Baicalin/ambroxol hydrochloride combined dry powder inhalation formulation targeting lung delivery for treatment of idiopathic pulmonary fibrosis: Fabrication, characterization, pharmacokinetics, and pharmacodynamics.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal lung disease caused by multiple factors. Currently, safe, and effective drugs for the treatment of IPF have been extremely scarce. Baicalin (BA) is used to treat pulmonary fibrosis, IPF, chronic obstructive pulmonary disease, and other lung diseases. Ambroxol hydrochloride (AH), a respiratory tract lubricant and expectorant, is often used to treat chronic respiratory diseases, such as bronchial asthma, emphysema, tuberculosis, and cough. The combination of BA and AH can relieve cough and phlegm, improve lung function, and potentially treat IPF and its symptoms. However, given the extremely low solubility of BA, its bioavailability for oral absorptions is also low. AH, on the other hand, has been associated with certain side effects, such as gastrointestinal tract and acute allergic reactions, which limit its applicability. Therefore, an efficient drug delivery system is urgently needed to address the mentioned problems. This study combined BA and AH as model drugs with L-leucine (L-leu) as the excipient to prepare BA/AH dry powder inhalations (BA/AH DPIs) using the co-spray drying method. We the performed modern pharmaceutical evaluation, which includes particle size, differential scanning calorimetry analysis, X-ray diffraction, scanning electron microscope, hygroscopicity, in vitro aerodynamic analysis, pharmacokinetics, and pharmacodynamics. Notably, BA/AH DPIs were found to be advantageous over BA and AH in treating IPF and had better efficacy in improving lung function than did the positive drug pirfenidone. The BA/AH DPI is a promising preparation for the treatment of IPF given its lung targeting, rapid efficacy, and high lung bioavailability.

The Flavonoid Components of Scutellaria baicalensis: Biopharmaceutical Properties and their Improvement using Nanoformulation Techniques.

Scutellaria baicalensis georgi, known as "Huangqin" in its dried root form, is a herb widely used in traditional Chinese medicine for "clearing away heat, removing dampness, purging fire and detoxification". Baicalin, baicalein, wogonin, and wogonoside are the main flavonoid compounds found in Scutellaria baicalensis. Scutellaria baicalensis flavonoid components have the potential to prevent and treat a host of diseases. The components of S. baicalensis have limited clinical application due to their low water solubility, poor permeability, and microbial transformation in vivo. Nanopharmaceutical techniques can improve their biopharmaceutical properties, enhance their absorption in vivo, and improve their bioavailability. However, due to the limited number of clinical trials, doubts remain about their toxicity and improvements in human absorption as a result of nanoformulations. This review summarizes the latest and most comprehensive information regarding the absorption, distribution, metabolism, and excretion of the Scutellaria baicalensis components in vivo. We examined the main advantages of nanodrug delivery systems and collected detailed information on the nanosystem delivery of the Scutellaria baicalensis components, including nanosuspensions and various lipid-based nanosystems. Lipid-based systems including liposomes, solid lipid nanoparticles, nanoemulsions, and self-micro emulsifying drug delivery systems are introduced in detail. In addition, we make recommendations for related and future research directions. Future research should further examine the absorption mechanisms and metabolic pathways of nanoformulations of the components of Scutellaria baicalensis in vivo, and accurately track the in vivo behavior of these drug delivery systems to discover the specific reasons for the enhanced bioavailability of nanoformulations of the scutellaria baicalensis components. The development of targeted oral administration of intact nanoparticles of Scutellaria baicalensis components is an exciting prospect.

The anti-tumor and renoprotection study of E-[c(RGDfK)2]/folic acid co-modified nanostructured lipid carrier loaded with doxorubicin hydrochloride/salvianolic acid A.

