Study on Electrical Performance of a U-Type Microfluidic Acceleration Switch Using Salt Solution as the Sensitive Electrode.

The threshold of microfluidic inertial switch is excessively dependent on the size of the passive valve structure and the gas-liquid surface energy of working liquid. How to achieve high threshold and anti-high overload using liquid with low viscosity and low surface tension is a challenging work. Based on the designed U-type microfluidic inertial switch, the electrical characteristic of salt solution at microscale as well as the threshold and dynamic electrical performance of switch were studied. The VOF and CSD modules in CFD software were employed to analyze the dynamic flow process, and then the air-liquid surface moving displacement curve was compared by the theoretical model. A self-designed acceleration test platform was utilized to measure the static threshold, dynamic threshold, and anti-high overload of the inertial switch. The results show that the U-type microfluidics inertial switch using salt solution as sensitive electrode has better performance in power connection and anti-high overload. In particular, it also has the ability to achieve a range of dynamic threshold by changing the placement of the contact electrode, which can achieve rapid power on and off.

[Clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis].

OBJECTIVE: To study the clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis and its effect on T lymphocyte subsets. METHODS: A total of 76 children with infectious mononucleosis, who were admitted to the hospital between July 2016 and June 2017, were enrolled and randomly divided into two groups: conventional treatment and pidotimod treatment (n=38 each). The children in the conventional treatment group were given antiviral therapy with ganciclovir for injection and symptomatic treatment. Those in the pidotimod treatment group were given pidotimod oral liquid in addition to the treatment in the conventional treatment group. The course of treatment was two weeks for both groups. The two groups were compared in terms of the recovery of clinical indices and the changes in peripheral blood T lymphocyte subsets. RESULTS: Compared with the conventional treatment group, the pidotimod treatment group had significantly shorter fever clearance time, time to the disappearance of isthmopyra, time to the relief of lymph node enlargement, time to the relief of hepatosplenomegaly, and length of hospital stay (P<0.05). After treatment, the pidotimod treatment group had significant reductions in the percentages of CD3+ and CD8+ T cells and had significantly lower percentages of CD3+ and CD8+ T cells than the conventional treatment group (P<0.001). The pidotimod treatment group had significant increases in the percentage of CD4+ T cells and CD4+/CD8+ ratio after treatment, which was significantly higher than those in the conventional treatment group (P<0.001). The conventional treatment group had no significant changes in T lymphocyte subsets after treatment (P>0.05). CONCLUSIONS: Pidotimod oral liquid has a good clinical effect as the adjuvant therapy for infectious mononucleosis and can improve cellular immune function, so it holds promise for clinical application.

Development of an LC-MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound.

Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO-HCT-high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine.

Rheological characterization of cataplasm bases composed of cross-linked partially neutralized polyacrylate hydrogel.

Viscoelasticity is a useful parameter for characterizing the intrinsic properties of the cross-linked polyacrylate hydrogel used in cataplasm bases. The aim of this study was to investigate the effects of various formulation parameters on the rheological characteristics of polyacrylate hydrogel. The hydrogel layers were formed using a partially neutralized polyacrylate (Viscomate(™)), which contained acrylic acid and sodium acrylate in different copolymerization ratios, as the cross-linked gel framework. Dihydroxyaluminum aminoacetate (DAAA), which produces aluminum ions, was used as the cross-linking agent. Rheological analyses were performed using a "stress amplitude sweep" and a "frequency sweep". The results showed that greater amounts of acrylic acid in the structure of Viscomate as well as higher concentrations of DAAA and Viscomate led to an increase in the elastic modulus (G'). However, greater amounts of acrylic acid in the structure of Viscomate and higher concentrations of DAAA had an opposite on the viscous modulus (G″); this might be owing to higher steric hindrance. The results of this study can serve as guidelines for the optimization of formulations for cataplasms.

Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency.

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 µm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery.

Study on Structural Design and Motion Characteristics of Magnetic Helical Soft Microrobots with Drug-Carrying Function.

