Inclusion complex of tamibarotene with hydroxypropyl-β-cyclodextrin: Preparation,characterization, in-vitro and in-vivo evaluation

The goal of this study was to improve the solubility and oral bioavailability of tamibarotene by complexing it with hydroxypropyl-β-cyclodextrin(HP-β-CD).The inclusion complex of tamibarotene with hydroxypropyl-β-cyclodextrin(Am80-HP-β-CD)was prepared through a freeze-drying method at the mole ratio of 1:1(Am80:HP-β-CD).Fourier transform infrared spectroscopy(FT-IR)and differential scanning calorimetry(DSC)indicated the formation of Am80-HP-β-CD.In vitro dissolution studies showed that the solubility and dissolution percentage of Am80-HP-β-CD was improved substantially compared to Am80.An improved dissolution with approximately 97%drug release in 3 min was observed,in comparison with Am80 with approximately 60% release in 45 min.In vivo studies indicated that the AUC0-∞ has increased 2.79 times and the Cmax 4.37 times after the formation of inclusion complex.The decrease of tmaxindicated the Am80-HP-β-CD inclusion complex can be absorbed into blood faster.In short,the solubility and bio-availability of Am80 has notably increased with the complexation of HP-β-CD.Therefore,using the inclusion technique is a promising method to improve the solubility of insoluble drugs.

Synthesis of Hydroxypropyl-β-cyclodextrin Bonded Silica-gel and its Application to Resolution

In order to set up a simple and effective method for resolution of optical isomers, hydroxypropyl-β-cyclodextrin was bonded to silica-gel, which can be used for preparation of thin-layer chromatography plates. Resolution of clenbuterol and propranolol were investigated on these thin-layer chromatography plates using different combinations of solvent systems at ambient temperature. The best simultaneous resolution was achieved in solvent system of acetonitrilen-butanol （50：50, v/v）. Rst values of resolution of clenbuterol hydrochloride and propranolol hydrochloride are 3.6 and 4.3, respectively. The spots of different enantiomers are separated clearly. The results showed that hydroxypropyl-β-cyclodextrin bonded silica-gel could be successful in resolution of chiral adrenergic drugs. The study offers a direct, rapid and reliable method for separation of this kind of optically active compounds.

Preparation and Evaluation of Insulin-loaded Nanoparticles based on Hydroxypropyl-β-cyclodextrin Modified Carboxymethyl Chitosan for Oral Delivery

Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan（CMC-HP-β-CD） were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterized by FT-IR spectroscopy and 1H-NMR spectra. The insulin-loaded nanoparticles were prepared through crosslinking with calcium ions, and the morphology and size of the prepared nanoparticles were characterized by transmission electron microscopy（TEM） and dynamic light scattering（DLS）. Cumulative release in vitro study was performed respectively in simulated gastric medium fluid（SGF, p H=1.2）, simulated intestinal fluid（SIF, p H=6.8） and simulated colonic fluid（SCF, p H=7.4）. The encapsulation efficiency of insulin was up to 87.14 ± 4.32% through high-performance liquid chromatography（HPLC）. Statistics indicated that only 15% of the encapsulated insulin was released from the CMC-HP-β-CD nanoparticles in 36 h in SGF, and about 50% of the insulin could be released from the nanoparticles in SIF, whereas more than 80% was released in SCF. In addition, the solution containing insulin nanoparticles could effectively reduce the blood glucose level of diabetic mice. The cytotoxicity test showed that the samples had no cytotoxicity. CMC-HP-β-CD nanoparticles are promising candidates as potential carriers in oral insulin delivery systems.

Preparation of Forsythiaside-hydroxypropyl-β-cyclodextrin Inclusion Complex and Its Characters

To overcome the chemical instability of forsythiaside,the forsythiaside-hydroxypropyl-β-cyclodextrin inclusion complex was prepared by triturating. The inclusion complex was found having a varied UV spectrum and melt temperature point. Inclusion complex has a higher stability to UV light and temperature over forythiaside itself. Pharmacological evidence showed that inclusion complex has little effect on pharmacokinetics by chicken intravenous injection. This study is favorable for developing preparations for forsythiaside and its clinical application.

