Sialic acid-decorated liposomes enhance the anti-cancer efficacy of docetaxel in tumor-associated macrophages.

Tumor-associated macrophages (TAMs) in the tumor microenvironment potentially enhance tumor growth and invasion through various mechanisms and are thus an essential factor in tumor immunity. The highly expressed siglec-1 receptors on the surfaces of TAMs are potential targets for cancer drug delivery systems. Sialic acid (SA) is a specific ligand for siglec-1. In this study, the sialic acid-polyethylene glycol conjugate (DSPE-PEG2000-SA) was synthesized to modify the surface of liposomes and target TAMs by interacting with the siglec-1 receptor. Three docetaxel (DTX)-loaded liposomes, conventional (DTX-CL), DSPE-PEG2000-coated (DTX-PL), and DSPE-PEG2000-SA-coated (DTX-SAPL) liposomes, were prepared, with a particle size of <100 nm, uniform polydispersity index (PDI) values, negative zeta potential, and % encapsulation efficiency (EE) exceeding 95 %. Liposomes showed high stability after 3 months of storage at 4 °C without significant changes in particle size, PDI, zeta potential, or % EE. DTX was released from liposomes according to the Weibull model, and DTX-SAPL exhibited more rapid drug release than other liposomes. In vitro studies demonstrated that DTX-SAPL liposome exhibited a higher uptake and cytotoxicity on RAW 264.7 cells (TAM model) and lower toxicity on NIH3T3 cells (normal cell model) than other formulations. The high cell uptake ability was demonstrated by the role of the SA-SA receptor. Biodistribution studies indicated a high tumor accumulation of surface-modified liposomal formulations, particularly SA-modified liposomes, showing high signal accumulation at the tumor periphery, where TAMs were highly concentrated. Ex vivo imaging showed a significantly higher accumulation of SA-modified liposomes in the tumor, kidney, and heart than conventional liposomes. In the anti-cancer efficacy study, DTX-SAPL liposomes showed effective inhibition of tumor growth and relatively low systemic toxicity, as evidenced by the tumor volume, tumor weight, body weight values, and histopathological analysis. Therefore, DSPE-PEG2000-SA-coated liposomes could be promising carriers for DTX delivery targeting TAMs in cancer therapy.

Sustained delivery of triamcinolone acetonide from a thermosensitive microemulsion gel system for the treatment of sensorineural hearing loss.

Intratympanic administration for the delivery of steroids has been extensively studied but limited because of low permeability of the drug through the row window membrane. Here, to effectively deliver poorly soluble triamcinolone acetonide (TA), microemulsions (ME) were prepared from Capmul MCM (oil), Cremophor RH40 (surfactant), and tetraglycol (cosurfactant) based on solubility studies, emulsifying ability test, and pseudoternary phase diagrams. Microemulsion gel (MEG) was prepared by mixing TA-ME with a poloxamer hydrogel base. The physicochemical properties of ME and MEG formulations were characterized, and the toxicity and oto-protective effectiveness were evaluated in vitro and in vivo. The ME-3 formulation showed a small droplet size (16.5 ± 0.2 nm), narrow PDI (0.067 ± 0.041), and enhanced TA solubility (2619.7 ± 57.6 µg/g). The optimized MEG demonstrated temperature-dependent gelation with a gelation time of 208 ± 10 sec at 37 °C. Slow degradation of the gel matrix sustained release of TA from MEG compared to the ME formulation. Both TA-ME and TA-MEG were found to be nontoxic to NIH3T3 cells at the test concentrations (0 to 5 µg/mL), and biocompatible after intratympanic administration to mice. The incorporation of ME into thermosensitive hydrogels prolonged retention of TA at the site of administration until 6 days. As a consequence, the enhanced drug absorption into the cochlea in TA-MEG group (approximately 2 times higher than other groups) protected hair cells, spiral ganglion neurons, and stria vascular cells from cisplatin-induced damage. Therefore, this injectable TA-loaded MEG is an effective and safe vehicle for the sustained delivery of triamcinolone acetonide into the inner ear.

Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs).

Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.

Application of supercritical fluid technology for solid dispersion to enhance solubility and bioavailability of poorly water-soluble drugs.