Magnetic soft microrobots have a wide range of applications in targeted drug therapy, cell manipulation, and other aspects. Currently, the research on magnetic soft microrobots is still in the exploratory stage, and most of the research focuses on a single helical structure, which has limited space to perform drug-carrying tasks efficiently and cannot satisfy specific medical goals in terms of propulsion speed. Therefore, balancing the motion speed and drug-carrying performance is a current challenge to overcome. In this paper, a magnetically controlled cone-helix soft microrobot structure with a drug-carrying function is proposed, its helical propulsion mechanism is deduced, a dynamical model is constructed, and the microrobot structure is prepared using femtosecond laser two-photon polymerization three-dimensional printing technology for magnetic drive control experiments. The results show that under the premise of ensuring sufficient drug-carrying space, the microrobot structure proposed in this paper can realize helical propulsion quickly and stably, and the speed of motion increases with increases in the frequency of the rotating magnetic field. The microrobot with a larger cavity diameter and a larger helical pitch exhibits faster rotary advancement speed, while the microrobot with a smaller helical height and a smaller helical cone angle outperforms other structures with the same feature sizes. The microrobot with a cone angle of 0.2 rad, a helical pitch of 100 µm, a helical height of 220 µm, and a cavity diameter of 80 µm achieves a maximum longitudinal motion speed of 390 µm/s.

Single- and multiple-dose pharmacokinetics of a novel tetramethylpyrazine reservoir-type transdermal patch versus tetramethylpyrazine phosphate oral tablets in healthy normal volunteers, and in vitro/in vivo correlation.

A novel reservoir-type transdermal system of 2,3,5,6-tetramethylpyrazine (TMP) was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. 2,3,5,6-Tetramethylpyrazine phosphate (TMPP) oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP C(max) of 1284/613.5 ng/mL was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean C(max) of 309/325 ng/mL at a median T(max) of 5/4 h, with steady state achieved at second application. The mean C(min) of the patch was 131±30.38 ng/mL, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm(2) TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/mL). TMP tablets and patch yielded similar steady-state plasma concentrations: C(av) (148.48±51.27, 156.41±40.31 ng/mL). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 µg/cm(2)/h. The predicted C(av) (163.9 ng/mL) was in agreement with the observed C(av) (156.4 ng/mL).

Tacrolimus nanocrystals microneedle patch for plaque psoriasis.

Plaque psoriasis is characterized by an abnormal thickening of the epidermis, which causes great difficulties for traditional topical drug delivery. Microneedles can pierce the thickened epidermis and deliver drugs to the skin for psoriasis treatment. Tacrolimus is a poorly water-soluble immunosuppressant used for the treatment of psoriasis. In this study, tacrolimus (TAC) nanocrystals (NCs) were produced using a bottom-up technique that dispersed TAC into a sodium hyaluronate-based microneedle patch (MNP), and its therapeutic efficacy was evaluated. The average particle size of the TAC NCs was 259.6 ± 2.3 nm. The mechanical strength of the microneedles was 0.41 ± 0.06 N/needle, which was sufficient to penetrate psoriatic skin. Microneedles were detached from the substrate 10 min after insertion into the psoriasis skin with an insertion depth of 258.8 ± 14.4 µm. The intradermal retention of the MNP (8.40 ± 0.33 µg/cm2) was six times that of the commercial ointment (1.40 ± 0.12 µg/cm2). In pharmacodynamic experiments, results indicated improvement in the phenotypic and histopathological features and reduction in the level of TNF-α, IL-17A, and IL-23 of psoriatic skin treated with TAC NCs MNP. Therefore, MNP loaded with TAC NCs may be a promising approach for psoriasis treatment.

Microneedle patch-assisted transdermal administration of recombinant hirudin for the treatment of thrombotic diseases.

The painless microneedle patch (MNP), widely explored for transdermal drug delivery of macromolecules, can overcome the limitations of traditional administrations of protein and polypeptide anticoagulant drugs. We constructed a recombinant hirudin-loaded microneedle patch, suitable for patients with thrombotic diseases requiring long-term preventive medication. The recombinant hirudin-loaded dissoluble microneedle patch (RHDMNP) was created using a mold casting technique and polyvinylpyrrolidone and polyvinyl alcohol were used as the matrix material with a 1:1.2 ratio. We prepared bilayer RHDMNPs with pyramidal appearance and 0.37 N/needle strength. The intradermal dissolution height of the microneedle reached approximately 78.67% of the total height, and 68.12% of the drug was delivered into the skin. The 12-hour cumulative permeation of the MNP was 21.69 ± 3.90 µg/cm2. The MNP showed a Tmax of 1.5 h, Cmax of 144 ± 71 ng/mL, and area under curve (AUC) of 495 ± 66 ng/mL·min compared to Tmax of 0.5 h, Cmax of 249 ± 89 ng/mL, and AUC of 944 ± 65 ng/mL·min for the subcutaneous injection group. Both in vivo and in vitro experiments showed that the RHDMNP exerted effective anticoagulant effects, prevented the incidence of acute pulmonary embolism, and revealed the potential for venous thrombosis prevention.

Experimental evaluation of DPF performance loaded over Pt and sulfur-resisting material for marine diesel engines.

Different from vehicle engines, Diesel Particulate Filter (DPF) inactivation is an unavoidable issue for low-speed marine diesel engines fueled with Heavy Fuel Oil (HFO). This paper introduced a sulfur resisting material in Silicon Carbide (SiC)-DPF to improve DPF performance. The results of bench-scale experiments showed that the Balance Point Temperature of the modified DPF module was 300°C and DPF modules had a good filtration performance, with Particulate Matters (PMs) residual being less than 0.6 g per cycle. In pilot-scale tests, PMs emissions of unit power decreased with engine load going up, filtration efficiency of nucleation mode PMs being only 36% under 100% load, while DPF still had a good performance in accumulation mode PMs control, being 94.2% under the same load. DPF modules showed excellent regeneration durability in the 205h endurance test, with a regeneration period of 1.5-2h under 380°C. There was no obvious degeneration in the DPF module structure, with no cracks or breakage. Besides, the DPF module could also control gaseous emissions, total emissions decreased by 10.53% for NO and 57.19% for CO, respectively. The results suggested that introducing sulfur-resisting material in DPF could greatly improve the DPF performance of low-speed marine diesel engines fueled with HFO.

The reference genome of camellia chekiangoleosa provides insights into camellia evolution and tea oil biosynthesis.

Camellia oil extracted from Camellia seeds is rich in unsaturated fatty acids (UFAs) and secondary metabolites beneficial to human health. However, no oil-tea tree genome has yet been published, which is a major obstacle to investigating the heredity improvement of oil-tea trees. Here, using both Illumina and PicBio sequencing technologies, we present the first chromosome-level genome sequence of the oil-tea tree species Camellia chekiangoleosa Hu. (CCH). The assembled genome consists of 15 pseudochromosomes with a genome size of 2.73 Gb and a scaffold N50 of 185.30 Mb. At least 2.16 Gb of the genome assembly consists of repetitive sequences, and the rest involves a high-confidence set of 64 608 protein-coding gene models. Comparative genomic analysis revealed that the CCH genome underwent a whole-genome duplication (WGD) event shared across the Camellia genus at ~57.48 MYA and a γ-WGT event shared across all core eudicot plants at ~120 MYA. Gene family clustering revealed that the genes involved in terpenoid biosynthesis have undergone rapid expansion. Furthermore, we determined the expression patterns of oleic acid accumulation- and terpenoid biosynthesis-associated genes in six tissues. We found that these genes tend to be highly expressed in leaves, pericarp tissues, roots, and seeds. The first chromosome-level genome of oil-tea trees will provide valuable resources for determining Camellia evolution and utilizing the germplasm of this taxon.

Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease.

Cardiovascular disease is the leading cause of global mortality, with anticoagulant therapy being the main prevention and treatment strategy. Recombinant hirudin (r-hirudin) is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous (SC) and intravenous (IV) administration, but there is a risk of haemorrhage via SC and IV. Thus, microneedle (MN) provides painless and sanitary alternatives to syringes and oral administration. However, the current technological process for the micro mould is complicated and expensive. The micro mould obtained via three-dimensional (3D) printing is expected to save time and cost, as well as provide a diverse range of MNs. Therefore, we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch. The results show that r-hirudin-loaded and hyaluronic acid (HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models. These results indicate that based on 3D printing technology, MNs combined with r-hirudin are expected to achieve diverse customizable MNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

[Intestinal lymphatic transport of breviscapine orally administered in rat].

Double cannulation model of conscious rat allowing simultaneous collection of mesenteric lymph and jugular venous blood was established to investigate the intestinal lymphatic transport of breviscapine orally administered in rat. The concentrations of breviscapine in plasma and lymph were determined by HPLC. The pharmacokinetics of breviscapine after oral and intravenous administration was evaluated in the conscious rat model. It was observed that scutellarin distributed from blood circulation to lymphatic system after intravenous injection. The cumulative lymphatic transport amount within 12 h was (2.78 +/- 0.25) microg, equivalent to 0.0792% of intravenous dose. After oral administration of scutellarin to double-cannulation rats, the cumulative lymphatic transport amount within 12 h was (0.92 +/- 0.08) microg, equal to 0.0083% of oral dose. The absolute bioavailability of breviscapine orally administered to double-cannulation rats was 4.91%, indicating that scutellarin was mainly absorbed into the bloodstream through the portal vein. Lymphatic transport of scutellarin appears to reflect high affinity for the lymph lipoproteins to chylomicron. This study provided a biopharmaceutics basis for developing oral lipid delivery system for the promotion of intestinal lymphatic transport to improve oral bioavailability of breviscapine.

CFRP Origami Metamaterial with Tunable Buckling Loads: A Numerical Study.

Origami has played an increasingly central role in designing a broad range of novel structures due to its simple concept and its lightweight and extraordinary mechanical properties. Nonetheless, most of the research focuses on mechanical responses by using homogeneous materials and limited studies involving buckling loads. In this study, we have designed a carbon fiber reinforced plastic (CFRP) origami metamaterial based on the classical Miura sheet and composite material. The finite element (FE) modelling process's accuracy is first proved by utilizing a CFRP plate that has an analytical solution of the buckling load. Based on the validated FE modelling process, we then thoroughly study the buckling resistance ability of the proposed CFRP origami metamaterial numerically by varying the folding angle, layer order, and material properties, finding that the buckling loads can be tuned to as large as approximately 2.5 times for mode 5 by altering the folding angle from 10° to 130°. With the identical rate of increase, the shear modulus has a more significant influence on the buckling load than Young's modulus. Outcomes reported reveal that tunable buckling loads can be achieved in two ways, i.e., origami technique and the CFRP material with fruitful design freedoms. This study provides an easy way of merely adjusting and controlling the buckling load of lightweight structures for practical engineering.

Hyalase-Mediated Cascade Degradation of a Matrix Barrier and Immune Cell Penetration by a Photothermal Microneedle for Efficient Anticancer Therapy.

For melanoma with high lethality and metastasis rate, traditional therapy has limited effects; local photothermal therapy (PTT) synergetic with immune therapy for cancer treatment can perhaps improve the situation. However, because of the natural existence of the tumor matrix barrier, the penetration depth of drugs and immune cells often dampens the efficacy of cancer treatment. Herein, we report an innovative synergetic PTT and immune therapy through dissolving microneedles for the codelivery of the hyaluronidase-modified semiconductor polymer nanoparticles containing poly(cyclopentadithiophene-alt-benzothiadiazole) and immune adjuvant polyinosinic-polycytidylic acid (PIC). Benefiting from the dissolution of an extracellular matrix of hyaluronidase, the semiconductor polymer nanoparticles and PIC penetrate the tumor deeply, under synergetic therapy with PTT, activating the immune cells and enhancing the T-cell immune response for inhibition of tumor growth and metastasis. This study provides a promising platform for effective melanoma treatment and a novel strategy to overcome the stromal barrier.

Inter-laboratory study of the skin distribution of 4-n-butyl resorcinol in ex vivo pig and human skin.

4-n-butyl resorcinol (4-nBR) is a highly effective tyrosinase inhibitor, and can be used in cosmetic product for depigmentation purpose. Its efficacy correlates with 4-nBR that absorbed by skin. In this study, skin distribution of 4-nBR within either human or pig skin ex vivo was studied and compared by three independent laboratories. Good agreement was observed in each compartment considering usual inter-lab variability. This study supports the use of pig skin as an alternative source of skin when the availability of human skin is a limiting factor.

Determination of palmatine in canine plasma by liquid chromatography-tandem mass spectrometry with solid-phase extraction.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method has been developed and validated for the determination of palmatine in canine plasma. Palmatine and jatrorrhizine (internal standard, I.S.) were extracted from plasma samples by solid-phase extraction (SPE) using Oasis HLB cartridges. The chromatographic separation was performed on a Waters XTerra MS C(18) reversed-phase column at 30 degrees C. The gradient mobile phase, delivered at 0.25 mL/min, was composed of a mixture of acetonitrile -0.1% (v/v) acetic acid aqueous solution adjusted to pH 2.8 with triethylamine. Positive electrospray ionization was utilized as the ionization source. Palmatine and the internal standard (I.S.) were determined using multiple reaction monitoring (MRM) of precursor-->product ion transitions at m/z 352-->336 and m/z 338-->322, respectively. The lower limit of quantification (LLOQ) was 0.1 ng/mL using 100 microL plasma samples and the linear calibration range was from 0.1 to 500 ng/mL. The inter-day and intra-day RSDs were lower than 9.9% and the recoveries of palmatine ranged from 87.3 to 100.9%. The mean extraction recoveries of palmatine and the I.S. were 99.2 and 96.8%, respectively. The method has been successfully applied to the pharmacokinetic studies of palmatine in beagle dogs after oral administration and intramuscular injection of palmatine.