BACKGROUND: Poor in vivo targeting of tumors by chemotherapeutic drugs reduces their anti-cancer efficacy in the clinic. The discovery of over-expressed components on the tumor cell surface and their specific ligands provide a basis for targeting tumor cells. However, the differences in the expression levels of these receptors on the tumor cell surface limit the clinical application of anti-tumor preparations modified by a single ligand. Meanwhile, toxicity of chemotherapeutic drugs leads to poor tolerance to anti-tumor therapy. The discovery of natural active products antagonizing these toxic side effects offers an avenue for relieving cancer patients' pain during the treatment process. Since the advent of nanotechnology, interventions, such as loading appropriate drug combinations into nano-sized carriers and multiple tumor-targeting functional modifications on the carrier surface to enhance the anti-tumor effect and reduce toxic and side effects, have been widely used for treating tumors. RESULTS: Nanocarriers containing doxorubicin hydrochloride (DOX) and salvianolic acid A (Sal A) are spherical with a diameter of about 18 nm; the encapsulation efficiency of both DOX and salvianolic acid A is greater than 80%. E-[c(RGDfK)2]/folic acid (FA) co-modification enabled nanostructured lipid carriers (NLC) to efficiently target a variety of tumor cells, including 4T1, MDA-MB-231, MCF-7, and A549 cells in vitro. Compared with other preparations (Sal A solution, NLC-Sal A, DOX solution, DOX injection, Sal A/DOX solution, NLC-DOX, NLC-Sal A/DOX, and E-[c(RGDfK)2]/FA-NLC-Sal A/DOX) in this experiment, the prepared E-[c(RGDfK)2]/FA-NLC-Sal A/DOX had the best anti-tumor effect. Compared with the normal saline group, it had the highest tumor volume inhibition rate (90.72%), the highest tumor weight inhibition rate (83.94%), led to the highest proportion of apoptosis among the tumor cells (61.30%) and the lowest fluorescence intensity of proliferation among the tumor cells (0.0083 ± 0.0011). Moreover, E-[c(RGDfK)2]/FA-NLC-Sal A/DOX had a low level of nephrotoxicity, with a low creatinine (Cre) concentration of 52.58 µmoL/L in the blood of mice, and no abnormalities were seen on pathological examination of the isolated kidneys at the end of the study. Sal A can antagonize the nephrotoxic effect of DOX. Free Sal A reduced the Cre concentration of the free DOX group by 61.64%. In NLC groups, Sal A reduced the Cre concentration of the DOX group by 42.47%. The E-[c(RGDfK)2]/FA modification reduced the side effects of the drug on the kidney, and the Cre concentration was reduced by 46.35% compared with the NLC-Sal A/DOX group. These interventions can potentially improve the tolerance of cancer patients to chemotherapy. CONCLUSION: The E-[c(RGDfK)2]/FA co-modified DOX/Sal A multifunctional nano-drug delivery system has a good therapeutic effect on tumors and low nephrotoxicity and is a promising anti-cancer strategy.

The Nanostructured lipid carrier gel of Oroxylin A reduced UV-induced skin oxidative stress damage.

Oxidative stress damage caused by sun exposure damages the appearance and function of the skin, which is one of the essential inducements of skin aging and even leads to skin cancer. Oroxylin A (OA) is a flavonoid with excellent antioxidant activity and has protective effects against photoaging induced by UV irradiation. However, the strong barrier function of the skin stratum corneum prevents transdermal absorption of the drug, which limits the application of OA in dermal drug delivery. Studies have shown that nanostructured lipid carriers (NLC) can promote not only transdermal absorption of drugs but also increase drug stability and control drug release efficiency, which has broad prospects for clinical applications. In this paper, NLC loaded with OA (OA-NLC) was prepared in order to improve the skin permeability and stability of OA. In vitro studies revealed that OA-NLC had better therapeutic effects than OA solution (OA-Sol) in the cellular model of UVB radiation. OA-Sol and OA-NLC were immobilized in a hydrogel matrix to facilitate application to the dorsal skin of mice. It was found that OA-NLC-gel showed significant antioxidant and anti-apoptotic activity compared to OA-Sol-gel, which was able to protect against skin damage in mice after UV radiation. These results suggest that OA-NLC can improve the deficiencies of OA in skin delivery and show better resistance to UV-induced oxidative damage. The application of OA-NLC to skin delivery systems has good prospects and deserves further development and investigation.

Baicalin-berberine complex nanocrystals orally promote the co-absorption of two components.