Many new chemical entities (NCEs) have been discovered with the development of the pharmaceutical industry. However, the main disadvantage of these drugs is their low aqueous solubility, which results in poor bioavailability, posing a challenge for pharmaceutical scientists in the field of drug development. Solid dispersion (SD) technology is one of the most successful techniques used to resolve these problems. SD has been widely used to improve the solubility and bioavailability of poorly water-soluble drugs using several methods such as melting, supercritical fluid (SCF), solvent evaporation, spray drying, hot-melt extrusion, and freeze-drying. Among them, SCF with carbon dioxide (CO2) has recently attracted great attention owing to its enhanced dissolution and bioavailability with non-toxic, economical, non-polluting, and high-efficiency properties. Compared with the conventional methods using organic solvents in the preparation of the formulation (solvent evaporation method), SCF used CO2 to replace the organic solvent with high pressure to avoid the limitation of solvent residues. The solubility of a substance in CO2 plays an important role in the success of the formulation. In the present review, the various processes involved in SCF technology, application of SCF to prepare SD, and future perspectives of SCF are described.

Local drug delivery using poly(lactic-co-glycolic acid) nanoparticles in thermosensitive gels for inner ear disease treatment.

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of -18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.

Docetaxel-loaded PLGA nanoparticles to increase pharmacological sensitivity in MDA-MB-231 and MCF-7 breast cancer cells.

This study aimed to develop docetaxel (DTX) loaded poly(lactic-coglycolic acid) (PLGA) nanoparticles (DTX-NPs) and to evaluate the different pharmacological sensitivity of NPs to MCF-7 and MDA-MB-231 breast cancer cells. NPs containing DTX or coumarin-6 were prepared by the nanoprecipitation method using PLGA as a polymer and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a surfactant. The physicochemical properties of NPs were characterized. In vitro anticancer effect and cellular uptake were evaluated in breast cancer cells. The particle size and zeta potential of the DTX-NPs were 160.5 ± 3.0 nm and -26.7 ± 0.46 mV, respectively. The encapsulation efficiency and drug loading were 81.3 ± 1.85% and 10.6 ± 0.24%, respectively. The in vitro release of DTX from the DTX-NPs was sustained at pH 7.4 containing 0.5% Tween 80. The viability of MDA-MB-231 and MCF-7 cells with DTX-NPs was 37.5 ± 0.5% and 30.3 ± 1.13%, respectively. The IC50 values of DTX-NPs were 3.92- and 6.75-fold lower than that of DTX for MDA-MB-231 cells and MCF-7 cells, respectively. The cellular uptake of coumarin-6-loaded PLGA-NPs in MCF-7 cells was significantly higher than that in MDA-MB-231 cells. The pharmacological sensitivity in breast cancer cells was higher on MCF-7 cells than on MDA-MB-231 cells. In conclusion, we successfully developed DTX-NPs that showed a great potential for the controlled release of DTX. DTX-NPs are an effective formulation for improving anticancer effect in breast cancer cells.

Formulation of solid dispersion to improve dissolution and oral bioavailability of poorly soluble dexibuprofen.

Dexibuprofen (DEXI) belongs to BCS class II drug with poor aqueous solubility resulting in poor bioavailability. To enhance solubility and bioavailability of DEXI, DEXI-loaded solid dispersion (SD) was formulated. DEXI-SDs were prepared by melting method and solvent evaporation method. Amphipathic polymer poloxamer 407 (pol 407) was selected based on solubility and dissolution tests. The ratio of DEXI:pol 407 was optimized as 1:2. The physicochemical properties, dissolution, and oral bioavailability of SD3 and SD6 were evaluated to compare preparation methods. The dissolution rate of DEXI from SD formulations was higher at pH 6.8 and pH 7.2 than at pH 1.2. Following oral administration in rats, the Cmax and AUClast of SD3 and SD6 formulations were significantly higher compared with raw DEXI. In addition, the SD6 formulation showed increased Cmax and AUClast by 1.34- and 1.33-fold, compared with those of SD3 formulation, respectively. These results demonstrated that SD formulation has excellent potential as a formulation for poorly soluble drug DEXI.

Potential and Applications of Nanocarriers for Efficient Delivery of Biopharmaceuticals.

