Advances in Structure Pharmaceutics from Discovery to Evaluation and Design.

Drug delivery systems (DDSs) play an important role in delivering active pharmaceutical ingredients (APIs) to targeted sites with a predesigned release pattern. The chemical and biological properties of APIs and excipients have been extensively studied for their contribution to DDS quality and effectiveness; however, the structural characteristics of DDSs have not been adequately explored. Structure pharmaceutics involves the study of the structure of DDSs, especially the three-dimensional (3D) structures, and its interaction with the physiological and pathological structure of organisms, possibly influencing their release kinetics and targeting abilities. A systematic overview of the structures of a variety of dosage forms, such as tablets, granules, pellets, microspheres, powders, and nanoparticles, is presented. Moreover, the influence of structures on the release and targeting capability of DDSs has also been discussed, especially the in vitro and in vivo release correlation and the structure-based organ- and tumor-targeting capabilities of particles with different structures. Additionally, an in-depth discussion is provided regarding the application of structural strategies in the DDSs design and evaluation. Furthermore, some of the most frequently used characterization techniques in structure pharmaceutics are briefly described along with their potential future applications.

Solvent-Free Loading of Vitamin A Palmitate into ß-Cyclodextrin Metal-Organic Frameworks for Stability Enhancement.

Cyclodextrin metal-organic frameworks (CD-MOFs) exhibit a high structural diversity, which contributes to their functional properties. In this study, we have successfully synthesized a novel type of ß-cyclodextrin metal-organic framework (ß-CD-POF(I)) that exhibits excellent drug adsorption capacity and enhances stability. Single-crystal X-ray diffraction analysis revealed that ß-CD-POF(I) possessed the dicyclodextrin channel moieties and long-parallel tubular cavities. Compared with the reported ß-CD-MOFs, the ß-CD-POF(I) has a more promising drug encapsulation capability. Here, the stability of vitamin A palmitate (VAP) was effectively improved by the solvent-free method. Molecular modeling and other characterization techniques like synchrotron radiation Fourier transform infrared spectroscopy (SR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and nitrogen adsorption isotherm were applied to confirm that the VAP was successfully encapsulated into the channel formed by the dicyclodextrin pairs. Furthermore, the mechanism of stability enhancement for VAP was determined to be due to the constraint and separation effects of ß-CD pairs on VAP. Therefore, ß-CD-POF(I) is capable of trapping and stabilizing certain unstable drug molecules, offering benefits and application possibilities. One kind of cyclodextrin particle with characteristic shapes of dicyclodextrin channel moieties and parallel tubular cavities, which was synthesized by a facile process. Subsequently, the spatial structure and characteristics of the ß-CD-POF(I) were primarily confirmed. The structure of ß-CD-POF(I) was then compared to that of KOH-ß-CD-MOF, and a better material for vitamin A palmitate (VAP) encapsulation was determined. VAP was successfully loaded into the particles by solvent-free method. The arrangement of spatial structure made cyclodextrin molecular cavity encapsulation in ß-CD-POF(I) more stable for VAP capture than that of KOH-ß-CD-MOF.

Particle Design and Inhalation Delivery of Iodine for Upper Respiratory Tract Infection Therapy.

Diseases caused by upper respiratory tract (URT) and pulmonary infections have been a serious threat to human health for millennia and lack of targeted effective therapeutic techniques. In this study, two kinds of cyclodextrin particles with typical particle shapes of nanocubes and microbars were synthesized through a facile process. Subsequently, the particles were used as carriers for loading and stabilizing iodine and characterizations were performed to demonstrate the loading mechanism. Next-generation impactor (NGI) experiments showed that iodine-loaded microbars (I2@microbars) had a deposition rate of 79.75% in URT, while iodine-loaded nanocubes (I2@nanocubes) were delivered to the deep lungs with a fine particle fraction (FPF) of 46.30%. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) indicated that the iodine-loaded nanocubes and microbars had similar bactericidal effect to povidone iodine solution. Cell viability studies and extracellular pro-inflammatory factor (TNF-α, IL-1ß, IL-6) evaluations demonstrate noncytotoxic effects of the blank carriers and anti-inflammatory effects of iodine-loaded samples. The irritation of the rat pharynx by I2@microbars was evaluated for the behavioral observations, body weight changes, histopathological studies, and TNF-α, IL-1ß, and IL-6 levels in pharyngeal tissues. The results showed that I2@microbars had no irritation to rat pharyngeal tissues at therapeutic doses. In conclusion, the present study provides novel treatment of URT infections via supramolecular cyclodextrin carriers for URT local therapy with iodine loading by a solvent-free method, which enhances the stability and reduces the inherent irritation without inhibiting their antimicrobial effects. Two kinds of cyclodextrin particles with typical shapes of microbars and nanocubes were synthesized by a facile process. Subsequently, iodine was successfully loaded into the particles by gas-solid interaction. The iodine-loaded microbars showed air dynamics characteristics for inhalation delivery to the upper respiratory tract with little alveolar deposition in the lungs.

