Enhanced Oral Bioavailability of Rivaroxaban-Loaded Microspheres by Optimizing the Polymer and Surfactant Based on Molecular Interaction Mechanisms.

This study aimed to develop microspheres using water-soluble carriers and surfactants to improve the solubility, dissolution, and oral bioavailability of rivaroxaban (RXB). RXB-loaded microspheres with optimal carrier (poly(vinylpyrrolidone) K30, PVP) and surfactant (sodium lauryl sulfate (SLS)) ratios were prepared. 1H NMR and Fourier transform infrared (FTIR) analyses showed that drug-excipient and excipient-excipient interactions affected RXB solubility, dissolution, and oral absorption. Therefore, molecular interactions between RXB, PVP, and SLS played an important role in improving RXB solubility, dissolution, and oral bioavailability. Formulations IV and VIII, containing optimized RXB/PVP/SLS ratios (1:0.25:2 and 1:1:2, w/w/w), had significantly improved solubility by approximately 160- and 86-fold, respectively, compared to RXB powder, with the final dissolution rates improved by approximately 4.5- and 3.4-fold, respectively, compared to those of RXB powder at 120 min. Moreover, the oral bioavailability of RXB was improved by 2.4- and 1.7-fold, respectively, compared to that of RXB powder. Formulation IV showed the highest improvement in oral bioavailability compared to RXB powder (AUC, 2400.8 ± 237.1 vs 1002.0 ± 82.3 h·ng/mL). Finally, the microspheres developed in this study successfully improved the solubility, dissolution rate, and bioavailability of RXB, suggesting that formulation optimization with the optimal drug-to-excipient ratio can lead to successful formulation development.

Development of Novel Tamsulosin Pellet-Loaded Oral Disintegrating Tablet Bioequivalent to Commercial Capsule in Beagle Dogs Using Microcrystalline Cellulose and Mannitol.

In this study, we developed a tamsulosin pellet-loaded orally disintegrating tablet (ODT) that is bioequivalent to commercially available products and has improved patient compliance using microcrystalline cellulose (MCC) and mannitol. Utilizing the fluid bed technique, the drug, sustained release (SR) layer, and enteric layer were sequentially prepared by coating MCC pellets with the drug, HPMC, Kollicoat, and a mixture of Eudragit L and Eudragit NE, respectively, resulting in the production of tamsulosin pellets. The tamsulosin pellet, composed of the MCC pellet, drug layer, SR layer, and enteric layer at a weight ratio of 20:0.8:4.95:6.41, was selected because its dissolution was equivalent to that of the commercial capsule. Tamsulosin pellet-loaded ODTs were prepared using tamsulosin pellets and various co-processed excipients. The tamsulosin pellet-loaded ODT composed of tamsulosin pellets, mannitol-MCC mixture, silicon dioxide, and magnesium stearate at a weight ratio of 32.16:161.84:4.0:2.0 gave the best protective effect on the coating process and a dissolution profile similar to that of the commercial capsule. Finally, no significant differences in beagle dogs were observed in pharmacokinetic parameters, suggesting that they were bioequivalent. In conclusion, tamsulosin pellet-loaded ODTs could be a potential alternative to commercial capsules, improving patient compliance.

Development of a sorafenib-loaded solid self-nanoemulsifying drug delivery system: Formulation optimization and characterization of enhanced properties.

Sorafenib, marketed under the brand name Nexavar®, is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivo study, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development.

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban.

The purpose of this study was to investigate the efficacy of hydrophilic polymers in a solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The developed solid dispersion consisted of two components, a drug and a polymer, and the drug was dispersed as amorphous particles in a polymer matrix using the spray drying method. Polymeric solid dispersions were evaluated using solubility tests, in vitro dissolution tests, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and particle size distribution analysis. To maximize physical stability against crystallization and improve the solubility and dissolution of RXB, it is important to select the appropriate polymer type and the optimal ratio of the polymer to the drug. The optimized polyvinyl alcohol (PVA)-based (1/0.5, w/w) and gelatin-based (1/5, w/w) solid dispersion formulations showed 6.3 and 3.6 times higher drug solubilities than pure RXB powder, respectively, and the final dissolution rate was improved by approximately 1.5 times. Scanning electron microscopy and particle size distribution analyses confirmed that the gelatin-based solid dispersion was smaller and more spherical than the PVA-based solid dispersion, suggesting that the gelatin-based solid dispersion had a faster initial dissolution rate. Differential scanning calorimetry and powder X-ray diffraction analyses confirmed that RXB had successfully changed from a crystalline form to an amorphous form, contributing to the improvement in its solubility and dissolution rate. This study provides a strategy for selecting suitable polymers for the development of amorphous polymer solid dispersions that can overcome precipitation during dissolution and stabilization of the amorphous state. In addition, the selected polymer solid dispersion improved the drug solubility and dissolution rate of RXB, a poorly soluble drug, and may be used as a promising drug delivery system.

Novel dapagliflozin di-L-proline cocrystal-loaded tablet: preparation, physicochemical characterization, and pharmacokinetics in beagle dogs and mini-pigs.

Dapagliflozin base and a commercial dapagliflozin propanediol hydrate cocrystal (DPF-PDHC) were highly hygroscopic and thermally unstable. In this study, to address this limitation, we prepared a novel dapagliflozin di-L-proline cocrystal (DPF-LPC) and evaluated its physicochemical characterization compared with DPF-PDHC. After the preparation of the DPF-LPC-loaded tablet, its dissolution, stability and bioequivalence in beagle dogs and mini-pigs were assessed. DPF-LPC was well prepared with a dapagliflozin base and L-proline in a molar ratio of 1:2. Similar to DPF-PDHC, DPF-LPC was highly lipophilic and crystalline in nature. However, these two cocrystals exhibited different melting points and crystalline structures, indicating their different cocrystal forms. Moreover, DPF-LPC exhibited less hygroscopicity and lower water content than DPF-PDHC. The DPF-LPC-loaded tablet composed of DPF-LPC, Comprecel M102, lactose monohydrate, crospovidone, magnesium stearate, and Opadry (coating) at a weight ratio of 15.6:104.4:100.0:8.0:2.0:7.0, was dissolution-equivalent to the commercial tablet. Moreover, it provided lower impurities than the commercial tablet, indicating its better stability. In the two animals, there were no significant differences in the plasma concentrations, AUC, Cmax, and Tmax values, suggesting that they were bioequivalent. Therefore, the novel DPF-LPC-loaded tablet with excellent stability and bioequivalence may be used as a potential alternative to the commercial DPF-PDHC-loaded tablet.

Acetaminophen and tramadol hydrochloride-loaded soft gelatin capsule: preparation, dissolution and pharmacokinetics in beagle dogs.

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

Development of rebamipide-loaded spray-dried microsphere using distilled water and meglumine: physicochemical characterization and pharmacokinetics in rats.

In this study, a novel rebamipide-loaded spray-dried microsphere (RSM) with enhanced drug solubility and oral bioavailability has been developed utilizing meglumine, an alkalizing agent. The influence of carriers on the drug solubility alone, and the solubility and dissolution of the drug in the RSM was investigated. Among the alkalizing agents and hydrophilic polymers tested, meglumine and polyvinyl alcohol (PVA) showed the highest drug solubility and dissolution rate, respectively. Many RSMs were manufactured with various amounts of meglumine and PVA using distilled water, and their drug solubility and dissolution were determined. The physicochemical properties, dissolution and pharmacokinetics of the chosen RSM in rats were assessed compared to the rebamipide powder and commercial tablet. Among the RSMs tested, the one composed of rebamipide, meglumine and PVA at a weight ratio of 3:1.75:6 showed the highest drug solubility and dissolution. This RSM with a smooth spherical form significantly decreased the particle size and modified the amorphous rebamipide. Furthermore, the drug solubility, dissolution, plasma concentrations, AUC and Cmax values of RSM were significantly higher than those of drug powder and commercial tablet. Thus, this RSN system developed with distilled water and meglumine is recommended as an oral water-soluble rebamipide-loaded pharmaceutical product.

Preparation and Characterization of a Lutein Solid Dispersion to Improve Its Solubility and Stability.

Lutein has been used as a dietary supplement for the treatment of eye diseases, especially age-related macular degeneration. For oral formulations, we investigated lutein stability in artificial set-ups mimicking different physiological conditions and found that lutein was degraded over time under acidic conditions. To enhance the stability of lutein upon oral intake, we developed enteric-coated lutein solid dispersions (SD) by applying a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), through a solvent-controlled precipitation method. The SD were characterized in crystallinity, morphology, and drug entrapment. In the dissolution profile of lutein SD, a F80 formulation showed resistance toward the acidic environment under simulated gastric conditions while exhibiting a bursting drug release under simulated intestinal conditions. Our results highlight the potential use of HPMCAS-LF as an effective matrix to enhance lutein bioavailability during oral delivery and to provide novel insights into the eye-care supplement industry, with direct benefits for the health of patients.

Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy.

PURPOSE: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity. METHODS: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy. RESULTS: The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues. CONCLUSION: Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.

Diagnostic and Treatment Strategies for COVID-19.

The world is facing lockdown for the first time in decades due to the novel coronavirus COVID-19 (SARS-CoV-2) pandemic. This has led to massive global economic disruption, placed additional strain on local and global public health resources and, above all, threatened human health. We conducted a review of peer-reviewed and unpublished data, written in English, reporting on the current COVID-19 pandemic. This data includes previously used strategies against infectious disease, recent clinical trials and FDA-approved diagnostic and treatment strategies. The literature was obtained through a systematic search using PubMed, Web of Sciences, and FDA, NIH and WHO websites. Of the 98 references included in the review, the majority focused on pathogen and host targeting, symptomatic treatment and convalescent plasma utilization. Other sources investigated vaccinations in the pipeline for the possible prevention of COVID-19 infection. The results demonstrate various conventional as well as potentially advanced in vitro diagnostic approaches (IVD) for the diagnosis of COVID-19. Mixed results have been observed so far when utilising these approaches for the treatment of COVID-19 infection. Some treatments have been found highly effective in specific regions of the world while others have not altered the disease process. The responsiveness of currently available options is not conclusive. The novelty of this disease, the rapidity of its global outbreak and the unavailability of vaccines have contributed to the global public's fear. It is concluded that the exploration of a range of diagnostic and treatment strategies for the management of COVID-19 is the need of the hour.

Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer.

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ±â€¯5.2 nm, a polydispersity index of 0.18 ±â€¯0.01, and zeta potential of -16.4 ±â€¯0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Revaprazan-loaded surface-modified solid dispersion: physicochemical characterization and in vivo evaluation.

The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (∼6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and Cmax, and a faster Tmax value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.

Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer.

PURPOSE: Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells. METHODS: PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells. RESULTS: PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei. CONCLUSION: PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

Novel revaprazan-loaded gelatin microsphere with enhanced drug solubility and oral bioavailability.

To develop a novel revaprazan-loaded gelatine microsphere with enhanced solubility and oral bioavailability, numerous gelatine microspheres were prepared using a spray-drying technique. The impact of gelatine amount on drug solubility in the gelatine microspheres was investigated. The physicochemical properties of the selected gelatine microsphere, such as shape, particle size and crystallinity, were evaluated. Moreover, its dissolution and pharmacokinetics in rats were assessed in comparison with revaprazan powder. Amongst the gelatine microspheres tested, the gelatine microsphere consisting of revaprazan and gelatine (1:2, w/w), which gave about 150-fold increased solubility, had the most enhanced drug solubility. It provided a spherical shape, amorphous drug and reduced particle size. Furthermore, it gave a higher dissolution rate and plasma concentration than did revaprazan powder. Particularly, it gave about 2.3-fold improved oral bioavailability in comparison with revaprazan powder. Therefore, this novel gelatine microsphere system is recommended as an oral pharmaceutical product of poorly water-soluble revaprazan.

Development of a novel celecoxib-loaded nanosuspension using a wet media milling process.

To develop a novel celecoxib (CXB)-loaded drug delivery system, numerous nanosuspensions were prepared with various polymers and surfactants using a wet media milling process, and their particle sizes were subsequently determined. A 24 full factorial design was used to identify the most appropriate preparation conditions. Pharmacokinetics of the selected nanosuspension were performed in rats and compared with those of a drug powder and a commercial CXB-loaded product. Among the carriers investigated, copovidone and sodium lauryl sulphate gave the smallest particle size of the drug in the nanosuspension. In particular, the nanosuspension prepared with 5% CXB, 4% copovidone, and 0.1% sodium lauryl sulphate, under the appropriate conditions, showed a particle size of approximately 190 nm, which was physically stable for at least 8 weeks. This nanosuspension provided a significantly higher plasma concentration and AUC in rats as compared with the drug powder and the commercial product. Thus, this novel CXB-loaded nanosuspension is a promising candidate with excellent stability and enhanced oral bioavailability.

Formulation of novel dry powder inhalation for fluticasone propionate and salmeterol xinafoate with capsule-based device.

The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose® SV003, Respitose® SV010, and Respitose® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.

PEGylated lipid bilayer-wrapped nano-graphene oxides for synergistic co-delivery of doxorubicin and rapamycin to prevent drug resistance in cancers.

