophobic Drugs Research Articles

Antibacterial Drug Development Using Starch Nanoparticles

Abstract: The naturally available carbohydrate polymer, starch, is biodegradable and biocompatible, making it suitable for drug encapsulation due to the presence of various hydroxy functionalities. Multidrug resistance in antibacterial agents can sometimes limit their use and pose toxicity issues due to dose-related problems resulting from the low bioavailability or solubility of hydrophobic drugs. To address this issue, antibiotics are delivered using nanocarriers that protect therapeutic agents from degradation and enhance the delivery of hydrophobic drugs. This review article discusses the utilization of starch nanoparticles as drug delivery vehicles or carriers for antibacterial agents.

Role of Polymeric Micelles in Ocular Drug Delivery: An Overview of Decades of Research.

Local drug delivery to the eye through conventional means has faced many challenges due to three essential barriers: (a) the complex structure of the cornea limiting drug absorption, (b) the capacity of ocular absorptive cells in drug metabolism, and (c) the washing effect of eye tears. Polymeric micelles (PMs) have been the focus of much interest for ocular drug delivery due to several advantages they provide for this application, including the capacity for the solubilization of hydrophobic drugs, nonirritability, nanoscopic diameter, and the clarity of their aqueous solution not interfering with vision. The potential to increase the release and residence time of incorporated medication at the site of absorption is also a bonus advantage for these delivery systems. This Review covers research conducted on single or mixed micelles prepared from small amphiphilic molecules, copolymers (diblock, triblock, and graft), and gel systems containing micelles. The purpose of this review is to provide an update on the status of micellar ocular delivery systems for different indications, with a focus on preclinical and clinical drug development. In this context, we are discussing the anatomy of the eye, various ocular barriers, different micellar formulations, and their benefits in ocular drug delivery, as well as the role of PMs in the management of ocular diseases both in preclinical models and in clinic. The encouraging preclinical effectiveness findings from experiments conducted in both laboratory settings and live animals have paved the way for the advancement of micellar systems in clinical trials for ocular administration and the first nanomicallar formulation approved for clinical use by the United States Food and Drug Administration (marketed as Cequa by Sun Pharmaceuticals).

Antimicrobial Photodynamic Therapy against Escherichia coli and Staphylococcus aureus Using Nanoemulsion-Encapsulated Zinc Phthalocyanine.

Multidrug-resistant microorganisms have become a significant public health threat, and traditional antibiotics are becoming ineffective. Photodynamic therapy (PDT) is a promising alternative that utilizes photosensitizers and light to produce Reactive Oxygen Species (ROS) that can kill microorganisms. Zinc phthalocyanine (ZnPc) is a promising photosensitizer due to its strong affinity for encapsulation in nanoemulsions and its antimicrobial properties. In this study, nanoemulsion was prepared using Miglyol 812N, a surfactant, and distilled water to dissolve hydrophobic drugs such as ZnPc. The nanoemulsion was characterized by its particle size, polydispersity index, Transmission Electron Microscope and Zeta potential, and the results showed that it was an efficient nanocarrier system that facilitated the solubilization of hydrophobic drugs in water. The use of ZnPc encapsulated in the nanoemulsion produced through the spontaneous emulsification method resulted in a significant reduction in cell survival percentages of gram-positive Staphylococcus aureus and gram-negative Escherichia coli by 85% and 75%, respectively. This may be attributed to the more complex cell membrane structure of E. coli compared to S. aureus. This demonstrates the potential of nanoemulsion-based PDT as an effective alternative to traditional antibiotics for treating multidrug-resistant microorganisms.

