Poor Aqueous Solubility Research Articles

Development of curcumin-loaded galactosylated chitosan-coated nanoparticles for targeted delivery of hepatocellular carcinoma

Curcumin (CUR) has good antitumor effects, but its poor aqueous solubility severely limits its clinical application and the systemic nonspecific distribution of the free drug in tumor patients is a key therapeutic challenge. In order to overcome the limitations of free drugs and improve the therapeutic efficacy, we developed novel galactosylated chitosan (GC)-modified nanoparticles (GC@NPs) based on poly (ethylene glycol) methyl ether-block-poly (lactide-co-glycolide) (PEG-PLGA), which can target asialoglycoprotein receptor (ASGPR) expressed on hepatocellular carcinoma cells and have excellent biocompatibility. The results showed that the drug loading (DL) of CUR was approximately 4.56 %. A favorable biosafety profile was maintained up to concentrations of 500 μg/mL. Furthermore, in vitro cellular assays showed that GC@NPs could be efficiently internalized by HepG2 cells via ASGPR-mediated endocytosis and successfully released CUR for chemotherapy. More importantly, in vivo anti-tumor experiments revealed that GC@NPs were able to accumulate effectively within tumor sites through EPR effect and ASGPR-mediated endocytosis, leading to superior inhibition of tumor growth compared to free CUR. Overall, GC@NPs are a promising CUR nanocarrier for enhanced tumor therapy with a good biosafety profile.

Preparation, characterization, and biological activity of the inclusion complex of dihydroquercetin and β-Cyclodextrin

Dihydroquercetin (DHQ) is a natural occurring dihydroflavonol that has strong antioxidant and antibacterial activities. However, its application is limited due to its poor solubility. This study aims to improve the aqueous solubility of DHQ by complexing DHQ with β-cyclodextrin (β-CD) to boost its biological activity. DHQ was encapsulated with β-CD by freeze drying at a 1:1-M ratio. The structure of DHQ/β-CD complex prepared was elucidated by using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, and 1H nuclear magnetic resonance (1H NMR). In addition, molecular docking further revealed two energetically favorable conformations of the DHQ/β-CD complex, in which DHQ interacted with β-CD via hydrogen bonds. Experimental results showed that the solubility of the DHQ increased 22.63-fold by encapsulating with β-CD. Also the dissolution rate, antioxidant activity and antibacterial activity of the DHQ were significantly improved by encapsulating. The encapsulating with β-CD solves the problem of the poor aqueous solubility of DHQ, and broadens the path for a more optimal use of the health promoting effect of DHQ in pharmaceutical and food products.

Nanofibers of Glycyrrhizin/Hydroxypropyl-β-Cyclodextrin Inclusion Complex: Enhanced Solubility Profile and Anti-inflammatory Effect of Glycyrrhizin.

Despite having a wide range of therapeutic advantages, glycyrrhizin (GL) has few commercial applications due to its poor aqueous solubility. In this study, we combined the benefits of hydroxypropyl β-cyclodextrin (HP-βCD) supramolecular inclusion complexes and electrospun nanofibers to improve the solubility and therapeutic potential of GL. A molecular inclusion complex containing GL and HP-βCD was prepared by lyophilization at a 1:2 molar ratio. GL and hydroxypropyl β-cyclodextrin inclusion complexes were also incorporated into hyaluronic acid (HA) nanofibers. Prepared NF was analyzed for physical, chemical, thermal, and pharmaceutical properties. Additionally, a rat model of carrageenan-induced hind paw edema and macrophage cell lines was used to evaluate the anti-inflammatory activity of GL-HP-βCD NF. The DSC and XRD analyses clearly showed the amorphous state of GL in nanofibers. In comparison to pure GL, GL-HP-βCD NF displayed improved release (46.6 ± 2.16% in 5min) and dissolution profiles (water dissolvability ≤ 6s). Phase solubility results showed a four-fold increase in GL solubility in GL-HP-βCD NF. In vitro experiments on cell lines showed that inflammatory markers like IL-1β, TNF-α, and IL-6 were significantly lower in GL-HP-βCD NF compared to pure GL (p < 0.01 and p < 0.05). According to in vivo results, the prepared nanofiber exhibits a better anti-inflammatory effect than pure GL (63.4% inhibition vs 53.7% inhibition). The findings presented here suggested that GL-HP-βCD NF could serve as a useful strategy for improving the therapeutic effects of GL.

