Effect of mPEG-PLGA on Drug Crystallinity and Release of Long-Acting Injection Microspheres: In Vitro and In Vivo Perspectives.

PURPOSE: Traditional progesterone (PRG) injections require long-term administration, leading to poor patient compliance. The emergence of long-acting injectable microspheres extends the release period to several days or even months. However, these microspheres often face challenges such as burst release and incomplete drug release. This study aims to regulate drug release by altering the crystallinity of the drug during the release process from the microspheres. METHODS: This research incorporates methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-PLGA) into poly(lactide-co-glycolide) (PLGA) microspheres to enhance their hydrophilicity, thus regulating the release rate and drug morphology during release. This modification aims to address the issues of burst and incomplete release in traditional PLGA microspheres. PRG was used as the model drug. PRG/mPEG-PLGA/PLGA microspheres (PmPPMs) were prepared via an emulsification-solvent evaporation method. Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were employed to investigate the presence of PRG in PmPPMs and its physical state changes during release. RESULTS: The addition of mPEG-PLGA altered the crystallinity of the drug within the microspheres at different release stages. The crystallinity correlated positively with the amount of mPEG-PLGA incorporated; the greater the amount, the faster the drug release from the formulation. The bioavailability and muscular irritation of the long-acting injectable were assessed through pharmacokinetic and muscle irritation studies in Sprague-Dawley (SD) rats. The results indicated that PmPPMs containing mPEG-PLGA achieved low burst release and sustained release over 7 days, with minimal irritation and self-healing within this period. PmPPMs with 5% mPEG-PLGA showed a relative bioavailability (Frel) of 146.88%. IN CONCLUSION: In summary, adding an appropriate amount of mPEG to PLGA microspheres can alter the drug release process and enhance bioavailability.

Antibacterial-Anti-Inflammatory-Bone Restoration Procedure Achieved by MIN-Loaded PLGA Microsphere for Efficient Treatment of Periodontitis.

The main development process of periodontitis involves periodontal pathogenic bacteria as the initiating factor causing the onset of destructive inflammation, which in turn stimulates the destruction of periodontal tissue. It is difficult to achieve the eradication of periodontitis due to the complex interaction among antibacterial, anti-inflammatory, and bone restoration. Herein, we propose an antibacterial-anti-inflammatory-bone restoration procedural treatment strategy with minocycline (MIN) for the efficient treatment of periodontitis. In brief, MIN was prepared into PLGA microspheres with tunable release behavior using different species of PLGA, respectively. The optimally selected PLGA microspheres (LA:GA with 50:50, 10 kDa, and carboxyl group) had a drug loading of 16.91%, an in vitro release of approximately 30 days, which also had a particle size of approximately 11.8 µm with a smooth appearance and a rounded morphology. The DSC and XRD results showed that the MIN was completely encapsulated in the microspheres as an amorphous state. Cytotoxicity tests demonstrated the safety and biocompatibility of the microspheres (cell viabilities at a concentration of 1-200 µg/mL were greater than 97%), and in vitro bacterial inhibition tests showed that the selected microspheres could achieve effective bacterial inhibition at the initial stage after administration. The favorable anti-inflammatory (low TNF-α and IL-10 levels) and bone restoration effects (BV/TV: 71.8869%; BMD: 0.9782 g/cm3; TB.Th: 0.1366 mm; Tb.N: 6.9318 mm-1; Tb.Sp: 0.0735 mm) were achieved in a SD rat periodontitis model after administering once a week for four weeks. The MIN-loaded PLGA microspheres were proved to be an efficient and safe treatment for periodontitis by procedural antibacterial, anti-inflammatory, and bone restoration.

Improved Core Viscosity Achieved by PDLLA10kCo-Incorporation Promoted Drug Loading and Stability of mPEG2k-b-PDLLA2.4k Micelles.

PURPOSE: This study aims to investigate the effect of poly(D, L-lactic acid)10K (PDLLA10K) incorporation on the drug loading and stability of poly(ethylene glycol)2K-block-poly(D, L-lactide)2.4K (mPEG2k-b-PDLLA2.4k) micelles. In addition, a suitable lyophilization protector was screened for this micelle to obtain favorable lyophilized products. METHODS: The incorporation ratios of PDLLA10k were screened based on the particle size and drug loading. The dynamic stability, core viscosity, drug release, stability in albumin, and in vivo pharmacokinetic characteristics of PDLLA10k incorporated micelles were compared with the original micelles. In addition, the particle size variation was used as an indicator to screen the most suitable lyophilization protectant for the micelles. DSC, FTIR, XRD were used to illustrate the mechanism of the lyophilized protectants. RESULTS: After the incorporation of 5 wt% PDLLA10K, the maximum loading of mPEG2k-b-PDLLA2.4k micelles for TM-2 was increased from 26 wt% to 32 wt%, and the in vivo half-life was increased by 2.25-fold. Various stability of micelles was improved. Also, the micelles with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as lyophilization protectants had minimal variation in particle size. CONCLUSIONS: PDLLA10k incorporation can be employed as a strategy to increase the stability of mPEG2k-b-PDLLA2.4k micelles, which can be attributed to the viscosity building effect. HP-ß-CD can be used as an effective lyophilization protectant since mPEG and HP-ß-CD form the pseudopolyrotaxanesque inclusion complexes.

Earth-abundant 3d-transition-metal catalysts for lignocellulosic biomass conversion.

Transformation of biomass to chemicals and fuels is a long-term goal in both science and industry. However, high cost is one of the major obstacles to the industrialization of this sustainable technology. Thus, developing catalysts with high activity and low-cost is of great importance for biomass conversion. The last two decades have witnessed the increasing achievement of the use of earth-abundant 3d-transition-metals in catalysis due to their low-cost, high efficiency and excellent stability. Here, we aim to review the fast development and recent advances of 3d-metal-based catalysts including Cu, Fe, Co, Ni and Mn in lignocellulosic biomass conversion. Moreover, present research trends and invigorating perspectives on future development are given.

The preparation and characterisation of tasteless core-shell clarithromycin microcapsules.

This study aims to fabricate core-shell clarithromycin (CAM) microcapsules to cover up the bitter taste of CAM by spray drying with aqueous polymer dispersion. Water dispersion of Eudragit EPO and Surelease® were innovatively used to encapsulate CAM into microcapsules via a one-step spray-drying method. The inlet air temperature, airflow rate, CAM-polymer ratio, and particle size of CAM were optimised based on drug content and T6% (the time taken for the drug to release equal to 6% w/w). The powder properties were assessed by measuring particle size and microstructure using SEM, FT-IR, and PXRD. Furthermore, selected batch was assessed for their drug content, encapsulation efficiency, in vitro release, bitterness, and stability studies. EPO-Surelease® (1: 4) microcapsules had an average diameter (D50) of 37.69 ± 3.61 µm with a span of 2.395. The drug contents and encapsulation efficiency of EPO-Surelease®(1:4) were 10.89% and 63.7%, respectively. EPO-Surelease® (1:4) microcapsules prepared by spray drying with aqueous polymer dispersion can effectively mask the bitter taste of CAM.

Chitosan-Coated Liposomes: The Strategy to Reduce Intestinal Toxicity and Improve Bioavailability of Oral Vinorelbine.

In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the risk of phlebitis is avoided with oral administration, oral vinorelbine is still not a highly patient-compliant route due to the severe gastrointestinal toxicity. Vinorelbine-loaded liposomes with high encapsulation efficiency and suitable particle size were prepared using the ammonium sulfate gradient method. Chitosan-coated liposomes showed the slowest in vitro release compared to uncoated liposomes and vinorelbine solution. No damage was observed in the intestinal epithelial cells of mice orally administered with coated vinorelbine liposomes due to the low presence of the free drug in the gastrointestinal tract and the LD50 was increased from 129.83 to 182.25 mg/kg compared to oral vinorelbine solution. In addition, the positive surface potential of chitosan-coating endowed liposomes with mucosal adhesive function, delaying the time to reach the peak plasma concentration of vinorelbine from 1 to 4 h after administration. And bioavailability was increased to 2.1-fold compared to vinorelbine solution. In short, a new strategy to address the severe gastrointestinal side effects of oral vinorelbine has been developed.

Co-delivery of gemcitabine and cisplatin via Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) micelle to improve the in vivo stability and antitumor effect.

PURPOSE: The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect. METHODS: A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles). RESULTS: Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T1/2z of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h (mPEG-PLG@CDDP), 5.463 h and 12.540 h (mPEG-PLG-GEM@CDDP) compared with GEM@CDDP solutions (T1/2z = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that GEM@CDDP-Sol was more toxic to kidneys and marrow compared with mPEG-PLG-GEM@CDDP micelles. CONCLUSIONS: By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles' formation and action process.

Preparation of mPEG-b-PLA/TM-2 Micelle Lyophilized Products by Mixed Lyoprotectors and Antitumor Effect In Vivo.

The objective of this study was to encapsulate the poorly water-soluble drug TM-2 into polymer micelles using mPEG2k-b-PLA2.4k to increase its aqueous solubility and improve its therapeutic effect for liver cancer. Furthermore, in order to achieve long-term storage, the micelle solution was successfully freeze-dried. This study theoretically clarified the possibility of enhancing the water solubility of TM-2 using mPEG2k-b-PLA2.4k micelles as well as the protective effects of mixed lyoprotectants. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) were performed, which showed that the drug has a good affinity with the polymer (χ = 0.489) according to Flory-Huggins theory and that lyoprotectants reduced the crystallinity of PEG in mPEG2k-b-PLA2.4k and played a space-protective role in the lyophilization process. In vivo experiments showed that micellization could improve the drug bioavailability and give a high therapeutic effect with a tumor inhibition rate of 84.5% under the tolerated dose.

Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin.

The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)-methoxy poly(ethylene glycol), PLA-PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA-PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA-PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA-PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1- and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

Toxicity Reduction and Efficacy Promotion of Doxorubicin in the Treatment of Breast Tumors Assisted by Enhanced Oral Absorption of Curcumin-Loaded Lipid-Polyester Mixed Nanoparticles.

Curcumin (CUR), a polyphenol derived from turmeric, exhibits anticancer and anti-inflammatory properties. However, it has poor water solubility, stability, and oral bioavailability. To overcome these limitations, lipid-polyester mixed nanoparticles (NPs) embedded in enteric polymer-EudragitL100-55(Eu) were formulated (CUR-NPs-Eu). NPs composed of mPEG-b-PCL have a hybrid core made up of middle chain triglyceride (MCT) and poly(ε-caprolactone) (PCL) for enhancing drug loading. The CUR-NPs with MCT content of 10% had a particle size of 121.2 ± 16.8 nm, ζ potential of -16.25 ± 1.38 mV, drug loading of 9.8%, and encapsulation efficiency of 87.4%. The transport of the CUR-NPs-Eu across Caco-2 monolayers is enhanced compared with CUR alone (1.98 ± 0.94 × 10-6 of curcumin versus 55.43 ± 6.06 × 10-6 cm/s of curcumin-loaded NPs) because of the non-disassociated nanostructure during absorption. The absolute bioavailability of CUR-NPs-Eu was 7.14%, which was drastically improved from 1.08% of the CUR suspension (CUR-Sus). Therefore, in the xenograft 4T1 tumor-bearing mice, increased drug accumulation in heart and tumor was noticed because of enhanced oral bioavailability of CUR. The chemosensitizing effect of CUR was attributed to its NF-κB reduction effect (148 ± 11.83 of DOX alone versus 104 ± 8.71 of combined therapy, ng/g tissue). The cardioprotective effect of CUR was associated with maintenance of cardiac antioxidant enzyme activity and down-regulation of NF-κB. This study provided a partial illustration of the mechanisms of chemosensitizing and cardioprotective effects of CUR utilizing the oral availability promotion effect brought by the NPs-Eu formulation. And these results further demonstrated that the capability of this NPs-Eu system in oral delivery of poorly soluble and poorly permeable drugs.

Novel Elastically Stretchable Metal-Organic Framework Laden Hydrogel with Pearl-Net Microstructure and Freezing Resistance through Post-Synthetic Polymerization.

Nanocomposite hydrogels (NCs) with mechanical properties suitable for a diverse range of applications can be made by combining polymer hydrogel networks with various inorganic nanoparticles. However, the mechanical properties and functions of conventional NCs are seriously limited by the poor structural or functional tunability of common nanofillers and by the low amounts of such fillers that can be added. Here, the fabrication of novel elastically stretchable and compressible nanocomposite hydrogels (MIL-101-MAAm/PAAm) with a distinctive pearl-net microstructure and a metal-organic framework (MOF) content in the range of 20-60 wt% through post-synthetic polymerization (PSP) is reported. The MOFs, which are compatible with polymers and have a high degree of modifiability in structure and functions, are used as nanofillers. Such MOF-laden hydrogels can withstand 500% tensile strain or 90% compressive strain without fracture and recover quickly upon unloading. They are also resistant to freezing at -25 °C. In addition, the problems associated with poor flexibility and processability of MOFs are overcome by the hybridization of hydrogel polymer matrices with MOFs. The results of this work not only provide a new perspective on preparing NCs but also indicate a promising path for applying MOFs in flexible devices.

Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption.

Panax quinquefolium saponin (PQS) composed of 45% pseudo-ginsenoside F11 (PF11), is a natural mixture of sterol compounds obtained from the American ginseng plant, having numerous promising benefits for health. However, low solubility and permeability limit the development of PQS as a therapeutic agent for oral administration. In this study, PQS liposomes (PQS-Lips) were prepared by thin layer hydration, an in situ single-pass intestinal perfusion (SPIP) model was used to verify the improvement of membrane permeability of PQS-Lips. PQS-Lips had a high encapsulation efficiency (EE) of 65%∼70%, a particle size about 100.0 nm, and a zeta potential of -60 mV with regular spherical surface. FTIR and DSC showed the PQS in liposomes were amorphous, indicating that hydrogen bonds formed between one or several hydroxyl groups in PQS and C-O group at the phospholipid polar terminal. In addition, PQS-Lips showed sustained release in vitro than PQS at pH 1.2 and pH 6.8, and PQS-Lips had good stability in simulated gastric and intestinal fluid. Then, the absorption rate (K a) and effective permeability coefficient (P eff) of PQS-Lips in the whole small intestine were significantly higher than those in PQS solution (PQS-Sol), which proved that the PQS-Lips could significantly increase the membrane permeability of PQS and promote its absorption in the small intestine. From the experimental results, it could be known that liposome technology could effectively improve the absorption of PQS in the small intestine.

Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu2+ Gradient Method.

Conventional combination chemotherapy often leads to unsatisfactory clinical outcomes due to the different distribution characteristics in vivo and the superimposed systemic toxicity of the drug cocktail. Co-encapsulated nano preparations have been gradually developed in recent years. In this work, cytarabine (Ara-C)/daunorubicin (DNR) liposomes were prepared by the pH gradient (ADL-pH) and Cu2+ gradient (ADL-Cu) methods. Ara-C did not show significant release from either ADL-Cu or ADL-pH in vitro during 168 h, which related to its logPoct. Different drug-loading patterns showed different release characteristics of DNR due to the different existence forms, ADL-pH contains the citrate form, while in ADL-Cu, there is the Cu2+ complex. To evaluate the release behavior, daunorubicin liposome (DL) and daunorubicin-Cu2+ complex (DNR-Cu) were prepared. The addition of EDTA in the release medium significantly increased the release rate of DNR from DL-Cu, while lower pH accelerated DNR release from both DL-pH and DL-Cu. The PK confirmed that ADL-Cu and ADL-pH could prolong the drug circulation time, and ADL-Cu had a mean retention time 1.5 times that of ADL-pH. Furthermore, both liposomes allowed the two drugs to maintain a relatively constant plasma concentration ratio for a prolonged time. Cytotoxicity assays showed that Ara-C/DNR with a molar ratio of 5:1 and 3:1 exhibited an excellent synergistic effect, which was more obvious at 5:1. In vitro antitumor results revealed that ADL-Cu exhibited more cytotoxicity than ADL-pH. All factors tested in this work suggest the considerable potential of ADL-Cu and ADL-pH for anticancer treatment.

In Vitro and In Vivo Evaluation of SP94 Modified Liposomes Loaded with N-14NCTDA, a Norcantharimide Derivative for Hepatocellular Carcinoma-Targeting.

The purpose of this research is to develop a liposomal drug delivery system, which can selectively target hepatocellular carcinoma (HCC) to deliver the antitumor agent N-14NCTDA, a C14 alkyl chain norcantharimide derivative of norcantharidin. N-14NCTDA-loaded liposomes were successfully prepared by lipid membrane hydration and extrusion methods. SP94, a targeting peptide for HCC cells, was attached to the liposomes loaded with N-14NCTDA by the post-insertion method to obtain SP94 modified liposomes (SP94-LPs). SP94-LPs had a significant cytotoxicity against Hep G2 cells with the IC50 of 15.395 ± 0.89 µg/mL, which is lower than that of NCTD-S (IC50 = 20.863 ± 0.56 µg/mL) and GAL-LPs (IC50 = 24.589 ± 1.02 µg/mL). Compared with conventional liposomes (Con-LPs), SP94-LPs showed greater cellular uptake in Hep G2 cells. Likewise, significant tumor suppression was achieved in H22 tumor-bearing mice which were treated with SP94-LPs. The tumor inhibition rate (IRw) of SP94-LPs was 82 ± 0.98%, obviously higher than that of GAL-LPs (69 ± 1.39%), Con-LPs (60 ± 2.78%), and NCTD-S (51 ± 3.67%). SP94-LPs exhibited a significant hepatocellular carcinoma-targeting activity in vitro and in vivo, which will provide a new alternative for hepatocellular carcinoma treatment in future. Graphical Abstract.

