Phase Solubility Experiments Research Articles

Utilizing phospholipid as an amphiphilic carrier for solid dispersion of ambrisentan: formulation and evaluation

ABSTRACT: The partial water solubility of ambrisentan poses a challenge to its oral administration despite being the second oral endothelin A-receptor antagonist approved in the United States. In this study, we aimed to improve ambrisentan’s solubility and bioavailability using an amphiphilic phospholipid carrier. Phospholipids, with their glycerol-bound, phosphorus-containing amphiphilic nature, are known to prolong drug lifespan by facilitating drug penetration across cell membranes through hydrogen bonds or van der Waals interactions. Moreover, phospholipid compounds have been shown to significantly enhance drug solubility, permeability, and bioavailability in various studies. We optimized the ratios of ambrisentan and phospholipid carriers (1:1, 1:3, and 1:5) based on saturation and phase solubility experiments. Solid dispersion was prepared using the solvent evaporation technique. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses confirmed the conversion of ambrisentan from a crystalline to an amorphous form in the solid dispersion. The solubility of ambrisentan in the solid dispersion increased by 13-fold with a 1:5 ratio of ambrisentan to phospholipid carrier. The release profile indicated rapid release of the active substance within the first 15 min, corresponding to the peak phospholipid concentration. Pharmacokinetic studies demonstrated higher bioavailability of the medicine compared to the pure drug. This study suggests that phospholipids can effectively enhance drug solubility and bioavailability in solid dispersion systems.

Inclusion Complexes of Ethanamizuril with β- and Hydroxypropyl-β-Cyclodextrin in Aqueous Solution and in Solid State: A Comparison Study.

Ethanamizuril (EZL) is a new anticoccidial drug developed by our Shanghai Veterinary Research Institute. Since EZL is almost insoluble in water, we conducted a study to improve the solubility of EZL by forming inclusion complexes with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). In this study, we performed molecular docking and then systematically compared the interactions of EZL with β-CD and HP-β-CD in both aqueous solution and the solid state, aiming to elucidate the solubilization effect and mechanism of cyclodextrins (CDs). The interactions were also examined in the solid state using DSC, PXRD, and FT-IR. The interactions of EZL with CDs in an aqueous solution were investigated using PSA, UV-vis spectroscopy, MS, 1H NMR, and 2D ROESY. The results of phase solubility experiments revealed that both β-CD and HP-β-CD formed inclusion complexes with EZL in a 1:1 molar ratio. Among them, HP-β-CD exhibited higher Kf (stability constant) and CE (complexation efficiency) values as well as a stronger solubilization effect. Furthermore, the two cyclodextrins were found to interact with EZL in a similar manner. The results of our FT-IR and 2D ROESY experiments are in agreement with the theoretical results derived from molecular simulations. These results indicated that intermolecular hydrogen bonds existing between the C=O group on the triazine ring of EZL and the O-H group of CDs, as well as the hydrophobic interactions between the hydrogen on the benzene ring of EZL and the hydrogen of CDs, played crucial roles in the formation of EZL/CD inclusion complexes. The results of this study can lay the foundation for the future development of high-concentration drinking water delivery formulations for EZL.

Inclusion complexes of nabumetone with β-cyclodextrins: Spectroscopic, spectrometric and calorimetric studies in solution

The complexation of nabumetone (NAB) with various cyclodextrins (CDs): β-cyclodextrin (β-CD), hydroxypropyl-β-CD (HPβCD), randomly methylated β-CD (RMβCD), and sulfobutylether sodium salt β-CD (SBEβCD), was investigated as a mean to increase the poor solubility of NAB both in water and simulated biorelevant media (pH = 1.0 (HCl) and pH = 4.5 and 6.8 (phosphate buffer)). An approximately 170 times increase in NAB solubility was achieved for SBEβCD in all media. The formation of 1:1 complexes was confirmed by phase-solubility measurements, spectrofluorimetric titration and high resolution mass spectrometry. Additionally, isothermal microcalorimetric titrations were employed to determine thermodynamic parameters (lgK, ΔrG0, ΔrH0, ΔrS0). Stability constants (lgK = 3.42; 3.41; 3.47 and 3.62 for NAB complexes with β-CD, HPβCD, RMβCD, and SBEβCD, respectively) agree with those obtained by phase-solubility experiments and spectrofluorimetric titrations. The inclusion was enthalpy and entropy favorable. NMR analyses showed two possible orientations of NAB in the β-CD cavity simultaneously exist in the solution, with a naphthalene ring inside the β-CD cavity and methoxy or butanone substituent oriented towards the narrow β-CD rim. All experimental results are in good agreement with those based on molecular modeling previously reported in the literature.

Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study.

We sought to determine the cyclodextrins (CDs) best suited to solubilize a patented succinimido-ferrocidiphenol (SuccFerr), a compound from the ferrociphenol family having powerful anticancer activity but low water solubility. Phase solubility experiments and computational modelling were carried out on various CDs. For the latter, several CD-SuccFerr complexes were built starting from combinations of one or two CD(s) where the methylation of CD oxygen atoms was systematically changed to end up with a database of ca. 13 k models. Modelling and phase solubility experiments seem to indicate the predominance of supramolecular assemblies of SuccFerr with two CDs and the superiority of randomly methylated β-cyclodextrins (RAMEβCDs). In addition, modelling shows that there are several competing combinations of inserted moieties of SuccFerr. Furthermore, the models show that ferrocene can contribute to high stabilization by making atypical hydrogen bonds between Fe and the hydroxyl groups of CDs (single bond with one OH or clamp with two OH of the same glucose unit).

Enhancing the Water Solubility of 9-Fluorenone Using Cyclodextrin Inclusions: A Green Approach for the Environmental Remediation of OPAHs

Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are toxic and carcinogenic compounds widely present in the natural environment, posing a serious threat to the environment and human health. However, the removal of OPAHs is mainly hindered by their low water solubility. Cyclodextrins (CDs) are frequently used to form inclusion complexes (ICs) with hydrophobic molecules to improve their solubility. In this study, we investigated the solubility enhancement ability of different CDs on 9-fluorenone, a common OPAH, through phase solubility experiments. We successfully prepared three solid ICs of 9-fluorenone with β-, hydroxypropyl-β-(HP-β-) and sulfobutylether-β-CD (SBE-β-CD) using the cooling crystallization method for the first time and characterized them via powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, etc. Molecular dynamics simulations were employed to investigate the binding modes and stable configurations of the ICs in the liquid phase and to explore the factors affecting their solubility enhancement ability. The results showed that all the CDs had a solubility enhancement effect on 9-fluorenone, with SBE-β-CD displaying the strongest effect, increasing the solubility of 9-fluorenone by 146 times. HP-β-CD, β-CD, α-CD, and γ-CD followed in decreasing order. Moreover, 9-fluorenone formed a ratio of 1:1 ICs to CDs. In addition, the interaction energy between SBE-β-CD and 9-fluorenone was the lowest among the CDs, which further validated the results of the phase solubility experiments from a theoretical perspective. Overall, this study provides a green method for the removal of 9-fluorenone pollutants in the environment and is expected to be applied to the removal and environmental remediation of other OPAHs.

Preparation and Evaluation of Novel Supersaturated Solid Dispersion of Magnolol : Theme: Advancements in Amorphous Solid Dispersions to Improve Bioavailability.

This article aimed to design a new type of supersaturated solid dispersion (NS-SD) loaded with Magnolol (Mag) to raise the oral bioavailability in rats. In the light of the solubility parameters, phase solubility experiments, inhibition precipitation experiment, and in vitro release experiment, Plasdone-630 (PS-630) was selected as the optimum carrier. In addition, Mag-NS-SD was prepared by adding Monoglyceride (MG) and Lecithin High Potency (LHP) into the Mag-S-SD (Mag:PS-630 = 1:3), so as to reduce the dosage of carrier and improve the release rate. Using central composite design of response surface method, the prescription was further optimized. As the optimized condition was Mag:PS-630: MG: LHP = 1:3:0.8:0.266, the drug release rate was the fastest. Besides, after 45min, the release rate was nearly 100%. The constructed Mag-S-SD and Mag-NS-SD were characterized by powder X-ray diffraction and infrared absorption spectrum. The XRD patterns of Mag-S-SD and Mag-NS-SD indicated that all APIs were amorphous. The IR spectra of Mag-S-SD and Mag-NS-SD demonstrated the existence of hydrogen bonding in the systems. Furthermore, in vivo pharmacokinetic study in rats revealed that compared with Mag and Mag-S-SD, Mag-NS-SD significantly increased the bioavailability (the relative bioavailability was 213.69% and 142.37%, separately). In this study, Mag-NS-SD was successfully prepared, which could improve the oral bioavailability and may increase the clinical application.