Baicalin (BA)-berberine (BBR) have been proposed as the couple in the prevention and treatment of numerous diseases due to their multiple functional attributes. However, with regard to certain factors involving unsatisfactory aqueous solubility and low bioavailability associated with its clinical application, there is need for continuous researches by scientist. In this study, after successfully preparing BA-BBR complex, BA-BBR complex nanocrystals were obtained through high-pressure homogenization and evaluated (in vitro and in vivo). The particle size, distribution, morphology, and crystalline properties for the optimal BA-BBR complex nanocrystals were characterized by the use of scanning electron microscope, dynamic light scattering, powder X-ray diffraction, and differential scanning calorimetry. The particle size and poly-dispersity index of BA-BBR complex nanocrystals were 318.40 ± 3.32 nm and 0.26 ± 0.03, respectively. In addition, evaluation of the in vitro dissolution extent indicated that BA and BBR in BA-BBR complex nanocrystals were 3.30- and 2.35-fold than BA-BBR complex. Subsequently, single-pass intestinal perfusion combined with microdialysis test and oral pharmacokinetics in SD rats was employed to evaluate the in vivo absorption improvement of BA-BBR complex nanocrystals. The pharmacokinetics results exhibited that the area under curve of BA and BBR in the BA-BBR complex nanocrystals group were 622.65 ± 456.95 h·ng/ml and 167.28 ± 78.87 h·ng/ml, respectively, which were separately 7.49- and 2.64-fold than the complex coarse suspension. In conclusion, the above results indicate that the developed and optimized BA-BBR complex nanocrystals could improve the dissolution rate and extent and oral bioavailability, as well as facilitate the co-absorption of the drug prescriptions BA and BBR.

Natural medicine combined with nanobased topical delivery systems: a new strategy to treat psoriasis.

Psoriasis, an autoimmune inflammatory skin disorder, is one of the commonest immune-mediated disease conditions affecting individuals globally. At the moment, the conventional methods applied against psoriasis treatment have various drawbacks involving limited efficacy, skin irritation, immunosuppression, etc. Therefore, it is important for scientists to find a more potent and alternative drug approach towards psoriasis therapeutics. Natural medicine still remains an important source for new drug discovery due to its therapeutical significance in various drug administration routes. However, the traditional formulation of topical therapies for psoriasis is limited in efficacy, which limits the use of natural medicine. Based on the aforementioned limitations, the use of nanocarriers in preparation of these topical herbal products could be tremendously beneficial in enhancing the efficacy of topical medications. Growing pieces of evidence have proposed that the utilization of nanocarriers in transdermal preparation as a prospective technique, with regards to better potency, directs drug absorption to site of action, and minimum toxicity effect respectively. In the course of this review, we emphasized the pathological mechanism of psoriasis, natural medicine formula, active components of natural medicine, and nanopreparations used in the treatment of psoriasis.

In vitro skin retention and drug permeation study of Tongluo-Qutong rubber plaster by UPLC/UV/MS/MS

Abstract Tongluo-Qutong rubber plaster (TQRP), a typical Chinese patent medicine that contains 13 different herbal remedies, is widely used in clinical practice for the treatment of cervical spondylosis and osteoarthritis. However, due to a lack of in vitro transdermal studies, the active ingredients of TQRP have not been fully elucidated. This presents a huge obstacle for quality evaluation, pharmacokinetic studies and clinical safety assessment of TQRP. In this work, a UPLC/UV/MS/MS method was established and validated to evaluate five analytes in TQRP. The validation demonstrated linearity (r > 0.99), specificity (no co-eluting peaks at the retention times of the analytes), and precision (RSD < 15%) within acceptable parameters. A skin permeation study was performed to determine the concentrations of drugs delivered to the dermis. The 24-hour cumulative permeation of ferulic acid, aleo-emodin, emodin and piperine were 303.68, 709.31, 671.06 and 25561.01 ng/cm2, respectively. According to the fitting data of the TQRP active components, skin permeation was mainly due to a combination of passive diffusion and drug release after matrix erosion

Development and evaluation studies of Corylin loaded nanostructured lipid carriers gel for topical treatment of UV-induced skin aging.

