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Yingchong Chen,1 Yuling Liu,2 Jin Xie,1 Qin Zheng,1 Pengfei Yue,1 Liru Chen,3 Pengyi Hu,1 Ming Yang1 1Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, People’s Republic of China; 2Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, People’s Republic of China; 3Beijing Hospital, Beijing 100730, People’s Republic of ChinaCorrespondence: Pengfei Yue; Ming YangKey Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, 1688 Meilingdadao Road, Nanchang 330004, People’s Republic of ChinaTel/ Fax +86 791 8711 8658Email ypfpharm@126.com; yangming_215@163.comPurpose: Nose-to-brain drug delivery is an effective approach for poorly soluble drugs to bypass the blood–brain barrier. A new drug intranasal delivery system, a nanosuspension-based in situ gel, was developed and evaluated to improve the solubility and bioavailability of the drug and to prolong its retention time in the nasal cavity.Materials and Methods: Breviscapine (BRE) was chosen as the model drug. BRE nanosuspensions (BRE-NS) were converted into BRE nanosuspension powders (BRE-NP). A BRE nanosuspension in situ gelling system (BRE-NG) was prepared by mixing BRE-NP and 0.5% gellan gum (m/v). First, the BRE-NP were evaluated in terms of particle size and by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Subsequently, the critical ionic concentration of the gellan gum phase transition, influence of the deacetylated gellan gum (DGG) concentration on the expansion coefficient (S%), water-holding capacity, rheological properties and in vitro release behaviour of the BRE-NG were investigated. The pharmacokinetics and brain distribution of the BRE-NG after intranasal administration were compared with those of the intravenously injected BRE-NP nanosuspensions in rats.Results: The rheology results demonstrated that BRE-NG was a non-Newtonian fluid with good spreadability and bioadhesion performance. Moreover, the absolute bioavailability estimated for BRE-NG after intranasal administration was 57.12%. The drug targeting efficiency (DTE%) of BRE in the cerebrum, cerebellum and olfactory bulb was 4006, 999 and 3290, respectively. The nose-to-brain direct transport percentage (DTP%) of the cerebrum, cerebellum and olfactory bulb was 0.975, 0.950 and 0.970, respectively.Conclusion: It was concluded that the in situ gel significantly increased the drug retention time at the administration site. Therefore, the nanosuspension-based in situ gel could be a convenient and effective intranasal formulation for the administration of BRE.Keywords: nose-to-brain, nanosuspensions, in situ gel, breviscapine, brain distribution

Maryam Dibaei,1 Mohammad-Reza Rouini,1 Behjat Sheikholeslami,1 Mahdi Gholami,2,3 Rassoul Dinarvand4,51Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Experimental Medicine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 5Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranBackground: Curcumin, a bioactive component with multiple characteristics, has been shown to have many therapeutic effects. However, there are several limitations regarding the use of curcumin such as instability, low solubility, poor bioavailability, and rapid elimination. Different approaches have been used to solve these problems.Materials and methods: In this study, surface-modified nanosuspension (NS) is investigated as a novel brain delivery system. Two different methods were used for the preparation of nanosuspensions with two different stabilizers. The surface of the nanosuspensions was coated with D-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS) and Tween 80 using physical adsorption. Curcumin NSs were prepared using two different top-down techniques by high-pressure homogenizer and probe sonicator. A validated sensitive and selective high-performance liquid chromatography method using fluorescence detection was used for the determination and quantification of curcumin. Pharmacokinetics and biodistribution of curcumin NSs and solutions after intravenous administration in rats were studied.Results: Higher levels of curcumin in the brain were detected when Tween 80-coated NS was used compared with the curcumin solution and TPGS coated NS (TPGS-NS) (P-value

