Quercetin nanocrystals for bioavailability enhancement: impact of different functional stabilizers on in vitro/in vivo drug performances.

The purpose of this study was to investigate the impact of different functional stabilizers on in vitro/in vivo drug performances after oral administration of drug nanocrystals. Quercetin nanocrystals (QT-NCs) respectively stabilized by five types of functional stabilizers, including hydroxypropyl methyl cellulose E15 (HPMC E15), poloxamer 407 (P407), poloxamer 188 (P188), D-α-tocopherol polyethylene glycol succinate (TPGS), and glycyrrhizin acid (GL), were fabricated by wet media milling technique. The particle size, morphology, physical state, drug solubility, drug dissolution in vitro, and orally pharmacokinetic behaviors of all QT-NCs were investigated. All QT-NCs with similar particle size about 200 nm were obtained by controlling milling speed and milling time. No significant differences in particles shape and crystalline nature were found for QT-NCs stabilized by different functional stabilizers. But the solubility and dissolution of QT-NCs were significantly influenced by the different functional stabilizers. The AUC0∼t of all QT-NCs after oral administration was in the following order: QT-NCs/P188 ≈ QT-NCs/HPMC E15 > QT-NCs/GL > QT-NCs/P407 ≈ QT-NCs/TPGS, and the Cmax showed an order of QT-NCs/P407 > QT-NCs/P188 ≈ QT-NCs/GL > QT-NCs/HPMC E15 > QT-NCs/TPGS. Both of QT-NCs/P407 and QT-NCs/TPGS exhibited faster oral absorption with Tmax at 0.5 h and 0.83 h, respectively, while the other three QT-NCs (QT-NCs/P188, QT-NCs/GL and QT-NCs/HPMC E15) showed a relatively slow absorption with same Tmax at 5.33 h. The longest MRT0∼t (11.72 h) and t1/2z (32.22 h) were observed for QT-NCs/HPMC E15. These results suggested that the different functional stabilizers could significantly influence on drug solubility, drug dissolution in vitro and orally pharmacokinetic behavior of QT-NCs, and it is possible to alter the drug dissolution in vitro, oral absorption and drug retention in vivo by changing the type of functional stabilizers in NCs preparation.

Topical delivery of pluronic F127/TPGS mixed micelles-based hydrogel loaded with glycyrrhizic acid for atopic dermatitis treatment.

OBJECTIVE: The purpose of this study was to develop pluronic F127/d-a-tocopheryl polyethylene glycol 1000 succinate mixed micelles-based hydrogel (MMs-gel) for topical delivery of glycyrrhizic acid (GL) to improve its skin permeability and atopic dermatitis (AD) treatment. SIGNIFICANCE: GL loaded MMs-gel (GL-MMs-gel) could be potentially used as a promising nanocarrier for the treatment of AD. METHODS: GL-MMs were prepared by thin film hydration method and then loaded into carbopol gel. The formulation of GL-MMs-gel was optimized by full factorial design and systematically characterized for drug content, pH, spreadability, in vitro drug release and percutaneous permeation, etc. The therapeutic effect of GL-MMs-gel was also investigated in AD-like skin lesion model in BALB/c mice and compared with GL solution-based gel (GL-sol-gel). RESULTS: Spherical GL-MMs with particle size of ∼30 nm were successfully incorporated into carbopol gel to form GL-MMs-gel with drug content of (98.80 ± 1.30) %, pH of 6.0 ± 0.08, and spreadability of (7.1 ± 0.2) cm. In vitro drug release profile of GL-MMs-gel exhibited a sustained-release behavior. The permeation flux for GL-MMs-gel (5.15 ± 0.33 µg/cm2/h) was significantly higher than that of GL-sol-gel (3.08 ± 0.34 µg/cm2/h) and GL-MMs-gel increased the accumulative amounts of GL in rats' skin 8.41 times than GL-sol-gel. The GL-MMs-gel was more effective than GL-sol-gel in suppressions of various AD symptoms including skin lesions, edema, high IgE levels, epidermal hyperplasia, and mast cell infiltration. CONCLUSION: All results revealed that MMs-gel could be a promising carrier for topical delivery of GL for the treatment of AD.

