A study on distribution and stability of drugs at the interface of a scutellarin-loaded emulsion.

This work mainly studies the interfacial behaviors of scutellarin on a newly developed emulsion and establishes a three-phase distribution model. The results showed that the concentration of scutellarin could decrease the interfacial tension and the gel-liquid crystal phase transition temperature of phospholipids. By observing the micromorphology of the emulsion, it is inferred that the drug exists on the emulsion interface. The distribution of drugs in three phases at different pH was calculated. The results showed that when pH was in the range of 3.0-8.0, the content of scutellarin in the oil phase was less than 0.25%; when pH < 7.4, more than 88% of the drugs were on the interface; when pH > 7.4, the drugs were mainly distributed in the aqueous phase. Therefore, the behavior of emulsions (pH 6.0) in vitro and in vivo is mainly composed of the behavior of drugs on the interface. The study above can explain some properties of the emulsions after loading scutellarin. Including the decrease of particle size and stability constant Ke, the increase of zeta potential, and the decreased chemical stability after the pH value went higher.

Evaluation of inhaled recombinant human insulin dry powders: pharmacokinetics, pharmacodynamics and 14-day inhalation.

OBJECTIVES: The present study was designed to assess the pharmacokinetic and pharmacodynamic performance of inhaled recombinant human insulin (rh-insulin) dry powders together with their safety profiles after 14-day inhalation. METHODS: In the pharmacokinetic and pharmacodynamic study, pulmonary surfactant (PS)-loaded and phospholipid hexadecanol tyloxapol (PHT)-loaded rh-insulin dry powders were intratracheally administered to male rats at the dose of 20 U/kg. Novolin R was used as control. Serum glucose and rh-insulin concentrations were determined by glucose oxidase method and human rh-insulin CLIA kit, respectively. For the safety study, rats were exposed to rh-insulin dry powders or air for 14-day by nose-only inhalation chambers. Bronchoalveolar lavage and histopathology examinations were performed after inhalation. KEY FINDINGS: There were no significant differences in the major pharmacokinetic and pharmacodynamic parameters between PS-loaded and PHT-loaded rh-insulin dry powders. The relative bioavailabilities and pharmacodynamic availabilities were 39.9%, 25.6% for PS-loaded dry powders and 30.1%, 23% for PHT-loaded dry powders, respectively. Total protein was the only injury marker that was significantly altered. Histopathology examinations showed the ranking of irritations (from slight to severe) were PHT-loaded rh-insulin, negative air control and PS-loaded rh-insulin. CONCLUSIONS: Both PS- and PHT-loaded rh-insulin dry powders were able to deliver rh-insulin systemically with appropriate pharmacokinetic, pharmacodynamic and safety profiles.

TPGS modified reduced bovine serum albumin nanoparticles as a lipophilic anticancer drug carrier for overcoming multidrug resistance.

In this study, a novel protein-polymer conjugate, d-α-tocopheryl polyethylene glycol succinate modified reduced bovine serum albumin (TPGS-Re-BSA, TRB), was synthesized for lipophilic anticancer drug delivery, and its unique ability to overcome drug resistance was explored. This conjugate was extensively characterized for its chemical structure, average molecular weight, secondary structure, degree of substitution, hydrophobicity, particle size and zeta potential. PTX-loaded nanoparticles (NPs) with diameters of 170-370 nm and drug loading efficiency of up to 13.62% were successfully prepared by the dialysis method. These drug-loaded NPs were found to exhibit a sustained release of PTX at pH 7.4, 6.5 and 5.5. Moreover, great anti-tumor activity in drug sensitive MCF-7 cells was observed in the in vitro anti-tumor studies. In particular, enhanced cytotoxicity and PTX-induced apoptosis were observed in the drug-resistant MCF-7/ADR cells compared to the Taxol and PTX-loaded BSA NPs. This could be attributed to the significant inhibition of P-gp activity and reduced ATP levels due to the presence of TRB NPs. Lastly, in vivo tumor inhibition assay verified the higher efficacy of TRB NPs. Overall, the results suggest that this TRB NPs could provide an effective carrier system for the delivery of anticancer agents.

Investigation of dual-sensitive nanogels based on chitosan and N-isopropylacrylamide and its intelligent drug delivery of 10-hydroxycamptothecine.