Amphiphilic Micelles as Superior Nanocarriers in Drug Delivery: from Current Preclinical Surveys to Structural Frameworks

AbstractThe designing of suitable carriers for the delivery of hydrophobic drugs is highly challenging for researchers. Solubilization of drugs is of immense importance for drug development since most drugs are water insoluble. Among various techniques employed for drug solubilization, the use of micellar solutions has been most common and prevalent for the solubilization of hydrophobic drugs now a days. The application of miceller systems for drug carriers shows some significance than that of other alternatives. Micelles can reside for longer time to afford gradual accumulation in the affected area in the body and more importantly their sizes allow them to accrue in the regions with leaky vasculature. Moreover, micelles can be obtained in a simple and reproducible way and their use for drug delivery has avoided many potential risks associated with other injectable formulations. These molecular self‐assembled nanostructures solubilize the drugs and protect them from undesirable external environments. Hence it is necessary to have appropriate knowledge on the self‐assembly phenomena associated with surfactant drug mixtures before proceeding for drug delivery. This review highlights details about important phenomenon associated with micellar systems and their role in drug delivery.

Self-Healable, Injectable Hydrogel with Enhanced Clotrimazole Solubilization as a Potential Therapeutic Platform for Gynecology.

Injectable, self-healing hydrogels with enhanced solubilization of hydrophobic drugs are urgently needed for antimicrobial intravaginal therapies. Here, we report the first hydrogel systems constructed of dynamic boronic esters cross-linking unimolecular micelles, which are a reservoir of antifungal hydrophobic drug molecules. The selective hydrophobization of hyperbranched polyglycidol with phenyl units in the core via ester or urethane bonds enabled the solubilization of clotrimazole, a water-insoluble drug of broad antifungal properties. The encapsulation efficiency of clotrimazole increases with the degree of the HbPGL core modification; however, the encapsulation is more favorable in the case of urethane derivatives. In addition, the rate of clotrimazole release was lower from HbPGL hydrophobized via urethane bonds than with ester linkages. In this work, we also revealed that the hydrophobization degree of HbPGL significantly influences the rheological properties of its hydrogels with poly(acrylamide-ran-2-acrylamidephenylboronic acid). The elastic strength of networks (GN) and the thermal stability of hydrogels increased along with the degree of HbPGL core hydrophobization. The degradation of the hydrogel constructed of the neat HbPGL was observed at approx. 40 °C, whereas the hydrogels constructed on HbPGL, where the monohydroxyl units were modified above 30 mol %, were stable above 50 °C. Moreover, the flow and self-healing ability of hydrogels were gradually decreased due to the reduced dynamics of macromolecules in the network as an effect of increased hydrophobicity. The changes in the rheological properties of hydrogels resulted from the engagement of phenyl units into the intermolecular hydrophobic interactions, which besides boronic esters constituted additional cross-links. This study demonstrates that the HbPGL core hydrophobized with phenyl units at 30 mol % degrees via urethane linkages is optimal in respect of the drug encapsulation efficiency and rheological properties including both self-healable and injectable behavior. This work is important because of a proper selection of a building component for the construction of a therapeutic hydrogel platform dedicated to the intravaginal delivery of hydrophobic drugs.

Biophysical Characterization of Interactions between Serum Albumin and Block Copolymer Micelles.

Block copolymer micelles have demonstrated great promise in the solubilization of hydrophobic drugs, but an understanding of the blood stability of the drug-laden micelles is needed for therapeutic advancement of micelle technologies. Following intravenous administration, mPEG-CL and mPEG-LA micelles have demonstrated quick release of their cargo and disassembly in blood, but the prevailing mechanisms of micelle disruption and key biomacromolecules driving this disruption have yet to be elucidated. Although protein interactions with solid polymeric nanoparticles have been characterized, not much is known regarding protein interactions with dynamic block copolymer micelles. Herein, we characterize the interaction of bovine and human serum albumins (BSA and HSA) with polymeric micelles, mPEG-CL and mPEG-LA, using protein fluorescence, isothermal titration calorimetry (ITC), and circular dichroism (CD) spectroscopy. We find that BSA and HSA have interactions with mPEG-CL, while only HSA is observed to weakly interact with mPEG-LA. Protein fluorescence suggests that binding of HSA to mPEG-CL and mPEG-LA is driven by electrostatic interactions. ITC suggests an interaction between serum albumin and mPEG-CL block copolymers driven by hydrogen bonding and electrostatic interactions in physiological MOPS-buffered saline, while mPEG-LA has no measurable interaction with either of the serum albumins. CD spectroscopy demonstrates that the protein secondary structure is intact in both proteins in the presence of mPEG-CL and mPEG-LA. Overall, BSA is not always predictive of polymeric interactions with HSA. Understanding of interactions between serum proteins and block copolymer micelles and the exact mechanisms of destabilization will direct the rational design of block copolymer systems for improving blood stability.