Green-step assembly of the supramolecular amphiphile constructed by sodium carboxymethyl cellulose and calixarene for facile loading of hydrophobic food bioactive compounds.

The use of biologically active compounds is often limited due to their poor aqueous solubility, which generally reduces their bioavailability and useful efficacy. In this regard, a wide search is currently underway for colloidal systems capable of encapsulating these compounds. In the creation of colloidal systems, long-chain molecules of surfactants and polymers are mainly used, which in an individual state do not always aggregate into homogeneous and stable nanoparticles. In the present work, cavity-bearing calixarene was used for the first time to order polymeric molecules of sodium carboxymethyl cellulose. A set of physicochemical methods demonstrated the spontaneous formation of spherical nanoparticles by non-covalent self-assembly contributed by macrocycle and polymer, and formed nanoparticles were able to encapsulate hydrophobic quercetin and oleic acid. The preparation of nanoparticles by supramolecular self-assembly without use of organic solvents, temperature and ultrasound effects can be an effective strategy for creating water-soluble forms of lipophilic bioactive compounds.

In-Silico Aided Screening and Characterization Results in Stability Enhanced Novel Roxadustat Co-Crystal

Roxadustat (RXD) is an approved drug substances for the treatment of renal anemia. It has poor aqueous solubility and photochemical stability. This study employs a comprehensive approach to enhance the stability and physicochemical properties RXD through coformer selection and characterization. The investigation integrates delta pKa analysis, molecular complementary assessment, molecular electrostatic potential surface analysis, and machine learning techniques to predict potential co-crystal formation and binding interactions between drug molecules and coformers. The co-crystal screening which lead to in a novel RXD-nicotinamide co-crystal (RXD-NA). Experimental characterization underscores the physical and chemical stability of the co-crystals. To elucidate the supramolecular synthons and understand the intermolecular interactions in the RXD-NA co-crystal, Hirshfeld surfaces analysis, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interaction (NCI) analysis were performed. Computational analysis of photo-isomer formation aligns with experimental observations, further enhancing our understanding of RXD-coformer interactions. RXD-NA co-crystal was found photo-chemically stable as compared to free base API drug substance. This integrated methodology provides a systematic framework for informed co-crystal design, holding promise for optimizing RXD formulations based on molecular interactions and stability considerations. Consequently, this study contributes valuable insights to the field of rational drug design and formulation optimization.

Nanoencapsulation of α-mangostin using chitosan-oleic acid complexes: Evaluation of storage stability, in vitro release properties in simulated digestive environment, and bioaccessibility

The mangosteen fruit possesses a potent antioxidant known as α-mangostin. However, the poor aqueous solubility of α-mangostin limits its incorporation into food products, as well as its oral bioaccessibility in the human gastrointestinal tract. Therefore, we utilized electrostatic complexation between chitosan and oleic acid to encapsulate α-mangostin as a strategy to overcome these limitations. As a result, a homogeneous nanoparticle suspension (average particle diameter = 830 nm) was achieved, as verified by scanning transmission electron microscopy and laser diffraction particle size analysis. Importantly, the aqueous solubility of α-mangostin was significantly improved (>800 times), as examined using high-performance liquid chromatography, enabling its effective incorporation into foods and beverages. The nanoparticles were stable and conveniently stored in a dark vial at 4 °C for more than 2 weeks. In the simulated gastric environment, the pH sensitivity of the chitosan-oleic acid complexes enabled the α-mangostin to remain encapsulated in the gastric phase (pH 3) and to be released in the intestinal phase (pH 7) with a bioaccessibility percentage greater than 50%. Overall, the novel synthesized α-mangostin-encapsulated nanoparticles are beneficial for the design of functional foods with enhanced quality, gastrointestinal stability, and delivery.