The work was to prepare and characterize a responsive drug delivery system built of chitosan-g-poly (N-isopropylacrylamide) (CTS-g-PNIPAAm) nanogels and to evaluate the effects of CTS molecular weight (Mw) on the loading and in vitro release of insoluble drug 10-hydroxycamptothecine (HCPT). The CTS-g-PNIPAAm copolymers were synthesized by radical polymerization. The Mw and physical chemistry properties such as diameter, second virial coefficient of grafted PNIPAAm were investigated by dynamic and static laser light scattering method. A series of cross-linked CTS-g-PNIPAAm nanogels were prepared with N, N'-methylenebisacrylamide initially added as a cross-linker. The thermal and pH-sensitive features of cross-linked CTS-g-PNIPAAm nanogels were studied by determining the variance of transmittance, changeable size and reversed zeta potential. The critical aggregation concentrations (CAC) of resultant nanogels decreased from 0.045 to 0.036 mg/mL with CTS Mw increased from 50 kDa to 700 kDa. The loading efficiency of the HCPT encapsulated into CTS-g-PNIPAAm nanogels increased in parallel with CTS Mw, while the cumulative release percentage of HCPT-loaded nanogels decreased with CTS Mw increasing at both 25 °C and 37 °C. Fitting results of HCPT release data to different mathematical models suggested a diffusion-controlled mechanism at 25 °C. However, the release behaviors were dominated by combined effects of polymer erosion and osmotic pressure driven at 37 °C. The cytotoxicity study of the CTS-g-PNIPAAm nanogels against hepatic L02 cells indicated that the resultant nanogels did not exhibit apparent cytotoxicity.

Development and evaluation of a dry powder formulation of liposome-encapsulated oseltamivir phosphate for inhalation.

This study aims to develop oseltamivir phosphate (OP) liposomes as inhalation powders by spray-drying based on the single factor investigation, which was mainly composed of lactose, L-leucine and mannitol. It was found that the ratio of OP and liposomes (1:10), inlet temperature (110 °C) and airflow rate (2.3 mL/min) showed optimized physical properties of OP liposomes. Deposition was evaluated after the aerosolization of powders at 600 L/h via the Aerolizer® into a twin-stage impinger. The concentrations of OP and oseltamivir carboxylate (OSCA) in rats plasma using LC-MS have been determined and performed via pharmacokinetic software DAS 2.0 package. The liposomal OP dry powders displayed an average particle size around 3.5 µm with fine particle fraction (FPF = 35.40%). In vitro evaluation demonstrated a sustained release pattern accounting for 20% drug release compared to that of OP solution up to 90% drug release in 2 h. And the cumulative release percentage was up to 50% in 20 h. Atrioventricular fitting results indicated that all preparations were best fitted with a two-compartment model. There was a significant difference in MRT, Cmax and Tmax (p < 0.01) between the two groups of liposomal OP dry powders and OP solution with t-test, which indicated that the drug released slowly from liposomal OP dry powders in the lung. To sum up, dry powders formulation of liposome-encapsulated OP for inhalation was suitable for pulmonary administration, which offering the opportunity to reduce dosing frequency.

Development of a thermally responsive nanogel based on chitosan-poly(N-isopropylacrylamide-co-acrylamide) for paclitaxel delivery.

A thermally responsive nanogel was developed through the radical polymerization based on chitosan (CTS) and N-isopropylacrylamide (NIPAAm) with acrylamide (AAm) blended to explore the possibility of increasing the volume phase transition temperature (VPTT). The thermally sensitive features of resultant nanogels were studied by determining variance of transmittance and changeable size. The VPTT of the CTS-poly(NIPAAm-co-AAm5.5) nanogel, coplymerized with 5.5% wt. AAm /wt. NIPAAm, was 38 °C in contrast to 32 °C of the CTS-poly(NIPAAm) polymer and the former was studied thereafter. The critical aggregation concentration of CTS-poly(NIPAAm-co-AAm5.5) nanogels was 1.11 µg/mL, much smaller than CTS-poly(NIPAAm) nanogels (5.00 µg/mL). Paclitaxel (PTX) was encapsulated in CTS-poly(NIPAAm-co-AAm5.5) nanogels with loading efficiency of about 9.06 ± 0.195% (n = 3). Thermally responsive PTX in vitro release fromPTX-loaded nanogels was verified. Coumarin-6-loaded nanogels showed thermally responsive cellular uptake because of electrostatic absorptive endocytosis. Furthermore, the half maximal inhibitory concentration of PTX-loaded nanogels was about 2.025 nmol/L, 10-fold improved relative to PTX solutions against SMMC 7721 cells. In vivo, PTX-loaded nanogels presented remarkably higher antitumor efficacy against human colon carcinoma cells HT-29 xenograft nude mice model after intravenous administration. Accordingly, our results reinforced the potential means of CTS-poly(NIPAAm-co-AAm5.5) nanogels for the combination of thermal therapy and chemotherapy.