We prepared nanostructured lipid carriers (NLC) to promote skin permeation of Corylin so that it can increase its effect on photoaging. Corylin-NLCs were prepared and characterized based on morphology, particle size, zeta potentials, FTIR and DSC. In vitro, we assess the cytotoxicity and lactate dehydrogenase (LDH) of HaCaT cells irradiated by UVB. Expression of antioxidant enzymes was evaluated by commercial kits. The effects of Corylin-NLC on apoptosis were confirmed by flow cytometry and western blotting. In vivo, we use UV irradiated mouse as the oxidative stress model to assess the therapeutic effect of Corylin loaded NLC gel. We identified the Corylin-NLCs can significantly suppress the LDH release, decrease MDA content, increase in CAT, SOD, GSH-Px activity, increase the expression of Bcl-2/Bax protein and reduce the expression of cleaved caspase-3/caspase-3 protein on UVB induced HaCaT cells. The histopathological lesions were significantly improved and observably decreased MDA level, increase in antioxidant enzymes activity in serum of mice by pretreatment of Corylin-NLCs gel. Overall, this study proposes a promising strategy for improving the therapeutic efficacy of photoaging.

Enhanced Anticancer Efficacy of Dual Drug-Loaded Self-Assembled Nanostructured Lipid Carriers Mediated by pH-Responsive Folic Acid and Human-Derived Cell Penetrating Peptide dNP2.

The poor ability of recognition and penetration of chemotherapeutic agents to tumor cells are still great challenges for targeted breast cancer treatment. Herein, we established a tumor-targeted nanostructured lipid carrier encapsulating gambogic acid (GA) and paclitaxel (PTX), which was co-modified with acid-cleavable folic acid (cFA) and a human-derived cell penetrating peptide dNP2 (CKIKKVKKKGRKKIKKVKKKGRK). The multi-functional nano-platform exhibited an enhanced targeting and penetrability to tumor tissues, which was accomplished by the combined action of cFA and dNP2. After intravenous injection, firstly, cFA could actively target the breast cancer tissues by the selective recognition of folate receptor (FR); then, upon arrival at the tumor microenvironment, the acid-cleavable FA and dNP2 dual modified nanostructured lipid carrier (cFA/dNP2-GA/PTX-NLC) exhibited sensitive cleavage of folic acid (FA), which could reduce the hindrance effect of FA to maximize the dNP2 cell-penetrating properties. The effect of different modification on cellular uptake, in vivo bio-distribution, and anticancer activity of NLCs proved our hypothesis that compared with NLCs modified by non-cleavable FA or a single ligand, cFA/dNP2-GA/PTX-NLC displayed more efficient intracellular delivery, stronger targeting ability in vivo, improved cytotoxicity on 4T1 cells, and produced the better therapeutic efficacy of GA and PTX. The strategy affords a feasible way to overcome the poor recognition and permeability of medicines in cancer treatment.

Dual drug-loaded nano-platform for targeted cancer therapy: toward clinical therapeutic efficacy of multifunctionality.

BACKGROUND: Poor targeting and penetration of chemotherapy drugs in solid tumors, and the development of resistance to chemotherapeutic agents are currently hindering the therapy of breast cancer; meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy. RESULTS: A multi-functional nano-platform containing gambogic acid (GA) and paclitaxel (PTX) was characterized by a small size, high encapsulation efficiency, slow release, long systemic circulation time in vivo, showed good targeting and penetrability to tumor tissues and tumor cells, and exhibited higher anti-tumor effect and lower systemic toxicity in BALB/c mice bearing 4T1 tumor. GA not only overcame the multidrug resistance of PTX by inhibiting P-glycoprotein (P-gp) activity in MCF-7/ADR cells, but also inhibited MDA-MB-231 cells migration and invasion, playing a crucial role in preventing and treating the lung metastasis of breast cancer caused by PTX; meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments. CONCLUSION: Our data described the better recognition and penetration of tumor cells of R9dGR-modified versatile nanosystems containing GA and PTX, which exerted one stone three birds clinical therapeutic efficacy of multifunctionality.

Preparation and Characterization of PLGA-PEG-PLGA Nanoparticles Containing Salidroside and Tamoxifen for Breast Cancer Therapy.