Jin Xie,1,* Yijing Luo,1,* Yang Liu,1 Yueqin Ma,1,2 Pengfei Yue,1,* Ming Yang1 1Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China; 2Department of Pharmaceutics, 94th Hospital of People’s Liberation Army, Nanchang, China *These authors contributed equally to this work Background: To improve the dissolution and bioavailability of poorly soluble drugs, novel nanosuspensions using co-processed nanocrystalline cellulose–sodium carboxymethyl starch (NCCS) as a synergetic stabilizer were first designed.Methods: Co-processed NCCS was prepared by means of homogenization. Poorly soluble baicalin (BCA) was used as a model drug. BCA nanosuspension (BCA-NS/NCCS) using co-processed NCCS as a dispersant was prepared via homogenization and further converted into the dried BCA nanosuspension particle (BCA-NP/NCCS) via spray drying. The influence of NCCS on the dispersion efficiency of BCA-NS/NCCS was investigated. Morphology and crystal characteristic of NCCS and BCA-NP were analyzed. The dissolution and bioavailability evaluation were performed to investigate the feasibility of NCCS as a stabilizer for BCA-NS/NCCS and BCA-NP.Results: The optimum 50% concentration of NCCS (nanocrystalline cellulose [NCC]:sodium carboxymethyl starch [SCS]=60:40) could be mostly beneficial for formation and stability of BCA-NS/NCCS. NCCS could completely prevent aggregation of BCA-NP during spray drying and enhance the redispersibility as well as dissolution of spray-dried BCA-NP, which might be attributed to “brick–concrete”-based barrier effect of NCCS and the swelling capacity of superdisintegrant SCS. The crystal state of NCC and BCA presented in BCA-NP/NCCS remained unchanged during the homogenization. The BCA-NP/NCCS exhibited a fast dissolution rate and significantly enhanced bioavailability of BCA. The AUC(0–∞) of the BCA-NP/NCCS (8,773.38±718.18 µg/L·h) was 2.01 times (P

Li Jun,1,2,* Yang Min,2,* Xu Wen-Rong11School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; 2Department of Intensive Care Unit, Chest Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200030, China*These authors contributed equally to this workBackground: In this study, fluvastatin (FVT) nanosuspensions containing cyclodextrin were developed to improve oral bioavailability.Methods: FVT nanosuspensions containing cyclodextrin were prepared by a high pressure homogenization technique. The nanosuspensions system was then characterized by transmission electron microscopy (TEM), particle size, differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). In addition, in vitro drug release properties, pharmacokinetics and pharmacodynamics were also investigated in detail.Results: After lyophilization, the nanosuspensions could be redispersed gently and with a narrow particle size distribution, but the particle size has no obvious change. The powder X-ray diffraction and differential scanning calorimetry of FVT nanosuspensions showed that FVT existed in amorphous form in nanosuspensions. In vitro release, FVT nanosuspensions have sustained-release properties. Meanwhile, FVT nanosuspensions could significantly modify the pharmacokinetic profile and increase the bioavailability of FVT by more than 2.4-fold in comparison with the FVT capsules group. In vivo irritation test showed that there was almost no evidence of hemorrhagic mucosal erosion and intestinal villus destruction in rat gastric mucosa.Conclusion: The combination of nanocrystallization and cyclodextrin complexation techniques is a new attempt to formulate poorly water-soluble FVT. Keywords: fluvastatin, HP-β-CD, nanosuspensions, bioavailability, irritation test

Qi Li,1 Fen Chen,2 Yun Liu,1 Shihui Yu,1 Xiumei Gai,1 Mingzhu Ye,1 Xinggang Yang,1 Weisan Pan1 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China; 2Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang 110016, People’s Republic of China Background: The objective of this study was to develop a more bio-available and safe nanosuspension of meloxicam (MX), which could dramatically improve inflammation targeting. Methods and results: MX-loaded bovine serum albumin (BSA) nanosuspensions were prepared using acid–base neutralization in aqueous solution and the prepared nanosuspensions were characterized. The results obtained showed that the prepared nanosuspensions had a narrow size distribution with a mean particle size of 78.67±0.22 nm, a polydispersity index of 0.133±0.01, and a zeta potential of -11.87±0.91 mV. The prepared MX nanosuspensions were spherically wrapped by BSA with a smooth surface as shown by transmission electron microscopy. Stability studies showed that the nanosuspensions were physically stable at 4°C with a shelf life of at least 6 months. In the in vitro dissolution test, the MX-loaded BSA nanosuspension (MX-BSA-NS) exhibited sustained release. In addition, an in vivo pharmacokinetic study in rats following intravenous injection showed that the half-life (t1/2), mean residence time (MRT), and area under the concentration–time curve (AUC0–∞) of MX-BSA-NS was increased by 169.83%, 150.13%, and 148.80%, respectively, in comparison with MX conventional solution (MX solution). Furthermore, results from inflammation targeting studies showed that the concentration of MX increased significantly in inflamed tissues but was reduced in normal tissues compared with the MX solution group after injection of MX-BSA-NS. Conclusion: The prepared MX-BSA-NS significantly increased the inflammation-targeting properties and bioavailability of MX, suggesting its potential as a promising formulation for the targeted drug delivery of MX in future clinical applications. Keywords: nanosuspensions, inflammation targeting, BSA, meloxicam, acid–base neutralization