[Study on preparation of breviscapine liposomes and chemicophysical properties].

OBJECTIVE: To prepare breviscapine pro-liposomes and evaluate its properties and stability, as well as its interaction with the mimic-membrane. METHODS: Breviscapine liposomes were prepared by thin film-lyophilization method. Phase inversion temperature was measured by electrical conductance method and coalescence kinetics was studied. Water/n-octanol trans-membrane diffusion model was designed to study the dynamic distribution behavior between two phases, through the determination of diffusion rate of breviscapine and liposomes. RESULTS: The phase inversion temperature was 63 degrees C, the activity energy for coalescence was 14.66 kJ/mol. The results suggested that breviscapine from liposomes staying on the interface were found more than the breviscapine infusion. CONCLUSION: Breviscapine liposomes prepared with thin film-lyophilization method have good physicochemical properties and stability, which is beneficial to treatment.

[Formulation and process optimization of doxorubicin-loaded PLGA nanoparticles and its in vitro release].

Doxorubicin-loaded PLGA nanoparticles (DOX-PLGA NPs) was prepared by double emulsion (W/O/W) solvent evaporation method with the biodegradable materials-poly (lactic-co-glycolic acid) (PLGA) used as carrier materials. Single-factor test was used to investigate the influence of the type and ratio of the organic phase, the amount of surfactant, PLGA concentration, the ratio of external water phase and oil phase (W/O), the ratio of doxorubicin and PLGA, ultrasonic time and stirring time on the preparation of nanoparticles. The best formulation and preparation conditions were optimized by orthogonal test based on single-factor test, evaluation indicator as particle size and entrapment efficiency, and the results were analyzed by overall desirability. And the in vitro release behaviors of the nanoparticles were studied as well. The size distribution, zeta potential, morphology of DOX-PLGA NPs were characterized by laser light scattering and transmission electron microscopy; encapsulation efficiency and releasing behavior of DOX-PLGA NPs in vitro were investigated by ultraviolet spectrophotometry. The results show that the DOX-PLGA NPs are regularly spherical in shape with the mean size of (189.2 +/- 5.3) nm, and the zeta-potential of the NPs is about (-28.32 +/- 0.52) mV. Drug loading and encapsulation efficiency are estimated to be (73.16 +/- 0.43) % and (1.51 +/- 0.07) %, respectively. The cumulative percentage of the drug released is 90.34%, and the in vitro release behavior made up of initial burst release and sustained-release could be described by the bidirectional kinetic equation. The results indicate that hydrophilic small-molecule drugs could be successfully entrapped into PLGA-NPs. With optimization of the formulation and preparation conditions, we obtained uniform and stable DOX-PLGA NPs with sustained release character in vitro and pH-sensitive property, which could provide the experimental basis for the development of a new anti-tumor sustained-release formulation.

A novel multi-unit tablet for treating circadian rhythm diseases.

This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5-mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit(®) NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease(®) were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases.

A nontoxic disulfide bond reducing method for lipophilic drug-loaded albumin nanoparticle preparation: formation dynamics, influencing factors and formation mechanisms investigation.

The purpose of this study was to establish a novel nontoxic disulfide bond reducing method for lipophilic drug-loaded albumin nanoparticle preparation and make a systematic investigation on this method. Cysteine (Cys) was used to break the disulfide bond of albumin and introduce the self-assembly of drug and albumin. Paclitaxel (PTX) and bovine serum albumin (BSA) were selected to be the model lipophilic drug and albumin. The particle formation dynamics, influencing factors and formation mechanisms were investigated by determining the characteristics of particles including the particle size and yield. Nanoparticles with diameter of 50-400 nm and drug loading efficiency up to 18.3% were prepared successfully. pH 7-8 was suitable for nanoparticle preparation. Temperature, BSA concentration and Cys concentration had positive effects on the particle size and yield. When PTX added was less than the maximal amount of PTX that could bind to BSA, particles with a spherical structure could be formed; otherwise nanoparticles with a core-shell structure could be formed. This novel nontoxic disulfide bond reducing method provides a common and safe method for preparing various kinds of albumin-based nanocarriers for a wide range of applications, from drug (especially the lipophilic drug) delivery to diagnosis of disease.

