Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: in vitro and in vivo studies

A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427?±?0.015?mm thick, weighed 55.89?±?0.79?mg, and had a surface pH of 6.34?±?0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959?±?0.106?mg/cm² for OD and 0.877?±?0.031?mg/cm² for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4?h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. C_max of OD in saliva was 37.04?μg/ml and that of DEX was 9.737?μg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.     

Ocular application of chitosan

Introduction: A major problem in ocular therapeutics with classical formulations is the maintenance of an effective drug concentration at the site of action for a long period of time. Enhancement of ocular bioavailability with increased dose penetration and longer retention time at desired sites can be achieved by recent formulations. Chitosan stands out with its unique structural advantageous characteristics for different types of formulations like in situ gelling systems, micro- and nanoparticles, inserts, etc.

Areas covered: In this review, the authors focus on ocular therapeutics and the characteristics that make chitosan more acceptable in ocular applications.

Expert opinion: Chitosan seems to be one of the most promising polymeric carriers for both hydrophilic and lipophilic drugs for ocular application.     

苦参碱壳聚糖微球的制备及体外释药

目的:以壳聚糖为囊材制备苦参碱结肠靶向给药微球及评价其体外释药情况。方法:用乳化化学交联法制备微球,以微球的粒径分布百分数、载药量及包封率为优化指标对影响微球制备的主要因素用正交试验设计优化制备条件;并对最佳制备工艺制得的微球进行3种不同递质(人工胃液、人工肠液及大鼠结肠液)中的体外释放度评价。结果:制得的苦参碱壳聚糖微球在电镜下,球形表面圆整,粒径分布适宜,微球平均粒径为(68.3±2.7)μm,平均载药量为(16.0±0.5)%,平均包封率为(66.3±4.2)%。苦参碱壳聚糖微球在人工胃液中2h不释药;在人工肠液中4h内释放不到1%,96h释药不到10%;在含大鼠结肠内容物的磷酸盐缓冲液(pH6.8)中4h释放10%左右,36h释药近50%,此后释药趋于缓慢,96h释药近80%。结论:苦参碱壳聚糖微球几乎不在上消化道释药,而是在结肠靶向释药。     

Mucoadhesive microspheres containing gentamicin sulfate for nasal administration: preparation and in vitro characterization

In this study, suitable microsphere formulations were designed in order to provide the absorption of a high polar drug through nasal mucosa. For this purpose, gentamicin sulfate (GS) was chosen as a model drug and used at different drug/polymer ratios in the microsphere formulations. The microspheres were prepared by spray drying technique. Hydroxypropyl methylcellulose was used as a mucoadhesive polymer in the formulations to increase the residence time of the microspheres on the mucosa. Sodium cholate was added into the formulations for increasing the absorption of GS through nasal mucosa. The in vitro characteristics of the microspheres were determined. The microspheres were evaluated with respect to the particle size, production yield, encapsulation efficiency, shape and surface properties, drug-polymer interaction, mucoadhesive property, in vitro drug release and suitability for nasal drug delivery.     

5-氟尿嘧啶结肠定位壳聚糖微球在大鼠体内的药物动力学及生物利用度考察

目的对结肠定位壳聚糖微球的体内药物动力学及生物利用度进行考察,为壳聚糖微球在结肠肿瘤治疗领域的应用提供理论依据。方法用HPLC法测定大鼠口服5-氟尿嘧啶壳聚糖微球(受试制剂)和5-氟尿嘧啶溶液(参比制剂)后不同时间点血浆中5-氟尿嘧啶的质量浓度,计算药物动力学参数和相对生物利用度。结果微球和溶液的ρmax分别为(30.16±2.870)mg.L-1和(13.23±2.817)mg.L-1,tmax分别为(8.333±1.505)h和(1.042±0.400)h,相对生物利用度为215.42%。结论5-氟尿嘧啶壳聚糖微球与溶液剂相比,具有一定的结肠定位性和缓释性,且相对生物利用度高。     