Jingyi Hong,1 Zhonghao Sun,1 Yijing Li,1 Yifei Guo,1 Yonghong Liao,1 Meifeng Liu,2 Xiangtao Wang1 1Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 2Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, China Abstract: Annonaceous acetogenins (ACGs) are a large family of fatty acid derived natural products that are exclusively isolated from the Annonaceae species. Many members of this diverse family have a broad spectrum of biological activities, the most impressive of which is anticancer activity. However, their poor solubility and severe toxicity restrict their clinical application, and their complicated composition hinders their formulation and drug delivery. In this study, β-cyclodextrin was modified with folic acid (FA) and then combined with soybean lecithin to prepare FA-modified ACGs nanosuspensions (FA-ACGs-NSps). The obtained FA-ACGs-NSps had a high drug payload of 57.59% and average particle size of 199.5 nm, and they exhibited sustained drug release within 142 hours. In comparison with ACGs-NSps, FA-ACGs-NSps showed significantly enhanced cytotoxicity and higher cell uptake toward folate receptor-positive 4T1 cell lines. An in vivo study demonstrated that FA-ACGs-NSps more effectively accumulated in tumors and enhanced the antitumor therapeutic efficacy with less toxicity in 4T1 tumor bearing mice. Therefore, FA-ACGs-NSps may be a promising drug delivery system for ACGs to improve their therapeutic window and may be suitable for clinical application to treat folate-positive tumors. Keywords: Annonaceous acetogenins, nanosuspensions, folate, targeted drug delivery, antitumor activity

Linjie Yang,1 Jingyi Hong,1 Jing Di,1 Yifei Guo,1 Meihua Han,1 Meifeng Liu,2 Xiangtao Wang1 1Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 2School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, People’s Republic of China Abstract: In this study, polyethylene glycol (PEG)ylated 10-hydroxycamptothecin (mPEG1000-HCPT) was synthesized and used as a stabilizer to prepare 10-hydroxycamptothecin (HCPT) nanosuspensions for their in vitro and in vivo antitumor investigation. The resultant HCPT nanosuspensions (HCPT-NSps) had a very high drug payload of 94.90% (w/w) and a mean particle size of 92.90±0.20 nm with narrow size distribution (polydispersity index of 0.16±0.01). HCPT-NSps could be lyophilized without the need of the addition of any cryoprotectant and then be reconstituted into nanosuspensions of a similar size by direct resuspension in water. HCPT was in crystalline form in HCPT-NSps. Using mPEG1000-HCPT as stabilizer, insoluble camptothecin and 7-ethyl-10-hydroxycamptothecin could also be easily made into nanosuspensions with similar features such as high drug payload, small particle size, and cryoprotectant-free freeze drying. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay indicated that the HCPT-NSps had a significantly higher cytotoxicity than HCPT injections, with 3.77 times lower IC50 value against HepG2 cells and 14.1 times lower IC50 value against MCF-7 cells. An in vivo study in H22 tumor-bearing mice after intravenous injection of HCPT-NSps demonstrated that HCPT-NSps significantly improved the antitumor efficacy compared to the commercially available HCPT injections (86.38% vs 34.97%) at the same dose of 5 mg/kg. Even at 1/4 of the dose, HCPT-NSps could also achieve a similar antitumor efficacy to that of HCPT injections. mPEG1000-HCPT may be a highly efficient stabilizer able to provide camptothecin-based drugs, and probably other antitumor agents containing aromatic structure, with unique nanosuspensions or nanocrystals for improved in vivo therapeutic efficacy. Keywords: 10-hydroxycamptothecin, nanosuspensions, stabilizer, antitumor efficacy

Hongzhi Qiao,1,2,* Lihua Chen,3,* Tianqi Rui,1,2 Jingxian Wang,1,2 Ting Chen,1,2 Tingming Fu,1,2 Junsong Li,1,2 Liuqing Di1,2 1College of Pharmacy, Nanjing University of Chinese Medicine, 2Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing, 3Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China *These authors contributed equally to this work Abstract: Andrographolide (ADG) is a diterpenoid isolated from Andrographis paniculata with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box–Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability (Papp) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (P