Chlorambucil-Bearing Hybrid Molecules in the Development of Potential Anticancer Agents.

Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features that can overcome the limitations mentioned above. Chlorambucil, an anticancer drug that is used to treat prostate and breast cancer, suffers from poor aqueous solubility and specificity, a short half-life, and severe side effects, including anaemia and bone marrow suppression. It compromises the immune system, resulting in treatment failure. Hence, its combination with other pharmacophores has been reported to result in effective anticancer agents with fewer side effects and high therapeutic outcomes. Furthermore, this review gives an update (2010 to date) on the developments of chlorambucil hybrid compounds with anticancer activity, and the structure-activity relationship (SAR), and also highlights future strategies for developing novel anticancer agents.

QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies.

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186nm, zeta potential of - 23.6mV, entrapment efficiency of 80.09%, and cumulative drug release at 12h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0-72h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.

Highly robust quantum mechanics and umbrella sampling studies on inclusion complexes of curcumin and β-cyclodextrin

The poor aqueous solubility of curcumin (CUR) obstructs its wide utilization in nutraceuticals, cosmetics, and pharmaceutical companies. This study is dedicated to investigate the stability of CUR inside the hydrophobic pocket of β-cyclodextrin (β-CD), hydroxypropyl-β-CD (HP-β-CD), and 2,6-Di-O-methyl-β-CD (DM-β-CD). Initially, molecular mechanics (MM) calculations and subsequently quantum mechanical (QM) calculations were performed on inclusion complexes to strengthen the MM results. We performed microsecond timescale MD simulations to observe the structural dynamics of CUR inside the cavity of CDs. We elucidated the most stable binding orientations of CUR inside the cavity of CDs based on binding free energy obtained from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. Furthermore, the two-layered ONIOM (B3LYP/6-311+G(2d,p):PM7) method with CPCM implicit water model was used to derive the complete energetics and thermodynamics of inclusion complexes at 1:1 stoichiometry. Each inclusion reaction was exothermic and spontaneous. The chemical reactivity and kinetic stability of inclusion complexes were described by HOMO-LUMO molecular orbital energies. In conclusion, our studies revealed that HP-β-CD had the highest binding affinity for CUR with the most negative complexation energy (−6520.69 kJ/mol) and Gibb's free energy change (−6448.20 kJ/mol). The atomic-level investigation of noncovalent interactions between CUR and the hydroxypropyl groups in HP-β-CD/CUR complex may be helpful to drive new derivatives of HP-β-CD with better host capacity. The computational strategy adopted here might serve as a benchmark for increasing the solubility of numerous clinically significant molecules.

Vitamin-E TPGS Based Microemulsion: An Approach for Solubility Enhancement of Poorly Water-Soluble Drugs

Poor aqueous solubility is the primary concern for dissolving new drug substances during early development. Several novel solubility enhancement techniques such as particle size reduction, salt formation, making solid dispersion, complex formation, use of cosolvent techniques, use of surfactants, physical and chemical modification, and PH adjustment using buffering agents have been explored extensively to resolve the issue of poor aqueous solubility of drug substances. Drug delivery in micro and nano-sized formulations is one of the ways to improve the solubility of these drug candidates over the physiological pH range. In recent years, combination methods have also been considered an interesting approach where more than one solubility enhancement technique is used. The present review focuses on the feasible approach for improving the solubility by forming Vitamin E TPGS-based suspension in micro or nano form by particle size reduction. Further, by granulation or spray drying techniques, these suspensions converted to a solid dosage form for oral drug delivery for patient compliance are being explore

Novel aspects of taxifolin pharmacokinetics: Dose proportionality, cumulative effect, metabolism, microemulsion dosage forms

Taxifolin (TFL) is a small drug molecule with a broad therapeutic potential limited by its poor aqueous solubility and excessive metabolism. Despite comprehensive research, some aspects of the TFL pharmacokinetics, e.g., dose proportionality and possible cumulative effect, remain unexplored. In the current study, we have tried to fill this gap. Our results revealed that the TFL pharmacokinetics in rats had nonlinear character in the dose range of 10–50 mg/kg after its single oral administration (AUC). For Cmax, the data are ambiguous: linearity was confirmed via the equivalence criterion and was disproved using the power model approach. Also, the cumulative drug effect was observed on the 4th day after its multiple-dose oral administration (25 mg/kg; compared to the 1st day). Interestingly, biologically active TFL metabolites such as aromadendrin and luteolin were putatively found in plasma samples, although they were previously detected only in feces. In addition, oil-in-water and water-in-oil microemulsions were fabricated to design novel drug delivery systems. These carrier dosage forms did not improve the TFL bioavailability but significantly affected its metabolism. To support pharmacokinetic studies, the bioanalytical liquid chromatography–tandem mass spectrometry method was developed and validated in the concentration range of 1–1000 ng/mL using candesartan as an internal standard. Liquid-liquid extraction with methyl tert-butyl ether was used to isolate the analytes from plasma followed by evaporation and reconstitution of the residues in acetonitrile. Thus, the present findings broaden our understanding of the TFL behavior in vivo and provide novel ideas and reference directions for its continued use in medical practice.

Design and development of lipid modified arginine based self-nanoemulsifying drug delivery systems for improved antibacterial activity of cefixime against S. aureus and E. coli

Cefixime (CEF) has numerous potential applications in the treatment of bacterial infections. However, due to its decreased cellular internalization, poor aqueous solubility, rapid intestinal hepatic metabolism, its clinical efficacy is limited. The purpose of this research was to develop an amphiphilic arginine (Amp-ARG) containing self-nanoemulsifying drug delivery system (SNEDDS) acting as a positively charged amphiphile for enhancing the antibacterial properties of CEF against E. coli and S. aureus. The self-emulsifying characteristics of various oils, including essential oils, were investigated using suitable surfactants and co-surfactants. Because of their high CEF solubilizing potential, transcutol®Hp, labrasol, and cinnamon oil were selected as co-surfactant, surfactant, and oil respectively, to develop the formulation of SNEDDs. The composition of the selected constituents was optimized via ternary phase diagram and the developed CEF loaded SNEDDS (CEF-SNEDDS) and Amp-ARG containing CEF-SNEDDS were investigated for morphological evaluation, droplet size, polysispersity index and zeta potential value. The developed SNEDDS was discovered to be extremely stable, having a spherical surface morphology and a nano range size. Furthermore, the CEF antibacterial activity was increased upon loading in the optimized SNEDDS. Interestingly, a significant antibacterial effect was observed for ARG-CEF-SNEDDS against both the investigated bacterial strains, including S. aureus and E. coli, owing to comparatively improved internalization of CEF mediated by the electrostatic interaction of the Amp-ARG polar head with the bacterial cell, followed by interaction with membrane lipid bilayers via their hydrophobic alkyl chain. Hence, the observed findings revealed the potential of the developed ARG-CEF-SNEDDS to be used as an effective candidate for bacterial infections.