Preparation,in vitro characterization,pharmacokinetic, and pharmacodynamic evaluation of chitosan-based plumbagin microspheres in mice bearing B16F1 melanoma

The present study was aimed to evaluate the anti-tumor efficacy and systemic toxicity of chitosan-based plumbagin microspheres in comparison to free plumbagin. The optimized formulation had a mean particle size of 106.35 μm with an encapsulation efficiency of 80.12%. Pharmacokinetic studies showed a 22.2-fold increase in elimination half-life (t_1/2) of plumbagin from chitosan microspheres as compared to free plumbagin. Administration of plumbagin microspheres resulted in a significant tumor growth inhibition and reduced systemic toxicity. These results suggest that chitosan-based microspheres could be a promising strategy for the systemic delivery of anti-cancer agents like plumbagin.     

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery,characterization and in vitro deposition study

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20?μm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40?μM of resveratrol.     

Glucosamine-anchored doxorubicin-loaded targeted nano-niosomes: pharmacokinetic,toxicity and pharmacodynamic evaluation

Background: Efficacy of anticancer drug is limited due to non-selectivity and toxicities allied with the drug; therefore the heart of the present work is to formulate drug delivery systems targeted selectively towards cancer cells with minimal toxicity to normal cells.

Purpose: Targeted drug delivery system of doxorubicin (DOX)-loaded niosomes using synthesized N-lauryl glucosamine (NLG) as a targeting ligand.

Methods: NLG-anchored DOX niosomes were developed using ethanol injection method.

Results: Developed niosomes had particle size <150?nm and high entrapment efficiency ～90%. In vivo pharmacokinetics exhibited long circulating nature of targeted niosomes with improved bioavailability, which significantly reduced CL and Vd than DOX solution and non-targeted niosomes (35 fold and 2.5 fold, respectively). Tissue-distribution study and enzymatic assays revealed higher concentration of DOX solution in heart while no toxicity to major organs with developed targeted niosomes was observed. Solid skin melanoma tumor model in mice manifested the commendable targeting potential of targeted niosomes with significant reduction in tumor volume and high % survival rate without drop in body weight in comparison with DOX solution and non-targeted niosomes of DOX.

Conclusion: The glucosamine-anchored DOX-loaded targeted niosomes showed its potential in cancer targeted drug therapy with reduced toxicity. Abbreviations ALT alanine transaminase

CL clearance

CPK creatinine phosphokinase

DOX doxorubicin

EDC.HCL ethyl carbidimide hydrochloride

GLUT glucose transporter

GSH glutathione S-transferase

LDH lactate dehydrogenase

LHRH luteinizing hormone-releasing hormone

MDA malonaldehyde

NHS N-hydroxy succinimide

NLG N-lauryl glucosamine

NTAR DoxNio non-targeted doxorubicin niosomes

PBS phosphate buffer saline

RGD argynyl glycyl aspartic acid

SGOT serum glutamate oxaloacetate transaminase

SGPT serum glutamate pyruvate transaminase

SOD superoxide dismutase

TAR DoxNio targeted doxorubicin niosomes

Vd volume of distribution

     

壳聚糖在靶向制剂中的应用进展

壳聚糖是一种天然高分子化合物，壳聚糖及其衍生物具有优良的生物相容性和生物可降解性，在制药业有广阔的应用前景。综述了近几年来壳聚糖及其衍生物在靶向制剂中的应用。     

Core shell methyl methacrylate chitosan nanoparticles: In vitro mucoadhesion and complement activation