During the past two decades, the clinical use of biopharmaceutical products has markedly increased because of their obvious advantages over conventional small-molecule drug products. These advantages include better specificity, potency, targeting abilities, and reduced side effects. Despite the substantial clinical and commercial success, the macromolecular structure and intrinsic instability of biopharmaceuticals make their formulation and administration challenging and render parenteral delivery as the only viable option in most cases. The use of nanocarriers for efficient delivery of biopharmaceuticals is essential due to their practical benefits such as protecting from degradation in a hostile physiological environment, enhancing plasma half-life and retention time, facilitating absorption through the epithelium, providing site-specific delivery, and improving access to intracellular targets. In the current review, we highlight the clinical and commercial success of biopharmaceuticals and the overall applications and potential of nanocarriers in biopharmaceuticals delivery. Effective applications of nanocarriers for biopharmaceuticals delivery via invasive and noninvasive routes (oral, pulmonary, nasal, and skin) are presented here. The presented data undoubtedly demonstrate the great potential of combining nanocarriers with biopharmaceuticals to improve healthcare products in the future clinical landscape. In conclusion, nanocarriers are promising delivery tool for the hormones, cytokines, nucleic acids, vaccines, antibodies, enzymes, and gene- and cell-based therapeutics for the treatment of multiple pathological conditions.

Use of a Spinal Thermal Massage Device for Anti-oxidative Function and Pain Alleviation.

Background: Elderly people are vulnerable to a variety of diseases, including chronic pain, which reduces their levels of physical fitness. Thermal massage has been shown to relieve pain and activate antioxidant enzymes. The objective of this study was to determine whether thermal massaging of the spinal column can reduce muscle pain and induce antioxidant function. Methods: This study included participants aged ≥60 years with lower back pain. The participants were assigned to either an experimental group who received spinal column thermal massage and standard rehabilitative treatment or a control group who received standard rehabilitative treatment only. Data from a total of 116 participants (61 and 55 in the control and experimental groups, respectively) were used for analysis. Participants were assessed before treatment and at 4 (POST1) and 8 weeks (POST2) post-treatment, using a pain numeric rating scale (PNRS) and the Roland and Morris Disability Questionnaire (RMDQ), and by measuring the serum levels of superoxide dismutase (SOD), serum glutathione-peroxidase (GPx), and serum catalase (CAT). Results: The extent of pain reduction, as measured by the PNRS, was greater in the experimental group. The RMDQ score in the control group decreased at POST1, but the decrease was not maintained at POST2, whereas the decrease in POST1 in the experimental group continued until POST2. SOD concentrations were significantly higher in the experimental group at POST1 and POST2, and GPx levels were significantly higher in the experimental group at POST2; however, there were no changes in CAT concentrations. Incidentally, there was a significant correlation between antioxidant activity and pain perception in the experimental group. Conclusions: The study findings suggest that spinal column thermal massage reduces pain more effectively, improves self-reported levels of disability, and increases the antioxidant enzyme levels. Thermal massage may, therefore, be useful in the prevention and treatment of diseases associated with oxidation.

Therapeutic effects of celecoxib polymeric systems in rat models of inflammation and adjuvant-induced rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA), an autoimmune inflammatory disease, is rapidly increasing in aging societies. In the current study, celecoxib (CXB) micelles were developed to improve the oral absorption and anti-inflammatory effects of CXB in cell studies and λ-carrageenan rat models, and to enhance the therapeutic effects of CXB on RA in complete Freund's adjuvant (CFA)-induced RA rat models. Moreover, CXB micelles and previously developed solid dispersion (SD6) formulations were evaluated. The physical properties of optimal CXB micelles (M3), such as crystallinity, thermal properties, and intramolecular interactions, were altered. Compared with the commercial product (Celebrex®), the M3 and SD6 formulations showed significantly improved anti-inflammatory effects in terms of nitric oxide reduction, 1.5-fold and 2.2-fold, respectively, at the cellular level. The relative bioavailability (BA) of the M3 and SD6 formulations was also significantly improved as oral bioavailability (167.2% and 219.8% respectively), compared with that of Celebrex®. In particular, M3 and SD6 significantly reduced inflammation and edema volume relative to Celebrex® in CFA-induced RA rat models. Moreover, both M3 and SD6 effectively suppressed CFA-induced pro-inflammatory cytokines (TNF-α and IL-1ß) in rat splenic tissues. In conclusion, polymeric systems improved the solubility, relative BA (%) and anti-inflammatory effects of CXB. Thus, CXB polymeric systems show potential as therapeutic agents against inflammation and RA and may need to be tested at the clinical level.

Chitosan-coated nanostructured lipid carriers of fenofibrate with enhanced oral bioavailability and efficacy.