Exploring the Assembly of Resorc[4]arenes for the Construction of Supramolecular Nano-Aggregates.

Many biologically active compounds feature low solubility in aqueous media and, thus, poor bioavailability. The formation of the host-guest complex by using calixarene-based macrocycles (i.e., resorcinol-derived cyclic oligomers) with a good solubility profile can improve solubilization of hydrophobic drugs. Herein, we explore the ability of resorc[4]arenes to self-assemble in polar solutions, to form supramolecular aggregates, and to promote water-solubility of an isoflavone endowed with anti-cancer activity, namely Glabrescione B (GlaB). Accordingly, we synthesized several architectures featuring a different pattern of substitution on the upper rim including functional groups able to undergo acid dissociation (i.e., carboxyl and hydroxyl groups). The aggregation phenomenon of the amphiphilic resorc[4]arenes has been investigated in a THF/water solution by UV–visible spectroscopy, at different pH values. Based on their ionization properties, we demonstrated that the supramolecular assembly of resorc[4]arene-based systems can be modulated at given pH values, and thus promoting the solubility of GlaB.

Boosting the mechanical strength and solubility-enhancement properties of hydroxypropyl-β-cyclodextrin nanofibrous films

2-hydroxypropyl-β-cyclodextrin (HPβCD) nanofiber films have high surface-to-volume ratio and show high dissolution rate of hydrophobic drugs. However, the solubility-enhancement effect of HPβCD films may not be enough to include an effective dose in a sublingually administrable film. Moreover, unmodified HPβCD films are very brittle and difficultly transported and/or handled. So, the addition of polyethylene glycol (PEG) as a plasticizer was suggested to improve their ultimate tensile strength (UTS) and solubilization of hydrophobic drugs. Accordingly, six nanofiber films were developed and characterized, using three molecular weights of PEG (400, 1500 and 6000 Da) with two concentrations each (1:100 and 2:100 PEG:HPβCD), in addition to the unmodified HPβCD nanofibrous film. The results revealed that adding 1:100 of PEG 400 increases the UTS (∼2-fold) and the average fiber diameter (AFD) (∼3-fold). Moreover, the addition of PEG 400 significantly increased the solubility of two hydrophobic model drugs; coumarin (up to 7.7-fold of the original solubility) and 2-nitroimidazole (up to 1.6-fold of the original solubility). However, with higher PEG concentration/molecular weight, both AFD and UTS of the films decreased. On the other hand, it was noted that the solubility of the two model drugs decreased upon using 1500-Da PEG, and then increased with 6000-Da PEG.

Recent trends of self-emulsifying drug delivery system for enhancing the oral bioavailability of poorly water-soluble drugs

The oral route is the most popular route for the clinical administration of drugs to treat various diseases. Before a drug is absorbed into the blood circulation, it must undergo dissolution and permeation. However, most drugs exhibit poor aqueous solubility, and their limited absorption leads to low oral bioavailability. The solubility of hydrophobic drugs can be improved by various ways, such as solid dispersion, salt formation, pH modification, and self-emulsifying drug delivery system (SEDDS) use. Among them, the SEDDS has garnered attention during recent years as it improves oral bioavailability, reduces drug dose, and increases drug protection from unsuitable environment in the gastrointestinal tract. SEDDS comprises lipid-based formulations. It can solve the problems related to the dissolution and bioavailability of the Biopharmaceutics Classification System Class II and IV drugs. Depending on the preparation procedure, drug-loaded SEDDS can be divided into micro- (SMEDDS) and nano- (SNEDDS) formulations. In this review, we summarize the classification system of lipid formulations, the mechanism underlying improved oral drug absorption by SEDDS, and recent advances in the SEDDS. The SEDDS is a potential formulation for drug delivery. Owing to its small particle size, large surface area, high encapsulation efficiency, and high drug loading, the SEDDS can improve the rate and extent of oral absorption by maximizing drug solubility in the intestinal absorption site. Moreover, because of the lipid-based formulation of SEDDS, it can stimulate and enhance lymphatic transport of drugs to avoid hepatic first-pass metabolism, and thus improve their bioavailability.