Effect of preparation methods on tosufloxacin tosylate/ hydroxypropyl-β-cyclodextrin inclusion complex

The main purpose of this work was to compare the effects of the four preparation methods on the TFLX/HP-β-CD inclusion complex. The effects of different preparation methods on the inclusion complex were investigated by SEM, DSC, PXRD, FT-IR and 1H NMR. All the characterization information indicated that the four preparation methods could cause interaction between TFLX and HP-β-CD, but the inclusion complex prepared by solvent evaporation has more reaction sites. Phase solubility experiments demonstrated that the inclusion reaction was spontaneous. In vitro dissolution experiments showed that the dissolution of the inclusion complex in water was: solvent evaporation method (64.39%) > grinding method (42.37%) > ultrasonic method (40.00%) > freezing method (36.08%), and all higher than pure TFLX and physical mixture. These results suggest that the solvent evaporation is the most suitable method for preparing TFLX/HP-β-CD inclusion complexes.

Evaluation and Characterization of Curcumin-β-Cyclodextrin and Cyclodextrin-Based Nanosponge Inclusion Complexation.

Cyclodextrin polymers and cyclodextrin-based nanosponges have been widely investigated for increasing drug bioavailability. This study examined curcumin’s complexation stability and solubilization with β-cyclodextrin and β-cyclodextrin-based nanosponge. Nanosponges were prepared through the cross-linking of β-cyclodextrin with different molar ratios of diphenyl carbonate. Phase solubility experiments were conducted to evaluate the formed complexes and evaluate the potential of using β-cyclodextrin and nanosponge in pharmaceutical formulations. Furthermore, physicochemical characterizations of the prepared complexes included PXRD, FTIR, NMR, and DSC. In addition, in vitro release studies were performed for the prepared formulations. The formation of β-cyclodextrin complexes enhanced curcumin solubility up to 2.34-fold compared to the inherent solubility, compared to a 2.95-fold increment in curcumin solubility when loaded in β-cyclodextrin-based nanosponges. Interestingly, the stability constant for curcumin nanosponges was (4972.90 M−1), which was ten times higher than that for the β-cyclodextrin complex, where the value was 487.34 M−1. The study results indicated a decrease in the complexation efficiency and solubilization effect with the increased cross-linker amount. This study’s findings showed the potential of using cyclodextrin-based nanosponge and the importance of studying the effect of cross-linking density for the preparation of β-cyclodextrin-based nanosponges to be used for pharmaceutical formulations.

Effect of polymers and cyclodextrins on solubility, permeability and distribution of enzalutamide and apalutamide antiandrogens

Solubility, lipophilicity and permeability are crucial issues determining the bioavailability of drugs. Antiandrogens enzalutamide and apalutamide with high antitumoral activity demonstrate poor solubility in aqueous media in a whole range of pH. In this study in order to enhance the solubility, the overall investigation of enzalutamide (ENZ) and apalutamide (APL) behavior in polyethylene glycol 6000 (PEG), pluronic F127 (F127), β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) solutions was carried out. The phase solubility experiments showed that all the excipients increase the solubility of the compounds. The following order of the excipients action on the solubility was estimated: PEG < TM-β-CD < β-CD < HP-β-CD < F127 for both investigated substances. Hanson solubility parameter was applied to explain the role of the solubilizer's nature on the solubility. The permeability through the cellulose membrane (MWCO 12–14 kDa) was assessed and demonstrated a decrease in the presence of all excipients. Since F127 and HP-β-CD revealed the best solubilizing ability, the permeability at several concentrations of these excipients was studied and discussed. In addition, the distribution coefficients in octanol/water system were evaluated for both compounds in the presence of HP-β-CD in aqueous phase. Both the permeability and distribution coefficients demonstrated a drastic decrease upon the excipient concentration growth. Interrelations of the above parameters with the solubility were revealed, graphically illustrated and discussed.

Cyclodextrin Complexation Improves the Solubility and Caco-2 Permeability of Chrysin

Chrysin is a bioflavonoid that can be found in natural products such as honey and propolis, and it possesses several biological effects such as antioxidant, anti-inflammatory, and anti-cancer activity. However, it is poorly soluble in water, and its bioavailability is limited. The aim of this research is to investigate the chrysin solubilization capacity of different β-cylcodextrin derivatives and compare their biological activities. Chrysin was complexed with β-cyclodextrin (βCD), hydroxypropyl-β-, (HPBCD) sulfobutylether-β-, (SBECD), and randomly-methylated-β-cyclodextrin (RAMEB) by the lyophilization method in 1:1 and 1:2 molar ratios. The solubilities of the chrysin–cyclodextrin complexes were tested, and the solubilization abilities of cyclodextrins were studied by phase solubility experiments. The cytotoxicity of the complexes was measured by the MTT method, and the permeability enhancement was tested on Caco-2 monolayers. The solubility study showed that the complexes formed with RAMEB had the highest solubility in water. The phase solubility experiments confirmed the strongest interaction between RAMEB and chrysin. In the viability test, none of the complexes showed cytotoxicity up to 100 µM concentration. The permeability study revealed that both at 1:1 and 1:2 ratios, the RAMEB complexes were the most effective to enhance chrysin permeability through the Caco-2 monolayers. In conclusion, cyclodextrins, especially RAMEB, are suitable for improving chrysin solubility and absorption.

Effects of inclusion of chrysin in cucurbit[8]uril on its stability, solubility and antioxidant potential

The host-guest interaction between cucurbit[8]uril(Q[8]) and chrysin(CHR) has been studied by means of 1H NMR, mass spectrometry(MS), differential thermal analysis(DTA), and UV-Vis spectrophotometry. The results show that CHR forms a 1:1 inclusion complex with Q[8], with a binding constant of CHR with Q[8] by UV absorption being 5.4×106. Phase solubility experiments show a 5.13-fold increase in the solubility of CHR through interaction with Q[8]{c(Q[8])=10‒4 mol/L}. A study of the evolution of UV absorption spectra with time shows that Q[8] significantly increases the stability of CHR. The antioxidant activity of CHR-Q[8] has been tested by the ABTS method. The CHR-Q[8] inclusion complex shows a better scavenging effect towards the ABTS radical than CHR, with respective IC50 values of 1.05×10–6 and 3.07×10–6 mol/L. In vitro release studies have shown that CHR-Q[8] has a sustained release effect.

Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation

The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.

Improvement of some pharmaceutical properties of mycophenolate mofetil (MMF) by para sulphonatocalix[4]resorcinarene inclusion complex

As a part of our investigations to unfold the chemistry of calixresorcinarene, we have focused on the formation of inclusion complex of a poorly soluble (43 μg ml−1 at pH 7) drug mycophenolate mofetil (MMF) an immunosuppressive agent and an inosine monophosphate dehydrogenase (IMPDH) inhibitor with para sulphonatocalix[4]resorcinarene (PSC4R). The complete complexation of the drug was achieved after 48 h of stirring with para sulphonatocalix[4]resorcinarene(PSC[4]R) in water and evaporation of water yield the solid complex. The interaction between para sulphonatocalix[4]resorcinarene(PSC[4]R) and MMF in solid state inclusion complexes was accomplished by aqueous phase solubility studies, Thermal Analysis, HPLC, PXRD, FT-IR, and UV–Vis spectroscopy. The results of the phase solubility experiments are in good conformity to signify the formation of 2:1 PSC4R: MMF complexes. The purpose of this study was to enhance solubility and resulting in high dissolution rate and bioavailability of this essentially water insoluble drug. The results of the in vivo study shows that there is a remarkable change in the toxicity of the pure drug MMF and complex did not produce any mortality up to 2200 mg kg−1.

Efficient Loading and Controlled Release of Benzophenone-3 Entrapped into Self-Assembling Nanogels

Benzophenone-3 (BZ-3), was successfully entrapped into nanogels prepared by a simple one-step method based on selfassembly of two water soluble polymers: a hydrophobically modified dextran (MD) and a β-Cyclodextrin polymer (pβ-CD). Isothermal titration microcalorimetry (ITC) and phase solubility experiments were performed at 4, 25 or 37°C to investigate the interaction of the hydrophobic BZ-3 with MD and pβ-CD. The BZ-3 entrapment efficiency, yield of nanogels formation, particle size, and BZ-3 release were also evaluated. BZ-3/pβ-CD interaction was characterized by association constants K= 5180 M-1 and K´= 2700 M-1, as determined by phase solubility and ITC experiments, respectively. Differences obtained in association constants values were discussed critically. Results indicate that both K and K´ decrease with increase in temperature. The strong interactions between BZ-3 and pβ-CD were characterized by a negative enthalpy change ( H) with entropic contribution (T S). Monodisperse nanogels were produced with an entrapment up to 75 % and yield up 84 %. BZ-3 was firmly entrapped into nanogels, as only the dilution of the nanogels led to its release. This system provides an advantage for sunscreen formulation to prevent systemic penetration of BZ-3. The ‘green’ (solvent free) preparation method, and the possibility of unlimited storage after freeze drying makes these nanogels valuable candidates for the entrapment of sun screen agents. Keywords: Nanogels, cyclodextrins, inclusion complexes, sunscreen, isothermal titration microcalorimetry, drug loading, sunscreen agents, UV rays, photoprotection, photo-sensitivity, permeability, modified dextran, centrifugation, supernatant, QELS, CDs, solubilization, MD, nanogel, thermodynamic, enthalpy, entropy, Temperature

Supramolecular interactions between losartan and hydroxypropyl-β-CD: ESI mass-spectrometry, NMR techniques, phase solubility, isothermal titration calorimetry and anti-hypertensive studies

In this work, low soluble supramolecular complex between the losartan potassium (Los) and hydroxypropil-β-cyclodextrin (HPβCD) were characterized throughout phase-solubility, NMR techniques (1H and 2D-ROESY) and isothermal titration calorimetry (ITC) in order to attain physical–chemical knowledge of the system. In addition, the hypertensive effect of composition Los/HPβCD was evaluated aiming to obtain a more efficient oral pharmaceutical composition. ESI mass spectrometry and ITC blank experiment demonstrate the presence of Los clusters at 30mM pure solution. Phase-solubility experiments showed a “Bs” type system, due to the formation of a less soluble complex than pure Los. NMR demonstrated the short distance interactions between the Los and the cyclodextrin, where several possibilities of interactions were observed. ITC data suggest an average 1:1 stoichiometry of Los and the cyclodextrin. The complex demonstrated efficiency in hypertension control, presenting antagonist action on the pressure effect of angiotensin II within 30h, as compared to Los alone, 6h, indicating that inclusion of Los in HPβCD enhanced the extent and duration of its antagonistic action. In this work, a model of interaction between Los and HPβCD was proposed based on dissociation of self-assembled Los followed by complexation with HPβCD.

Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.

Characterization of ternary complexes of meloxicam-HPβCD and PVP or L-arginine prepared by the spray-drying technique

Ternary complexes of meloxicam (ME) (a poorly water soluble anti-inflammatory drug) with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and either a hydrophilic polymer, namely, polyvinyl pyrrolidone (PVP) or a basic amino acid such as L-arginine, were prepared by the spray-drying technique. The solubilizing efficiency, physical properties and dissolution behaviour of each ternary system of ME-HPbetaCD with either PVP or L-arginine were compared with those of the corresponding binary system of ME-HPbetaCD. Tablets compressed from the ternary system of ME-HPbetaCD-L-arginine were compared with plain and commercial tablets. Phase solubility experiments suggested the formation of an inclusion complex of AL type. Ternary system of ME-HPbetaCD-L-arginine exhibited a stability constant 30.3 times higher than the binary system of ME-HPbetaCD, while the ternary system of ME-HPbetaCD-PVP increased the stability constant 2.2 times only. The prepared complexes were characterized by scanning electron microscopy, differential scanning calorimetry and infra red spectroscopy. Ternary solid complexes indicated the presence of strong interactions between the components. The dissolution behaviour of ME from different ternary complexes was higher than its dissolution from the binary system. Tablets compressed from ternary complexes of ME-HPbetaCD-L-arginine highly improved drug release compared to plain and commercial tablets.