Fenofibrate is frequently used to lower cholesterol levels in cardiovascular disease. Owing to its poor solubility and high gastrointestinal permeability, it is classified as a Biopharmaceutics Classification System class II compound. The aim of this study was to improve the solubility and bioavailability of fenofibrate by formulating it as fenofibrate-loaded nanostructured lipid carriers (FFB-NLCs) and coating it with a biodegradable polymer to allow controlled drug release. Chitosan-coated nanostructured lipid carriers (CF-NLCs) were prepared via an ultrasonication method using chitosan as the biodegradable polymer, stearic acid as the solid lipid, oleic acid as the liquid lipid, and Tween 80 as the surfactant. To study encapsulation efficiency and solubility conditions, stearic acid/oleic acid ratios were varied as 80/20, 70/30, 60/40, and 50/50 (mg/mg), by adjusting chitosan ratio. Chitosan is an adhesive polymer, coating the surface of the NLC to improve its bioavailability. All NLC formulations demonstrated a particle size of approximately 200 nm and a polydispersity index below 0.3. The encapsulation efficiencies of the NLC formulations were above 85%. For CF-NLCs, the solubility and encapsulation efficiency of fenofibrate were increased when compared with those of a commercial fenofibrate formulation. The pharmacokinetic and pharmacodynamic parameters of fenofibrate in the form of CF-NLCs were improved after oral administration. CF-NLCs can be used for allowing controlled release and improving the bioavailability and stability of fenofibrate.

Design and evaluation of the anticancer activity of paclitaxel-loaded anisotropic-poly(lactic-co-glycolic acid) nanoparticles with PEGylated chitosan surface modifications.

This study aimed to evaluate the anticancer activity of paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNPs) based on their shapes and surface modifications in breast cancer cells. We hypothesized that anisotropic-PNPs (AT-PNPs) with PEGylated chitosan (CP) surface modifications and high aspect ratios exhibit higher anticancer activity than PNPs and AT-PNPs with CP surface modifications and low aspect ratios. Six types of PNPs and AT-PNPs with different shapes and surface modifications were successfully prepared. The cellular uptake and cytotoxicity of the AT-PNPs were higher than those of the PNPs, while the cellular uptake and cytotoxicity of the PNPs and AT-PNPs with CP were higher than those of the uncoated PNPs and AT-PNPs. Moreover, all the particles remained stable for 4 months. In conclusion, this study primarily described the preparation of CP-AT-PNPs, and the CP-AT-PNPs2 developed herein are expected to demonstrate promising anticancer effects in animal experiments and clinical studies.

Design of Coenzyme Q10 solid dispersion for improved solubilization and stability.

Solubilization and stabilization of poorly soluble drugs are important issues in the pharmaceutical industry. Herein, a Coenzyme Q10 (CQ10) solid dispersion (SD) formulation was designed to enhance CQ10 solubility, dissolution (%), and stability. CQ10 SD formulations were prepared with a dual polymer system using a melting method. The physicochemical properties of the SD formulations were evaluated. Poloxamer 407 (Kolliphor® P407) was chosen as the main solubilizer based on solubility test results, and polyvinylpyrrolidone (Kollidon® 17) was selected as the co-solubilizer based on pre-dissolution test results. Moreover, Aerosil®200 was chosen as the carrier based on pre-dissolution test results. The SD7 formulation (weight ratio, CQ10 : Aerosil® 200 : P407®: K17® = 1 : 4 : 4 : 1) showed 29-/95-/26-fold enhancement if dissolution (%), compared to that of commercial products at pH 1.2 buffer, distilled water, and pH 6.8 buffer, respectively. Moreover, the SD7 formulation was more stable than the other SD formulations at room temperature following 9 months of storage. In conclusion, a CQ10 SD formulation with significantly improved dissolution (%) and stability was developed. Thus, the SD7 formulation is expected to show improved bioavailability and effectiveness in the treatment of aging-related and cardiovascular diseases.

Optimization of Polyarginine-Conjugated PEG Lipid Grafted Proliposome Formulation for Enhanced Cellular Association of a Protein Drug.