Pluronic F127 and D-α-Tocopheryl Polyethylene Glycol Succinate (TPGS) Mixed Micelles for Targeting Drug Delivery across The Blood Brain Barrier.

A novel polymeric mixed micelle composed of Pluronic F127 and D-α-tocopheryl polyethylene glycol succinate (TPGS) was developed to improve the delivery of fluorescent dyes and protein across the blood brain barrier (BBB). Rhodamine 123 (Rho123) and DiR loaded mixed micelles, composed of Pluronic F127 and TPGS with proportion of 4:1 (FT), were prepared by thin-film hydration, and ß-galactosidase (ß-Gal) loaded FT mixed micelles were prepared by self-assembly. The brain-targeted capability of FT mixed micelles were evaluated both in vitro and in vivo. The FT mixed micelles showed that a average particle size of 20.03 nm, and a low CMC of 0.0031% in water. The in vitro release of Rho123 from Rho123 loaded FT mixed micelles (FT/Rho123) presented a sustained-release property. FT/Rho123 also showed higher efficiency for the accumulation in brain capillary endothelial cells (BCECs) and brain tissues. ß-Gal, a model protein, was also delivered and accumulated efficiently in the brain by spontaneous loading in the FT mixed micelles. Therefore, the results indicated that F127/TPGS mixed micelles may be considered as an effective nanocarrier for the brain-targeted delivery of diagnostic and therapeutic drugs.

Lymphatic transport of orally administered probucol-loaded mPEG-DSPE micelles.

CONTEXT: Transporting drugs through the lymphatic system has attracted increasing attention. Lipid-based formulations have been proved to be an effective way to improve systemic bioavailability of highly lipophilic drugs by increasing intestinal lymphatic transport. OBJECTIVE: The formulation of polymer micelle was developed for probucol to improve its intestinal lymphatic transport. MATERIALS AND METHODS: Methoxy-polyethylenelglycol-distearyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer was chosen to develop the micelles for probucol. The physicochemical properties were characterized. Caco-2 cell model, unconscious and conscious lymph duct cannulated rat models were established for in vitro and in vivo evaluation of lymphatic transport. RESULTS: In vitro evaluation in the Caco-2 cell model showed that the micellar formulation could significantly increase the uptake and transport of probucol. The study in unconscious and conscious lymph duct cannulated rat models further verified the significant enhancement of lymphatic transport of probucol by mPEG-DSPE micelles. DISCUSSION AND CONCLUSION: These results suggested that mPEG-DSPE micellar formulation could provide a useful alternative approach for improving the lymphatic transport of hydrophobic compounds.

Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats.

The present study examined the effects of lipid vehicle and intestinally based efflux processes on intestinal lymphatic transport of paclitaxel (PTX) in the mesenteric lymph duct-cannulated anesthetized rat model. PTX solution alone, PTX solution pretreated with the P-glycoprotein (P-gp) inhibitor verapamil and/or PTX and a 2:1 (w/w) mixture of linoleic acid:glycerol monooleate were administered intraduodenally to anesthetized rats. Coadministration of a mixture of linoleic acid-monoolein significantly increased the extent of intestinal lymphatic transport of PTX, but it had little impact on the absolute oral bioavailability of PTX. In contrast, pretreatment with verapamil increased both the extent of lymphatic transport (3.5-fold) and absolute oral bioavailability (1.8-fold). Further increase in the lymphatic transport (6.5-fold) and absolute oral bioavailability (1.8-fold) was achieved by the combination of pretreatment with verapamil and coadministration with the linoleic acid-monoolein mixture. These data indicate that the application of lipid vehicle holds promise for selectively targeted lymphatic delivery of PTX. P-gp inhibition can result in both increased intestinal lymphatic levels and absolute oral bioavailability of PTX.