Improve Drug Solubility Research Articles

Rebamipide nanocrystal with improved physicomechanical properties and its assessment through bio-mimicking 3D intestinal permeability model.

This study investigated the formulation and characterization of rebamipide nanocrystals (REB-NCs) to enhance the solubility and permeability of rebamipide, an anti-ulcer medication known for its low aqueous solubility and permeability, classified as BCS class IV. Employing high-pressure homogenization and wet milling techniques, we successfully achieved nanonization of rebamipide, resulting in stable nanosuspensions that were subsequently freeze-dried to produce REB-NCs with an average particle size of 223 nm. Comprehensive characterization techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) confirmed the crystalline nature of the nanocrystals and their compatibility with the selected excipients. The saturation solubility study revealed a remarkable three-fold enhancement in PBS pH 7.4 compared to rebamipide API, indicating the effectiveness of the nanocrystal formulation in improving drug solubility. Furthermore, 3D in-vitro permeability assessments conducted on Caco-2 cell monolayers demonstrated an noticeable increase in the permeability of REB-NCs relative to the pure active pharmaceutical ingredient (API), highlighting the promise of this formulation to enhance drug absorption. The dissolution profile of the nanocrystal tablets exhibited immediate release characteristics, significantly outperforming conventional formulations in terms of the dissolution rate. This research underscores the potential of nanomilling as a scalable, environment-friendly, and less toxic approach to significantly enhance the bioavailability of rebamipide. By addressing the challenges associated with the solubility and permeability of poorly water-soluble drugs, our outcome offers insightful information into developing efficient nanomedicine strategies for enhancing therapeutic outcomes.

Application of Hydrogenated Soya Lecithin in Solid Dispersion and Oily Gel, and the Study of Skin-Applied Formulations

I have been studying the improvement of drug solubility using solid dispersion and skin-applied formulations. When preparing solid dispersions using phosphatidylcoline (PC) as a carrier, drug with hydrogen-donating groups interacts with PC to produce amorphous solid dispersions with high drug content; this overcomes improves drug absorption. The drug was solubilized and supersaturated in the oil-based gel formed with hyadrogenated lecithin; this facilitates drug permeation through the skin. The promoting effect differs with the nature of the oil used because of the skin penetration of the oil itself and the accompanying increase in drug solubility and diffusion coefficient in the skin. At actual application volumes of 10 µL/cm2 or less, the skin penetration of poorly-absorbable drugs depends on the molecular weight and surface tension of the oil. The penetration of the oil vehicle into the upper stratum corneum influences the reach of the drug into the stratum corneum; a high drug concentration near the 7th layer of the stratum corneum promotes migration through the skin by increasing the linear concentration gradient in deeper layers. In addition, we performed a risk assessment, in collaboration with toxicologists, for dermal safety that included the toxicity potential of substances and the parts related to skin transfer.

Rapid screening of ternary amorphous formulations by a spray drying robot

Spray drying is commonly used for producing amorphous solid dispersions to improve drug solubility. The development of such formulations typically relies on comprehensive excipient and composition screening, which requires the preparation of many spray-dried powder samples. This is both labour-intensive and time-consuming when carried out manually. In the present work, the formulation screening task was automated by coupling a laboratory spray dryer operated in a semi-continuous mode with custom-made add-ons, allowing for rapid, computer-controlled production of formulation samples with systematically varying composition. The practical use of the spray drying robot in formulation development was demonstrated on a case study of poorly water-soluble model drugs simvastatin and ezetimibe. Six different polymers and several drug:polymer ratios were screened for the enhancement of dissolution properties. From a pool of 28 spray-dried samples, ternary compositions containing Eudragit L100-55 were identified as the most suitable ones for further processing and characterisation. The ability to populate the formulation design space rapidly and automatically made it possible to construct maps of physico-chemical properties such as glass transition temperature or dissolution rate. The spray drying robot thus enables the acceleration of early formulation development and a deeper understanding of composition-property relationships for multi-component spray dried powders.

