Chengying Shen

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.

Hepatoprotective effects of lignans extract from Herpetospermum caudigerum against CCl4-induced acute liver injury in mice

ETHNOPHARMACOLOGICAL RELEVANCE Herpetospermum caudigerum (HCD) is traditionally used for the treatment of liver diseases, cholic diseases, and dyspepsia as a well-known Tibetan medicine in China. The present study was designed to investigate the hepatoprotective effect of HCD and ascertain its active ingredients and possible mechanism. MATERIALS AND METHODS Mice were orally administrated with different parts (seeds, testa and kernel) and fractions of HCD. The hepatoprotective activities of different parts (seeds, testa and kernel) and three fractions (petroleum ether fraction, ethyl acetate fraction and aqueous fraction) with different polarities of HCD and herpetrione (HPE) isolated from HCD were determined using a mouse model of CCl4-induced liver injury based on the analysis of serum ALT and AST activities and the changes of antioxidant parameters like malondialdehyde (MDA) content, glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the liver. Moreover, the chemical analysis of different parts and fractions of HCD was later analyzed by HPLC. RESULTS Our results showed that the ethyl acetate fraction and HPE significantly alleviated liver injury as indicated by the decreased levels of serum ALT and AST and reduce the pathological tissue damage induced by CCl4. Moreover, they decreased the MDA content and increased the levels of SOD, GSH and GSH-Px. Chemical analysis indicated that the ethyl acetate fraction were rich in HPE. CONCLUSIONS The lignans extract of Herpetospermum caudigerum is effective for the prevention of CCl4-induced hepatic damage in mice and HPE may be partially responsible for the pharmacological effect of hepatoprotection. The hepatoprotective effect may be related to its free radical scavenging effect, inhibiting lipid peroxidation and increasing antioxidant activity.

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

Abstract 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.

Formulation and optimization of a novel oral fast dissolving film containing drug nanoparticles by Box-Behnken design-response surface methodology.

Abstract Objective: The purpose of this study was to design and optimize a novel drug nanoparticles-loaded oral fast dissolving film (NP-OFDF) using Box–Behnken design–response surface methodology. Methods: Drug nanosuspensions produced from high pressure homogenization were transformed into oral fast dissolving film containing drug nanoparticles by casting methods. Herpetrione (HPE), a novel and potent antiviral agent with poor water solubility that was extracted from Herpetospermum caudigerum, was studied as the model drug. The formulations of oral fast dissolving film containing HPE nanoparticles (HPE-NP-OFDF) were optimized by employing Box-Behnken design–response surface methodology and then systematically characterized. Results: The optimized HPE-NP-OFDF was disintegrated in water within 20 s with reconstituted nanosuspensions particle size of 299.31 nm. Scanning electron microscopy (SEM) images showed that well-dispersed HPE nanoparticles with slight adhesion to each other were exposed on the surface of film or embedded in film. The X-ray diffractogram (XRD) analysis suggested that HPE in the HPE-NP-OFDF was in the amorphous state. In-vitro release study, approximate 77.23% of HPE was released from the HPE-NP-OFDF within 5 min, which was more than eight times compared with that of HPE raw materials (9.57%). Conclusion: The optimized HPE-NP-OFDF exhibits much faster drug release rates compared to HPE raw material, which indicated that this novel NP-OFDF may provide a potential opportunity for oral delivery of drugs with poor water solubility.

Application of spray granulation for conversion of mixed phospholipid-bile salt micelles to dry powder form: influence of drug hydrophobicity on nanoparticle reagglomeration

The aim of this study was to investigate the feasibility of using spray granulation as a drying method to convert phospholipid (PL)-sodium deoxycholate (SDC)-mixed micelles (MMs) containing a water-insoluble drug to a solid dosage form and to evaluate how drugs with significantly different physicochemical properties affect the spray granulation process and subsequent in vitro and in vivo processes. Cucurbitacin B (Cu B) and glycyrrhizin (GL) were used as the model drugs. After spray granulation, the dried Cu B-PL/SDC-MM powder was completely redispersible within 15 minutes in vitro. Meanwhile, the area under the curve during 24 hours (AUC0–24) and peak serum concentration from the dried powder were significantly (P<0.05) lower than the values from Cu B-PL/SDC-MMs in vivo. However, a better result was obtained for GL, ie, the drug was redispersed completely within 5 minutes in vitro. Further, absorption from the dried GL-PL/SDC-MM powder was increased to the same level as that for GL-PL/SDC-MMs in vivo compared with the control group. The difference in these results can be found in Cu B and GL. Cu B nanoparticles reagglomerated when released, resulting in slower redispersibility and less absorption compared with the original PL-SDC-MMs. However, no agglomeration or delay was observed for GL. A possible explanation is the difference in surface hydrophobicity between Cu B and GL. The results of this study not only show that spray granulation is an effective drying technique that can complement spray-drying and freeze-drying, but also confirm that the physicochemical properties of a drug have a significant influence on the in vitro and in vivo performance of the dried powder obtained after spray granulation.

Hyperoside nanocrystals for HBV treatment: process optimization, in vitro and in vivo evaluation

Abstract The aim of this study was to develop hyperoside (Hyp) nanocrystals to enhance its dissolution rate, oral bioavailability and anti-HBV activity. Hyp nanocrystals were prepared using high pressure homogenization technique followed by lyophilization. A Box–Behnken design approach was employed for process optimization. The physicochemical properties, pharmacokinetics and anti-HBV activity in vivo of Hyp nanocrystal prepared with the optimized formulation were systematically investigated. Hyp nanocrystals prepared with the optimized formulation was found to be rod shaped with particle size of 384 ± 21 nm and PDI of 0.172 ± 0.027. XRPD studies suggested slight crystalline change in drug. Dissolution rate obtained from Hyp nanocrystals were markedly higher than pure Hyp. The nanocrystals exhibited enhanced Cmax (7.42 ± 0.73 versus 3.80 ± 0.66 mg/L) and AUC0 − t (193.61 ± 16.30 versus 91.92 ± 17.95 mg·h/L) with a 210.63% increase in relative bioavailability. Hyp nanocrystals exhibited significantly greater anti-HBV activity than Hyp. These results suggested that the developed nanocrystals formulation had a great potential as a viable approach to enhance the bioavailability of Hyp.

Influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions

Abstract The purpose of this paper was to study the influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions. Four drug nanosuspensions were produced by high-pressure homogenization technique, which were the same in stabilizer and similar in particle size. Differential scanning calorimetry and powder X-ray diffraction analysis showed that the crystalline state of the nanocrystals did not change. In vitro permeation study demonstrated that the drug nanosuspensions have a higher rate of permeation that ranged from 1.69- to 3.74-fold compared to drug microsuspensions. Correlation analysis between drug physicochemical properties and Jss revealed that log P and pKa were factors that influenced the in vitro transdermal absorption of hydrophobic drug nanosuspensions, and drugs with a log P value around 3 and a higher pKa value (when pKa < pH+2) would gain higher Jss in this paper.

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

Abstract 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.

Nanostructured lipid carrier based topical gel of Ganoderma Triterpenoids for frostbite treatment

The objective of this study was to prepare nanostructured lipid carrier (NLC)-based topical gel of Ganoderma Triterpenoids (GTs) and evaluate their effects on frostbite treatment. GT-NLCs was prepared by the high pressure homogenization method and then characterized by morphology and analyses of particle size, zeta potential, entrapment efficiency (EE), and drug loading (DL). The NLCs was suitably gelled for skin permeation studies in vitro and pharmacodynamic evaluation in vivo, compared with the GT emulgel. The GT-NLC remained within the colloidal range and was uniformly dispersed after suitably gelled by carbopol preparation. Transmission electron microscopy (TEM) study showed GT-NLCs was spherical in shape. The EE (%) and DL (%) could reach up to (81.84 ± 0.60)% and (2.13 ± 0.12)%, respectively. The result of X-ray diffractograms (XRD) showed that GTs were in an amorphous state in the NLC-gel. In vitro permeation studies through rat skin indicated that the amount of GTs permeated through skin of GT-NLCs after 24 h was higher than that of GT emulsion, and GT-NLCs increased the accumulative amounts of GTs in epidermis 7.76 times greater than GT emulsion. GT-NLC-gel was found to possess superior therapeutic effect for frostbite, compared with the GT emulgel. The NLC based topical gel of GTs could improve -their therapeutic effect for frostbite.