Nanoparticles (NPs) containing the hydrophilic drug salidroside (Sal) and the hydrophobic drug tamoxifen (Tam) were prepared using a triblock copolymer poly(lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-PLGA to achieve synergism in the treatment of breast cancer. The double emulsion (w/o/w) method was used to prepare Sal-Tam NPs with an average particle size of 275.3 ± 44.0 nm, a polydispersity index of 0.302 ± 0.102, and a zeta potential of - 6.98 ± 2.99. The entrapment efficiency of the hydrophilic and hydrophobic components was 32.63% ± 0.73% and 49.18% ± 3.04%, respectively. On differential scanning calorimetry, the NPs showed the amorphous nature of both Sal and Tam. The sustained release of Sal and Tam from the NPs was significantly prolonged under physiological conditions (pH 7.4). The CCK-8 assay using the 4T1 cell line revealed a 1.7-fold decrease in the IC50 value for Sal-Tam NPs when compared with free Tam. The in vivo anti-tumor effect was assessed in BALB/c mice, and the results demonstrated that these NPs decreased the tumor volume compared with saline and showed high anti-tumor activity. A pharmacokinetic study showed significant enhancement of the bioavailability of Tam in Sal-Tam NPs compared with free Tam in suspension. The intracellular and mitochondrial anti-oxidative effect of Sal was thought to be attributed to the promising anti-tumor effect of drug co-delivery. This study confirmed that the use of Sal-Tam NPs may be a promising approach in breast cancer therapy.

Brain targeting of Baicalin and Salvianolic acid B combination by OX26 functionalized nanostructured lipid carriers.

In order to deliver Salvianolic acid B (Sal B) and Baicalin (BA) to the brain tissue to repair neuron damage and improve cerebral ischemia-reperfusion injury (IRI), in our previous study, a nanostructured lipid carrier (NLC) containing BA and Sal B, and modified by the transferrin receptor monoclonal antibody OX26 (OX26-BA/Sal B-NLC) was constructed. The present study is to evaluate its in vitro release behavior, in vitro and in vivo targeting ability, in vitro pharmacodynamics and brain pharmacokinetics. The results showed that the release mechanism of the formulation was in line with the Weibull model release equation. The in-vitro and in-vivo targeting ability study exhibited that OX26 modified formulations was obviously higher than that of non-modified and solution groups. The results of in vitro preliminary study to investigate the protective effect of OX26-BA/Sal B-NLC on oxygen-glucose deprivation/reperfusion injured cells showed that it could decrease the injury. Furthermore, the results of brain microdialysis study showed that the OX26-modified preparation group could significantly increase the content of BA in the brain. In the solution group and the unmodified group, Sal B can only be detected at few time points, while OX26-modified BA/Sal B-NLC could be detected within 4 h. These results indicating that OX26-modified NLC can promote the brain delivery of Sal B and BA combination.

Quantification of Nineteen Bioactive Components in the Ancient Classical Chinese Medicine Formula of Wen-Dan Decoction and Its Commercial Preparations by UHPLC-QQQ-MS/MS.

A UHPLC-QQQ-MS/MS method was developed to quantify the significant constituents in Wen-Dan Decoction (WDD), a traditional Chinese medicine. Analysis of 19 compounds was conducted on an ACQUITY UPLC® BEH C18 Column (2.1 × 50 mm, 1.7 µm) using elution with a gradient elution of acetonitrile and 0.05% (v/v) formic acid in water. A triple quadrupole mass spectrometer was operated in negative ionization mode and positive ionization mode by multiple reaction monitoring (MRM), respectively. All calibration curves showed acceptable linearity (r ≥ 0.9950). The RSDs of intra- and inter-day precisions of low, mid and high concentrations were ≤ 8.88%. The repeatabilities (RSDs ≤ 7.17%) and stabilities (RSD ≤ 4.79%) of the samples were qualified. The recoveries were found in the range of 93.07 ± 3.86 to 103.98 ± 2.98% with the RSD varying between 1.30 and 7.86%. The final rapid, sensitive, precise, accurate and reliable UHPLC-QQQ-MS/MS method was used for the simultaneous quantification of 19 constituents in WDD and its commercial preparations. The strategy of combining the contents of the 19 chemicals in a daily dose of the WDD preparations with the hierarchical cluster analysis and the 3D principal component analysis was employed to effectively distinguish the WDD preparations provided by the different suppliers, which represents a contribution to the evaluation and control of the quality of WDD (or other decoctions consisting of the same herbs) and the preparations of WDD in other dosage forms such as tablets and granules.

Preparation, optimization and cellular uptake study of tanshinone I nanoemulsion modified with lactoferrin for brain drug delivery.