Oral self-microemulsifying drug delivery system for honokiol's stress responses attenuation and anti-Cryptocaryon irritans efficacy enhancement in Trachinotus ovatus

In this study, an oral self-micro-emulsifying drug delivery system of honokiol (HN-SMEDDS) was developed to overcome honokiol's disadvantages, such as poor aqueous solubility and induced stress responses. The safeties of HN-SMEDDS and honokiol dimethyl sulfoxide aqueous solution (HN-DMSO) were evaluated by comparing their hemolytic activity and acute toxicity in pompano (Trachinotus ovatus). The one-h-ten-percent hemolytic concentration (EC10) of HN-SMEDDS on pompano erythrocytes was 1.206 mg/mL, 33.5 times that of HN-DMSO. And the minimum lethal doses (MLD) for HN-SMEDDS and HN-DMSO in pompano were 1000 mg/kg and 500 mg/kg, respectively. The 14-d relative percent survival (RPS) was calculated after orally administering substance HN-SMEDDS at various doses in pompano cryptocaryoniasis, revealing an optimal dose of 400 mg/kg. To assess efficacy, a comparison was carried out between the oral administration of HN-SMEDDS and HN-DMSO in treating pompano cryptocaryoniasis. This comparison was based on the 14-d RPS and the quantification of C. irritans trophonts in the right second gill (NCTG). In the challenged pompanos treated with HN-SMEDDS and HN-DMSO, the 14-d RPS and 7-d NCTG reached 68.89 ± 3.14% and 6.3 ± 2.1 individuals, and 53.33 ± 0.00% and 30.7 ± 2.1 individuals, respectively. Furthermore, stress-related markers, encompassing mRNA levels of cyp1a, hsp70, gst, and sod in the liver, spleen, and kidney, along with activities of ACP, CAT, SOD, GSH, and T-AOC in these organs and serum, were compared between the pompanos administered with HN-SMEDDS and HN-DMSO. The impact of HN-SMEDDS on the mRNA levels of cyp1a in the liver and kidney, hsp70 in all the analyzed tissues, gst in the liver and spleen, sod in the spleen, as well as the activities of ACP and CAT in liver, spleen, and serum, GSH content in spleen and kidney, SOD in the liver, kidney, and serum, and the T-AOC in liver, spleen, kidney, and serum, were significantly smaller than those of HN-DMSO. Compared to HN-DMSO, HN-SMEDDS could markedly reduce the stress responses of fish and enhance the efficacy of honokiol.

Targeted co-delivery of curcumin and erlotinib by MoS2 nanosheets for the combination of synergetic chemotherapy and photothermal therapy of lung cancer

BackgroundCurcumin (Cur), a bioactive component of Chinese traditional medicine, has demonstrated inhibitory properties against cancer cell proliferation while synergistically enhancing the anticancer efficacy of erlotinib (Er). However, the individual limitations of both drugs, including poor aqueous solubility, lack of targeting ability, short half-life, etc., and their distinct pharmacokinetic profiles mitigate or eliminate their combined antitumor potential.ResultsIn this study, we developed a molybdenum disulfide (MoS2)-based delivery system, functionalized with polyethylene glycol (PEG) and biotin, and co-loaded with Cur and Er, to achieve efficient cancer therapy. The MoS2-PEG-Biotin-Cur/Er system effectively converted near-infrared (NIR) light into heat, thereby inducing direct photothermal ablation of cancer cells and promoting controlled release of Cur and Er. Biotin-mediated tumor targeting facilitated the selective accumulation of MoS2-PEG-Biotin-Cur/Er at the tumor site, thus enhancing the synergistic antitumor effects of Cur and Er. Remarkably, MoS2-PEG-Biotin-Cur/Er achieved the combination of synergistic chemotherapy and photothermal therapy (PTT) upon NIR irradiation, effectively suppressing lung cancer cell proliferation and inhabiting tumor growth in vivo.ConclusionsThe as-synthesized MoS2-PEG-Biotin-Cur/Er, featuring high targeting ability, NIR light-responsive drug release, and the integration of synergistic chemotherapy and PTT, may provide a promising strategy for the treatment of lung cancer in clinical practice.Graphical