Cross-linked γ-cyclodextrin metal-organic framework-a new stationary phase for the separations of benzene series and polycyclic aromatic hydrocarbons.

The cross-linked γ-cyclodextrin metal-organic framework (CL-CD-MOF) was synthesized by crosslinking γ-cyclodextrin metal-organic framework (γ-CD-MOF) with diphenyl carbonate to separate benzene series and polycyclic aromatic hydrocarbons (PAHs). The separation ability of the CL-CD-MOF packed column was assessed in both reverse-phase (RP-) and normal-phase (NP-) modes. The retention mechanisms of these compounds were discussed and confirmed by combining molecular simulations in detail. It was found that baseline separation could be obtained in RP-HPLC mode and it was superior to commercial C18 column in separating xylene isomers. The interaction between CL-CD-MOF and analytes, such as dipole-dipole interaction, π-electron transfer interaction, hydrophobic interaction, and van der Waals force, may dominate the chromatographic separation, and CL-CD-MOF column had a certain shape recognition ability. In addition, the composition of the mobile phase also had a crucial effect. Moreover, the column demonstrated satisfactory stability and repeatability (the relative standard deviations of retention time, peak height, peak area, and half peak width for six replicate separations of the tested analytes were within the ranges 0.17-1.1%, 0.96-1.9%, 0.23-1.7%, and 0.32-1.9%, respectively) and there was no significant change in the separation efficiency for at least 3 years of use. Thermodynamic characteristics indicated that the process of separations on the CL-CD-MOF column was both negative enthalpy change (ΔH) and entropy change (ΔS) controlled. The excellent performance made CL-CD-MOF a promising HPLC stationary phase material for separation and determination of benzene series and PAHs.

A Secure and Lightweight Fine-Grained Data Sharing Scheme for Mobile Cloud Computing.

With the explosion of various mobile devices and the tremendous advancement in cloud computing technology, mobile devices have been seamlessly integrated with the premium powerful cloud computing known as an innovation paradigm named Mobile Cloud Computing (MCC) to facilitate the mobile users in storing, computing and sharing their data with others. Meanwhile, Attribute Based Encryption (ABE) has been envisioned as one of the most promising cryptographic primitives for providing secure and flexible fine-grained "one to many" access control, particularly in large scale distributed system with unknown participators. However, most existing ABE schemes are not suitable for MCC because they involve expensive pairing operations which pose a formidable challenge for resource-constrained mobile devices, thus greatly delaying the widespread popularity of MCC. To this end, in this paper, we propose a secure and lightweight fine-grained data sharing scheme (SLFG-DSS) for a mobile cloud computing scenario to outsource the majority of time-consuming operations from the resource-constrained mobile devices to the resource-rich cloud servers. Different from the current schemes, our novel scheme can enjoy the following promising merits simultaneously: (1) Supporting verifiable outsourced decryption, i.e., the mobile user can ensure the validity of the transformed ciphertext returned from the cloud server; (2) resisting decryption key exposure, i.e., our proposed scheme can outsource decryption for intensive computing tasks during the decryption phase without revealing the user's data or decryption key; (3) achieving a CCA security level; thus, our novel scheme can be applied to the scenarios with higher security level requirement. The concrete security proof and performance analysis illustrate that our novel scheme is proven secure and suitable for the mobile cloud computing environment.