Formulation of pluronic F127/TPGS mixed micelles to improve the oral absorption of glycyrrhizic acid.

Background: Glycyrrhizic acid (GL), a pentacyclic triterpenoid glycoside, has been used as a hepatoprotective agent for the treatment of acute and chronic hepatitis. However, its poor solubility and permeability across the gastrointestinal mucosa limit its clinical efficacy. This study aimed to develop mixed micelles based on pluronic F127 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral bioavailability of GL.Methods: GL loaded pluronic F127/TPGS mixed micelles (GL-F127/TPGS-MMs) were prepared by thin film hydration method, and their physicochemical properties including particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), and drug release were characterized. Furthermore, the pharmacokinetic and biodistribution studies of GL-F127/TPGS-MMs were evaluated in rats and compared with GL solution.Results: GL-F127/TPGS-MMs were found to be of spherical shape with particle size of (27.41 ± 4.90) nm, EE% of 95.38% and DL% of 12.99%. The results of XRD and DSC indicated that GL was encapsulated in the micelles. Drug release of GL-F127/TPGS-MMs demonstrated a sustained release behavior as compared to GL solution. The pharmacokinetic and biodistribution studies showed a significantly higher oral absorption and liver accumulation of glycyrrhetinic acid (GA) after oral administration of GL-F127/TPGS-MMs as compared to GL solution.Conclusion: These results suggested F127/TPGS-MMs might be a potential nanocarrier for oral delivery of GL.

Effective mucoadhesive water-soluble polymers for the solidification transformation of phospholipid-bile salts-mixed micelles.

Cucurbitacin B (Cu B), formulated in the phospholipid-bile salts-mixed micelles (PL-BS-MMs), was transformed into dry powders by solidification process. Solidification methods for this transformation included freeze-drying, spray-drying or vacuum-drying, and different grades of process parameters called conservative, moderate and aggressive have been used in each solidification method, respectively. Saccharides (mannose, trehalose and glucose), polyethylene glycol (PEG) and mucoadhesive water-soluble polymers (carrageenan, hydroxpropylmethylcellulose (HPMC) and gelatin) were selected as the stabilizer, respectively. The influence of different stabilizers on the redispersibility of solid Cu B-PL/SDC-MMs was systemically investigated, such as the redispersibility index (RDI). The results showed that there were significant differences in RDI from samples stabilized by different stabilizers. The solid Cu B-PL/SDC-MMs stabilized by mucoadhesive water-soluble polymers (carrageenan, HPMC and gelatin) have better redispersibility under different solidification approaches, compared with those samples stabilized by other stabilizers. The results indicated that the mucoadhesive water-soluble polymers could effectively counter various stresses from the solidification process and prevent the nanocrystal surface from agglomeration. The combined action between steric hindrance and increased viscosity appeared to effectively avoid irreversible particle aggregation.

Nanogel for dermal application of the triterpenoids isolated from Ganoderma lucidum (GLT) for frostbite treatment.

OBJECTIVE: The purpose of this study was to formulate stable Ganoderma lucidum (GLT) nanogels suitable for topical delivery with a view to improve the therapeutic effect for frostbite. METHODS: GLT nanosuspensions were formulated using the high-pressure homogenization technique and then suitably gelled for characterized. In order to confirm the advantages of GLT nanogel for dermal application, skin permeation studies in vitro and pharmacodynamic evaluation in vivo were studied and compared with GLT-carbopol gel. RESULTS: The particle size analysis and SEM studies revealed that GLT nanosuspensions were still stably kept their particle size after suitably gelled by carbopol preparation. The drug content, pH, and spreadability of the GLT nanogel was found to be 99.23 ± 1.8%, 6.07 ± 0.1, and 26.42 (g·cm)/s, which were within acceptable limits. In vitro permeation studies through rat skin indicated that the amount of GLT permeated through skin of GLT nanogel after 24 h was higher than GLT-carbopol gel, and GLT nanogel increased the accumulative amount of GLT in epidermis five times than GLT-carbopol gel. No oedema and erythema were observed after administration of GLT nanogel on the rabbits' skin. Pharmacodynamic study showed that GLT nanogel was more effective than GLT-carbopol gel in treatment of frostbite. CONCLUSION: The GLT nanogel possess superior therapeutic effect for frostbite compared with the GLT-carbopol gel, which indicates that nanogels are eligible for the use as a suitable nanomedicine for dermal delivery of poorly soluble drugs such as GLT.