Evaluation of insulin lispro and biosynthetic human insulin in pulmonary absorption: in vivo and in vitro studies.

OBJECTIVE: To compare the pulmonary absorption characteristics of two insulin solutions-humalog (insulin lispro) and Novolin R (Biosynthetic Human insulin) with in vivo and in vitro methods. METHODS: Investigate the pharmacodynamics in Sprague Dawley (SD) rat model (in vivo studies) and permeability across Rana catesbeiana pulmonary membrane (in vitro studies) of Biosynthetic Human insulin (BHI) and insulin lispro (LI) at different doses. RESULTS: Both of the insulins could reduce blood glucose levels promptly after pulmonary administration. But LI showed a better tendency on hypoglycemic effect than BHI in the in vivo studies. In the in vitro studies, the apparent permeability coefficient (Papp) for BHI and LI were almost constant with increasing concentrations, which implied that insulin maybe passively diffuse through the Rana catesbeiana pulmonary membrane barrier. Interestingly, the Papp of LI was obviously higher than that of BHI, indicating that the permeability of LI across Rana catesbeiana pulmonary membrane was more effective than that of BHI. CONCLUSION: These in vitro and in vivo results suggested that LI was easier to be absorbed in the lung than BHI and Rana catesbeiana pulmonary membrane had a potential ability, as a transport model, to predict in vivo pulmonary absorption of insulin.

Enhanced pulmonary absorption of recombinant human insulin by pulmonary surfactant and phospholipid hexadecanol tyloxapol through Calu-3 monolayers.

Natural pulmonary surfactant (PS) and its artificial substitute phospholipid hexadecanol tyloxapol (PHT) are effective absorption enhancers on promoting recombinant human insulin (Rh-ins) absorption in vivo, but the in vitro efficacy and underlying mechanism remains unclear. In the current study, the permeation promoting effects of PS and PHT of insulin through Calu-3 monolayers in Transwell were evaluated. The viability of Calu-3 cells on conducting the permeation study was confirmed by TER and Electron Microscopy. Both PS and PHT significantly enhanced the permeation of Rh-ins and FD4 through calu-3 cells, with PS having a greater absorption enhancing effect than that of PHT. PS and PHT may interact directly with the tight junctions between cells and then result in intercellular permeation of peptide drugs. LDH release assay showed no significant acute toxicity of PS and PHT. The results indicated that these absorption enhancing agents may be useful as an absorption enhancer for pulmonary delivery of peptide and protein drugs.

An excellent delivery system for improving the oral bioavailability of natural vitamin E in rats.

This study set out to develop a novel and stable nanoemulsion formulation of natural vitamin E with increased oral bioavailability. The natural vitamin E nanoemulsion was prepared by a modified emulsification technique. The physicochemical characteristics of natural vitamin E nanoemulsion were characterized and its pharmacokinetics study was performed as well. The experimental results showed droplet diameters ranging from 20 to 400 nm (average, 87.7 nm) with a negative electrostatic potential (-23.5 ± 1.5 mv). The pharmacokinetics study of this nanoemulsion and corresponding soft capsule was carried out using noncompartment model method. Compared with the marketed soft capsule, the C (max) of the natural vitamin E nanoemulsion was higher, while the T (max) was shorter. Thus, plasma concentration-time profiles in rats dosed with nanoemulsion showed a 1.6-fold enhancement in the area under the curve of natural vitamin E compared with the marketed soft capsule. The antioxidative effects of the natural vitamin E nanoemulsion and the marketed soft capsule were also evaluated by the levels of superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration in serum and liver tissue. According to the SOD activity and the MDA concentration determined, the nanoemulsion was superior to the marketed soft as an antioxidative agent. The overall results demonstrated that the nanoemulsion drug delivery system could be a promising strategy for the delivery of natural vitamin E, which showed great potential for clinical application.

Preparation of cationic biodegradable dextran microspheres loaded with BSA and study on the mechanism of protein loading.