MOF Capacitates Cyclodextrin to Mega-Load Mode for High-Efficient Delivery of Valsartan.

PURPOSE: To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF). METHODS: VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) 13C solid-state nuclear magnetic resonance spectroscopy ( 13C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles. RESULTS: As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD)2, and nanoclusters in the confined spherical cages of (γ-CD)6 confirmed by SAXS and 13C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD)6 are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion. CONCLUSIONS: The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.

A Strongly Unforgeable Certificateless Signature Scheme and Its Application in IoT Environments.

With the widespread application of the Internet of Things (IoT), ensuring communication security for IoT devices is of considerable importance. Since IoT data are vulnerable to eavesdropping, tampering, forgery, and other attacks during an open network transmission, the integrity and authenticity of data are fundamental security requirements in the IoT. A certificateless signature (CLS) is a viable solution for providing data integrity, data authenticity, and identity identification in resource-constrained IoT devices. Therefore, designing a secure and efficient CLS scheme for IoT environments has become one of the main objectives of IoT security research. However, the existing CLS schemes rarely focus on strong unforgeability and replay attacks. Herein, we design a novel CLS scheme to protect the integrity and authenticity of IoT data. In addition to satisfying the strong unforgeability requirement, the proposed scheme also resists public key replacement attacks, malicious-but-passive key-generation-centre attacks, and replay attacks. Compared with other related CLS schemes without random oracles, our CLS scheme has a shorter private key, stronger security, and lower communication and computational costs.

Crystal Transformation of ß-CD-MOF Facilitates Loading of Dimercaptosuccinic Acid.

The ß-cyclodextrin-metal-organic framework (ß-CD-MOF), a potential drug delivery carrier, presents a densely packed laminated crystal structure (CCDC number 1041782) that prevents drug from entering inside the molecular voids in most CD units. In this paper, it was demonstrated that dimercaptosuccinic acid (DMSA), an instable small molecule chemical drug, was successfully loaded in ß-CD-MOF with a high molar ratio of 1:1.35 (ß-CD-MOF:DMSA) determined by high-performance liquid chromatography. The drug loading mechanism of ß-CD-MOF/DMSA was supported by a series of experimental characterizations and molecular simulations. The morphology observations revealed that crystalline particles of ß-CD-MOF transformed to reticular microstructure after drug loading evidenced by powder X-ray diffraction (PXRD), scanning electron microscope (SEM), synchrotron radiation Fourier transform infrared spectroscopy (SR-FTIR), and etc. It is of interest to note that the stability of DMSA was well improved by ß-CD-MOF, but decreased by γ-CD-MOF, indicating different protective capacities between the two types of CD-MOFs. Thus, it is hypothesized that the transformation from laminated molecular arrangement of ß-CD-MOF to reticular microstructure leads to an enhanced drug-loading capability for delivery of specific drugs.

Synchrotron Radiation Microcomputed Tomography Guided Chromatographic Analysis for Displaying the Material Distribution in Tablets.

One unusual and challenging scientific field that has received only cursory attention to date is the three-dimensional (3D) microstructure and spatial distribution of drug(s) and formulation materials in solid dosage forms. This study aims to provide deeper insight into the relationships between the microstructure of multiple-unit pellet system (MUPS) tablets and the spatial distribution of the active pharmaceutical ingredient (API) and excipients to facilitate the design of quantitative models for drug delivery systems. Synchrotron radiation X-ray microcomputed tomography (SR-µCT) was established as a 3D structure elucidation technique, which, in conjunction with liquid chromatography coupled to mass spectrometry (LC-MS) or liquid chromatography with evaporative light-scattering detector (LC-ELSD) enables chemical analysis of tablets. On the basis of the specific interior construction of theophylline MUPS tablets, the spatial distribution of materials was acquired by quantifying microregion samples that had been validated by SR-µCT for their locations in the MUPS tablets. The 3D structure of the MUPS tablets was catalogued as three structural domains: a matrix layer (ML), a protective cushion layer (PCL), and pellets (PL). Compared with the components in the ML, components in the PL had a larger proportion of theophylline, sucrose, and diethyl phthalate and a smaller proportion of lactose and sodium lauryl sulfate, whereas glyceryl monostearate was found to account for a large portion of the PCL. Microstructural characterization-guided zonal chemical determination represents a new approach for quality assessment and the development of drug delivery systems with in-depth insight into their constituent layers on a new scale.