Therapeutic effects of nanogel containing triterpenoids isolated from Ganoderma lucidum (GLT) using therapeutic ultrasound (TUS) for frostbite in rats.

OBJECTIVE: The aim of this study was to evaluate the effect of therapeutic ultrasound (TUS) on dermal delivery and therapeutic effect for frostbite of nanogel containing triterpenoids isolated from Ganoderma lucidum (GLT). METHODS: GLT nanosuspension (GLT-NS) was prepared by high pressure homogenization and then suitably gelled to obtain GLT nanogel. The effects of TUS on GLT releasing from GLT nanogel and GLT permeation through the excised rat abdominal skin were evaluated. Moreover, a comparative study was also undertaken between different treatments of frostbite in rats: topical application of GLT nanogel (alone), TUS (alone) and GLT nanogel + TUS (plus). RESULTS: In the in vitro release study, TUS has no influence on drug release from the nanogel. Results of the in vitro transdermal study indicated that TUS significantly increased the cumulative amount of GLT permeating across and into the skin and reduced the lag time in comparison with passive diffusion (without TUS). As evidenced by the significant increase of wound healing area and the improvement in frostbite, TUS applied with simultaneous treatment method could improve the therapeutic effect of the GLT nanogel for frostbite. CONCLUSION: The present study revealed that the TUS can be effectively used to actively enhance topical delivery of GLT from nanogel and improve the therapeutic effect for frostbite in rats.

Mucoadhesive buccal films containing phospholipid-bile salts-mixed micelles as an effective carrier for Cucurbitacin B delivery.

Cucurbitacin B (Cu B), a potent anti-cancer agent, suffers with the problems of water-insoluble, gastrointestinal side effects and non-specific toxicity via oral administration and drawbacks in patient's compliance and acceptance through injections. An integration of nanoscale carriers with mucoadhesive buccal films drug delivery system would resolve these issues effectively with greater therapeutic benefits and clinical significance. Thus, the drug loaded mucoadhesive buccal film was developed and characterized in this study and the carboxymethyl chitosan (CCS) was chosen as a bioadhesive polymer, glycerol was chosen as a plasticizer and phospholipid-bile salts-mixed micelles (PL-BS-MMs) was selected as the nanoscale carriers. The CCS-films containing Cu B loaded PL-SDC-MMs was evaluated for the mechanical properties, mucoadhesion properties, in vitro water-uptake, in vitro release and morphological properties, respectively. The optimal CCS-films containing Cu B loaded PL-SDC-MMs was easily reconstituted in a transparent and clear solution with spherical micelles in the submicron range. The in vivo study revealed a greater and more extended release of Cu B from nanoscale CCS-films compared to that from a conventional CCS films (C-CCS-films) and oral marketed tablet (Hulusupian). The absorption of Cu B from CCS-films containing Cu B loaded PL-SDC-MMs resulted in 2.69-fold increased in bioavailability as compared to conventional tablet formulation and 10.46 times with reference to the C-CCS-films formulation. Thus, this kind of mucoadhesive buccal film might be an alternative safe route for delivery of Cu B with better patient compliance and higher bioavailability for the treatments.

Development and characterization of an orodispersible film containing drug nanoparticles.

In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC0-24h, Cmax and decrease in Tmax, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs.