[Optimization and in vitro characterization of resveratrol-loaded poloxamer 403/407 mixed micelles].

The objectives of this study are to prepare resveratrol loaded mixed micelles composed of poloxamer 403 and poloxamer 407, and optimize the formulation in order to achieve higher drug solubility and sustained drug release. Firstly, a thin-film hydration method was utilized to prepare the micelles. By using drug-loading, encapsulation yield and particle size of the micelles as criteria, influence of three variables, namely poloxamer 407 mass fraction, amount of water and feeding of resveratrol, on the quality of the micelles was optimized with a central composite design method. Steady fluorescence measurement was carried out to evaluate the critical micelle concentration of the carriers. Micelle stability upon dilution with simulated gastric fluid and simulated intestinal fluid was investigated. The in vitro release of resveratrol from the mixed micelles was monitored by dialysis method. It was observed that the particle size of the optimized micelle formulation was 24 nm, with drug-loading 11.78%, and encapsulation yield 82.51%. The mixed micelles increased the solubility of resveratrol for about 197 times. Moreover, the mixed micelles had a low critical micelle concentration of 0.05 mg · mL(-1) in water and no apparent changes in particle size and drug content were observed upon micelles dilution, indicating improved kinetic stability. Resveratrol was released from the micelles in a controlled manner for over 20 h, and the release process can be well described by Higuchi equation. Therefore, resveratrol-loaded poloxamer 403/407 mixed micelles could improve the solubility of resveratrol significantly and sustained drug release behavior can be achieved.

Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram.

Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

Exploring the influence of microstructure and phospholipid type of liposomes on their interaction with lung.

Liposome is a promising carrier for pulmonary drug delivery and the nano-sized liposomes have been widely investigated in the treatment of lung diseases. However, there still lack the knowledge of micron-sized liposomes for lung delivery, which have more advantages in terms of drug loading and sustained drug release capacity. The micron-sized liposomes can be classified into multilamellar liposome (MLL) and multivesicular liposome (MVL) according to their microstructure, thus, this study focused on exploring how the micron-sized liposomes with different microstructure and phospholipid composition influence their interaction with the lung. The MLL and MVL were prepared from different types of phospholipids (including soya phosphatidylcholine (SPC), egg yolk phosphatidylcholine (EPC), and dipalmitoyl phosphatidylcholine (DPPC)) with geometric diameter around 5 µm, and their in vitro pulmonary cell uptake, in vivo lung retention and organ distribution were investigated. The results showed that the microstructure of liposomes didn't affect pulmonary cellular uptake, in vivo lung retention and organ distribution. MLL and MVL prepared with the same phospholipid had similar cellular uptake in both NR8383 cells and A549 cells, and both of them possessed prolonged lung retention and limited distribution in other organs during 72 h. Notably, the phospholipid type presented remarkable influence on liposomes' interaction with the lung. SPC-based liposomes exhibited higher cellular uptake than the DPPC-based ones in both NR8383 cells and A549 cells, also possessed a better lung retention behavior. In conclusion, this study might provide theoretical knowledge for designing micron-sized liposomes intended for lung delivery.

Tunable rigidity of PLGA shell-lipid core nanoparticles for enhanced pulmonary siRNA delivery in 2D and 3D lung cancer cell models.

Faced with the threat of lung cancer-related deaths worldwide, small interfering RNA (siRNA) can silence tumor related messenger RNA (mRNA) to tackle the issue of drug resistance with enhanced anti-tumor effects. However, how to increase lung tumor targeting and penetration with enhanced gene silencing are the issues to be addressed. Thus, the objective of this study is to explore the feasibility of designing non-viral siRNA vectors for enhanced lung tumor therapy via inhalation. Here, shell-core based polymer-lipid hybrid nanoparticles (HNPs) were prepared via microfluidics by coating PLGA on siRNA-loaded cationic liposomes (Lipoplexes). Transmission electron microscopy and energy dispersive spectroscopy study demonstrated that HNP consists of a PLGA shell and a lipid core. Atomic force microscopy study indicated that the rigidity of HNPs could be well tuned by changing thickness of the PLGA shell. The designed HNPs were muco-inert with increased stability in mucus and BALF, good safety, enhanced mucus penetration and cellular uptake. Crucially, HNP1 with the thinnest PLGA shell exhibited superior transfection efficiency (84.83%) in A549 cells, which was comparable to that of lipoplexes and Lipofectamine 2000, and its tumor permeability was 1.88 times that of lipoplexes in A549-3T3 tumor spheroids. After internalization of the HNPs, not only endosomal escape but also lysosomal exocytosis was observed. The transfection efficiency of HNP1 (39.33%) was 2.26 times that of lipoplexes in A549-3T3 tumor spheroids. Moreover, HNPs exhibited excellent stability during nebulization via soft mist inhaler. In conclusion, our study reveals the great potential of HNP1 in siRNA delivery for lung cancer therapy via inhalation.

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-ß-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-ß-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

Inhaled Macrophage Apoptotic Bodies-Engineered Microparticle Enabling Construction of Pro-Regenerative Microenvironment to Fight Hypoxic Lung Injury in Mice.

Oxygen therapy cannot rescue local lung hypoxia in patients with severe respiratory failure. Here, an inhalable platform is reported for overcoming the aberrant hypoxia-induced immune changes and alveolar damage using camouflaged poly(lactic-co-glycolic) acid (PLGA) microparticles with macrophage apoptotic body membrane (cMAB). cMABs are preloaded with mitochondria-targeting superoxide dismutase/catalase nanocomplexes (NCs) and modified with pathology-responsive macrophage growth factor colony-stimulating factor (CSF) chains, which form a core-shell platform called C-cMAB/NC with efficient deposition in deeper alveoli and high affinity to alveolar epithelial cells (AECs) after CSF chains are cleaved by matrix metalloproteinase 9. Therefore, NCs can be effectively transported into mitochondria to inhibit inflammasome-mediated AECs damage in mouse models of hypoxic acute lung injury. Additionally, the at-site CSF release is sufficient to rescue circulating monocytes and macrophages and alter their phenotypes, maximizing synergetic effects of NCs on creating a pro-regenerative microenvironment that enables resolution of lung injury and inflammation. This inhalable platform may have applications to numerous inflammatory lung diseases.

Interactions of Inhaled Liposome with Macrophages and Neutrophils Determine Particle Biofate and Anti-Inflammatory Effect in Acute Lung Inflammation.

Since most current studies have focused on exploring how phagocyte internalization of drug-loaded nanovesicles by macrophages would affect the function and therapeutic effects of infiltrated neutrophils or monocytes, research has evaluated the specificity of the inhaled nanovesicles for targeting various phagocytes subpopulations. In this study, liposomes with various charges (including neutral (L1), anionic (L2), and cationic at inflammatory sites (L3)) were constructed to investigate how particle charge determined their interactions with key phagocytes (including macrophages and neutrophils) in acute lung injury (ALI) models and to establish correlations with their biofate and overall anti-inflammatory effect. Our results clearly indicated that neutrophils were capable of rapidly sequestering L3 with a 3.2-fold increase in the cellular liposome distribution, compared to that in AMs, while 70.5% of L2 were preferentially uptaken by alveolar macrophages (AMs). Furthermore, both AMs and the infiltrated neutrophils performed as the potential vesicles for the inhaled liposomes to prolong their lung retention in ALI models, whereas AMs function as sweepers to recognize and process liposomes in the healthy lung. Finally, inhaled roflumilast-loaded macrophage or neutrophil preferential liposomes (L2 or L3) exhibited optimal anti-inflammatory effect because of the decreased AMs phagocytic capacity or the prolonged circulation times of neutrophils. Such findings will be beneficial in exploiting a potential pathway to specifically manipulate lung phagocyte functions in lung inflammatory diseases where these cells play crucial roles.

Effect of novel stabilizers--cationic polymers on the particle size and physical stability of poorly soluble drug nanocrystals.

In this study, a novel class of stabilizer, cationic polymer, was introduced into the system of nanocrystals. Taking itraconazole as a poorly soluble model drug, the influence of three cationic polymers-chitosan, N-trimethyl chitosan, and polyethyleneimine-on the properties of the nanocrystals prepared by high-pressure homogenization method was investigated. Physicochemical properties of the nanoparticles were characterized. It was demonstrated that the cationic polymers could act as both an electrostatic and steric stabilizer to facilitate particle size reduction. Factors influencing charge density and stretching state of the cationic polymers influenced the magnitude of the particle. The electrostatic stabilization effect is more prominent than that of the steric stabilizing mechanism. Drug crystalline state was not changed by the addition of cationic polymers. Physical stability of the nanocrystals with cationic polymers was remarkably improved. The in vivo antifungal efficacy of the nanocrystals was dependent on physicochemical properties and pH. FROM THE CLINICAL EDITOR: Cationic polymer stabilizers were used to modify the surface of nanocrystals and the resulting stabilizing mechanisms were compared. The electrostatic stabilization effect was found to be stronger than the steric one. Crystallinity of itraconazole was unchanged by the addition of cationic polymers, while drug physical stability remarkably improved.

The depolymerization of sodium alginate by oxidative degradation.

Alginate has been extensively used as a carrier for macromolecules and as gene delivery vehicle. Both properties are molecular weight (Mw) dependent. Herein, we investigated factors affecting the oxidative depolymerization of alginate. The depolymerization process occurred mainly in the first 1 h. The Mw of the depolymerized alginate was influenced by the reaction temperature. At temperature 20 and 30°C, Mw of the alginate fragment kept constant and further Mw decrease was observed at 40°C. Along with the increase of hydrogen peroxide concentration, the Mw of the fragments decreased gradually. Influence of alginate initial concentration was marginal. A linear decrease of Mw was observed when the system pH was in the range of 5-7, whereas no further change was found when the system pH decreased from 7 to 8. Fourier transformed infrared spectroscopy spectra revealed that degradation undergoes by the breakage of the glycosidic bonds of polymers. No structural change was observed during the depolymerization process by UV spectroscopy. Cloud point pH increase was found for alginate 30 k. In summary, this method is an effective and convenient approach for preparing low Mw oligosaccharides from sodium alginate and may be potentially useful for the drug delivery system design with alginate.

Elucidating inhaled liposome surface charge on its interaction with biological barriers in the lung.

Liposome is the promising nanocarrier for pulmonary drug delivery and surface charge is its basic property. However, there is a lack of knowledge about relationship between the liposomal surface charge and its interaction with biological barriers in the lung. Therefore, the purpose of this research is to elucidate the influence of liposome surface charge on its in vivo fate. Firstly, liposomes with positive, negative and neutral surface charge were constructed and characterized, their compatibility towards pulmonary cells was studied. Then their interaction with different biological barriers in lung, including mucus, trachea, bronchoalveolar lavage fluid (BALF) and alveolar macrophage, were investigated. Their retention behavior in lung and systemic exposure were further explored. It was demonstrated that neutrally and negatively charged liposomes were safer than positively charged ones. In the conducting airway, liposome with positive surface charge could better enhance trachea distribution but only within 2 h. In the respiratory region, both neutrally and negatively charged liposomes presented improved mucus permeability, good stability in BALF containing pulmonary surfactant, decreased macrophage uptake, prolonged lung retention and decreased systemic exposure to other organs, with neutrally charged liposome showing superior performance than the negatively charged ones. While the positively charged liposome was not stable in lung microenvironment with aggregation observed, leading to increased alveolar macrophage uptake, thereby lower pulmonary retention and higher risk of systemic exposure. In conclusion, liposomal surface charge is a tunable formulation factor to modulate the interaction with biological barriers in the lung and thus in vivo fate of inhaled liposomes.

Design of biotin decorated enterocyte targeting muco-inert nanocomplexes for enhanced oral insulin delivery.

The natural mucus cover has been a major obstacle to prevent enterocyte targeting particles from contact with the receptors. Thus, mucus penetration and intestinal targeting should be designed into one system. Based on the concept that biotin specifically recognizes epithelium receptors, enterocyte targeting muco-inert nanocomplexes were designed. Firstly, biotinylated chitosan (CS-Biotin) copolymers with different degree of substitution were synthesized and characterized. The nanocomplexes between CS-Biotin and insulin were prepared via self-assembly method. Thereafter, the nanocomplexes were fabricated by coating with various molecular weight hyaluronic acid (HA), which improved penetration efficiency in the mucus layer and small intestine in a HA molecular weight dependent manner. In vivo study indicated that hypoglycemic effect of the nanocomplexes was biotin modification degree and HA molecular weight dependent, with HA (200)-coated CS-Biotin21.8%/Insulin polyelectrolyte complex presenting the best performance. In conclusion, biotin decorated muco-inert nanocomplexes with HA coating are a promising platform for oral insulin delivery.

Design of folic acid decorated virus-mimicking nanoparticles for enhanced oral insulin delivery.