Improvement in Thermal Stability of Sucralose by γ-Cyclodextrin Metal-Organic Frameworks.

PURPOSE: To explain thermal stability enhancement of an organic compound, sucralose, with cyclodextrin based metal organic frameworks. METHODS: Micron and nanometer sized basic CD-MOFs were successfully synthesized by a modified vapor diffusion method and further neutralized with glacial acetic acid. Sucralose was loaded into CD-MOFs by incubating CD-MOFs with sucralose ethanol solutions. Thermal stabilities of sucralose-loaded basic CD-MOFs and neutralized CD-MOFs were investigated using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD). RESULTS: Scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) results showed that basic CD-MOFs were cubic crystals with smooth surface and uniform sizes. The basic CD-MOFs maintained their crystalline structure after neutralization. HPLC-ELSD analysis indicated that the CD-MOF crystal size had significant influence on sucralose loading (SL). The maximal SL of micron CD-MOFs (CD-MOF-Micro) was 17.5 ± 0.9% (w/w). In contrast, 27.9 ± 1.4% of sucralose could be loaded in nanometer-sized basic CD-MOFs (CD-MOF-Nano). Molecular docking modeling showed that sucralose molecules preferentially located inside the cavities of γ-CDs pairs in CD-MOFs. Raw sucralose decomposed fast at 90°C, with 86.2 ± 0.2% of the compound degraded within only 1 h. Remarkably, sucralose stability was dramatically improved after loading in neutralized CD-MOFs, with only 13.7 ± 0.7% degradation at 90°C within 24 h. CONCLUSIONS: CD-MOFs efficiently incorporated sucralose and maintained its integrity upon heating at elevated temperatures.

Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes.

In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug-cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB-CD complexation equilibrium at this gradient were introduced. The transfer of PAB-CD complex into the internal aqueous phase of niosomes at 60 °C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug-carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (ΔG) indicated the strongest PAB-carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD-cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug-CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug.

Prediction of Rate Constant for Supramolecular Systems with Multiconfigurations.

The control of supramolecular systems requires a thorough understanding of their dynamics, especially on a molecular level. It is extremely difficult to determine the thermokinetic parameters of supramolecular systems, such as drug-cyclodextrin complexes with fast association/dissociation processes by experimental techniques. In this paper, molecular modeling combined with novel mathematical relationships integrating the thermodynamic/thermokinetic parameters of a series of isomeric multiconfigurations to predict the overall parameters in a range of pH values have been employed to study supramolecular dynamics at the molecular level. A suitable form of Eyring's equation was derived and a two-stage model was introduced. The new approach enabled accurate prediction of the apparent dissociation/association (k(off)/k(on)) and unbinding/binding (k-r/kr) rate constants of the ubiquitous multiconfiguration complexes of the supramolecular system. The pyronine Y (PY) was used as a model system for the validation of the presented method. Interestingly, the predicted k(off) value ((40 ± 1) × 10(5) s(-1), 298 K) of PY is largely in agreement with that previously determined by fluorescence correlation spectroscopy ((5 ± 3) × 10(5) s(-1), 298 K). Moreover, the k(off)/k(on) and k-r/kr for flurbiprofen-ß-cylcodextrin and ibuprofen-ß-cyclodextrin systems were also predicted and suggested that the association processes are diffusion-controlled. The methodology is considered to be especially useful in the design and selection of excipients for a supramolecular system with preferred association and dissociation rate constants and understanding their mechanisms. It is believed that this new approach could be applicable to a wide range of ligand-receptor supramolecular systems and will surely help in understanding their complex mechanism.

[Determination of the interaction kinetics between meloxicam and ß-cyclodextrin using the quantitative high-performance affinity chromatography coupled with mass spectrometry].