A review on nanotechnology based ophthalmic drug delivery system

The field of ophthalmic drug delivery has witnessed significant advancements through the integration of nanotechnology. Despite having numerous conventional dosage forms employed in the ocular drug delivery system the problem of less bioavailability and less retention time is a significant concern. Along with it there are various barriers also involved that affects the drug permeability, solubility due to the lower residence time of the drug on ocular surface. To overcome these problems the nanotechnology approach can be most suitable. All nanocarriers have emerged as a promising career for precise drug targeting to ocular tissues. Their small size, biocompatibility and surface modification enable improved drug solubility, sustained release and enhanced bioavailability. Moreover nanotechnology facilitates the incorporation of therapeutic agents for various ocular conditions, including glaucoma, macular degeneration and infections. These advancements aim to overcome the challenges and barriers in ocular drug delivery system. This review underscores the immense potential of nanotechnology to revolutionize ophthalmic drug delivery, offering the prospect of more efficient and patient-friendly treatments for ophthalmic disorders.
 Keywords: Ocular drug delivery, Nanotechnology, Nanocarriers, Intraocular pressure, Ophthalmic barriers

Sustained delivery of statistically optimized transfersomal gel of miconazole nitrate for vaginal candidiasis

Miconazole nitrate (MN), an antifungal drug with poor solubility, is used in the treatment of vaginal candidiasis. Conventional vaginal formulations have lower residence time and poor drug penetration resulting in the recurrence of the infection. Hence, transfersomes were formulated that would alleviate fungal infection by improving drug solubility and allowing effective permeation through the vaginal mucus and epithelium. MN-loaded transfersomes (MN-TF) were prepared by the thin film method. The optimization of the MN-TF was done by using 32 full factorial design. The Lipoid S100® and Tween 80® were selected as the phospholipid and edge activator, respectively. The responses, such as particle size, PDI, and entrapment efficiency were studied and found to be 180.70±2.11 nm, 0.293±0.012, and −13.2±1.3 mV, respectively. The optimized MN-TF was incorporated into the thermosensitive gel. The morphological study through TEM confirmed the nano size of the formulation. The FTIR study showed compatibility between the drug and excipients. The microbiological screening was performed against Candida albicans which showed a higher zone of inhibition for MN-TF than the marketed gel. The ex vivo transvaginal permeation study was done for MN-TF gel and compared with the marketed gel Daktarin®. The permeability of the MN-TF was increased by 5.8-folds as compared to the marketed gel. The HET-CAM assay for the MN-TF gel demonstrated no irritation and hence was nontoxic and safe for vaginal administration. Therefore, the MN-TF gel had sustained drug release.

Characterization, Antifungal Evaluation against Candida spp. Strains and Application of Nystatin: β-cyclodextrin Inclusion Complexes.

Nystatin (Nys) is a fungicidal drug commonly prescribed for candidiasis disease in several administration routes. However, Nys is a class IV drug, according to the Biopharmaceutical Classification System, that possesses limited bioavailability and is used for local activity. This study developed and characterized nystatin:β-cyclodextrin (Nys:βCD) inclusion complexes and evaluated their activity against Candida spp. Complexes were characterized by physicochemical techniques and drug dissolution profiles. The susceptibility of C. albicans, C. krusei, C. parapsilosis, C. glabrata, C. guilliermondii, C. tropicalis, and C. auris was assessed using the broth microdilution method. The applicability of Nys:βCD inclusion complex was evaluated by incorporating it into a temporary soft material for denture stomatitis treatment. Nys was better complexed in a 1:1 molar ratio by freeze-drying and spray-drying methods. The inclusion complexes show bi-exponential release, an initial burst release followed by a sustained manner, presenting higher dissolution efficiency than raw Nys. The 1:1 freeze-drying Nys:βCD complex presents antifungal activity against all evaluated Candida strains, showing the maintenance of the drug effectiveness. The inclusion complex incorporated into a tissue conditioner material for denture stomatitis treatment effectively inhibited more than 90% of C. albicans biofilm growth during 7 and 14 days, in a half dose compared to raw Nys. This work represents a significant contribution to treating a wide variety of diseases caused by the Candida species, optimizing the drug bioavailability and compliance to the treatment due to improved drug solubility, dissolution, and sustained delivery.

Evaluation of mucosal immune profile associated with Zileuton nanocrystal-formulated BCS-II drug upon oral administration in Sprague Dawley rats