Preparation,Characterization and Antioxidant Activity of Inclusion Complex of Bakuchiol with Hydroxypropyl-β-cyclodextrin

Bakuchiol isolated from Psoralea corylifolia is a naturally occurring prenylated phenolic monoterpene with a variety of bioactivities.The aim of this study was to improve the water solubility and thermal stability of bakuchiol through complexing it with hydroxypropyl-β-cyclodextrin(HP-β-CD).The bakuchiol/HP-β-CD inclusion complex's behavior and characterization were investigated by ultraviolet-visible(UV-vis)spectroscopy,Fourier transform infrared spectroscopy(FT-IR),thermogravimetric analysis(TGA),X-ray diffraction(XRD),1H nuclear magnetic resonance(NMR),and two-dimensional(2D)NMR.The obtained results indicated the formation of 1∶1 inclusion complex for bakuchiol with HP-β-CD.Water solubility of bakuchiol was significantly improved by complexation with HP-β-CD as demonstrated by phase solubility studies.The encapsulation of bakuchiol was confirmed by UV-vis,FT-IR,and XRD.The thermal stability was effectively enhanced by TGA and derivative thermogravimetry(DTG)analysis.In vitro antioxidant activity showed that bakuchiol/HP-β-CD inclusion complex had a little higher antioxidant ability than free bakuchiol.Moreover,we got the possible inclusion mode for the bakuchiol/HP-β-CD inclusion complex through NMR analysis.These results suggest that the inclusion complex can be a potentially useful approach in the design of novel formulations of bakuchiol for medical applications.

Solubility Enhancement of Domperidone Fast Disintegrating Tablet Using Hydroxypropyl-<i>β</i>-Cyclodextrin by Inclusion Complexation Technique

Domperidone Maleate (DOM), an antiemetic drug, has been used in treatment of adults and children. It has low aqueous solubility and hence low bioavailability. In present study, an attempt has been made to enhance the solubility of DOM by inclusion complexation with Hydroxypropyl-β-Cyclodextrin (HP-β-CD) using kneading technique and formulation of fast disintegrating tablets by using Sodium Starch Glycolate as superdisintegrant. Solubility analysis of DOM in different concentrations of HP-β-CD was carried out. Design of experiment (DOE) is done by using MINITAB 15.1 software to find out the variable for dissolution and disintegration time. HP-β-CD and SSG were identified as the variable for disintegration time and dissolution. For optimization of the concentration of HP-β-CD and SSG, two factors at two levels design through central composite design (CCD) were used which gave 13 formulations. All formulations are evaluated for characteristics such as weight variation, hardness, friability, disintegration time and dissolution of drug. Solubility of DOM increases linearly with increase in concentration of HP-β-CD. The optimum concentration of HP-β-CD is found to be in 1:2 molar ratios and SSG of 7%. The In-Vitro dissolution studies of optimized formulation and market sample were carried out in USP type II apparatus at different time intervals of 5, 10, 15 and 30 minutes at 50 rpm in 0.1 N HCl. The dissolution and disintegration time of optimized formulation is found better than market sample.

Water-Based Environmentally Friendly Pesticide Formulations Based on Cyclodextrin/Pesticide Loading System

Difenoconazole(DIF)is a representative variety of broad-spectrum triazole fungicides and liposoluble pesticides.However,the water solubility of DIF is so poor that its application is limited in plant protection.In addition,the conventional formulations of DIF always contain abundant organic solvents,which may cause pollution of the environment.In this study,two DIF/cyclodextrins(CDs)inclusion complexes(ICs)were successfully prepared,which were DIF/β-CD IC and DIF/hydroxypropyl-β-CD IC(DIF/HP-β-CD IC).The effect of cyclodextrins on the water solubility and the antifungal effect of liposoluble DIF pesticide were investigated.According to the phase solubility test,the molar ratio and apparent stability constant of ICs were obtained.Fourier transform infrared spectroscopy,thermal gravity analysis,X-ray diffraction and scanning electron microscopy were used systematically to characterize the formation and characteristics of ICs.The results noted that DIF successfully entered the cavities of two CDs.In addition,the antifungal effect test proved the better performance of DIF/HP-β-CD IC,which exceeded that of DIF emulsifiable concentrate.Therefore,our study provides informative direction for the intelligent use of liposoluble pesticides with cyclodextrins to develop water-based environmentally friendly formulations.

硝酸益康唑温度敏感型凝胶的制备及体外评价

目的:制备含硝酸益康唑-HP-β-CD的温度敏感型凝胶,评价其体外制剂学特征。方法:冷冻干燥法制备硝酸益康唑的HP-β-CD包合物并进行表征制备温度敏感型凝胶,考察处方因素泊洛沙姆407、泊洛沙姆188、HP-β-CD、HPMC和PEG400对凝胶胶凝温度和相变时间的影响。制备含硝酸益康唑或其HP-β-CD包合物的温度敏感性凝胶并进行体外释放特性评价。结果:红外光谱和X-射线粉末衍射结果表明硝酸益康唑与HP-β-CD形成了包合物,蒸馏水中溶解度增加38倍,相溶解度实验结果显示硝酸益康唑和HP-β-CD是按1∶n(n>1)形成包合物,提高温度有利于包合物形成。处方中泊洛沙姆407和泊洛沙姆188用量增加,凝胶的相转变温度降低,且相变时间缩短;HP-β-CD使凝胶的LCST升高。含硝酸益康唑或硝酸益康唑包合物凝胶的体外释放速度缓慢,凝胶中加入HPMC可使药物释放速度进一步延迟。结论:初步制备同时具有溶解度改善和缓释作用特征的硝酸益康唑温度敏感性凝胶。