Novel cationic surfactants with cleavable carbamate fragment: Tunable morphological behavior, solubilization of hydrophobic drugs and cellular uptake study

The new cationic surfactants containing octyl and dodecyl carbamate moiety in the head group and hexadecyl tail were synthesized and characterized. They demonstrate versatile self-assembling behavior strongly controlled by structural characteristics of amphiphilic molecules. The octyl derivative at a concentration of 0.06 mM forms micelles, which can undergo structural rearrangement with the increase of surfactant content in the solutions (above 0.01 M). Compound with a dodecyl substituent, upon reaching a critical concentration, forms large aggregates without passing through the micellar stage. Combination of different techniques makes it possible to assume that morphological transitions between micelles and vesicles probably occurs with the variation in structural characteristics and concentration of surfactants. This is supported by dynamic light scattering and transmission electron microscopy, as well as changes in characteristics of spectral probes sensitive to micropolarity and packing parameters of aggregates. Aggregates formed showed high solubilization capacity, exceeding that of typical cationic micelles, toward Orange OT hydrophobic dye and poorly water soluble anti-inflammatory drugs, indomethacin and meloxicam. Carbamate-containing surfactants demonstrated the ability to penetrate through cell membrane, delivering the solubilized hydrophobic substances into the cell, which was testified by flow cytometry and fluorescence microscopy with DAPI and Nile Red dyes.

Cationic Surfactants: Self-Assembly, Structure-Activity Correlation and Their Biological Applications.

The development of biotechnological protocols based on cationic surfactants is a modern trend focusing on the fabrication of antimicrobial and bioimaging agents, supramolecular catalysts, stabilizers of nanoparticles, and especially drug and gene nanocarriers. The main emphasis given to the design of novel ecologically friendly and biocompatible cationic surfactants makes it possible to avoid the drawbacks of nanoformulations preventing their entry to clinical trials. To solve the problem of toxicity various ways are proposed, including the use of mixed composition with nontoxic nonionic surfactants and/or hydrotropic agents, design of amphiphilic compounds bearing natural or cleavable fragments. Essential advantages of cationic surfactants are the structural diversity of their head groups allowing of chemical modification and introduction of desirable moiety to answer the green chemistry criteria. The latter can be exemplified by the design of novel families of ecological friendly cleavable surfactants, with improved biodegradability, amphiphiles with natural fragments, and geminis with low aggregation threshold. Importantly, the development of amphiphilic nanocarriers for drug delivery allows understanding the correlation between the chemical structure of surfactants, their aggregation behavior, and their functional activity. This review focuses on several aspects related to the synthesis of innovative cationic surfactants and their broad biological applications including antimicrobial activity, solubilization of hydrophobic drugs, complexation with DNA, and catalytic effect toward important biochemical reaction.