Nanocrystal drug formulation involves several critical manufacturing procedures that result in complex structures to improve drug solubility, dissolution, bioavailability, and consequently the efficacy of poorly soluble Biopharmaceutics Classification System (BCS) II and IV drugs. Nanocrystal formulation of an already approved oral drug may need additional immunotoxic assessment due to changes in the physical properties of the active pharmaceutical ingredient (API). In this study, we selected Zileuton, an FDA-approved drug that belongs to BCS-II for nanocrystal formulation. To evaluate the efficacy and mucosal immune profile of the nanocrystal drug, 10-week-old rats were dosed using capsules containing either API alone or nanocrystal formulated Zileuton (NDZ), or with a physical mixture (PM) using flexible oral gavage syringes. Control groups consisted of untreated, or placebo treated animals. Test formulations were administrated to rats at a dose of 30 mg/kg body weight (bw) once a day for 15 days. The rats treated with NDZ or PM had approximately 4.0 times lower (7.5 mg/kg bw) API when compared to the micron sized API treated rats. At the end of treatment, mucosal (intestinal tissue) and circulating cytokines were measured. The immunological response revealed that NDZ decreased several proinflammatory cytokines in the ileal mucosa (Interleukin-18, Tumor necrosis Factor-α and RANTES [regulated upon activation, normal T cell expressed and secreted]). A similar pattern in the cytokine profile was also observed for the micron sized API and PM treated rats. The cytokine production revealed that there was a significant increase in the production of IL-1β and IL-10 in the females in all experimental groups. Additionally, NDZ showed an immunosuppressive effect on proinflammatory cytokines both locally and systemically, which was similar to the response in micron sized API treated rats. These findings indicate that NDZ significantly decreased several proinflammatory cytokines and it displays less immunotoxicity, probably due to the nanocrystal formulation. Thus, the nanocrystal formulation is more suitable for oral drug delivery, as it exhibited better efficacy, safety, and reduced toxicity.

Recent advances in porous nanomaterials‐based drug delivery systems for osteoarthritis

AbstractOsteoarthritis (OA) is a common degenerative disease that develops over time, characterized mainly by inflammatory joints, cartilage deterioration, and ultimately loss of normal joint function. Some of the limitations that restrict the effectiveness of current OA treatment procedures include minimal penetration of medications into cartilage and lack of vascularity, leading to insufficient bioavailability and systemic toxicity. To increase the effectiveness of treatment, it is necessary to create novel non‐invasive OA treatment techniques. Porous nanomaterials (PNMs) show great promise as sustained drug delivery systems (DDSs) due to their functionality, variable porosity, and high loading capacity. In addition, they can provide targeted drug delivery, facilitate controlled release of drugs, and prolong drug circulation and retention time while reducing adverse reactions and improving drug solubility. First, the current treatment methods and challenges are summarized. Subsequently, recent advances in DDSs for OA treatment based on PNMs with various pore sizes and structures are presented. Lastly, the parameters that affect the performance of DDSs are discussed by giving some suggestions for their design. The purpose of this review is to provide new insights into PNM‐based DDS design and to inspire readers to adopt the smart design of intra‐articular DDSs in the future.

Nano-Warriors against Drug-Resistant Tuberculosis: Unleashing Nanoparticles for Enhanced Treatment

Tuberculosis (TB) is a global health crisis, with millions of cases and deaths annually. Drug-resistant strains like multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB further complicate treatment. Conventional TB treatment, reliant on lengthy drug regimens, faces issues of non-compliance, drug resistance, and side effects. Nanoparticles (NPs) offer a promising solution. NPs, with their small size and unique properties, can enhance TB drug delivery. They improve drug solubility and stability, minimize side effects, and enable targeted therapy. NPs encapsulate drugs, shielding them from degradation during delivery and ensuring controlled drug release at the infection site. NPs' controlled release leads to prolonged drug efficacy, reducing dosing frequency and improving patient compliance. Moreover, NPs can encapsulate multiple drugs, a critical advantage in combating drug-resistant TB strains. In conclusion, NPs hold immense promise in TB treatment. They address the limitations of traditional therapies by improving drug delivery, bioavailability, and targeting drug-resistant TB. Ongoing research in nanoparticles-based formulations offers hope for more effective and patient-friendly TB treatments.

Solubility and Dissolution Enhancement of Atorvastatin Calcium using Phospholipid Solid Dispersion Technique

Atorvastatin (ATR) is a poorly water-soluble anti-hyperlipidemic drug. The drug belongs to the class II group according to the biopharmaceutical classification system (BCS) with low bioavailability due to its low solubility. Solid dispersion is an effective technique for enhancing the solubility and dissolution of drugs. Phospholipid solid dispersion (PSD) using phosphatidylcholine (PC) as a carrier with or without adsorbent (magnesium aluminum silicate, silicon dioxide 15nm, silicon dioxide 30nm, calcium silicate) was used to prepare ATR PSD using different drug: PC: adsorbent ratios by solvent evaporation method. The resulted PSD was evaluated for its percentage yield, drug content, solubility, dissolution rate, Fourier transformation infrared spectroscopy (FTIR), powder X-ray diffraction study (PXRD), and differential scanning calorimetry (DSC). The prepared (PSD) showed improvement in drug solubility in all prepared formulas. The best result was obtained with F5 (ATR: PC: MAS 1:3:4). The solubility was increased by 21 folds compared to the pure drug with enhanced dissolution and decrease crystallinity.