Mucus penetration and intestinal cells targeting are two main strategies to improve insulin oral delivery efficiency. However, few studies are available regarding the effectiveness of combining these two strategies into one nano-delivery system. For this objective, the folic acid (FA) decorated virus-mimicking nanoparticles were designed and influence of FA graft ratio on the in vitro and in vivo properties of insulin loaded nanoparticles was studied systemically. Firstly, using folic acid as active ligand, different folic acid grafted chitosan copolymers (FA-CS) were synthesized and characterized. Thereafter, using insulin-loaded poly(n-butylcyanoacrylate) nanoparticles as the core, virus-mimicking nanoparticles were fabricated by coating of positively charged FA-CS copolymer and negatively charged hyaluronic acid. Irrespective of the FA graft ratio, all the nanoparticles showed good stability, similar insulin release in the gastrointestinal fluid, excellent and similar penetration in mucus. The nanoparticles permeability in intestine was FA graft ratio and segment dependent, with FA graft ratio at/over 12.51% presenting better effect in the order of duodenum > jejunum ≈ ileum. Both mechanism studies and confocal microscopy observation demonstrated FA-mediated process was involved in the transport of FA decorated nanoparticles. In vivo studies revealed hypoglycemic effect of the nanoparticles was FA graft ratio dependent, a saturation phenomenon was observed when FA graft ratio was at/over 12.51%. In conclusion, folic acid decorated virus-mimicking nanoparticles presented improved insulin absorption, implying combining mucus penetration and active transcellular transport is an effective way to promote oral insulin absorption, while the modification ratio of active ligand needs optimization.

Inhalable PLGA microspheres: Tunable lung retention and systemic exposure via polyethylene glycol modification.

Polyethylene glycol (PEG) modification is one of the promising approaches to overcome both mucus and alveolar macrophage uptake barriers in the deep lung for sustained therapy of pulmonary diseases such as asthma. To investigate the feasibility of using PEG-modified microspheres to bypass both barriers, we prepared a collection of polyethylene glycol-distearoyl glycero-phosphoethanolamine (PEG-DSPE)-modified poly (lactide-co-glycolide) (PLGA) microspheres bearing specific PEG molecular weights (0.75, 2, 5, and 10 kDa) and PEG-DSPE/PLGA molar ratios (0.25:1 and 1:1). Drug release, mucus penetration, and macrophage uptake were evaluated in vitro, and the corresponding in vivo activities of microspheres in rats were investigated. It was found that the PEG2000-DSPE/PLGA 1:1 group showed enhanced mucus permeability and reduced macrophage uptake in vitro compared to the PEG2000-DSPE/PLGA 0.25:1 group. At high PEG molar ratios, only the PEG 2000-based group showed significantly prolonged lung retention in vivo compared to the control group. The systemic exposure of the PEG2000-DSPE/PLGA 1:1 group was significantly lower than that of the PEG2000-DSPE/PLGA 0.25:1 group (39% of AUC reduction). Additionally, when using the same molar ratio of 1:1, the PEG 2000 group significantly lowered the systemic drug exposure compared to that of the PEG 5000 and 10000 groups (48% and 33% of AUC reduction, respectively), thus making it a promising sustained lung delivery candidate for pulmonary disease treatment.

Exploring the influence of inhaled liposome membrane fluidity on its interaction with pulmonary physiological barriers.

Liposomes are promising vectors for pulmonary drug delivery, and have been used in marketed inhalation products. Membrane fluidity is an important property of liposomes. However, the influence of liposome membrane fluidity on its interaction with pulmonary physiological barriers is still unclear and needs elucidation. Here, a series of PEGylated DPPC (1,2-dihexadecanoyl-rac-glycero-3-phosphocholine) liposomes with different membrane fluidity were prepared, and their interaction with different pulmonary physiological barriers, including the mucus permeation capacity, macrophage uptake, trachea distribution and retention behavior, was investigated. The liposomes exhibited sizes of around 100 nm, near-neutral surface charge, and the membrane fluidity increased with increasing cholesterol ratio. In vitro studies showed that the liposomes with lower membrane fluidity presented optimal mucus permeation efficiency, while those with higher membrane fluidity displayed lower macrophage uptake. An in vivo trachea distribution study revealed that liposomes with low or medium membrane fluidity exhibited enhanced trachea permeation. No significant difference in lung retention was found among these liposomes. In conclusion, the mucus permeation and macrophage phagocytosis behavior of liposomes could be well tuned by changing their membrane fluidity.

Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery.

Contact lenses are ideal medical devices to sustain the release of ophthalmic drugs. However, the incorporation of drug loaded system can cause visual obstruction and poor oxygen/light permeability which restrict the application of contact lens for long-term wearing. Inspired by the physiological structure of our human eyes, we assume a circular-ring type inner layer embedded CLs might be a good solution to address the above-mentioned problems. In this study, taking betaxolol hydrochloride (BH) as a model drug, its complex with ion exchange resin was used as a carrier for adjusting drug loading amount, which is being dispersed into circular-ring shape Eudragit® S100 film as an inner layer, silicone-based hydrogel as the outer layer. Influence of resin particle size and drug/S100 ratio on drug release profiles was investigated. It was demonstrated that using resin as a carrier can not only increase drug loading amount but also sustain drug release, with the drug release rate well-tuned by either changing particle size of the resin or S100 ratio. Meanwhile S100 can well function as a pH-triggered drug release matrix, with limited drug leakage in the storage medium. Light transmittance of over 97% was achieved in the novel circular-ring layer-embedded CLs. Oxygen permeability coefficient (Dk) of the circular-ring film embedded CLs was 31.1 ± 3.7 barrer, similar to that of pure CLs. The sustained drug release behavior of this circular-ring embedded CLs was also well demonstrated in vivo. A level A IVIVC between in vitro drug release and in vivo drug concentration in tear fluid of the circular-ring embedded CLs was established. In conclusion, this circular-ring embedded contact lens is very promising for ophthalmic drug delivery with enhanced compatibility, sustained and pH triggered drug release characteristics.

Comparison of thermosensitive in situ gels and drug-resin complex for ocular drug delivery: In vitro drug release and in vivo tissue distribution.

Conventional ophthalmic eye drops are limited by their rapid elimination rate and short time of action. Ion exchange resin has been used to achieve sustained ocular drug delivery but the high selectivity of drug molecules restricts its broad application. In situ gel system seems to be a good strategy to address these problems but the influence of in situ gel type on the sustained release behavior and tissue distribution after ocular application is unclear. Therefore, in this study, using betaxolol hydrochloride as a model drug, poloxamer 407 and methylcellulose as the carriers, two thermosensitive in situ gel systems were prepared and characterized. Influence of formulation composition type and concentration on in vitro drug release was studied. Tissue distribution after ocular delivery of two different thermosensitive in situ gels was studied and compared with commercial BH eye drop (Betoptic S®). In vitro studies demonstrated that addition of 4% HPMC 606W in 15% P407 solution and 5% PEG4000 in 2% MC solution obtained gels with appropriate gelation temperature and similar sustained drug release rate. In vivo tissue distribution study indicated that they presented similar drug concentration in cornea, iris-ciliary and aqueous humor irrespective of gel type, with higher drug concentration achieved after 4 h compared to the commercial resin suspension eye drops. The AUC and MRT of the two in situ gel eye drops were 2 times higher than that of the commercial resin suspension eye drops in cornea. In conclusion, the two thermosensitive in situ gels have prolonged drug release after ocular drug delivery compared with ion exchange resin eye drops, implying their potential applications in clinic with broad drug adoptability.

Engineering large porous microparticles with tailored porosity and sustained drug release behavior for inhalation.

Sustained drug delivery is considered as an effective strategy to improve the treatment of local lung diseases. In this context, inhalation administration of large porous microparticles (LPPs) represents promising prospects. However, one major challenge with said delivery technology is to control the drug release pattern (especially to decrease the burst release) while maintaining a low mass density/high porosity, which is of high significance for the aerodynamic behavior of LPP systems. Here, we show how to engineer drug-loaded, biodegradable LPPs with varying microstructure by means of a premix membrane emulsification-solvent evaporation (PME-SE) method using poly(vinyl pyrrolidone) (PVP) as the pore former. The influence of PVP concentration on the physicochemical properties, in-vitro drug release behavior and in-vitro aerodynamic performance of the drug-loaded microparticles was tested. We demonstrated that the PME-SE technique led to LPPs with favorable pore distribution characteristics (i.e., low external but high internal porosity) as a function of the PVP concentration. In general, more PVP conditioned a larger discrepancy of the internal vs. external porosity. When the external porosity of the LPP formulation (15% of PVP during the manufacturing process) was less than 3%, the burst release of the embedded drug was significantly reduced compared to LPPs prepared by a "conventional" emulsification solvent evaporation method. All the formulations prepared by the PME-SE method had aerodynamic properties suitable for inhalation. This is the first report indicating that the microstructure of LPPs can be tailored using the PME-SE technology with PVP as a suitable pore former. Doing so, we designed LPP formulations having full control over the drug release kinetics and aerodynamic behavior.