In this study, polyethylene glycol (PEG)ylated 10-hydroxycamptothecin (mPEG 1000 -HCPT) was synthesized and used as a stabilizer to prepare 10-hydroxycamptothecin (HCPT) nanosuspensions for their in vitro and in vivo antitumor investigation. The resultant HCPT nanosuspensions (HCPT-NSps) had a very high drug payload of 94.90% (w/w) and a mean particle size of 92.90±0.20 nm with narrow size distribution (polydispersity index of 0.16±0.01). HCPT-NSps could be lyophilized without the need of the addition of any cryoprotectant and then be reconstituted into nanosuspensions of a similar size by direct resuspension in water. HCPT was in crystalline form in HCPT-NSps. Using mPEG 1000 -HCPT as stabilizer, insoluble camptothecin and 7-ethyl-10-hydroxycamptothecin could also be easily made into nanosuspensions with similar features such as high drug payload, small particle size, and cryoprotectant-free freeze drying. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay indicated that the HCPT-NSps had a significantly higher cytotoxicity than HCPT injections, with 3.77 times lower IC 50 value against HepG2 cells and 14.1 times lower IC 50 value against MCF-7 cells. An in vivo study in H22 tumor-bearing mice after intravenous injection of HCPT-NSps demonstrated that HCPT-NSps significantly improved the antitumor efficacy compared to the commercially available HCPT injections (86.38% vs 34.97%) at the same dose of 5 mg/kg. Even at 1/4 of the dose, HCPT-NSps could also achieve a similar antitumor efficacy to that of HCPT injections. mPEG 1000 -HCPT may be a highly efficient stabilizer able to provide camptothecin-based drugs, and probably other antitumor agents containing aromatic structure, with unique nanosuspensions or nanocrystals for improved in vivo therapeutic efficacy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The purpose of this work was to explore the particle size reduction effect of carvedilol on dissolution and absorption. Three suspensions containing different sized particles were prepared by antisolvent precipitation method or in combination with an ultrasonication process. The suspensions were characterized for particle size, surface morphology, and crystalline state. The crystalline form of carvedilol was changed into amorphous form after antisolvent precipitation. The dissolution rate of carvedilol was significantly accelerated by a reduction in particle size. The intestinal absorption of carvedilol nanosuspensions was greatly improved in comparison with microsuspensions and solution in the in situ single-pass perfusion experiment. The in vivo evaluation demonstrated that carvedilol nanosuspensions and microsuspensions exhibited markedly increased C(max) (2.09- and 1.48-fold) and AUC(0-t) (2.11- and 1.51-fold), and decreased T(max) (0.34- and 0.48-fold) in contrast with carvedilol coarse suspensions. Moreover, carvedilol nanosuspensions showed good biocompatibility with the rat gastric mucosa in in vivo gastrointestinal irritation test. The entire results implicated that the dissolution rate and the oral absorption of carvedilol were significantly affected by the particle size. Particle size reduction to form nanosized particles was found to be an efficient method for improving the oral bioavailability of carvedilol.

Background: Drug nanosuspensions are very promising for enhancing the dissolution and bioavailability of drugs that are poorly soluble in water. However, the poor stability of nanosuspensions, reflected in particle growth, aggregation/agglomeration, and change in crystallinity state greatly limits their applications. Solidification of nanosuspensions is an ideal strategy for addressing this problem. Hence, the present work aimed to convert drug nanosuspensions into pellets using fluid-bed coating technology., Methods: Indomethacin nanosuspensions were prepared by the precipitation-ultrasonication method using food proteins (soybean protein isolate, whey protein isolate, β-lactoglobulin) as stabilizers. Dried nanosuspensions were prepared by coating the nanosuspensions onto pellets. The redispersibility, drug dissolution, solid-state forms, and morphology of the dried nanosuspensions were evaluated., Results: The mean particle size for the nanosuspensions stabilized using soybean protein isolate, whey protein isolate, and β-lactoglobulin was 588 nm, 320 nm, and 243 nm, respectively. The nanosuspensions could be successfully layered onto pellets with high coating efficiency. Both the dried nanosuspensions and nanosuspensions in their original amorphous state and not influenced by the fluid-bed coating drying process could be redispersed in water, maintaining their original particle size and size distribution. Both the dried nanosuspensions and the original drug nanosuspensions showed similar dissolution profiles, which were both much faster than that of the raw crystals., Conclusion: Fluid-bed coating technology has potential for use in the solidification of drug nanosuspensions.