The purpose of this study was to develop an oral proliposomal powder of protein using poly-l-arginine-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) (PLD) for enhancing cellular association upon reconstitution and to compare its effects with a non-grafted and PEGylated formulation. Cationic proliposome (CATL), PLD-grafted CATL (PLD-CATL), PEGylated CATL (PEG CATL), and PLD grafted-PEG CATL (PLD-PEG CATL) were prepared and compared. Successful conjugation between poly-l-arginine and DSPE-PEG was confirmed by 1H NMR and FT-IR. PLD was successfully grafted onto the proliposomal powder during the slurry process. Although reconstituted liposomal sizes of CATL and PLD-CATL were increased by agglomeration, PEGylation reduced the agglomeration and increased the encapsulation. The viabilities of cells treated with both CATL and PLD-CATL formulations were low but increased following PEGylation. With regard to cellular association, PLD-CATL enhanced cellular association/uptake more rapidly than did CATL. Upon PEGylation, PEG CATL showed a lower level of cellular association/uptake compared with CATL while PLD-PEG CATL did not exhibit the rapid cellular association/uptake as seen with PLD-CATL. However, PLD-PEG CATL still enhanced the higher cellular association/uptake than PEG CATL did without PLD. In conclusion, proliposomes with PLD could accelerate cellular association/uptake but also caused high cellular toxicity. PEGylation reduced cellular toxicity and also changed the cellular association pattern of the PLD formulation.

Antibacterial effect of traditional food ingredients for healthcare on Helicobacter pylori.

BACKGROUND: The development of antibacterial materials using various traditional food ingredients will be valuable to inhibit Helicobacter pylori in the future. The vegetables and herbs used in this study were food ingredients that normal people eat every day. This paper can be used as a resource for healthcare. OBJECTIVE: This paper presents the design to investigate the antibacterial effect of 20 vegetables and herbs used as traditional food ingredients on H. pylori. METHODS: The antibacterial effect on H. pylori was studied using the disk diffusion test on the activity of H. pylori. For the control group, 50 mg/ml of Metronidazol, a widely used antibiotic, was used. In particular, four herbs of Artemisia argyi, Scutellaria baicalensis, Annona muricata and Agrimonia pilosa were selected to measure the microbial viability assay, MTT assay, and antioxidant activity owing to the DPPH free radical elimination ability. RESULTS: The measurement results showed that Annona muricata and Agrimonia pilosa had an antibacterial effect on H. pylori and all four herbs were safe in terms of cytotoxicity. The measurement results on the antioxidant activity showed that Scutellaria baicalensia was the best. Annona muricata and Agrimonia pilosa also had an antioxidant activity. CONCLUSIONS: The study results on antibacterial effect of traditional food ingredients of vegetables and herbs on H. pylori showed that Scutellaria baicalensis, Annona muricata and Agrimonia pilosa can be considered as healthcare functional materials through the inhibition of H. Pylori.

Comparison of paclitaxel solid dispersion and polymeric micelles for improved oral bioavailability and in vitro anti-cancer effects.

The purpose of this study was to develop paclitaxel (PTX) formulations with solid dispersion (SD) and micelles (M) in order to improve solubility and oral absorption in rats. In addition, the enhanced anti-cancer effects of PTX formulations were compared in various breast cancer cell lines. The SD formulations with various copolymers were prepared using a solvent evaporation method, and micelles with Soluplus® mixed with d-α-tocopheryl polyethylene glycol-1000-succinate (TPGS) were prepared using a film hydration method. The physical properties of SD and M formulations were evaluated. The dissolution (%) of SD4 and SD9 formulations, and the solubility of M2 were significantly higher than those of PTX. The SD formulations and micelles were also stable for 3 and 1 month, respectively. The anti-cancer effects of SD4, SD9, and M2 significantly increased in breast cancer cells, whereas the blank formulations were not toxic to normal cells. The SD4, SD9 and M formulations improved the permeability of Cou-6 compared to Cou-6 solution in Madin-Darby canine kidney cells (MDCK line). The SD formulations and micelles had enhanced bioavailability (BA) compared to that of PTX, showing relative BA values of 667.3% (SD4), 359.6% (SD9), and 365.4% (M2). This study demonstrates the technologies to increase the anti-cancer effects and BA of PTX, via SD and micelle formulations, and, to our knowledge, is the first comparison of the two formulations.

Improvement of the dissolution rate and bioavailability of fenofibrate by the supercritical anti-solvent process.

