Inhalation of taraxasterol loaded mixed micelles for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)is a chronic and fatal lung disease characterized by pulmonary inflam-mation,oxidative stress,and excessive extracellular matrix(ECM)deposition.Current anti-fibrotic drugs for IPF treatment in the clinic lack selectivity and demonstrate unsatisfactory efficacy,highlighting the urgent necessity for a novel therapeutic strategy.Taraxasterol(TA),which has biological activities against lung injury induced by various factors,is a potential anti-IPF drug due to its anti-inflammatory,antiox-idant and lung-protective effects.However,the protective effect of TA on IPF has not been confirmed,and its clinical application is limited due to its poor aqueous solubility.In this study,we demonstrated that TA could inhibit epithelial-mesenchymal transition(EMT)and migration of A549 cells by inhibiting the transforming growth factor-β1(TGF-β1)/Smad signaling pathway.To improve the aqueous solubility and pulmonary administration performance of TA,we prepared TA loaded methoxy poly(ethylene glycol)-poly(d,l-lactide)(mPEG-PLA)/d-α-tocopheryl polyethylene glycol succinate(TPGS)mixed polymeric mi-celles(TA-PM).Then a MicroSprayer^(R) Aerosolizer was used to deliver TA-PM once every two days for three weeks to evaluate their therapeutic effects on bleomycin(BLM)-induced IPF mice.Our results demonstrated that inhaled TA-PM significantly inhibited BLM-induced inflammation,oxidative stress and fibrosis in lung tissue.Furthermore,TA-PM exhibited high pulmonary deposition and retention by pul-monary administration,along with a favorable safety profile.Overall,this study emphasizes the potential of inhaled TA-PM as a promising treatment for IPF,providing a new opportunity for their clinical appli-cation.

Preparation and property of mPEG-PLA/pluronic mixed micelles and their role in solubilization of propofol

Novel mixed polymeric micelles formed by biocompatible polymers,mPEG-PLA and Pluronic P105,were fabricated and used as a nanocarrier to solubilize the poorly soluble anesthetic drug propofol.Propofol was added directly to an aqueous solution of mPEG-PLA/Pluronic P105 mixed micelles and stirred into a micellar solution.The average particle size and size distribution of micelles were evaluated by the dynamic light scattering technology.Drug loading content,encapsulation efficiency and free drug concentration were determined by using ultracentrifugation and lyophilization.In vitro release characteristic of propofol formulation was investigated by dialysis method.The physical stability of mixed micelles was also assessed under storage condition（4 oC） after six months.Sleep-recovery studies in male Sprague-Dawley rats,at a dose of 10 mg/kg were performed to compare the pharmacodynamic profiles of propofol in mixed micelles with that of commercial lipid emulsion（CLE）.The results indicated that solubilization of propofol in the mixed micelles was more efficient than that in mPEG-PLA alone.Micelles with the optimized composition of mPEG-PLA/Pluronic P105/Propofol（10：4：5,w/w/w） had particle size of about 90 nm with narrow distribution（polydispersity index of about 0.2）.The content of free propofol in the aqueous phase of mixed micelles was significantly lower than that in CLE（P〈0.05）.There was no remarkable differences for particle size,polydispersity index,and free drug concentration when the mix micelles were stored at 4 oC for six months,suggesting that the propofol-loaded mixed micelles were stable for at least six months.The accumulative release of mixed micelles was significantly higher than that of CLE at the corresponding time points,suggesting that quick release rate for mixed micelles might produce favorable pharmacological effect.No significant differences in the unconsciousness time and recovery time of righting reflex were observed between the mixed micelles and CLE（P〉0.05）.In conclusion,the mixed micelle of mPEG-PLA and pluronic copolymer may be a promising candidate for intravenous delivery of propofol in clinic.

Docetaxel-loaded mixed micelles composed of Solutol HS15 and Pluronic F127 or folate-conjugated F127: preparation, optimization and in vitro comparative characterization

In this study, two kinds of docetaxel （DTX）-loaded mixed micelles, composed of Solutol HS15 （HS 15）/Pluronic F127 （F 127） or folate-conjugated F127, （SF-DTX and FSF-DTX）, were prepared by the thin-film hydration method and evaluated in vitro. Both SF-DTX and FSF-DTX were spherical with diameter close to 23 nm. They had high encapsulating efficiency （99.05% and 90.28% for SF-DTX and FSF-DTX, respectively） and sustained-release property. SF and FSF were able to enhance the cellular accumulation of DTX in KBv cells and reduce ATP content in A-549 cells. They also were able to reverse multidrug resistance （MDR）. In vitro cytotoxicity and cellular accumulation of DTX suggested an active targeting of FSF-DTX. It could be concluded from the results that the novel F 127/HS 15 system could serve as a potential nanocarrier with the ability of overcoming MDR, and folate-conjugated F 127/HS 15 might achieve active targeting at the same time.

A pharmacokinetic study of puerarin formulated in mixed micelles in Beagle dogs by HPLC

We developed an HPLC method to study the pharmacokinetics ofpuerarin in Beagle dogs after oral administration of puerarin or puerarin mixed micelles （PMMS）. Beagle dogs were divided into two groups randomly, and the blood samples were collected at fixed time intervals after single oral administration ofpuerarin or PMMS at a dosage of 120 mg/kg. Following sample preparation, analytes were separated on a C18 column （DIKMA, 150 mm×4.6 mm, 5 μm） with a guard column （DIKMA, 8 mm×4 mm） and eluted with methanol-water （25：75, v/v）. Theophylline was used as the internal standard. WinNonlin 6.1 （Pharsight, USA） was used to calculate the pharrnacokinetic parameters. The pharmacokinetic parameters for puerarin and PMMS in Beagle dogs were as follows： AUC, 515.96 and 2796.43 min μg/mL; Tmax, 61.48 and 202.91 min; CL/F, 232.58 and 42.91 mL/min/kg, respectively. The relative bioavailability of PMMS to puerarin was 542.0%. Our results showed that the mixed micelle preparation significantly improved the bioavailability of puerarin by delaying absorption and reducing clearance.

Interaction of antipsychotic drug with novel surfactants: Micellization and binding studies

The interaction of cationic gemini surfactants(alkanediyl-α,ω-bis(alkyl dimethylammonium bromide)) with an antipsychotic drug(chlorpromazine hydrochloride(CPZ)) has been investigated. Various micellar and interfacial parameters have been deliberated by surface tension measurement to report the nature of interactions between drug and novel surfactant mixtures. The behavior of mixed systems, their compositions and activities of components have been analyzed in the light of Rubingh's theory. The results indicate synergism in the binary mixtures.The binding study between CPZ and surfactants has been done by spectroscopic techniques such as UV–visible and fluorescence. The results are discussed in the light of the use of gemini surfactants as promising drug delivery agents for phenothiazine drugs, and hence, improve their bioavailability.

Therapeutic uses of animal biles in traditional Chinese medicine:An ethnopharmacological,biophysical chemical and medicinal review

Forty-four different animal biles obtained from both invertebrates and vertebrates (including human bile) have been used for centuries for a host of maladies in traditional Chinese medicine (TCM) beginning with dog, ox and common carp biles approximately in the Zhou dynasty (c. 1046-256 BCE). Overall, different animal biles were prescribed principally for the treatment of liver, biliary, skin (including burns), gynecological and heart diseases, as well as diseases of the eyes, ears, nose, mouth and throat. We present an informed opinion of the clinical efficacy of the medicinal uses of the different animal biles based on their presently known principal chemical components which are mostly steroidal detergent-like molecules and the membrane lipids such as unesterified cholesterol and mixed phosphatidylcholines and sometimes sphingomyelin, as well as containing lipopigments derived from heme principally bilirubin glucuronides. All of the available information on the ethnopharmacological uses of biles in TCM were collated from the rich collection of ancient Chinese books on materia medica held in libraries in China and United States and the composition of various animal biles was based on rigorous separatory and advanced chemical identification techniques published since the mid-20th century collected via library (Harvard’s Countway Library) and electronic searches (PubMed and Google Scholar). Our analysis of ethnomedical data and information on biliary chemistry shows that specific bile salts, as well as the common bile pigment bilirubin and its glucuronides plus the minor components of bile such as vitamins A, D, E, K, as well as melatonin (N-acetyl-5-methoxytryptamine) are salutary in improving liver function, dissolving gallstones, inhibiting bacterial and viral multiplication, promoting cardiac chronotropsim, as well as exhibiting anti-inflammatory, anti-pyretic, anti-oxidant, sedative, anti-convulsive, anti-allergic, anti-congestive, anti-diabetic and anti-spasmodic effects. Pig, wild boar and human biles diluted with alcohol were shown to form an artificial skin for burns and wounds one thousand years ago in the Tang dynasty (618-907 CE). Although various animal biles exhibit several generic effects in common, a number of biles appear to be advantageous for specific therapeutic indications. We attempt to understand these effects based on the pharmacology of individual components of bile as well as attempting to identify a variety of future research needs.