Nano-graphene oxide (nGO) is a carbon allotrope studied for its potential as carrier for chemotherapeutic delivery and its photoablation effects. However, interaction of nGO with blood components and the subsequent toxicities warrant a hybrid system for effective cancer drug delivery. Combination chemotherapy aids in effective cancer treatment and prevention of drug resistance. Therefore, in this study, we attempted to prepare polyethylene glycosylated (PEGylated) lipid bilayer-wrapped nGO co-loaded with doxorubicin (DOX) and rapamycin (RAPA), GOLDR, for the prevention and treatment of resistant cancers. Our results revealed a stable GOLDR formulation with appropriate particle size (∼170 nm), polydispersity (∼0.19) and drug loading. Free drug combination (DOX and RAPA) presented synergistic anticancer effects in MDA-MB-231, MCF-7, and BT474 cells. Treatment with GOLDR formulation maintained this synergism in treated cancer cells, which was further enhanced by the near infrared (NIR) laser irradiation-induced photothermal effects of nGO. Higher chromatin condensation and apoptotic body formation, and enhanced protein expression of apoptosis-related markers (Bax, p53, p21, and c-caspase 3) following GOLDR treatment in the presence of NIR laser treatment clearly suggests its superiority in effective chemo-photothermal therapy of resistant cancers. The hybrid nanosystem that we developed provides a basis for the effective use of GOLDR treatment in the prevention and treatment of resistant cancer types.

Synergistic anticancer activity of combined histone deacetylase and proteasomal inhibitor-loaded zein nanoparticles in metastatic prostate cancers.

The development of resistance and subsequent metastasis makes prostate cancer a leading cause of cancer-related death among men. Hence, nanoparticle-based combination chemotherapeutics could be a viable treatment strategy. We aimed to prepare vorinostat (Vor) and bortezomib (Bor) combination-loaded zein nanoparticles (ZNP, ZNP/VB) for treating metastatic prostate cancers. Our results revealed the successful preparation of ZNP/VB with a small particle size (~160nm) and polydispersity index (~0.20). Importantly, controlled and pH-dependent drug release profiles were observed. ZNP/VB exhibited high uptake in different prostate cancer cells and, thereby, exhibited higher cytotoxicity and apoptosis. Additionally, the enhanced anti-migration effect of and induction of pro-apoptotic proteins by ZNP/VB suggest its potential effectiveness in cancer treatment. ZNP/VB showed enhanced in vivo antitumor effects compared to that observed for each free drug and their combination, with minimal toxicity. Taken together, ZNP/VB could be a potential formulation for the effective treatment of metastatic prostate cancers.

Cefdinir Solid Dispersion Composed of Hydrophilic Polymers with Enhanced Solubility, Dissolution, and Bioavailability in Rats.

The aim of this work was to develop cefdinir solid dispersions (CSDs) prepared using hydrophilic polymers with enhanced dissolution/solubility and in vivo oral bioavailability. CSDs were prepared with hydrophilic polymers such as hydroxypropyl-methylcellulose (HPMC; CSD1), carboxymethylcellulose-Na (CMC-Na; CSD2), polyvinyl pyrrolidone K30 (PVP K30; CSD3) at the weight ratio of 1:1 (drug:polymer) using a spray-drying method. The prepared CSDs were characterized by aqueous solubility, differential scanning calorimetry (DSC), powder X-ray diffraction (p-XRD), scanning electron microscopy (SEM), aqueous viscosity, and dissolution test in various media. The oral bioavailability of CSDs was also evaluated in rats and compared with cefdinir powder suspension. The cefdinir in CSDs was amorphous form, as confirmed in the DSC and p-XRD measurements. The developed CSDs commonly resulted in about 9.0-fold higher solubility of cefdinir and a significantly improved dissolution profile in water and at pH 1.2, compared with cefdinir crystalline powder. Importantly, the in vivo oral absorption (represented as AUCinf) was markedly increased by 4.30-, 6.77- and 3.01-fold for CSD1, CSD2, and CSD3, respectively, compared with cefdinir suspension in rats. The CSD2 prepared with CMC-Na would provide a promising vehicle to enhance dissolution and bioavailability of cefdinir in vivo.

Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design.

The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1), ratio of HPMC to drug in the SR layer (X 2), and ratio of Eudragit RL PO to drug in the SR layer (X 3). The dependent variables assessed were % drug released in distilled water at 30 min (Y 1), % drug released in pH 1.2 at 2 h (Y 2), and % drug released in pH 6.8 at 12 h (Y 3). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.