The association rate constant and dissociation rate constant are important parameters of the drug-cyclodextrin supermolecule systems, which determine the dissociation of drugs from the complex and the further in vivo absorption of drugs. However, the current studies of drug-cyclodextrin interactions mostly focus on the thermodynamic parameter of equilibrium constants (K). In this paper, a method based on quantitative high performance affinity chromatography coupled with mass spectrometry was developed to determine the apparent dissociation rate constant (k(off,app)) of drug-cyclodextrin supermolecule systems. This method was employed to measure the k(off,app) of meloxicam and acetaminophen. Firstly, chromatographic peaks of drugs and non-retained solute (uracil) on ß-cyclodextrin column at different flow rates were acquired, and the retention time and variance values were obtained via the fitting the peaks. Then, the plate heights of drugs (H(R)) and uracil (H(M,C)) were calculated. The plate height of theoretical non-retained solute (H(M,T)) was calculated based on the differences of diffusion coefficient and the stagnant mobile phase mass transfer between drugs and uracil. Finally, the k(off,app) was calculated from the slope of the regression equation between (H(R)-H(M,T)) and uk/(1+k)2, (0.13 ± 0.00) s(-1) and (4.83 ± 0.10) s(-1) for meloxicam and acetaminophen (control drug), respectively. In addition, the apparent association rate constant (k(on,app)) was also calculated through the product of K (12.53 L x mol(-1)) and k(off,app). In summary, it has been proved that the method established in our study was simple, efficiently fast and reproducible for investigation on the kinetics of drug-cyclodextrin interactions.

[Release kinetics of single pellets and the multi-pellet system of tamsulosin hydrochloride sustained release pellets].

The release behavior of single pellet was investigated by LC/MS/MS method with tamsulosin hydrochloride (TSH) as the model drug of the research and then the pellets were divided into four groups according to the drug loading. Comparison of dissolution profiles of each group and capsule were performed using f1 and f2 factor methods to study the difference and similarity. The release profiles of single pellet, each group and capsule were analyzed using principle component analysis (PCA). The particle system was built through Matlab to get the target release profile. The result of this research demonstrated the release behavior of single pellet correlated well with the drug loading. While the dissolution profile of capsule as a reference, the similarity factor of dissolution profiles of the lower drug loading groups were 62.2, 67.1, 53.9, respectively and, 43.3 for highest drug loading group. The particle systems with different pellet distribution and same release profiles were built through release behavior of single pellet. It is of significance to investigate the release behavior of single pellets for studying the release regularity of multiple-unit drug delivery system.

Rapid isolation of extracellular vesicles using covalent organic frameworks combined with microfluidic technique.

Extracellular vesicles (EVs) are nano-sized lipid-membrane vesicles involved in intercellular communication and reflecting the physiological and pathological processes of their parental cells. Rapid isolation of EVs with low cost is an essential precondition for downstream function exploration and clinical applications. In this work, we designed a novel EVs isolation device based on the boronated organic framework (BOF) coated recyclable microfluidic chip (named EVs-BD) to separate EVs from cell culture media. Using a reactive oxygen species responsive phenylboronic ester compound, the highly porous BOF with a pore size in the range of 10-300 nm was prepared by crosslinking γ-cyclodextrin metal-organic frameworks. A mussel-inspired polydopamine (PDA)/polyethyleneimine (PEI) coating was employed to pattern BOF on the PDMS substrate of microfluidic channels. The EVs-BD was demonstrated to offer distinct advantages over the traditional ultracentrifugation method, such as operation simplicity and safety, reduced time and expense, and low expertize requirements. All things considered, a novel approach of EV acquisition has been successfully developed, which can be customized easily to meet the requirements of various EV-relevant research.

Supramolecular Structure of the ß-Cyclodextrin Metal-Organic Framework Optimizes Iodine Stability and Its Co-delivery with l-Menthol for Antibacterial Applications.