AIM: The aim of this study was to investigate the feasibility of cationic biodegradable dextran microspheres loaded with bovine serum albumin (BSA) posterior to gel formation (postloading). METHOD: Positively charged microspheres were prepared by polymerization of hydroxylethyl methacrylate-derivatized dextran (dex-HEMA) and dimethyl aminoethyl methacrylate (DMAEMA) in an aqueous two-phase system and net positive surface charge increased with increasing amounts of DMAEMA. Loading efficiency of dextran microspheres for BSA was analyzed through fluorescence microscopy and measured. The BSA release from the cationic dextran microspheres in vitro was investigated. RESULTS: BSA could penetrate into cationic dextran microspheres, but neutral dextran microspheres could not. Protein-loading efficiency (98.1--100%) by postloading was higher compared with by preloading (60.2--75.9%), when the incubated protein concentration was below 1.5 mg/ml. Even though BSA is incorporated in the hydrogel network based on electrostatic interaction, a controlled release can be achieved by varying the initial network density of the microspheres. CONCLUSION: These findings suggest that it is a feasible method to prepare dextran microspheres with high surface-charge density to efficiently adsorb oppositely charged protein based on electrostatic interactions.

Importance of powder residence time for the aerosol delivery performance of a commercial dry powder inhaler Aerolizer(®).

BACKGROUND: The performance of dry powder aerosol delivery systems depends not only on the powder formulation but also on the dry powder inhalers (DPIs). Effects of turbulence, grid, mouthpiece, inlet size, air flow, and capsule on the DPIs performance have been investigated previously. Considering powder dispersion in DPIs is a time-dependent process, the powder residence time in DPIs is supposed to have a great impact on DPIs efficiency. This study sought to investigate the effect of powder residence time on the performance of a commercial DPI Aerolizer(®). METHODS: A standard Aerolizer(®) (SD) and five modified devices (MD1, MD2, MD3, MD4, and MD5) were employed for this research. Computational fluid dynamics analysis was used to calculate the flow field and the powder residence time in these devices. Recombinant human interleukin-2 inhalation powders and a twin impinger were used for the deposition experiment. RESULTS: The powder mean residence time in the secondary atomization zone of the devices was increased from 0 ms for SD to 0.33, 0.96, 1.42, 1.76, and 2.14 ms for MD1, MD2, MD3, MD4, and MD5, respectively. At a flow rate of 60 L/min, with an increase in the powder residence time in these devices, a significant gradual and increasing trend in the powder respirable fraction was observed from 29.1%± 1.1% (MD1) to 32.6% ± 2.2% (MD2), 37.1% ± 1.1% (MD3), and 43.7% ± 2.1% (MD4). There was no significant difference in the powder respirable fraction between SD and MD1 or between MD4 and MD5. CONCLUSIONS: Within a certain range, increasing the powder residence time could improve the performance of Aerolizer(®) by increasing the powder-air interaction time (the main reason) and increasing the powder-device compaction (the secondary reason). Combination of high turbulence level and sufficient powder residence time could further improve the device performance.

[Study on the release and mechanism of carbon nanotubes loaded with verapamil hydrochloride in vitro].

OBJECTIVE: The aim of this study was to load Verapamil Hydrochloride to carboxylated multi-walled carbon nanotubes( c-CNTs) and discuss the mechanism of drug release which could act as an effective basis for c-MWNTs used as drug carriers of controlled and sustained release delivery system. METHODS: Raw CNTs were treated with mixed strong acid to obtain c-CNTs. Raman, IR, SEM and HR-TEM were used to characterize the CNTs and investigate the loading sites for drugs. The release behavior of the drug delivery system in vitro and the release model were studied. RESULTS: The raw CNTs were successfully grafted with carboxyl group by acid treatment. The water-soluble ability of c-CNTs was greatly improved. The length of c-CNTs was 200-300nm. Meanwhile, the ends of c-CNTs were opened. The results of the drug loading experiment showed that the more adding drugs, the larger loading content of drugs. Most of the drugs were loaded into the inner pores of c-CNTs when adding drugs was no more than 0.1 as quantity as c-CNTs. As the quantity of adding drugs increased, the drugs were loaded both in the inner pores and on the out-wall of c-CNTs. The release results in vitro showed release mechanism had something with the quantity of adding drugs. CONCLUSION: C-CNTs can be used as carriers of sustained and controlled release delivery system. Ideal release behavior of drugs can be achieved by choosing appropriate formula.

A new mathematical equation for the evaluation of the compression behavior of pharmaceutical materials.

A new mathematical equation characterizing the compression of pharmaceutical materials is presented. This equation presumed that the rate of change of the compressible volume of powder with respect to the pressure is proportional to the compressible volume. The new model provided a good fit to several model substances employing non-linear regression techniques. The validity of the model had been verified with experimental results of various pharmaceutical powders according to the Akaikes informatics criterion (AIC) and the sum of squared deviations (SS). The parameter of the new model might reflect quantitatively the fundamental compression behaviors of the powders. It had demonstrated that the proposed model could well predict the compaction characteristics of solid particles like the Kawakita model.

[Chitosan-coated ophthalmic submicro emulsion for pilocarpine nitrate].

The study is to design chitosan-coated pilocarpine nitrate submicro emulsion (CS-PN/SE) for the development of a novel mucoadhesive submicro emulsion, aiming to prolong the precorneal retention time and improve the ocular absorption. CS-PN/SE was fabricated in two steps: firstly, pilocarpine nitrate submicro emulsion (PN/SE) was prepared by high-speed shear with medium chain triglycerides (MCT) as oil phase and Tween 80 as the main emulsifier, and then incubated with chitosan (CS) acetic solution. The preparation process was optimized by central composite design-response surface methodology. Besides the particle size, zeta potential, entrapment efficiency and micromorphology were investigated, CS-PN/SE's precorneal residence properties and miotic effect were especially studied using New Zealand rabbits as the animal model. When CS-PN/SE was administered topically to rabbit eyes, the ocular clearance and the mean resident time (MRT) of pilocarpine nitrate were found to be dramatically improved (P < 0.05) compared with PN/SE and pilocarpine nitrate solution (PNs), since the K(CS-PN/SE) was declined to 0.006 4 +/- 0.000 3 min(-1) while MRT was prolonged up to 155.4 min. Pharmacodynamics results showed that the maximum miosis of CS-PN/SE was as high as 46.3%, while the miotic response lasted 480 min which is 255 min and 105 min longer than that of PNs and PN/SE, respectively. A larger area under the miotic percentage vs time curve (AUC) of CS-PN/SE was exhibited which is 1.6 folds and 1.2 folds as much as that of PNs and PN/SE, respectively (P < 0.05). Therefore, CS-PN/SE could enhance the duration of action and ocular bioavailability by improving the precorneal residence and ocular absorption significantly.

Relationships between liposome properties, cell membrane binding, intracellular processing, and intracellular bioavailability.

Positive surface charge enhances liposome uptake into cells. Pegylation, used to confer stealth properties to enable in vivo applications of cationic liposomes, compromises internalization. The goal of this study was to determine the quantitative relationships between these two liposome properties (separately and jointly), liposomes binding to cell membrane, and the subsequent internalization and residence in intracellular space (referred to as intracellular bioavailability). The results, obtained in pancreatic Hs-766T cancer cells, revealed nonlinear and inter-dependent relationships, as well as substantial qualitative and quantitative differences. The proportionality constant K of intracellular and membrane-bound liposomes at equilibrium (i.e., I(eq) and B(eq)) showed a positive triphasic relationship with surface charge and a negative biphasic relationship with pegylation. Near-neutral liposomes showed little internalization of the membrane-bound moiety, increasing to a constant K value for medium charge liposomes (+15 to +35 mV zeta potential), followed by a further increase for highly charged liposomes (greater than or equal to +46 mV). The decline of pegylation with K value showed a breakpoint at 2%. The negative consequences of pegylation (%PEG) were partially offset by increasing charge (ZP). The best-fitting regression equations are: B(eq) = -1.36 × %PEG + 0.33 × ZP; I(eq) = -1.52 × %PEG + 0.34 × ZP. It suggested that 1% pegylation increase can be offset with 4 mV ZP. The differences are such that it may be possible to balance these parameters to simultaneously maximize the stealth property and intracellular bioavailability of cationic liposomes.

Preparation and evaluation of glyceryl monooleate-coated hollow-bioadhesive microspheres for gastroretentive drug delivery.

The purpose of this study was to produce hollow and bioadhesive microspheres to lengthen drug retention time in the stomach. In these microspheres, ethylcellulose was used as the matrix, Eudragit EPO was employed to modulate the release rate, and glyceryl monooleate (GMO) was the bioadhesive polymer in situ. The morphological characteristics of the microspheres were defined using scanning electron microscopy. The in vitro release test showed that the release rate of drug from the microspheres was pH-dependent, and was not influenced by the GMO coating film. The prepared microspheres demonstrated strong mucoadhesive properties with good buoyancy both in vitro and in vivo. Pharmacokinetic analysis indicated that the elimination half-life time of the hollow-bioadhesive microspheres was prolonged, and that the elimination rate was decreased. In conclusion, the hollow-bioadhesive synergic drug delivery system may be advantageous in the treatment of stomach diseases.