The purpose of this study was to improve solubility and oral bioavailability of fenofibrate via solid dispersion (SD) using a supercritical anti-solvent (SAS) process with amphipathic polymers P407 and TPGS. Solid dispersion techniques have been widely used to enhance the solubility and dissolution profiles of poorly soluble drugs. Fenofibrate is classified as a Biopharmaceutics Classification System class II compound because of its low solubility and high gastrointestinal permeability. Two copolymers were selected based on solubility and dissolution tests. Their physicochemical properties were compared with those prepared by conventional solvent evaporation (CSE). The SD formulations containing fenofibrate were successfully prepared using the SAS and CSE methods. The dissolution rate (%) of fenofibrate at 60 min was significantly improved compared with the solution of raw fenofibrate (19.5% ±â€¯3.7%) by 95.1% ±â€¯2.5% and 93.7% ±â€¯4.1% using the SAS and the CSE process, respectively. This approximately four-fold increase in dissolution rate indicates that oral bioavailability can be enhanced. In addition, pharmacokinetic study was analyzed using the area under the curve (AUC) and Cmax values of SAS-SD and CSE-SD in rats. The AUC was 2.1 times higher and Cmax was 1.9 times higher in SAS-SD, indicating higher concentrations of fenofibrate in the blood. In a pharmacodynamic study to evaluate the efficacy of the drug in hyperlipidemic rat models, SAS-SD showed strong lipid-lowering effects including cholesterol (1.9-fold) and triglycerides (3.3-fold), than CSE-SD. Taken together, these results suggested that SAS-SD has excellent potential as a formulation for the poorly soluble drug fenofibrate.

Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs.

Approximately 40% of new chemical entities (NCEs), including anticancer drugs, have been reported as poorly water-soluble compounds. Anticancer drugs are classified into biologic drugs (monoclonal antibodies) and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Even though IV injection is the fastest route of administration and ensures complete bioavailability, this route of administration causes patient inconvenience to visit a hospital for anticancer treatments. In addition, IV administration can cause several side effects such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity. Oral administration is the preferred route for drug delivery due to several advantages such as low cost, pain avoidance, and safety. The main problem of NCEs is a limited aqueous solubility, resulting in poor absorption and low bioavailability. Therefore, improving oral bioavailability of poorly water-soluble drugs is a great challenge in the development of pharmaceutical dosage forms. Several methods such as solid dispersion, complexation, lipid-based systems, micronization, nanonization, and co-crystals were developed to improve the solubility of hydrophobic drugs. Recently, solid dispersion is one of the most widely used and successful techniques in formulation development. This review mainly discusses classification, methods for preparation of solid dispersions, and use of solid dispersion for improving solubility of poorly soluble anticancer drugs.

Design of novel proliposome formulation for antioxidant peptide, glutathione with enhanced oral bioavailability and stability.

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1-F4) and positive proliposomes (F5-F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was -8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action.

Amorphous multi-system of celecoxib improves its anti-inflammatory activity in vitro and oral absorption in rats.

In the present study, a multi-system for solid dispersion (SD) of celecoxib (CXB) was designed to improve its solubility and anti-inflammatory effects in vitro as well as oral absorption in rats. The SD formulations were prepared by a solvent evaporation with a multi-system as the solubilizer; an alkalizer; and fumed silica (Aerosil® 200). The physicochemical properties of the SD formulations were evaluated. Polyoxyl 15 hydroxystearate (HS 15®) was chosen as the solubilizer based on the apparent solubility test. The optimal SD formulation (SD6, CXB: HS 15®: K30®: meglumine: Aerosil® 200 = 200: 50: 50: 100: 100, weight ratio) improved the dissolution (%) over 2-fold compared to that by the commercial product (Celebrex®) at pH 1.2, in distilled water (DW), and in a pH 6.8 buffer (sodium lauryl sulfate [SLS], 0.25% w/v). The SD6 formulation altered physical properties such as crystallinity, thermal stability, and intra-molecular interaction. Moreover, SD6 showed a good stability for 6 months. The anti-inflammatory effect of SD6 significantly improved 2.2-fold compared to that of Celebrex® in the cell study. The relative bioavailability (BA) of SD6 was significantly improved to 209.4% compared to that of Celebrex®. In conclusion, intra-molecular interactions between CXB and solubilizers in multi-systems increase its solubility, dissolution (%), anti-inflammatory effects in vitro, and the relative BA (%) in rats. Thus, SD6 would be effective for the treatment of inflammation in rats and should be evaluated in detail in future clinical studies.