去甲氧基姜黄素羟丙基-β-环糊精在体肠吸收特征

目的研究去甲氧基姜黄素羟丙基-β-环糊精(DECD)及去甲氧基姜黄素(DE)的在体肠吸收情况。方法使用DE以环糊精包合技术制备DECD,光谱法测定其理化性质,显微照相观察其形态,马尔文粒径测定仪测定DECD的zeta电位。采用大鼠在体肠段单向灌流模型,并建立紫外分光光度法测定DECD及DE在大鼠体内各肠段的吸收速率常数(Ka)、表观渗透系数(Papp)和吸收百分率。结果成功制得DECD,其溶解度为2.30g/L,是DE的38.33倍;zeta电位为-32.2mV。在体肠吸收实验显示DECD的Ka及Papp皆为回肠>十二指肠>空肠>结肠,且其Ka、Papp与吸收百分率较DE均有所提高。结论 DECD能够明显改善DE在大鼠小肠内的吸收情况。

Multicomponent cyclodextrin system for improvement of solubility and dissolution rate of poorly water soluble drug

The purpose of the present study was to investigate the interaction of Cinnarizine(CIN)with Hydroxypropyl-β-Cyclodextrin(HPβCD)in the presence of Hydroxy Acids(HA).Various binary and ternary systems of CIN with HPβCD and HA were prepared by kneading and coevaporation methods.For the ternary systems,HA were tried in three different concentrations.The interaction in solution phase was studied in detail by the phase solubility method,and the solid phase interactions were characterized by Fourier Transform Infrared(FTIR)spectroscopy,Differential Scanning Calorimetry(DSC),X-Ray Diffractometry(XRD),Scanning Electron Microscopy(SEM)and Proton Nuclear Magnetic Resonance(^1H-NMR).Phase solubility revealed the positive effect of HA on the complexation of CIN with HPβCD.Solid phase characterization confirmed the formation of inclusion complex in the ternary systems.Solubility and dissolution studies illustrated that out of three different concentrations tried,HA were most effective at the 1 M concentration level.Ternary systems were very effective in improving the solubility as well as dissolution profile of CIN than the CIN–HPβCD binary systems.FTIR,^1H-NMR and Molecular docking studies gave some insight at molecular level that actually which part of CIN was interacting with the HPβCD.Molecular docking and free energy calculation even enlighten the role of tartaric acid in increasing solubility of CIN in the ternary system.

肉桂精油纳米乳液的抑菌性和稳定性研究

为改善精油的稳定性及抑菌性能,利用羟丙基-β-环糊精(HPCD)与酪蛋白酸钠(SC)共同乳化肉桂精油(CEO)制备纳米乳液,探究乳液的粒径、抑菌性的变化及乳液在不同温度下的储存稳定性。结果表明,相比单独使用酪蛋白酸钠稳定的乳液,HPCD的添加可以显著降低酪蛋白酸钠-精油乳液的粒径及PDI值。1%酪蛋白酸钠和3%HPCD共同稳定的肉桂精油纳米乳液对大肠杆菌和金黄色葡萄球菌的生长有良好的抑制作用,当精油添加量为10%时,大肠杆菌浓度降低了2.62 lg(CFU/mL),金黄色葡萄球菌浓度降低了0.85 lg(CFU/mL);乳液在4、25、40℃下储存过程中的粒径、乳化指数的变化表明,1%酪蛋白酸钠和3%HPCD共同乳化的肉桂精油纳米乳液具备良好的稳定性。当精油体积分数为10%时,乳液的粒径、乳化指数随着储藏时间的延长有所增加,但荧光显微镜显示乳液中油滴仍然分布相对均匀。

The efficacy of topical spray containing Centella asiatica extract on excision wound healing in rats

Centella asiatica (Linn.) belongs to the family of Apiaceae(Umbeliferae). It has been widely used for traditional medicine, especially for wound healing, anti-inflammatory,antipsoriatic, antiulcer, antibacterial and antifungal. The biologically active ingredients of Centella asiatica are believed to be triterpenes, particularly asiatic acid, madecassic acid,asiaticoside and madecassoside (Fig. 1).