Interaction of nonionic surfactant AEO_9 with ionic surfactants

The interaction in two mixtures of a nonionic surfactant AEO9 (C12H25O(CH2CH2O)9H) and different ionic surfactants was investigated. The two mixtures were AEO9/sodium dodecyl sulfate (SDS) and AEO9/cetyltrimethylammonium bromide (CTAB) at molar fraction of AEO9, A EO9 α =0.5. The surface properties of the surfactants, critical micelle concentration (CMC), effectiveness of surface tension reduction (γCMC), maximum surface excess concentration (Γmax) and minimum area per molecule at the air/solution interface (Amin) were determined for both individual surfactants and their mixtures. The significant deviations from ideal behavior (attractive interactions) of the nonionic/ionic surfactant mixtures were determined. Mixtures of both AEO9/SDS and AEO9/CTAB exhibited synergism in surface tension reduction efficiency and mixed micelle formation, but neither exhibited synergism in surface tension reduction effectiveness.

Novel hydrophobically associative polyacrylamide with tunable viscosity

Hydrophobically associative polyacrylamide （HAPAM） were prepared in aqueous solution by radical copolymerization of novel cationic surface-active monomer, dimethylhexadecyl（3-acrylamidopropyl）ammonium bromide （DMHAB）, with acrylamide （AM） in the presence of DMHAB/CTAB mixed micelles. The length of hydrophobic microblock （NH） in HAPAM is controlled by the molar fraction of DMHAB in mixed micelles, which can be mediated by the ratio of CTAB to DMHAB. The results of steady-state fluorescence probe and viscometry experiments showed the ability of HAPAM association was determined by the length of the hydrophobic microblock. HAPAM with tunable association ability are promising materials for thickening agent.

INTERACTION OF POLY(SODIUM SULFODECYL METHACRYLATE)WITH CETYLTRIMETHYL AMMONIUM BROMIDE IN AQUEOUS SOLUTION

The interaction of poly(sodium sulfodecyl methacrylate) (PSSM) with cetyltrimethyl ammonium bromide (CTAB)was studied. It was found that the precipitate formed from PSSM and CTAB will be dissolved by excessive CTAB, resultingin the appearance of two maxima of the solution viscosity at the molar ratio (CTAB/-SO_3^-) of≈ 0.68 and≈1.30,respectively. The first one is related closely to the aggregation of polymer chains via CTAB molecules and the second oneshould be ascribed to the formation of the mixed micelles comprising surfactant and the polymer's hydrophobic chains. Theeffect of NaCl on the viscosity, the transmittance of the aqueous solution and the solubility of oil-soluble dye (dimethyl yellow) in the mixed system were also investigated.

Wormlike Micelle Formation and Rheological Behavior in the Aqueous Solutions of Mixed Sulfate Gemini Surfactant without Spacer Group and Dodecyltrimethylammonium Bromide

The rheological behavior of the aqueous solutions of mixed sulfate gemini surfactant with no spacer group, referred to as d-C12S, and dodecyltrimethylammonium bromide （C12TABr） at a total concentration of 100 mmol,L-1 but different molar ratios of ClzTABr to d-C12S （a1） was investigated using steady rate and frequency sweep measurements. The wormlike micelles were formed over a narrow a1 range of 0.20-0.27. The viscoelastic solutions exhibited Maxwell fluid behavior. At the optimum molar ratio of 0.25, the zero-shear viscosity was as high as 600 paos and the length of the mixed wormlike micelle was about 0.45-0.85 pm. The present result provides an exam- ple to construct long wormlike micelles by anionic gemini surfactant.