Osteotropic β-cyclodextrin for local bone regeneration

An osteotropic alendronate-β-cyclodextrin conjugate (ALN-β-CD) was developed as a bone-targeting delivery system for improved treatment of skeletal diseases. The conjugate shows very strong binding to hydroxyapatite (HA, main component of the skeleton). Its ability in forming molecular inclusion complex with prostaglandin E 1 (PGE 1, a potent bone anabolic agent) was confirmed by phase solubility experiments and differential scanning calorimetry (DSC). In a bilateral rat mandible model, ALN-β-CD/PGE 1 molecular complex was shown to stimulate strong local bone anabolic reaction. In the control study, ALN-β-CD itself was also found to be bone anabolic. To investigate this finding, other control groups were studied. The histomorphometry data suggest that ALN-β-CD itself could generate more new bone at the injection site than its complex with PGE 1. Alendronate (ALN) injection could also cause new bone formation, which locates peripheral to the site of injection. PGE 1, saline or ethanol injections do not have anabolic effect. These findings were also confirmed by micro-CT evaluation of mandibular bones. It is clear that the bone anabolic effect of ALN-β-CD is independent of mechanical stimuli of the periosteum or ALN injection alone. Further studies are warranted to understand the working mechanism of ALN-β-CD as a bone anabolic agent.

Novel biomineral-binding cyclodextrins for controlled drug delivery in the oral cavity

A biomineral-binding alendronate-β-cyclodextrin conjugate (ALN-β-CD, Fig. 1) was developed as a novel drug delivery system. “Click” chemistry was used in conjugation of alendronate (ALN) to β-cyclodextrin (β-CD). The delivery system shows very strong binding to hydroxyapatite (HA, main component of tooth enamel). Its ability in forming molecular inclusion complex with dexamethsone (Dex, model drug) was investigated independently with phase solubility experiments, isothermal titration calorimetry (ITC), Job plot and 1H NMR. The stoichiometry of ALN-β-CD/Dex molecular complex was determined as 1:1, and the binding constant of the complex obtained from ITC study is 3.8 × 10 3 M −1, which is similar to the binding constant of β-CD/Dex. In vitro data indicate that the ALN-β-CD/Dex complex bound to HA could gradually release Dex upon repeated extraction with phosphate buffer saline (PBS). This novel drug delivery system may have great potential in improving treatment of diseases in the oral cavity.

Sistemas de liberação controlada com bupivacaína racêmica (S50-R50) e mistura enantiomérica de bupivacaína (S75-R25): efeitos da complexação com ciclodextrinas no bloqueio do nervo ciático em camundongos

Bupivacaine-induced side effects have led to the search for new local anesthetics (LA) with similar potency and lower toxicity, such as bupivacaine enantiomeric mixture (S75-R25). Drug-delivery systems for LA in carriers, such as cyclodextrins (CD), have been developed to improve anesthetic potency and therapeutic index of those drugs. This study aimed at preparing, characterizing and evaluating the anesthetic efficacy of inclusion complexes of bupivacaine enantiomeric mixture (S75-R25) and racemic bupivacaine (S50-R50) with hydroxypropylb- cyclodextrin (HPb-CD) comparing them to clinically available preparations.Inclusion complexes were obtained by mixing appropriate volumes of HPb-CD and S50-R50 or S75-R25 to final 1:1 or 1:2 molar ratios and were characterized by phase solubility experiments. Affinity constants (K) were determined between HPb-CD and each LA. Motor and sensory blocks induced by plain or complexed LA formulations were evaluated in mice by sciatic nerve block. Three LA concentrations were used during the experiment: 0.125, 0.25 and 0.5%.Solubility experiments results were indicative of S50-R50:HPb-CD and S75-R25:HPb-CD complexation, with similar affinity constant (K) values: 14.7 M-1 and 14,3 M-1, respectively. In vivo experiments have shown that complexation has enhanced differential nerve blockade induced by LA: i) motor blockade duration induced by S75-R25 was similar, to the induced by but less intense S50-R50 ( p < 0.001). S50-R50HPb-CD and S75-R25HPb-CD complexes have decreased onset (p < 0.01 and p < 0.05, respectively), without changing motor block intensity (Emax) as compared to plain drugs; ii) sensory block evaluation has revealed higher analgesic intensity with S50-R50HPb-CD (2-fold, p < 0.001) and S75-R25HPb-CD (1.5-1.8-fold, p < 0.01 and p < 0.001, respectively) with both molar ratios (1:1 and 1:2, LA:CD), in addition to prolonging analgesic effect as compared to S50-R50 and S75-R25.More pronounced analgesic effects obtained by complexation with HPb-CD have shown that both formulations, S50-R50HPb-CD and S75-R25HPb-CD, are very useful for postoperative pain relief, requiring lower LA concentrations. Nevertheless, it is worth noticing that S75-R25 - being less toxic than racemic bupivacaine - is an interesting alternative for the development of more effective and safe drug-delivery systems as compared to racemic bupivacaine (S50-R50).