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.

Recent Advances and Future Challenges of Nano-based Drug Delivery System

Nano drug delivery systems play a crucial role in addressing key challenges encountered in conventional drug delivery methodologies, making them of significant importance in the field of medicine. These systems offer enhanced drug bioavailability by improving drug solubility and stability, thereby maximizing therapeutic efficacy. Their ability to achieve targeted drug delivery to specific tissues, cells, or subcellular compartments minimizes off-target effects and reduces systemic toxicity. Additionally, nano drug delivery systems present opportunities for combination therapy, where multiple drugs or therapeutic agents can be encapsulated within a single nanoparticle, promoting synergistic effects and personalized treatment strategies. Overall, the utilization of nano drug delivery systems holds great promise in enhancing therapeutic outcomes, mitigating adverse effects, and advancing the field of precision medicine. Nano drug delivery systems have demonstrated remarkable potential through various examples, mesoporous nanoparticles, nanomaterials, polymeric nanoparticles, carbon nanotubes, dendrimers, liposomes, metallic nanoparticles, and nanomedicine etc.

Nanocarriers in Tuberculosis Treatment: Challenges and Delivery Strategies.

The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis, as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The rise of MDR strains endangers future TB control. Despite these concerns, the hunt for an efficient treatment continues. One breakthrough has been the use of nanotechnology in medicines, presenting a novel approach for TB treatment. Nanocarriers, such as lipid nanoparticles, nanosuspensions, liposomes, and polymeric micelles, facilitate targeted delivery of anti-TB drugs. The benefits of nanocarriers include reduced drug doses, fewer side effects, improved drug solubility, better bioavailability, and improved patient compliance, speeding up recovery. Additionally, nanocarriers can be made even more targeted by linking them with ligands such as mannose or hyaluronic acid. This review explores these innovative TB treatments, including studies on nanocarriers containing anti-TB drugs and related patents.

Mechanisms of Drug Solubility Enhancement Induced by β-Lactoglobulin-Based Amorphous Solid Dispersions.

Protein-based amorphous solid dispersions (ASDs) have emerged as a promising approach for enhancing solubility in comparison to crystalline drugs. The dissolution behavior of protein-based amorphous solid dispersions (ASDs) was investigated in various pH media. ASDs of four poorly soluble model drugs with acidic (furosemide and indomethacin), basic (carvedilol), and neutral (celecoxib) properties were prepared by spray drying at 30 wt % drug loading with the protein β-lactoglobulin (BLG). The effect of spray-dried BLG (SD-BLG) solubility and protein binding ability with dissolved drugs in solution were investigated to retrieve the mechanisms governing the improvement of drug solubility from the BLG-based ASDs. Powder dissolution results showed that all ASDs obtained a higher maximum concentration (Cmax) compared to the respective pure crystalline drugs. It was found that the solubility increase of the drugs from the ASDs was to a large extent dependent on the solubility of the pure SD-BLG at the investigated pH values (low solubility at pH near the isoelectric point (pI) of BLG). Furthermore, drug-protein interactions in a solution were observed, in particular at pH values where the drugs were neutral. These drug-protein interactions also resulted, to some extent, in the stabilization of the drug in supersaturation.

Controlling the positive ion electrospray ionization of poly(ethylene glycols) when using ultra-high-performance supercritical fluid chromatography-mass spectrometry.

Poly(ethylene glycols) are complex polymers often added to pharmaceutical formulations to improve drug solubility and delivery. One of the main challenges when using chromatographic techniques coupled to mass spectrometry is the unselective ionization of poly(ethylene glycols) oligomers. Additionally, when the chain length is large enough, multiple charged species are formed, further complicating the mass spectra and processing. This study uses the advanced oligomer separation provided by supercritical fluid chromatography with a mass spectrometry approach that selectively ionizes poly(ethylene glycols) as ammoniated molecules to simplify data analysis and facilitate batch-to-batch comparisons. Several visual representations of the response of the ionization events based on the polymer molecular weight and the repeating unit were used to elucidate trends in ionization. Evaluation of the influence of the oligomer length and end-group on the electrospray ionization of the polymer allowed the development of a process to enable selective ionization for these complex polymers.