Poly(methyl vinyl ether-co-maleic acid) Hydrogels Containing Cyclodextrins and Tween 85 for Potential Application as Hydrophobic Drug Delivery Systems

Hydrogels have been extensively investigated as a platform for drug delivery. However, their use for the delivery of hydrophobic drugs has been limited by their incompatibility with hydrophobic drug molecules. The chemical modification of the structure of the hydrogels to include hydrophobic moieties has been proven to be a good alternative to increase the stability and solubility of hydrophobic drugs in the polymer matrix of the hydrogel. The inclusion of hydroxypropyl-β-cyclodextrins (HPBCD) and Tween® 85 (T85) within hydrogel matrices has the potential to improve hydrophobic drug loading and release. HPBCD have the ability to host hydrophobic drug molecules in their cone-like structure, forming inclusion complexes through host-guest interactions. On the other hand, T85 is an amphiphilic molecule and, consequently, has the potential to increase hydrophilic drug loading within the hydrogels. In the present work, a new type of hydrogel made from poly(methyl vinyl ether-co-maleic acid) (GAN) and poly(ethylene glycol) (PEG) containing T85 and HPBCD was synthesized for hydrophobic drug release. Hydrogels were based on GAN crosslinked (PEG) and HPBCD and/or T85 via an esterification in the solid state (solvent free). The synthesised hydrogels were characterised using Fourier transform infrared (FTIR) spectroscopy, swelling studies and contact angle measurements. The hydrogels showed swellings ranging from 140 to 180%. The inclusion of T85 in the hydrogels improved the wettability of the materials. On the other hand, the inclusion of HPBCD within the hydrogels decreased the wettability as the contact angle between the hydrogels and water increased with the HPBCD content. Finally, the materials were loaded with an ophthalmic drug, dexamethasone (DX). HPBC-containing hydrogels showed a higher DX uptake and, consequently, also a higher capacity of DX release. On the other hand, T85 containing hydrogels did not show any improvement over the hydrogels containing only GAN and PEG. The hydrogels were able to provide sustained DX release over periods of 6 h.

Characterization and Optimization of Capryol-90, Polysorbate-80, And Peg-400 Proportion in Mefenamic Acid Self Nanoemulsifying Drug Delivery System (SNEDDS) With Simplex-Lattice-Design

Mefenamic acid as pain relief drug belongs to the biopharmaceutics classification system (BCS) class II which is practically insoluble in water causing extremely low dissolution in gastrointestinal tract. The self nanoemulsifying drug delivery system (SNEDDS) is a new innovation pharmaceutical dosage form that has effectively known to increase solubilization of hydrophobic drug in polar solvent. In this study the capryol-90 was selected as oil phase in SNEDDS as it showed maximal solubility of mefenamic acid (20 mg/mL). Combination of polysorbate-80 and PEG-400 as a generally regarded as safe (GRAS) excipient were used as surfactant and co-surfactant in SNEDDS due to its high HLB property that can increase mefenamic acid solubility in water. The ternary phase diagram of capryol-90, polysorbate-80, and PEG-400 was constructed in advance to obtain the component concentration of spontaneous nanoemulsion region. Model simplex-lattice-design cooperated in Design-Expert®10 was used to define SNEDDS mefenamic acid formula. Optimized mefenamic acid SNEDDS formula consisted of 20% capryol-90, 31.62% polysorbate-80, and 48.38% PEG-400. Characterization study of Optimized mefenamic acid SNEDDS formula showed improvement of drug content (102.820 ± 4.950)%, emulsification time (421.015 ± 1.290) second, and viscosity (0.927 ± 0.017) mm2/s 30oC. One way ANOVA statistical analysis result of optimal formula SNEDDS (105.210 ± 4.425)% of drug content, commercial generic caplet (0.917 ± 0.094)%, and mefenamic acid powder capsule (10.446 ± 0,333)% gave significant value (sig*) below than 0.05. Optimal formula proved that SNEDDS can significantly increase mefenamic acid dissolution of pH 7.4 (ileum fluid). The optimal formula of mefenamic acid SNEDDS successfully formed an uniformity droplet size (PDI 0.18) with mean size 241.9 nm and the surface charge has a value of -16.5 mV respectively.

Effect of Surfactant-Bile Interactions on the Solubility of Hydrophobic Drugs in Biorelevant Dissolution Media.