Design of self-polymerized insulin loaded poly(n-butylcyanoacrylate) nanoparticles for tunable oral delivery.

Macromolecular drugs, characterized by low stability and large molecular weight, still faced various difficulties by oral administration. And controlling drugs' release rate to reach the physiological concentration in the blood was recognized as one of the main challenges in this field but no studies are available so far. Thus, the objective of this study was to investigate the effect of insulin release rate on its in vitro and in vivo behavior when other obstacles (drug stability, mucus penetration and retention in gastrointestinal tract) was firstly overcome. Using n-butylcyanoacrylate (BCA) as the carrier, insulin-loaded Poly (n-butylcyanoacrylate) nanoparticles (Ins/PBCA NPs) were prepared by self-polymerization and the release rate of insulin was controlled by adjusting the mass ratio of Insulin/BCA. The NPs exhibited good stability in gastric fluid with controlled release in intestine and the release rate increased with the increase of Insulin/BCA mass ratio. All the Ins/PBCA NPs with different release rate showed excellent mucus penetration (>60%, 10 min) and strong gastrointestinal retention (~70%, 12 h). Especially, all the NPs showed promising hypoglycemic effect with the extent depending on drug release rate. Ins/BCA = 2/10 NPs exhibited fast hypoglycemic effect, while Ins/BCA = 2/15 NPs showed slow and outstanding performance. In conclusion, Ins/PBCA NPs could not only overcome the oral barriers of insulin delivery but also provide desired hypoglycemic effect by controlling insulin release rate.

Influence of morphology and drug distribution on the release process of FITC-dextran-loaded microspheres prepared with different types of PLGA.

The aim of the present work was to understand the collaborative roles and the comprehensive effects of polymer nature, morphology, drug distribution and release behaviour for PLGA microspheres prepared by the double emulsion method. The morphology and drug distribution of the FITC-dextran-loaded microspheres were investigated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM), respectively. The results show that the morphology and release profiles depend on the polymer nature. For the capped PLGA RG502, the porosity, pore size and drug distribution had no pronounced influence on the release profile beyond the initial release. No significant changes in size and morphology were found and there was negligible water uptake during the release process. PEG addition as a pore maker indicated a possible way to modify the release rate at the second release stage. However, in the case of the uncapped PLGA RG503H, release profiles were dependent upon changes in porosity, pore size and drug loading. Increases in porosity, internal pore size and loading resulted in a continuous release profile. Previous studies have shown the importance of different process parameters on morphology and drug release, but in this work it is clear that polymer nature is a determining factor.

Effect of polysorbate 80 on the intranasal absorption and brain distribution of tetramethylpyrazine phosphate in rats.

Drug delivery to the brain is limited by the blood-brain barrier (BBB). Intranasal delivery is a non-invasive route of drug administration which can bypass the BBB and contributed to a direct and rapid transport of drugs to the brain. However, intrinsic drug distribution to the brain after intranasal administration may not be sufficient to achieve required clinical efficacy. In this study, taking 2,3,5,6-tetramethylpyrazine (TMPP) as a model drug, the feasibility of using polysorbate 80 as an absorption enhancer and message guider to increase drug distribution in the brain was employed. After intravenous/intranasal administration of TMPP formulations with/without polysorbate 80, drug concentration in both plasma and brain was measured at specific time points, and the pharmacokinetic parameters were compared. It was demonstrated that compared with intravenous administration, brain targeting efficiency of TMPP was improved remarkably by intranasal route. Upon intranasal administration, the addition of polysorbate 80 significantly increased TMPP concentration in both plasma and brain linearly up to polysorbate 80 concentration 2%. Based on drug targeting efficiency, drug targeting index, and nose-to-brain direct transport percentage, polysorbate 80 decreased the nose-to-brain direct transport ratio of TMPP in a polysorbate 80 concentration-dependent manner although the total brain targeting efficiency was unchanged, with significantly enhanced absolute drug concentration in the brain achieved. In summary, polysorbate 80 is a promising excipient to increase drug concentration in both plasma and brain via intranasal route.