Harnessing the Potential of Biosurfactants for Biomedical and Pharmaceutical Applications.

Biosurfactants (BSs) are microbial compounds that have emerged as potential alternatives to chemical surfactants due to their multifunctional properties, sustainability and biodegradability. Owing to their amphipathic nature and distinctive structural arrangement, biosurfactants exhibit a range of physicochemical properties, including excellent surface activity, efficient critical micelle concentration, humectant properties, foaming and cleaning abilities and the capacity to form microemulsions. Furthermore, numerous biosurfactants display additional biological characteristics, such as antibacterial, antifungal and antiviral effects, and antioxidant, anticancer and immunomodulatory activities. Over the past two decades, numerous studies have explored their potential applications, including pharmaceuticals, cosmetics, antimicrobial and antibiofilm agents, wound healing, anticancer treatments, immune system modulators and drug/gene carriers. These applications are particularly important in addressing challenges such as antimicrobial resistance and biofilm formations in clinical, hygiene and therapeutic settings. They can also serve as coating agents for surfaces, enabling antiadhesive, suppression, or eradication strategies. Not least importantly, biosurfactants have shown compatibility with various drug formulations, including nanoparticles, liposomes, micro- and nanoemulsions and hydrogels, improving drug solubility, stability and bioavailability, and enabling a targeted and controlled drug release. These qualities make biosurfactants promising candidates for the development of next-generation antimicrobial, antibiofilm, anticancer, wound-healing, immunomodulating, drug or gene delivery agents, as well as adjuvants to other antibiotics. Analysing the most recent literature, this review aims to update the present understanding, highlight emerging trends, and identify promising directions and advancements in the utilization of biosurfactants within the pharmaceutical and biomedical fields.

Novel Meta-iodobenzylguanidine and Etoposide Complex: Physicochemical Characterization and Mathematical Modeling of Anticancer Activity.

It is hypothesized that meta-iodobenzylguanidine (MIBG) complexation with etoposide (VP-16) will improve drug solubility and specificity towards BE(2)C neuroblastoma (NB) cells, 90% of which are known to be MIBG avid. After MIBG and VP-16 interaction, the dry complex was analyzed for crystalline structure, surface morphology, solubility, and size distribution by X-ray powder diffraction (P-XRD), scanning electron microscopy (SEM), infrared (FTIR) and UV spectroscopy, and dynamic light scattering. After exposure to the complex, the cell viability and decay rates were assessed by the MTS assay and estimated using exponential decay models (EDM). Multi-factorial ANOVA and an independent t-test were used to assess for cell viability and solubility data, respectively. The resulting (1: 3 w/w) VP-16: MIBG complex had a mean diameter and zeta potential of 458.5nm and 0.951mV, respectively. It dramatically increased the drug apparent water solubility (~ 12-folds). This was ascribed to the formation of a VP-16/MIBG nanocrystalline state mainly governed by cation-π interactions, evidenced by FTIR, SEM, and P-XRD data following the complexation. The EDM relating percent cell viability to drug concentration yielded an excellent fit (r2 > 0.95) and enabled to estimate the IC50 values of both native drug and its complex: 6.2μM and 5.23μM, respectively (indicating a conservation of drug anticancer activity). The statistical results were consistent with those of the exponential decay models, indicating that MIBG does not inhibit the anticancer activity of VP-16. This study indicates that the VP-16/MIBG complexation improves VP-16 solubility without antagonizing its anticancer activity. Moreover, the efficiency of the EDM for drug IC50 estimation provides alternative mathematical method for such in vitro cytotoxicity studies.

A mannitol-modified emodin nano-drug restores the intestinal barrier function and alleviates inflammation in a mouse model of DSS-induced ulcerative colitis