Biorelevant dissolution media (BDM) methods are commonly employed to investigate the oral absorption of poorly water-soluble drugs. Despite the significant progress in this area, the effect of commonly employed pharmaceutical excipients, such as surfactants, on the solubility of drugs in BDM has not been characterized in detail. The aim of this study is to clarify the impact of surfactant-bile interactions on drug solubility by using a set of 12 surfactants, 3 model hydrophobic drugs (fenofibrate, danazol, and progesterone) and two types of BDM (porcine bile extract and sodium taurodeoxycholate). Drug precipitation and sharp nonlinear decrease in the solubility of all studied drugs is observed when drug-loaded ionic surfactant micelles are introduced in solutions of both BDM, whereas the drugs remain solubilized in the mixtures of nonionic polysorbate surfactants + BDM. One-dimensional and diffusion-ordered 1H NMR spectroscopy show that mixed bile salt + surfactant micelles with low drug solubilization capacity are formed for the ionic surfactants. On the other hand, separate surfactant-rich and bile salt-rich micelles coexist in the nonionic polysorbate surfactant + bile salt mixtures, explaining the better drug solubility in these systems. The nonionic alcohol ethoxylate surfactants show intermediate behavior. The large dependence of the drug solubility on surfactant-bile interactions (in which the drug molecules do not play a major role per se) highlights how the complex interplay between excipients and bile salts can significantly change one of the key parameters which governs the oral absorption of poorly water-soluble drugs, viz. the drug solubility in the intestinal fluids.

Selection of Aptamers for Hydrophobic Drug Docetaxel To Improve Its Solubility

With the development of combinatorial chemistry and high-throughput screening, the number of hydrophobic drug candidates continues to increase. However, the low solubility of hydrophobic drugs could induce erratic absorption patterns and affect the drug efficacy. Aptamers are artificially selected highly water-soluble oligonucleotides that bind to ions, small molecules, proteins, living cells, and even tissues. Herein, to increase the solubility of hydrophobic drug, we screened the aptamer by exploiting DNA library immobilization selection strategy and microfluidic technology. The highly water-soluble aptamer might influence the dissolving capacity of its target. To demonstrate the concept, docetaxel (DOC), a second-generation taxoid cytotoxic with significant antitumor agent activity, was chosen as the model. It is generally known that the clinical application of docetaxel is limited greatly owing to its poor water solubility and serious side effects. After seven rounds of selection, two docetaxel-specif...

Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self-Assembly and Transport Behavior.

Herein, a new series of non-ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C-10 and C-18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10-5 m and hydrodynamic diameters in the 8-10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self-assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non-cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1-anilinonaphthalene-8-sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 1055 m-1 and 1.43 × 106 m-1 , respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.

Salt effect on solubilization of hydrophobic drugs in block copolymeric micelles and investigation of their in vitro and in vivo oral efficiency

Here, we explored the phase and micellar behavior of a hydrophilic ethylene oxide-propylene oxide (EO-PO) branched octablock copolymer Tetronic®1107 (T1107; mol.wt.: 15000 g.mol−1, %PEO = 70, and HLB 18–23) in water and in aqueous NaCl solutions by dynamic light scattering (DLS) and small angle neutron scattering (SANS). Solubilization of two poorly water soluble antioxidant and anticancer drugs viz. curcumin and quercetin in the micelles was investigated by UV-spectrophotometry. The copolymer self-assembles to form nanosize micelles in dilute solution. The results also demonstrated that micelles markedly enhanced apparent solubility of the drugs and in vitro release profiles. Different kinetic models demonstrated drug release from micelles by the diffusion process. Cytotoxic effect of the drugs against Caco-2 cell line, permeability across Caco-2 cell monolayer, pharmacokinetic parameters and tissue distribution in Wistar rats performed for free and solubilized drugs, demonstrated marked effects of micelles on cytotoxicity, permeability and pharmacokinetics.

PH-Responsive self-assembly of cationic surfactants with a star-shaped tetra-carboxylate acid and the solubilization of hydrophobic drugs.