Preparation of Hydroxypropyl-β-cyclodextrin Cross-linked Multi-walled Carbon Nanotubes and Their Application in Enantioseparation of Clenbuterol

A method of cross-linking multi-walled carbon nanotubes by a nucleophilic substitution of brominated multi-walled carbon nanotubes using hydroxypropyl-β-cyclodextrin anions was studied. The modified multi-walled carbon nanotube samples were characterized using thermogravimetric analysis, energy-dispersive X-ray spectroscopy, transmission electron microscopy, scanning electron microscopy, Raman spectroscopy and Fourier transform infrared spectroscopy. The hydroxypropyl-β-cyclodextrin modified multi-walled carbon nanotubes were used as a chiral stationary phase additive for thin-layer chromatography to separate clenbuterol enantiomers, and the chiral separation factor was increased.

Physicochemical Properties and Gastric Mucosa Irritation of Cantharidin-hydroxypropyl-β-cyclodextrin Inclusion Complex

Objective To increase the solubility and relieve the mucous irritation of cantharidin (CA) by preparing cantharidin-hydroxypropyl-β-cyclodextrin (CA/HP-β-CD) inclusion complex. Methods The inclusion complex was prepared by co-evaporation method and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and nuclear magnetic resonance (NMR). Results The disappearance of CA as well as the shift of exothermic peaks shown in DSC results indicated the complexation phenomenon. XRD results showed that the crystalline CA pattern had disappeared, and in NMR results, H-5 shifted from δ 3.731 to 3.695 after complexation and H-2 shifted from δ 3.626 to 3.598, which suggested that part of the drug had entered the HP-β-CD cavity to form an inclusion complex. The solubility increased 10.3 times after complexation and the mucous irritation of CA was relieved remarkably. Conclusion Through complexation with HP-β-CD, the solubility and dissolution rate of CA are improved significantly, and the irritation of musous is relieved.

Impact of solids on biphasic biodegradation of phenanthrene in the presence of hydroxypropyl-β-cyclodextrin(HPCD)

The consequence of polycyclic aromatic hydrocarbons(PAHs)in the environment is of great concern.The hydrophobic properties of PAHs significantly impact phase distribution causing limited bioavailability.Enhanced biodegradation has been extensively carried out by surfactants and the redeployment effect was recognized.However,the quantitative relationship concerning the impact of solids was rarely reported.A batch of biphasic tests were carried out by introducing Mycobacterium vanbaalenii PYR-1 and hydroxypropyl-β-cyclodextrin(HPCD)into a mixture of phenanthrene solution and various glass beads(GB37-63,GB105-125,and GB350-500).The comparative results demonstrated that HPCD had little effect on microbial growth and was not degradable by bacterium.A model was proposed to describe the biodegradation process.The regression results indicated that the partition coefficient kd(1.234,0.726 and 0.448 L·g–1)and the degradation rate k(0 mmol·L^(–1):0.055,0.094,and 0.112;20 mmol·L^(–1):0.126,0.141,and 0.156;40 mmol·L^(–1):0.141,0.156 and 0.184 d^(–1))were positively and negatively correlated with the calculated total surface area(TSA)of solids,respectively.Degradation enhanced in the presence of HPCD,and the enhancing factor f was calculated(20 mmol·L^(–1):15.16,40.01,and 145.5;40 mmol·L^(–1):13.29,37.97,and 138.4),indicating that the impact of solids was significant for the enhancement of biodegradation.

中等取代度的羟丙基-β-环糊精对依托泊苷的包埋特性分析

目的:研究取代度为6.7的羟丙基-β-环糊精对难溶性药物依托泊苷的包埋特性。方法:采用红外分光光度法、差示扫描量热法、X-射线衍射法对包合物进行了研究。结果:羟丙基-β-环糊精与依托泊苷形成了1∶1的包合物,提高依托泊苷在水中的溶解度约75.1倍。结论:本实验的研究内容在提高药物的溶解度、稳定性和生物利用度等方面有广阔前景。

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.

Contrary Photodegradative Characterization of Two Organic Compounds by Complexing with Cyclodextrins

The effectiveness of the solubilization and photodegradation of β-cyclodextrin （β-CD） and hydroxypropyl-β- cyclodextrin （HPCD） on two hydrophobic organic compounds （HOC） of methyl parathion and pentachlorophenol was investigated. The results indicate that the solubilization or photodegradation of two HOC were influenced by complexing with β-CD or HPCD. The solubility of pentachlorophenol （PCP） was increased linearly with β-CD concentration. The solubility of methyl parathion （MPT） was increased with the increase of β-CD concentration initially, however, as the β-CD concentration was enhanced above 3 g/L, the solubility was decreased with increase of β-CD concentration. The solubilities of two HOC were increased linearly with the increase of HPCD concentration. Although the photodegradation of MPT was improved, the photodegradation of PCP was restrained by complexation of HOC with β-CD or HPCD. In a word, the effectiveness of photodegradation or solubilization of HPCD was more significant than that of β-CD. One potential application of such a method was the in situ remediation of hydrophobic organic pollutants in contaminated soil and groundwater or industrial waste streams.