Tanshinone I (TSI) is one of the bioactive compound obtained from the root of Salvia miltiorrhiza which is a well-known traditional Chinese medicine (TCM) used for the treatment of various diseases. Although TSI possesses several pharmacological effects, it has poor water solubility, blood-brain barrier (BBB) permeability and brain bioavailability. Therefore, in the present study, we developed TSI nanoemulsion (TSI-NE) modified with a brain targeting ligand (Lactoferrin (Lf)) to improve the BBB permeability. Pseudo-ternary phase diagrams were used to optimize the formulation. The optimal TSI-NE and TSI-Lf-NE were prepared and characterized. Finally, the uptake of TSI-Lf-NE by mouse brain microvascular endothelial cell line (bEnd.3 cells) was assessed using Coumarin-6 as a fluorescent probe. The results of the study showed that the stable optimal formulation of O/W nanoemulsion was successfully developed and modified with Lf. The cellular uptake study has shown that the fluorescence intensity (FI) increased with time over the incubation period. The FI at all time intervals increased in the following order: Coumarin-6-Solution＜Coumarin-6-NE＜Coumarin-6-Lf-NE. The results suggest that the BBB permeability of Coumarin-6-Lf-NE was better than those of Coumarin-6-NE and Coumarin-6 solution. Lf modified nanoemulsion has great potential for improving the brain delivery of TSI.

Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment.

Cancer is a major public health problem, and is now the world's leading cause of death. Traditional Chinese medicine (TCM)-combination therapy is a new treatment approach and a vital therapeutic strategy for cancer, as it exhibits promising antitumor potential. Nano-targeted drug-delivery systems have remarkable advantages and allow the development of TCM-combination therapies by systematically controlling drug release and delivering drugs to solid tumors. In this review, the anticancer activity of TCM compounds is introduced. The combined use of TCM for antitumor treatment is analyzed and summarized. These combination therapies, using a single nanocarrier system, namely codelivery, are analyzed, issues that require attention are determined, and future perspectives are identified. We carried out a systematic review of >280 studies published in PubMed since 1985 (no patents involved), in order to provide a few basic considerations in terms of the design principles and management of targeted nanotechnology-based TCM-combination therapies.

A nano-cocrystal strategy to improve the dissolution rate and oral bioavailability of baicalein.

Baicalein (BE) is one of the main active flavonoids representing the variety of pharmacological effects including anticancer, anti-inflammatory and cardiovascular protective activities, but it's very low solubility, dissolution rate and poor oral absorption limit the therapeutic applications. In this work, a nano-cocrystal strategy was successfully applied to improve the dissolution rate and bioavailability of BE. Baicalein-nicotinamide (BE-NCT) nano-cocrystals were prepared by high pressure homogenization and evaluated both in vitro and in vivo. Physical characterization results including scanning electron microscopy, dynamic light scattering, powder X-ray diffraction and differential scanning calorimetry demonstrated that BE-NCT nano-cocrystals were changed into amorphous state with mean particle size of 251.53 nm. In the dissolution test, the BE-NCT nano-cocrystals performed 2.17-fold and 2.54-fold enhancement than BE coarse powder in FaSSIF-V2 and FaSSGF. Upon oral administration, the integrated AUC0 -  t of BE-NCT nano-cocrystals (6.02-fold) was significantly higher than BE coarse powder (1-fold), BE-NCT cocrystals (2.87-fold) and BE nanocrystals (3.32-fold). Compared with BE coarse powder, BE-NCT cocrystals and BE nanocrystals, BE-NCT nano-cocrystals possessed excellent performance both in vitro and in vivo evaluations. Thus, it can be seen that nano-cocrystal is an appropriate novel strategy for improving dissolution rate and bioavailability of poor soluble natural products such as BE.

Study of penetration mechanism of labrasol on rabbit cornea by Ussing chamber, RT-PCR assay, Western blot and immunohistochemistry.

Labrasol, as a non-ionic surfactant, can enhance the permeation and absorption of drugs, and is extensively used in topical, transdermal, and oral pharmaceutical preparations as an emulsifier and absorption enhancer. Recent studies in our laboratory have indicated that labrasol has a strong absorption enhancing effect on different types of drugs in vitro and in vivo. This study was performed to further elucidate the action mechanism of labrasol on the corneal penetration. In this research, the fluorescein sodium, a marker of passive paracellular transport of tight junction, was selected as the model drug to assess the effect of labrasol on in vitro corneal permeability. To investigate the continuous and real-time influence of labrasol on the membrane permeability and integrity, the Ussing chamber system was applied to monitor the electrophysiological parameters. And, furthermore, we elucidated the effect of labrasol on excised cornea at the molecular level by application of RT-PCR, Western blot, and immunohistochemical staining. The results indicated that labrasol obviously enhance the transcorneal permeability of fluorescein sodium, and the enhancement was realized by interacting with and down-regulating the associated proteins, such as F-actin, claudin-1 and ß-catenin, which were contributed to cell-cell connections, respectively.