This work involved the construction of pH-responsive self-assembly systems from a pH-sensitive four-arm carboxylate acid (4EOCOOH) and either the cationic single chain surfactant dodecyl trimethyl ammonium bromide (DTAB) or the cationic gemini surfactant hexamethylene-1,6-bis(dodecyldimethylammonium bromide) (12-6-12). It was found that the constructed oligomeric-like structures from the mixtures of 4EOCOOH with DTAB or 12-6-12 greatly enhance the aggregation ability of the mixtures, thus improving the pH-responsivity. In particular, surfactant concentrations significantly affect the pH-responsivity at a fixed 4EOCOOH concentration. At higher surfactant concentrations, the pH-responsivity is suppressed, while at lower surfactant concentrations, the mixed aggregates gradually change from micelles to unstable large spherical aggregates or vesicles, and then to stable spherical aggregates, with decreasing pH. Moreover, the surfactant/4EOCOOH systems have different solubilization abilities for three hydrophobic drugs. For quercetin and baicalein, the systems support much better solubilization at lower pH values, while for indomethacin, the systems show better solubilization at higher pH values. In particular, compared with DTAB, 12-6-12 is more efficient in constructing pH-responsive systems, and the 12-6-12/4EOCOOH mixture shows better ability for solubilizing hydrophobic drugs. This work will be helpful in the design of high-efficiency, pH-responsive surfactant systems for solubilizing hydrophobic drugs by simply mixing pH-sensitive molecules with surfactants.

Nonionic Microemulsions as Solubilizers of Hydrophobic Drugs: Solubilization of Paclitaxel.

The strategy using nonionic microemulsion as a solubilizer for hydrophobic drugs was studied and is demonstrated in this work. The aqueous phase behaviors of mixed nonionic surfactants with various oils at 37 °C are firstly constructed to give the optimal formulations of nonionic microemulsions with applications in the enhanced solubilization of the model hydrophobic drug, paclitaxel, at 37 °C. Briefly, the suitable oil phase with paclitaxel significantly dissolved is microemulsified with appropriate surfactants. Surfactants utilized include Tween 80, Cremophor EL, and polyethylene glycol (4.3) cocoyl ether, while various kinds of edible oils and fatty esters are used as the oil phase. On average, the apparent solubility of paclitaxel is increased to ca. 70–100 ppm in the prepared microemulsions at 37 °C using tributyrin or ethyl caproate as the oil phases. The sizes of the microemulsions attained are mostly from ca. 60 nm to ca. 200 nm. The cytotoxicity of the microemulsion formulations is assessed with the cellular viability of 3T3 cells. In general, the cell viability is above 55% after 24 h of cultivation in media containing these microemulsion formulations diluted to a concentration of total surfactants equal to 50 ppm and 200 ppm.

The Effective Solubilization of Hydrophobic Drugs Using Epigallocatechin Gallate or Tannic Acid-Based Formulations

Hydrotropic solubilization of hydrophobic drugs requires supramolar amounts of hydrotropes with potential toxicity issues. We investigated the use of epigallocatechin gallate (EGCG) and tannic acid at millimolar concentrations, as hydrotrope-like solubilizing agents. Paclitaxel, docetaxel, amphotherecin B, curcumin, or rapamycin were dried down with EGCG or tannic acid from ethanol and then redissolved in aqueous media. Following centrifugation and filtration, the drug solubility was measured using HPLC. The uptake of docetaxel into cells from EGCG-based solutions was measured using radiolabeled drugs. Both EGCG and tannic acid effectively increased the aqueous solubility of all drugs from low levels (μg/mL) to high levels (mg/mL) in a concentration-dependent fashion at millimolar concentrations. Solutions were generally stable at room temperature over 24 h. Compared with micellar formulations, EGCG-based solutions of docetaxel demonstrated markedly improved drug uptake or transport levels in all cell lines. The use of these additives may provide improved formulation of various hydrophobic drugs using oral, parenteral, localized, or device-associated delivery systems.