Therapeutic Deep Eutectic Solvents Research Articles

Therapeutic deep eutectic solvent with saponin, optimized through response surface methodology, exert potent in vivo antimicrobial effects against Pseudomonas aeruginosa.

Therapeutic deep eutectic solvents (THEDES) are a type of deep eutectics that can be used as active pharmaceutical ingredients (APIs) by enhancing the drug bioavailability, by increasing the solubility of APIs in aqueous solutions or by increasing their permeability through biological barriers. In this study, we demonstrate the utility of designer THEDES, based on Quillaja Saponin (SAP), a triterpene natural product to unravel the antimicrobial potential of such THEDES. THEDES were prepared by gently mixing and heating five different α- hydroxy acids- malic, citric, tartaric, glycolic, lactic acids and SAP with water as a third component in the THEDES. The antimicrobial assays were performed with the as-prepared SAP-THEDES and among the panel of bacterial strains, saponin-malic acid THEDES [SMA-THEDES] displayed potent activity in disassembling PA biofilms, demonstrating that the SMA-THEDES can serve as therapeutic antibacterial biomaterials. To further optimize, a Box-Behnken- response surface methodology (RSM) experimental design was done and at the optimum conditions of SAP (1.014m.mol), Malic acid (1.003m.mol), Water (0.117m.mol), SMA-THEDES exhibited maximum MIC of P. aeruginosa with the minimum absorbance at 590nm of 0.105. The effectiveness of SMA-THEDES as antibiofilm agents on P. aeruginosa with the mechanism studies have been explored. The colony count from the in vivo infection zebrafish model in the treatment group showed a decline of > 2 fold for SMA-THEDES. Toxicity studies did not reveal any abnormality in liver and brain enzyme levels. Liver morphology images show no severe cytological alterations when treated with SMA-THEDES and were almost similar to the normal liver.

Harnessing therapeutic deep eutectic solvents in self-emulsifying systems to improve CBD delivery

In this study, Cannabidiol crystals (CBD) were used as a BCS class II model drug to generate a novel therapeutic deep eutectic solvent (THEDES) with easy preparation using caprylic acid (CA). The hydrogen bonding interaction was confirmed by different techniques such as FT-IR and NMR, resulting in a hydrophobic system suitable for liquid formulations. The CBD-based THEDES, combined with a specific mixture of surfactants and co-surfactants, successfully formed a self-emulsifying drug delivery system (SEDDS) that generated uniform nano-sized droplets once dispersed in water. Hence, the THEDES showed compatibility with the self-emulsifying approach, offering an alternative method to load drugs at their therapeutic dosage. Physical stability concerns regarding the unconventional oily phase were addressed through stress tests using multiple and dynamic light scattering, demonstrating the robustness of the system. In addition, the formulated SEDDS proved effective in protecting CBD from the harsh acidic gastric environment for up to 2 h at pH 1.2. Furthermore, in vitro studies have confirmed the safety of the formulation and the ability of CBD to permeate Caco-2 cells when formulated. This investigation highlights the potential incorporation of THEDES in lipid-based formulations like SEDDS, expanding the avenues for innovative oral drug delivery approaches.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the “deep eutectic” region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds’ physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids.In the current work, we probed the “deep eutectic” phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound’s glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the “deep eutectic” region there was still an ideal, or thermodynamically preferrable “THEDES point”, which would exhibit excellent stability upon exposure to stress storage conditions.The discoveries of this study bring the literature one step closer to fully understanding the “therapeutic deep eutectic” phenomenon. Through correlation between parent reagents’ physicochemical properties and the synthesised products’ characteristics, we establish a more educated process for the prediction and engineering of THEDES.

Structural insights into novel therapeutic deep eutectic systems with capric acid using 1D, 2D NMR and DSC techniques with superior gut permeability.