Goserelin Acetate Loaded Poloxamer Hydrogel in PLGA Microspheres: Core-Shell Di-Depot Intramuscular Sustained Release Delivery System.

This study aimed to prepare and optimize goserelin acetate (GOS) loaded hydrogel poly(d,l-lactic acid-co-glycolic acid) (PLGA) microsphere that is suitable for long-acting clinical treatment, investigate its structure, and regulate the initial release manner. Here, the PLGA microsphere containing Poloxamer hydrogel loaded with ∼15% (w/w) GOS was prepared by double-emulsion-solvent evaporation method and evaluated in terms of microscopic structure, physicochemical properties, and release manner in vitro and in vivo. Raman volume imaging and scanning electron microscopy studies revealed a core-shell Di-Depot structure of the microsphere, in which multi-GOS-loaded hydrogel depots were distributed in the core region. Under the interaction of hydrogel and PLGA depots, high encapsulation efficiency (94.16%) and low burst release (less than 2%) were achieved, along with the accompanying prolonged administration interval (49 days); an enhanced relative bioavailability 9.36-fold higher than that of Zoladex implant was also observed. Also, by addition of 1-5% acetic acid, the lag time was shortened to 6 days. The strategy for regulating the initial release provides new insights for manipulating the release behavior of the PLGA microspheres. The desirable property of the Poloxamer hydrogel PLGA microsphere indicated its promising application in controlled release drug delivery system.

Tumor-targeted drug delivery and sensitization by MMP2-responsive polymeric micelles.

Low tumor specificity and multidrug resistance (MDR) remain challenging for many anticancer drugs. In this study, the micelles assembled by a matrix metalloproteinase 2 (MMP2)-sensitive self-assembling efflux inhibitor (PEG2k-pp-PE) were developed and evaluated in various cancer models. In vitro, the PEG2k-pp-PE micelles enhanced the cellular uptake and tissue penetration and sensitized the cancers to drug treatments in MDR cancer cells and their three-dimensional multicellular spheroids. Their efflux inhibitory capability was comparable to those of the well-known small-molecule P-glycoprotein (P-gp) inhibitor and polymeric P-gp inhibitor. In vivo, the PEG2k-pp-PE micelles could specifically and effectively deliver the loaded cargoes to the tumor, as evidenced by the enhanced drug accumulation and prolonged drug retention in the tumor tissue, resulting in the improved anticancer activity. Our results suggest that the PEG2k-pp-PE micelles may have great potential to be a simple but multifunctional nanocarrier for concurrent tumor-targeted drug delivery and sensitization of resistant cancers.

Preparing of aspirin sustained-release granules by hot-melt granulation and micro-crystal coating.

In this work, aspirin (ASP) sustained granules were prepared using micro-crystal coating and hot-melt granulation, respectively. In the process of micro-crystal coating, PVP was used to form the isolation layer and then coated with either Eudragit RS/RL30D or ethyl cellulose (EC) as sustained-release layers to prepare sustained granules (the granules from this method were denoted m-cG). And in the process of hot-melt granulation, the granules were obtained with stearyl alcohol as a binder and EC as matrix material to prepare sustained granules (the granules were denoted h-mG). The in vitro release of ASP sustained-release granules was investigated by dissolution apparatus and the stability of the granules was studied. Since both methods effectively prevented the hydrolysis of ASP, the sustained granules by micro-crystal coating and hot-melt granulation were stable. However, there was a clear difference in the in vitro release of h-mG and m-cG. The h-mG was completely released in 4 h, while the m-cG with EC as sustained-release layer released 80% in 24 h and the m-cG with the Eudragit RS/RL 30 D as sustained-release layer released completely in 5 h. The results showed that micro-crystal coating was more suitable for the preparation of ASP sustained granules, and the granules with EC as sustained layer could achieve a better sustained-release effect.

mPEG5k- b-PLGA2k/PCL3.4k/MCT Mixed Micelles as Carriers of Disulfiram for Improving Plasma Stability and Antitumor Effect in Vivo.

The clinical application of disulfiram (DSF) in cancer treatments is hindered by its rapid degradation in the blood circulation. In this study, methoxy poly(ethylene glycol)- b-poly(lactide- co-glycolide)/poly(ε-caprolactone) (mPEG5k- b-PLGA2k/PCL3.4k) micelles were developed for encapsulation of DSF by using the emulsification-solvent diffusion method. Medium chain triglyceride (MCT) was incorporated into the mixed polymeric micelles to improve drug loading by reducing the core crystallinity. Differential scanning calorimetry (DSC) results implied that DSF is likely present in an amorphous form within the micelles, and is well dispersed. DSF is encapsulated within the core and the reservoir is stabilized by the hydrophilic shell to prevent rapid diffusion of DSF from the core. The DSF mixed micelles (DSF-MMs) showed good drug loading (5.90%) and a well-controlled particle size (86.4 ± 13.2 nm). The mixed micelles efficiently protected DSF from degradation in plasma, with 58% remaining after 48 h, while almost 90% of DSF was degraded after the same period for the DSF solution (DSF-sol), which was used as a control. The pharmacokinetics study showed that the maximum plasma concentration and bioavailability of DSF were improved by using the DSF-MMs (2 and 2.5 times that of the DSF-sol). The TIRs (tumor inhibition rates) of 5-FU, DSF-sol, and DSF-MMs were 63.46, 19.57, and 69.98%, respectively, implying that DSF-MMs slowed the growth of a H22 xenograft tumor model effectively.

Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye.

The aim of this work was to design a novel ocular delivery carrier based on liposomes loaded with azithromycin (AZM) for the treatment of dry eye (DE) disease. To improve the drug loading efficiency, an AZM-cholesteryl hemisuccinate (CHEMS) ion pair (ACIP) was first prepared, and the successful formation of the ACIP was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD), which demonstrated a stable interaction between CHEMS and AZM. The ACIP-loaded liposome (ACIP-Lip) appeared as spherical particles under TEM, with a uniform particle size of 60 ± 2 nm and zeta potential of -20.3 ± 4.6 mV. The entrapment efficiency (EE) and drug loading (DL) of ACIP-Lip were greatly improved to 95.6 ± 2.0 and 9.2 ± 0.7%, respectively, which was attributed to the enhanced loading capacity of the liposomes through use of the ion pair and addition of MCT. ACIP-Lip also exhibited a high stability during a 3 month storage period at both 4 and 25 °C. In vitro release of AZM from ACIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4, which is beneficial for ocular therapy. Furthermore, the corneal permeation of AZM was enhanced by ACIP-Lip, demonstrating an apparent permeability coefficient ( Papp × 106) of 8.92 ± 0.56 cm/s, which was approximately 2-fold greater that of the AZM solution. Finally, an in vivo pharmacodynamical study showed that the essential symptoms of DE rats were significantly improved by ACIP-Lip, as it was highly efficient and superior compared to hyaluronic acid sodium eye drops available on the market. Hence, ACIP-Lip is a promising formulation for DE treatment.

Progesterone PLGA/mPEG-PLGA Hybrid Nanoparticle Sustained-Release System by Intramuscular Injection.

PURPOSE: To prepare sustained-release PLGA/mPEG-PLGA hybrid nanoparticles of progesterone (PRG), and evaluate the descending required administration dosage in vivo. METHODS: PRG hybrid nanoparticles (PRG H-NPs) based on PLGA/mPEG-PLGA were compared with PRG nanoparticles (PRG-NPs) of pure PLGA as the matrix and PRG-oil solutions. Nanoparticles (NPs) were formed by the method of nanoemulsion, and the pharmacokinetics of the sustained-release PRG H-NPs in male Sprague dawley (SD) rats were investigated. The rats were randomly divided into four groups, each group received: single dose of PRG H-NPs (14.58 mg/kg, i.m.) and PRG-NPs (14.58 mg/kg, i.m.), repeated dosing for 7 days of PRG-oil (2.08 mg/kg, i.m.) solution (Oil-L) and a higher dosage of PRG-oil (6.24 mg/kg, i.m.) solution (Oil-H), respectively. RESULTS: In the pharmacokinetic test, the PRG H-NPs exhibited a comparatively good sustained-release effect against the PRG-NPs without mPEG-PLGA and PRG-oil solution. The pharmacokinetic parameters of the PRG H-NPs, PRG-NPs, Oil-L and Oil-H were AUC0-t(ng·h·mL-1) 8762.1, 1546.1, 1914.5, and 12,138.9, t1/2 (h)52.7, 44.1, 8.4 and 44.6 respectively. CONCLUSIONS: Owing to the modification of PEG, PRG H-NPs can act as safe delivery platforms for sustained-release of drugs with a lower dosage required.