A strategy to improve the oral availability of baicalein: The baicalein-theophylline cocrystal.

Baicalein (BE) is a flavonoid compound derived from the roots of Scutellaria baicalensis. It has widely been used as anti-oxidant, anti-virus, anti-bacteria, anti-inflammatory and anti-allergic therapies. Due to its poor water solubility (16.82 µg/ml), the therapeutic effectiveness and oral bioavailability of Baicalein are highly limited. The purpose of this study was to investigate the possibility of baicalein-theophylline (BE-TH) cocrystals to achieve the simultaneous enhancement in dissolution and oral bioavailability of BE. The cocrystal had the new characteristic of scanning electron microscopy, differential scanning calorimetry thermograms and X-ray powder diffraction. Compared with coarse powder of BE, BE-TH cocrystals had significantly improved the solubility of BE. The dissolution test showed that the BE-TH cocrystals demonstrated 2.2-fold and 7.1-fold higher rate of dissolution than that of BE coarse powder in HCl (pH = 1.2) and phosphate buffer (PBS, pH = 6.8), respectively. Moreover, the cocrystals exhibited a 5.86-fold higher area under the curve in rats after the oral administration. This investigation enriched the present understanding of cocrystals on their behavior in vitro and in vivo, and built the groundwork for future development of BE as a promising compound into efficacious drug products.

Increasing efficacy and reducing systemic absorption of brimonidine tartrate ophthalmic gels in rabbits.

Systemic absorption of ocularly administered Brimonidine Tartrate has been reported to give rise to several side-effects. Hence, it has become crucial to develop a delivery system that could increase efficacy and reduce systemic absorption. Therefore, the present work aims to develop Brimonidine Tartrate gels with different concentrations (0.05%, 0.1%, and 0.2% w/v, respectively) using Carbopol 974 P and HPMC E4M, and compare the therapeutic efficacy and systemic absorption with that of eye drop (0.2%, w/v) by UPLC-MS/MS. The result of histological analysis did not show any morphological or structural changes after the administration of formulations. In vitro residence time studies demonstrated that the gels exhibited a better precorneal residence time as compared with the eye drop. The gels with lower concentrations of the drug (0.05% and 0.1%, w/v) could significantly decrease intraocular pressure (IOP) in both normal and water-loaded rabbits as compared to the eye drop. Finally, the values of the ratio of AUC(0→∞) in comparison to eye drop showed the gels with lower concentrations of Brimonidine Tartrate could decrease the systemic absorption. From the result, it can be concluded the 0.1% ophthalmic gel has a potential to improve therapeutic efficacy and reduce the potential toxicity caused by systemic absorption.

Pharmacokinetic and ocular microdialysis study of oral ginkgo biloba extract in rabbits by UPLC-MS/MS determination.

OBJECTIVES: The purpose of this work was to determine and investigate the absorption of ginkgo terpenoids (GT) in plasma and aqueous humour after oral administration of ginkgo biloba extract (GBE) by UPLC-MS/MS method. METHODS: The UPLC-MS/MS determination of GT employed the multiple reaction monitoring mode using an electrospray negative ionization. The rabbits were orally administered the suspension of GBE at a dose of 500 mg/kg. Serial plasma and dialysate samples were collected at the corresponding time and then analysed by UPLC-MS/MS. KEY FINDINGS: In plasma, the mean AUC from 0 to 48 h was 14.12, 12.59, 23.75, 1.51 h µg/ml for GLJ and 5.34 h µg/ml for GLA, GLB, GLC, GLJ and BLL, respectively. In aqueous humour, the five ginkgo terpenoids have been detected. Compared with the other four GT, BLL has better absorption in the eyes. CONCLUSIONS: A selective and reproducible UPLC-MS/MS method was developed and validated to determine and investigate the absorption of ginkgo terpenoids in plasma and aqueous humour of rabbits after oral administration of GBE. The main five ginkgo terpenoids could be absorbed into eyes.