Therapeutic deep eutectic solvents (THEDSs) are the best exemplification of green alternative formulations of active pharmaceutical ingredients (APIs) that offer superlative properties of APIs. Previously, THEDESs of risperidone, fentanyl and levofloxacin with capric acid (CA) were developed by our group. These APIs share cyclic tertiary amine nuclei. Herein, DESs of two drugs bearing cyclic tertiary amine nucleus, namely, droperidol and aripiprazole, in the presence of CA, were investigated as model drugs. Comprehensive analyses were conducted using liquid-state 1D and 2D NMR and differential scanning calorimetry (DSC) to elucidate the regiochemistry and thermodynamic mechanisms bringing about those THEDESs. Everted gut sac technique was used to study the flux of the developed THEDESs. 1D and 2D NMR techniques analyses revealed the importance of cyclic tertiary amine nuclei in forming interactions with CA. This was confirmed by the downfield shift of the protons proximal to the tertiary amine groups compared to the individual drugs. Diffusion NMR analysis (DOSY) showed a significant reduction in the diffusion coefficient of CA in the mixed system compared with CA in isolation. Thermal analysis of the two drugs revealed that the drugs have a low tendency to recrystallise upon melting but rather vitrify from a melt to form an amorphous solid. Interestingly, the superior absorption and flux of the THEDES formulation of droperidol was demonstrated using the ERIS. Collectively, this work provides a green method to attain liquid formulations of APIs with enhanced pharmacokinetic features.

THEDES as a drug product intermediate for improved melt-extrusion processibility of thermally labile active ingredients

Hot melt extrusion (HME) is extensively employed in the pharmaceutical industry, but its utilization of heat raises concerns over drugs’ thermal stability. Strategies to improve stability and processibility of thermolabile materials via salt formation and co-crystals engineering are found in the literature. In this work, it was attempted to use therapeutic deep eutectic solvents (THEDES) as a mean to achieve improved drug thermal stability through the formation of a charge-assisted strong hydrogen boding network. Thermogravimetric studies on THEDES formed using a thermolabile drug, lidocaine, with different non-steroidal anti-inflammatory agents (NSAIDs) were employed to test this hypothesis. The resulted three THEDESs in this study were all tested to be more thermally stable than the corresponding parent compounds, confirming the stabilizing effect from the THEDES bonding network. This investigation reintroduces THEDES as a drug product intermediate with improved processibility for HME.  

Therapeutic deep eutectic solvents based on natural product matrine and caprylic acid: Physical properties, cytotoxicity and formation of surfactant free microemulsion

Deep eutectic solvents (DESs), as a new type of green solvent, have drawn much attention in various fields. DESs constructed from active pharmaceutical ingredients (APIs), termed as therapeutic deep eutectic solvent (THEDES), have displayed great potential applications in pharmaceutic fields. In this work, a new type of THEDES based on matrine and caprylic acid was prepared. The physical properties like density, viscosity, and electric conductivity of THEDESs were measured at various matrine and caprylic acid ratios in the temperature range from 298.15 K to 333.15 K. Further analysis by Walden plot suggested the “poor ionic liquid” behavior of the THEDESs studied herein. Moreover, it has been shown that these THEDESs displayed slightly higher cytotoxicity than that of matrine. Moreover, surfactant free microemulsions (SFMEs) consisted of 1,2-propanediol (PG), isopropyl myristate (IPM) and THEDESs were constructed and characterized. It was further found that curcumin, a poorly soluble API, displayed much higher solubility and stability in this SFME as compared to these in commonly used solvents.

Therapeutic Liquid Eutectic Solvents in Lipid Nanoparticles as Drug Vehicles—A Proof of Concept

Tuberculosis is an infectious disease caused by the bacterial complex Mycobacterium tuberculosis. Despite the decline in the incidence and mortality of this disease over the years, the emergence of new strains of tuberculosis resistant to existing tuberculostatic drugs is currently one of the largest public health problems. The engineering and development of new drugs is a complex process; therefore, the modification and enhancement of the drugs already marked is a better and faster solution. Ethambutol (ETB) is an antimycobacterial drug used to treat tuberculosis; however, it is highly hygroscopic and is sparingly soluble in water. Therapeutic Deep Eutectic Solvents (THEDESs) are known to improve drug solubility, permeability, and hygroscopicity, among others. In this study, three THEDESs of ETB were synthesized with sucralose, glucose and glycerol and then encapsulated in nanostructured lipid carriers to improve their stability. This work is a proof of concept on the possibility of encapsulating the THEDESs, and results show that the encapsulation of ETB is possible, yielding formulations with a loading capacity superior to 8.5% and able to incorporate THEDESs and not just ETB.

Insight into the physicochemical properties and bioactivities of therapeutic deep eutectic solvents based on matrine and fatty acids

• THEDESs based on matrine and fatty acids were developed. • Physicochemical properties of THEDESs were investigated. • Antibacterial and anti-cancer activities and cytotoxicity of THEDESs were studied. Deep eutectic solvents (DESs), as a new type of green solvent, have shown great advantages of easy preparation, no purification needed after synthesis and great potential for application in various fields. Recently, a new type of drug delivery system called therapeutic deep eutectic solvent (THEDES) was developed when combining active pharmaceutical ingredients (APIs) into DES. Herein, we have constructed a series of new THEDES based on matrine (API) and fatty acids. Their physicochemical properties and bioactivities were investigated. In a temperature range from 298.15 K to 338.15 K, both density and viscosity declined with the increasing temperature. Besides, the density of THEDES decreased with the increasing alkyl chain length of fatty acids due to the enhancement of free volume, while the alkyl chain length displayed no influence on the viscosity of THEDES. Moreover, THEDESs showed better antibacterial activity on S. aureus as compared with matrine and the mixture solution of matrine and fatty acids at the same concentration. THEDESs also displayed better cell antiproliferative activities and higher cytotoxicity than that of matrine. Therefore, the results presented herein provides important basis for the further applications of matrine in the form of THEDES.

Therapeutic deep eutectic solvents assisted the encapsulation of curcumin in alginate-chitosan hydrogel beads

Alginate (ALG)-Chitosan (CHI) hydrogel beads have been broadly studied as vehicles for controlled drug delivery applications. However, encapsulation of poorly-water soluble compounds is somehow limited by the need to use emulsifying agents and/or organic solvents. This study aimed to encapsulate curcumin in ALG-CHI beads using as drug solubilizing vehicles deep eutectic solvents (DES). Using this approach hydrogel beads were successfully produced using extrusion-dripping method. The beads were vacuum-dried and freeze-dried which impairs their morphology, shape and dimensions features, as well as physicochemical properties. Vacuum-dried beads showed superior performance and were further evaluated as curcumin carriers for drug release control. The results indicated that swelling, degradation and in vitro release studies were influenced by the pH, highlighting the suitability of these systems for intestinal drug delivery. These outcomes indicate that the encapsulation of curcumin in pH-responsive ALG-CHI hydrogel beads using DES can be successfully accomplished, holding a great promise as encapsulation strategy of poorly water-soluble compounds for intestinal-targeted delivery of curcumin.

Untangling the bioactive properties of therapeutic deep eutectic solvents based on natural terpenes

Abstract Treatment of microbial-related infections remains a clinical challenge that has been slowly aggravating over recent years, due to the dissemination of resistance against currently applied treatment protocols. In this current scenario, the design of novel treatment approaches is of great importance, being a prominent focus of the scientific community. In recent years deep eutectic systems (DES) have gained the attention of the scientific community due to their remarkable physicochemical and biological properties, versatility, and compliance with the green chemistry metrics. In this work, DES containing a monoterpenoid (thymol (THY) and menthol (ME)) in combination with ibuprofen (IBU) were formulated and characterized via thermal analyses and NMR spectroscopy. The biological activity of the most promising formulations was then explored, with focus on its antimicrobial and anticancer activity. Both ME and THY-based formulations presented relevant antibacterial activity against the panel of microorganisms tested. Among the THY-based formulation tested, THY:IBU 3:1 M ratio, showed the highest antibacterial activity, affecting all tested microorganisms, while ME:IBU 3:1 M ratio was only effective against Gram-positive bacteria and Candida albicans. Furthermore, both ME and THY-based formulations revealed cytotoxic effect towards the cancer cell model used (HT29), where ME:IBU 3:1 stood out as the most selective towards cancer cells without compromising normal cells viability. Overall, the results obtained highlight the potential use of terpene-based THEDES formulations that, due to their enhanced thermal properties, may represent a versatile alternative in several biomedical applications where an effective antimicrobial or anticancer therapeutic action remains a challenge.

Development of Polycaprolactone-Based metronidazole matrices for intravaginal extended drug delivery using a mechanochemically prepared therapeutic deep eutectic system.