BackgroundUlcerative colitis (UC) is an inflammatory disease of the colon that is characterized by mucosal ulcers. Given its increasing prevalence worldwide, it is imperative to develop safe and effective drugs for treating UC. Emodin, a natural anthraquinone derivative present in various medicinal herbs, has demonstrated therapeutic effects against UC. However, low bioavailability due to poor water solubility limits its clinical applications.MethodsEmodin-borate nanoparticles (EmB) were synthesized to improve drug solubility, and they modified with oligomeric mannitol into microgels (EmB-MO) for targeted delivery to intestinal macrophages that express mannose receptors. UC was induced in a mouse model using dextran sulfate sodium (DSS), and different drug formulations were administered to the mice via drinking water. The levels of inflammation-related factors in the colon tissues and fecal matter were measured using enzyme-linked immunosorbent assay. Intestinal permeability was evaluated using fluorescein isothiocyanate dextran. HE staining, in vivo imaging, real-time PCR, and western blotting were performed to assess intestinal barrier dysfunction.ResultsBoth EmB and EmB-MO markedly alleviated the symptoms of UC, including body weight loss, stool inconsistency, and bloody stools and restored the levels of pro- and anti-inflammatory cytokines. However, the therapeutic effects of EmB-MO on the macroscopic and immunological indices were stronger than those of EmB and similar to those of 5-aminosalicylic acid. Furthermore, EmB-MO selectively accumulated in the inflamed colon epithelium and restored the levels of the gut barrier proteins such as ZO-1 and Occludin.ConclusionsEmB-MO encapsulation significantly improved water solubility, which translated to greater therapeutic effects on the immune balance and gut barrier function in mice with DSS-induced UC. Our findings provide novel insights into developing emodin-derived drugs for the management of UC.

Berberine-loaded MSC-derived sEVs encapsulated in injectable GelMA hydrogel for spinal cord injury repair

After spinal cord injury (SCI), local inflammatory response and fibrous scar formation severely hinder nerve regeneration. Berberine (Ber) has a powerful regulatory effect on the local microenvironment, but its limited solubility and permeability through the blood–brain barrier severely limit its systemic efficacy. Human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived small extracellular vesicles (sEVs) are natural nanocarriers with high cargo loading capacity, and can cross the blood–brain barrier. Most importantly, sEVs can improve drug solubility and drug utilization. Therefore, they can overcome many defects of Ber application. This experiment aimed to design a Ber-carrying hUC-MSCs-derived sEVs and GelMA hydrogel. Ber was loaded into sEVs (sEVs-Ber) by ultrasonic co-incubation with a drug loading capacity (LC) of 15.07%. The unhindered release of up to 80% of sEVs-Ber from GelMA hydrogel was accomplished for up to 14 days. And they could be directly absorbed by local cells of injury, allowing for direct local delivery of the drug and enhancing its efficacy. The experimental results confirmed injecting GelMA-sEVs-Ber into spinal cord defects could exert anti-inflammatory effects by regulating the expression of inflammatory factors. It also demonstrated the anti-fibrotic effect of Ber in SCI for the first time. The modulatory effects of sEVs and Ber on the local microenvironment significantly promoted nerve regeneration and recovery of motor function in post-SCI rats. These results demonstrated that the GelMA-sEVs-Ber dual carrier system is a promising therapeutic strategy for SCI repair.

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption.

Coamorphous formulation is a useful approach for enhancing the solubility of poorly water-soluble drugs via intermolecular interactions. In this study, a hydrogen-bonding-based coamorphous system was developed to improve drug solubility, but it barely changed the apparent permeability (Papp) of the drug. This study aimed to design a novel coamorphous salt using ionic interactions to improve drug permeability and absorption. Telmisartan (TMS), with an acidic group, was used to form a coamorphous salt with basic amlodipine (AML). Evaluation of the physicochemical properties confirmed the formation of a coamorphous salt via ionic interactions between the amine group of AML and the carboxyl group of TMS at a molar ratio of 1:1. The coamorphous salt of TMS/AML enhanced the partitioning of both drugs into octanol, indicating increased lipophilicity owing to the interaction between TMS and AML. The coamorphous salt dramatically enhanced TMS solubility (99.8 times that of untreated TMS) and decreased AML solubility owing to the interaction between TMS and AML. Although the coamorphous salt showed a decreased Papp in the permeation study in the presence of a thicker unstirred water layer (UWL) without stirring, Papp increased in the presence of a thinner UWL with stirring. The oral absorption of TMS from the coamorphous salt increased by up to 4.1 times compared to that of untreated TMS, whereas that of AML remained unchanged. Although the coamorphous salt with increased lipophilicity has a disadvantage in terms of diffusion through the UWL, the UWL is thin in human/animal bodies owing to the peristaltic action of the digestive tract. Dissociation of the coamorphous salt on the membrane surface could contribute to the partitioning of the neutral form of drugs to the membrane cells compared with untreated drugs. As a result, coamorphous salt formation has the advantage of improving the membrane permeation and oral absorption of TMS, owing to the enhanced solubility and supply of membrane-permeable free TMS on the surface of the membrane.