The spread of upper respiratory tract (URT) infections harms people's health and causes social burdens. Developing targeted treatment strategies for URT infections that exhibit good biocompatibility, stability, and strong antimicrobial effects remains challenging. The dual antimicrobial and antiviral effects of iodine (I2) in combination with the cooling sensation of l-menthol in the respiratory tract can simultaneously alleviate URT inflammation symptoms. However, as both I2 and l-menthol are volatile, addressing stability issues is crucial. In this study, a potassium iodide ß-cyclodextrin metal-organic framework [ß-CD-POF(I)] with appropriate particle size was used to coload and deliver I2 and l-menthol. Primarily, ß-CD-POF(I) was employed as the most efficient carrier to significantly enhance the stability of I2, surpassing any other known protection strategies in the pharmaceutical field (CD complexations, PVP conjugations, and cadexomer iodine). The mechanism underlying the improvement in stability of I2 by ß-CD-POF(I) was investigated through scanning electron microscopy with energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and molecular docking. The results revealed that the key processes involved in improving stability were the inclusion of I2 by ß-CD cavities in ß-CD-POF(I) and the formation of polyiodide anion between iodine ions and I2. Furthermore, the potential of ß-CD-POF(I) to load and deliver drugs was validated, and coloading of l-menthol and I2 demonstrated reliable stability. ß-CD-POF(I) achieved a rate of URT deposition ≥95% in vitro, and the combined antibacterial effects of coloaded I2 and l-menthol was better than I2 or PVP-I alone, with no irritation noted following URT administration in rabbits. Therefore, the stable coloading of drugs by ß-CD-POF(I), leading to enhanced antimicrobial effects, provides a new strategy for treating URT infections.

Glycyrrhetinic acid loaded in milk-derived extracellular vesicles for inhalation therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors ß1 (TGF-ß1), Smad3 and inflammatory cytokines IL-6, IL-1ß and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.

Purification of gamma-cyclodextrin via selective coordination with potassium ions to form metal-organic frameworks.

Efficient purification of gamma-cyclodextrin (γ-CD) is always challenging due to its structural similarity to other CDs and low crystallinity in water. In addressing this issue, an approach was proposed based on the formation mechanism of cyclodextrin metal-organic frameworks (CD-MOFs). This method involved the selective coordination of CDs mixture with potassium ions in water, facilitated by ethanol-induced crystallization, leading to the purification of γ-CD. The results showed that potassium ions enhanced γ-CD crystallization, and ethanol was crucial to selectively coordinating potassium ions with γ-CD. The characterizations revealed that the resulting CD-MOFs exhibited a small particle size, high surface area, and high thermal stability, and was identical to γ-CD-MOF, further indicating the final γ-CD with high purity. The separation factors of γ-CD/α-CD and γ-CD/ß-CD were 309 and 260, respectively. Moreover, this method was validated through its application to the industrial enzymatic CDs mixture. The purification of γ-CD could achieve 99.99 ± 0.01 % after four crystallization cycles. Therefore, selectively coordinating with potassium ions to form MOFs provided a valuable reference for the purification of γ-CD and even the direct synthesis of γ-CD-MOF from CDs mixture. This advancement will also benefit the future production and application of γ-CD.

Enhanced ophthalmic bioavailability and stability of atropine sulfate via sustained release particles using polystyrene sulfonate resin.

Atropine sulfate (ATS) eye drops at low concentrations constitute a limited selection for myopia treatment, with challenges such as low ophthalmic bioavailability and inadequate stability. This study proposes a novel strategy by synthesizing ophthalmic sodium polystyrene sulfonate resin (SPSR) characterized by a spherical shape and uniform size for cationic exchange with ATS. The formulation of ATS@SPSR suspension eye drops incorporates xanthan gum and hydroxypropyl methylcellulose (HPMC) as suspending agents. In vitro studies demonstrated that ATS@SPSR suspension eye drops exhibited sustained release characteristics, and tropic acid, its degradation product, remained undetected for 30 days at 40 °C. The ATS levels in the tear fluids and aqueous humor of New Zealand rabbits indicated a significant increase in mean residence time (MRT) and area under the drug concentration-time curve (AUC0-12h) for ATS@SPSR suspension eye drops compared to conventional ATS eye drops. Moreover, safety assessment confirmed the non-irritating nature of ATS@SPSR suspension eye drops in rabbit eyes. In conclusion, the cation-responsive sustained-release ATS@SPSR suspension eye drops enhanced the bioavailability and stability of ATS, offering a promising avenue for myopia treatment.

Visualization of nasal powder distribution using biomimetic human nasal cavity model.

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.