The engineering of crystalline multi-component drug systems, including cocrystals and salts, is now an established method of modifying the physicochemical properties and dissolution behaviour of an active ingredient. Remarkably, liquid drug systems, including therapeutic ionic liquids and therapeutic deep eutectic solvents (THEDES), remain largely unexplored as an untapped reservoir for drug modification. In this work, the formation of a THEDES containing metronidazole (MET), the preferred first-line treatment for bacterial vaginosis (BV), was explored. The formed THEDES was evaluated for its dissolution behaviour from a simple polycaprolactone (PCL) matrix, in order to achieve an extended release, balanced with an appropriate onset of action, hence offering improved MET intravaginal application. To minimise handling of the liquid THEDES, an end-to-end continuous process that enables feeding of the raw materials in their respective solid forms, and collection of a solidified final formulation is presented. The concurrent THEDES formation and formulation were carried out using a bench scale (approx. 10g) twin-screw hot melt extruder. The chosen parent reagents have shown sufficiently strong reactivity and resulted in successful and complete conversion to THEDES while in the presence of PCL, during the extrusion process. The formulated THEDES-PCL matrix exhibited significantly improved onset of drug release followed by a controlled delivery of MET over a total 7-day period in SVF, proving itself as a viable alternative to oral therapy.

A brief review on eutectic mixture and its role in pharmaceutical field

Eutectic mixture (EM) is as a mixture of more than one substance that does not interact individually to create a new entity but in a particular ratio that exhibits a lower range of melting point than it had in individual. EM should be formulated in such a way that it should have major advantages in pharmaceutical industries. EM can be a mixture of Active Pharmaceutical Ingredients (APIs), or different ratios of APIs and excipients, or various excipients. Deep eutectic solvents containing APIs (API-DES) considered as an innovative approach to form different APIs in the liquid state. This new approach of liquid form is versatile and plays an important role in drug delivery. The selection of ideal hydrogen bond-donor (HBD) and hydrogen bond-acceptor (HBA) is an essential parameter. Ionic liquids (IL), derivatives of deep eutectic solvents (DES) have got much attention since it can replace harmful organic solvent by their extraordinary properties. Therapeutic deep eutectic solvents (THEDESs) are considered to be an exceptional option in the advancement of biomedicine. This can be utilized for improvising drug solubility, bioavailability as well as drug permeation through the skin. Natural deep eutectic solvent (NADES) can be considered as an alternate option, replacing harsh solvents. It has special characteristics of better biodegradability and biocompatibility. These NADES mainly used to separate and purification of natural compounds. This review focuses on the eutectic mixture and its application in the area of drug delivery systems, and pharmaceutical and pharmacological fields.

Unveil the Anticancer Potential of Limomene Based Therapeutic Deep Eutectic Solvents

Deep eutectic solvents have been recently reported as an interesting alternative to improve the therapeutic efficacy of conventional drugs, hence called therapeutic deep eutectic solvents (THEDES). The main objective of this work was to evaluate the potential of limonene (LIM) based THEDES as new possible systems for cancer treatment. LIM is known to have antitumor activity, however it is highly toxic and cell viability is often compromised, thus this compound is not selective towards cancer cells. Different THEDES based on LIM were developed to unravel the anticancer potential of such systems. THEDES were prepared by gently mixing saturated fatty acids menthol or ibuprofen (IBU) with LIM. Successful THEDES were obtained for Menthol:LIM (1:1), CA:LIM (1:1), IBU:LIM (1:4) and IBU:LIM(1:8). The results indicate that all the THEDES present antiproliferative properties, but IBU:LIM (1:4) was the only formulation able to inhibit HT29 proliferation without comprising cell viability. Therefore, IBU:LIM (1:4) was the formulation selected for further assessment of anticancer properties. The results suggest that the mechanism of action of LIM:IBU (1:4) is different from isolated IBU and LIM, which suggest the synergetic effect of DES. In this work, we unravel a methodology to tune the selectivity of LIM towards HT29 cell line without compromising cell viability of healthy cells. We demonstrate furthermore that coupling LIM with IBU leads also to an enhancement of the anti-inflammatory activity of IBU, which may be important in anti-cancer therapies.

Therapeutic Role of Deep Eutectic Solvents Based on Menthol and Saturated Fatty Acids on Wound Healing.