Strategies for improving hydrophobic drugs solubility and bioavailability

Nowadays various drugs synthesized by various computational drug designs as well as various drugs have complex structure. Due to their complex structure, higher molecular weight which will increases solubility issues. Solubility is the most important and challenging task for researchers. Bioavailability and absorption of a drug depends on solubility of drug and thus we achieve pharmacological response. But poor aqueous solubility is a rate limiting step in bioavailability which made drug development more difficult. Drugs having low bioavailability require to be administered at a higher dose to achieve desired drug concentration in the systemic circulation and reach the target site. Thus, instead of getting desired effects drug produces side effects in the gastrointestinal tract. Hence, with the advancement of chemical science, the need of development of pharmaceutical technologies is also increasing. New techniques have been developed with a focus on enhancement of the solubility and oral bioavailability of poorly water-soluble drugs. The present review focuses on new technologies which are being used to resolve solubility issue of poorly soluble drugs which is the rate limiting step in bioavailability.

Preparation, characterization and in vitro anticancer efficacy of biotin-conjugated, silibinin loaded bovine serum albumin nanoparticles

Silibinin (SBN) is a natural, plant-derived bioactive flavonolignan, possessing wide range of pharmaceutical activities including anticancer. However, poor aqueous solubility and low oral bioavailability restrict its clinical applications. Protein based nanomedicines have emerged as a potential solution to improve the delivery of hydrophobic anticancer agents like SBN. Further, Biotin functionalization of delivery vehicle can provide the added advantage of increased aqueous solubility, controlled drug release and site-specific delivery at the tumor. In the present work, we have prepared biotin conjugated bovine serum albumin nanoparticles (Biotin@BSA-NPs) for the efficient delivery of SBN to cancer cells. The prepared SBN loaded Biotin@BSA-NPs (Biotin@SBN-BSA-NPs) showed nanoscale size (∼157 nm), high monodispersity (PDI 0.102), high encapsulation efficiency (∼83%), and controlled pH-dependent drug release. Biotin@SBN-BSA-NPs reveals dose-dependent and time-dependent cytotoxicity against human cervical cancer (HeLa) cells. The cellular uptake study, MTT assay and AO-EtBr staining assay demonstrate that Biotin@SBN-BSA-NPs had significant anticancer potential, induction of apoptosis and higher uptake compared to pure SBN. Thus, prepared Biotin@SBN-BSA-NPs could be a potential targeted drug delivery system for hydrophobic anticancer bioactive compounds like SBN.

Physico-chemical studies of inclusion complex between hydrocortisone and cyclodextrins

Hydrocortisone (HC) is widely utilized in the pharmaceutical field for various administration routes, including oral, parenteral, and topical routes. However, its application in ocular disease treatment as a solution is limited due to its poor aqueous solubility. To address this limitation, in this study we aimed to investigate different types of cyclodextrins (CDs) to identify the most effective CD for improving the inherent solubility of HC. Results from scanning electron microscopy, rheology and differential scanning calorimetry (DSC) demonstrated the formation of inclusion complexes, while isothermal titration calorimetry (ITC) investigations accurately determined the thermodynamic parameters associated with the formation of complexes between HC and HPβCD or βCD, at 25 and 37 °C. Additionally, phase solubility studies in PBS buffer at 37 °C confirmed the formation of stable inclusion complexes. Collectively, results indicated that HPβCD was the most effective CD in enhancing the intrinsic solubility of HCs in PBS highlighting its potential for improving the solubility and formulation of HC-based pharmaceutical products.

Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics.

Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, and bioavailability. To overcome the bottlenecks of ALO, salts with maleic acid (MLE) and oxalic acid (OXA) were synthesized using the solvent-assisted grinding method. The novel multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SEM images. The crystal structures of these salts with variable stoichiometry were obtained using Rietveld refinement from the high-resolution PXRD data. The proton from the dicarboxylic acid is transferred to the most basic pyrimidine "N" of ALO. The N-H···N hydrogen-bonded ALO homodimer is replaced by the N+-H···O- ionic interactions in ALO-OXA (2:1:0.4) and ALO-MLE (1:1:1) salt hydrates. The organic salts improved solubility and dissolution up to 5-fold and the diffusion permeability up to 12 times compared to the native drug in a luminal pH 6.8 phosphate buffer medium. The salt hydrates were exceptionally stable during storage at 30 ± 5 °C and 75 ± 5% relative humidity. Superior dissolution and diffusion permeability of the ALO-MLE salt resulted in improved pharmacokinetics (peak plasma concentration) that offers a promising solid dosage form with enhanced bioavailability and lower dosage formulation.

Novel tetrahydrocurcumin integrated mucoadhesive nanocomposite κ-carrageenan/xanthan gum sponges: a strategy for effective local treatment of oral cancerous and precancerous lesions

Oral cancer is one of the leading causes of death worldwide. Oral precancerous lesions (OPL) are the precursors of oral cancer, with varying degrees of progression. Tetrahydrocurcumin (THC) is a major metabolite of curcumin with superior anticancer properties against various types of cancer. However, THC’s clinical outcome is limited by its poor aqueous solubility. Herein, we developed novel mucoadhesive biopolymer-based composite sponges for buccal delivery of THC, exploiting nanotechnology and mucoadhesion for efficient prevention and treatment of oral cancer. Firstly, THC-nanocrystals (THC-NC) were formulated and characterized for subsequent loading into mucoadhesive composite sponges. The anticancer activity of THC-NC was assessed on a human tongue squamous carcinoma cell line (SCC-4). Finally, the chemopreventive activity of THC-NC loaded sponges (THC-NC-S) was examined in DMBA-induced hamster OPL. The selected THC-NC exhibited a particle size of 532.68 ± 13.20 nm and a zeta potential of −46.08 ± 1.12 mV. Moreover, THC-NC enhanced the anticancer effect against SCC-4 with an IC50 value of 80 µg/mL. THC-NC-S exhibited good mucoadhesion properties (0.24 ± 0.02 N) with sustained drug release, where 90% of THC was released over 4 days. Furthermore, THC-NC-S had a magnificent potential for maintaining high chemopreventive activity, as demonstrated by significant regression in the dysplasia degree and a decline in cyclin D1 (control: 40.4 ± 12.5, THC-NC-S: 12.07 ± 5.2), culminating in significant amelioration after 25 days of treatment. Conclusively, novel THC-NC-S represent a promising platform for local therapy of OPL, preventing their malignant transformation into cancer.

Elucidating Berberine's Therapeutic and Photosensitizer Potential through Nanomedicine Tools.

Berberine, an isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been gaining interest due to anti-inflammatory and antioxidant activities, as well as neuro and cardiovascular protective effects in animal models. Recently, photodynamic therapy demonstrated successful application in many fields of medicine. This innovative, non-invasive treatment modality requires a photosensitizer, light, and oxygen. In particular, the photosensitizer can selectively accumulate in diseased tissues without damaging healthy cells. Berberine's physicochemical properties allow its use as a photosensitising agent for photodynamic therapy, enabling reactive oxygen species production and thus potentiating treatment efficacy. However, berberine exhibits poor aqueous solubility, low oral bioavailability, poor cellular permeability, and poor gastrointestinal absorption that hamper its therapeutic and photodynamic efficacy. Nanotechnology has been used to minimize berberine's limitations with the design of drug delivery systems. Different nanoparticulate delivery systems for berberine have been used, as lipid-, inorganic- and polymeric-based nanoparticles. These berberine nanocarriers improve its therapeutic properties and photodynamic potential. More specifically, they extend its half-life, increase solubility, and allow a high permeation and targeted delivery. This review describes different nano strategies designed for berberine delivery as well as berberine's potential as a photosensitizer for photodynamic therapy. To benefit from berberine's overall potential, nanotechnology has been applied for berberine-mediated photodynamic therapy.