The breakthroughs achieved in green solvents promote the emergence of therapeutic deep eutectic solvents (THEDES), which possess intriguing possible applications in the biomedical field. Herein, the main aim was to unravel the biomedical potential of hydrophobic THEDES based in menthol and saturated fatty acids with different chain lengths (e.g., stearic acid (SA), myristic acid (MA), and lauric acid (LA)). Our comprehensive strategy resulted in the thermophysical characterization of different formulations, which allow one to identify the most suitable molar ratio, as well as the intermolecular interactions behind the successful formation of THEDES. The evaluation of their biological performance was also performed toward bacteria and HaCaT cells. Among the different formulations of THEDES, the one based on menthol and SA establishes stronger hydrogen bonding interactions, being also the most promising formulation because it did not elicit any relevant cytotoxicity, and potentiated wound healing, while presenting antibacterial properties against Staphylococcus epidermis and Staphylococcus aureus strains, some of which were methicillin resistant. This work provides clues on the future use of THEDES based on menthol:SA in wound dressings.

Design of arginine-based therapeutic deep eutectic solvents as drug solubilization vehicles for active pharmaceutical ingredients.

The solvation of lidocaine in three newly designed deep eutectic solvents is studied using combined experimental and theoretical methods that include density functional theory and molecular dynamics methods. The intermolecular forces between lidocaine and the hydrogen bond acceptors and hydrogen bond donors of the deep eutectic solvents were analysed regarding the type and the strength of inter- and intra-molecular bonding. The structure, composition and properties of the lidocaine solvation shells are analysed together with the possible lidocaine-clustering around the studied deep eutectic solvents and their constituent molecules. Furthermore, the changes in the solvent structures upon lidocaine solubilization are also studied. Natural product-based eutectic solvents showed considerably high solvation of lidocaine in all three deep eutectics based on the strong solute-solvent intermolecular interactions accompanied by a slight volume expansion and minor solvent structural changes. These non-toxic and almost null-volatile therapeutic deep eutectic solvents can be considered as suitable solubilization media for developing pharmaceutical applications and they can be considered as effective drug delivery vehicles for active pharmaceutical ingredients.

Properties of Therapeutic Deep Eutectic Solvents of l-Arginine and Ethambutol for Tuberculosis Treatment.

The treatment for tuberculosis infection usually involves a prolonged regimen of multiple antibacterial drugs, which might lead to various secondary effects. For preventing drug resistance and side-effects of anti-tuberculosis drugs, new methods for improving the bioavailability of APIs were investigated. The strategy proposed consists of the preparation of therapeutic deep eutectic solvents (THEDES), that incorporate l-arginine and ethambutol. The eutectic mixtures were prepared by mixing the components at a certain molar ratio, until a clear liquid solution was formed. The prepared mixtures were characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM) and nuclear magnetic resonance spectroscopy (1H and 13C-NMR). The solubility and permeability of the drugs when they are in the THEDES form was evaluated at 37 °C, in phosphate buffered saline (PBS). Solubility studies showed an increase of the solubility of ethambutol when incorporated in the eutectic system. The cytotoxicity was evaluated using a model cell line (Caco-2), comparing the cytotoxicity of the API incorporated in the eutectic system. We observed that the cell viability in the THEDES was affected by the presence of citric acid, and higher cytotoxicity values were observed. Nonetheless, these findings do not compromise the possibility to use these systems as new delivery systems for ethambutol and arginine.

Design of Functional Therapeutic Deep Eutectic Solvents Based on Choline Chloride and Ascorbic Acid

In this work, we report the preparation of novel therapeutic deep eutectic solvents (THEDES) based on choline chloride (CC) and ascorbic acid (AA), in which dexamethasone (DEX) was successfully solubilized. THEDES were synthesized and characterized for thermal behavior and polarized optic microscopy to confirm the formation of a eutectic mixture. The solubility profile of DEX solubilized in THEDES was greatly improved when compared with DEX in powder form. Additionally, the diffusion and permeability of DEX were also slightly increased. The antioxidant properties of AA were maintained up to 6 months when the compound is in THEDES form. Biological tests were also performed, and the results indicate that cell viability varies in a dose-dependent manner. After the half maximal effective concentration (EC50) was determined, a controlled drug delivery system was successfully developed by supercritical fluid sintering of a starch:poly-e-caprolactone blend doped with THEDES containing solubilized DEX. The presen...

Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts.

The amorphization of the readily crystallizable therapeutic ingredient and food additive, menthol, was successfully achieved by inclusion of neat menthol in mesoporous silica matrixes of 3.2 and 5.9 nm size pores. Menthol amorphization was confirmed by the calorimetric detection of a glass transition. The respective glass transition temperature, Tg = -54.3 °C, is in good agreement with the one predicted by the composition dependence of the Tg values determined for menthol:flurbiprofen therapeutic deep eutectic solvents (THEDESs). Nonisothermal crystallization was never observed for neat menthol loaded into silica hosts, which can indicate that menthol rests as a full amorphous/supercooled material inside the pores of the silica matrixes. Menthol mobility was probed by dielectric relaxation spectroscopy, which allowed to identify two relaxation processes in both pore sizes: a faster one associated with mobility of neat-like menthol molecules (α-process), and a slower, dominant one due to the hindered mobility of menthol molecules adsorbed at the inner pore walls (S-process). The fraction of molecular population governing the α-process is greater in the higher (5.9 nm) pore size matrix, although in both cases the S-process is more intense than the α-process. A dielectric glass transition temperature was estimated for each α (Tg,dielc(α)) and S (Tg,dielc(S)) molecular population from the temperature dependence of the relaxation times to 100 s. While Tg,dielc(α) agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, Tg,dielc(S) is close to the value determined by calorimetry for the silica composites due to a dominance of the adsorbed population inside the pores. Nevertheless, the greater fraction of more mobile bulk-like molecules in the 5.9 nm pore size matrix seems to determine the faster drug release at initial times relative to the 3.2 nm composite. However, the latter inhibits crystallization inside pores since its dimensions are inferior to menthol critical size for nucleation. This points to a suitability of these composites as drug delivery systems in which the drug release profile can be controlled by tuning the host pore size.

A comparison between pure active pharmaceutical ingredients and therapeutic deep eutectic solvents: Solubility and permeability studies

THEDES, so called therapeutic deep eutectic solvents are here defined as a mixture of two components, which at a particular molar composition become liquid at room temperature and in which one of them is an active pharmaceutical ingredient (API). In this work, THEDES based on menthol complexed with three different APIs, ibuprofen (ibu), BA (BA) and phenylacetic acid (PA), were prepared. The interactions between the components that constitute the THEDES were studied by NMR, confirming that the eutectic system is formed by H-bonds between menthol and the API. The mobility of the THEDES components was studied by PFGSE NMR spectroscopy. It was determined that the self-diffusion of the species followed the same behavior as observed previously for ionic liquids, in which the components migrate via jumping between voids in the suprastructure created by punctual thermal fluctuations. The solubility and permeability of the systems in an isotonic solution was evaluated and a comparison with the pure APIs was established through diffusion and permeability studies carried out in a Franz cell. The solubility of the APIs when in the THEDES system can be improved up to 12 fold, namely for the system containing ibu. Furthermore, for this system the permeability was calculated to be 14×10−5cm/s representing a 3 fold increase in comparison with the pure API. With the exception of the systems containing PA an increase in the solubility, coupled with an increase in permeability was observed. In this work, we hence demonstrate the efficiency of THEDES as a new formulation for the enhancement of the bioavailability of APIs by changing the physical state of the molecules from a solid dosage to a liquid system.

Design of controlled release systems for THEDES—Therapeutic deep eutectic solvents, using supercritical fluid technology

Deep eutectic solvents (DES) can be formed by bioactive compounds or pharmaceutical ingredients. A therapeutic DES (THEDES) based on ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), and menthol was synthesized and its thermal behavior was analyzed by differential scanning calorimetry (DSC). A controlled drug delivery system was developed by impregnating a starch:poly-ϵ-caprolactone polymeric blend (SPCL 30:70) with the menthol:ibuprofen THEDES in different ratios (10 and 20wt%), after supercritical fluid sintering at 20MPa and 50°C. The morphological characterization of SPCL matrices impregnated with THEDES was performed by scanning electron microscopy (SEM) and micro-computed tomography (micro-CT). Drug release studies were carried out in a phosphate buffered saline. The results obtained provide important clues for the development of carriers for the sustainable delivery of bioactive compounds.