BACKGROUND AND THE PURPOSE OF THE STUDY: Studies show that chitosan nanoparticles increase mucoadhesivity and penetration of large molecules across mucosal surface. The aim of the present study was to investigate the use of thiolated chitosan in the development of polysaccharide-coated nanoparticles in order to confer specific functionality to the system. METHODS: Methyl methacrylate nanoparticles were coated with thiolated chitosan using a radical polymerization method. Thiolation was carried out using glutathione (GSH) to improve mucoadhesivity and permeation enhancing properties of chitosan. Mucoadhesion studies were carried out by calculating the amount of mucin adsorbed on nanoparticles in a specific period of time. Complement consumption was assessed in human serum (HS) by measurement of the hemolytic capacity of the complement system after contact with nanoparticles. RESULTS: The FT-IR and (1)HNMR spectra both confirmed the synthesis and showed the conjugation of thiolated chitosan to methyl methacrylate (MMA) homopolymer. Nanoparticles were spherical having a mean diameter within the range of about 334-650 nm and their positive zeta potential values indicated the presence of the cationic polysaccharide at the nanoparticle surface. Increasing the amount of thiolated chitosan led to mucoadhesivity and complement activation. However there was not dose dependent correlation between these phenomenons and the absence of thiolated chitosan led to particles with larger size, and without ability to activate complement process. MAJOR CONCLUSION: It can be concluded that nanoparticles could be used for the mucosal delivery of peptides and proteins. Results show that the thiolated chitosan had higher mucoadhesion and complement activation than unmodified chitosan.     

Preparation of novel solid lipid microparticles loaded with gentamicin and its evaluation in vitro and in vivo

Objective: To formulate and evaluate solid-reversed-micellar-solution (SRMS)-based solid lipid microparticles (SLMs) for intramuscular administration of gentamicin.

Methods: SRMS formulated with Phospholipon® 90G and Softisan® 154 were used to prepare gentamicin-loaded SLMs. Characterizations based on size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release of gentamicin from the SLMs was performed in phosphate buffer while in vivo release studies were conducted in rats.

Results: Maximum EE% of 90.0, 91.6 and 83.0% were obtained for SLMs formed with SRMS 1:1, 1:2 and 2:1, respectively. Stable, spherical and smooth SLMs of size range 9.80?±?1.46?µm to 33.30?±?6.42?µm were produced. The release of gentamicin in phosphate buffer varied widely with the lipid contents. Moreover, significant (p?<?0.05) amount of gentamicin was released in vivo from the SLMs.

Conclusion: SRMS-based SLMs would likely offer a reliable means of delivering gentamicin intramuscularly.     

Mucoadhesive glycol chitosan nanoparticles for intranasal delivery of hepatitis B vaccine: enhancement of mucosal and systemic immune response

In this study, for the first time, glycol chitosan (GC) nanoparticles (NPs) were prepared and evaluated to obtain systemic and mucosal immune responses against nasally administered hepatitis B surface antigen (HBsAg). Size, zeta potential and morphology of the NPs were investigated as a function of preparation method. NPs with high loading efficacy (?>?95%) and positively charged surface were obtained with an average particle size of approximately 200?nm. The structural integrity of HBsAg in NPs was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and further confirmed by measuring the in vitro antigenicity using an enzyme immunoassay. During in vivo studies, GC NPs showed the lowest nasal clearance rate and better mucosal uptake when compared with chitosan (CS) NPs. The immunogenicity of NPs-based delivery system(s) was assessed by measuring anti-HBsAg antibody titer in mice serum and secretions after intranasal administration. The alum-based HBsAg vaccine injected subcutaneously was used as positive control. Results indicated that alum-based HBsAg induced strong humoral but negligible mucosal immunity. However, GC NPs induced stronger immune response at both of the fronts as compared to generated by CS NPs. This study demonstrates that this newly developed system has potential for mucosal administration of vaccines.     

Development and in vivo evaluation of chitosan nanoparticles for the oral delivery of albumin

Albumin is used as a plasma expander in critically ill patients and for several other clinical applications mainly via intravenous infusion. Oral administration of albumin can improve patient compliance although limited oral bioavailability of proteins is still a major challenge. Although nanomaterials have been extensively utilized for improving oral delivery of proteins, albumin has been utilized only as either a model drug or as a carrier for drug delivery. In the current study, for the first time, chitosan nanoparticles have been developed and extensively optimized to improve oral bioavailability of albumin as a therapeutic protein. Several characterizations have been performed for the albumin-loaded nanoparticles (e.g. drug encapsulation efficiency, DSC, FTIR, particle size, zeta potential, morphology, release kinetics, and enzymatic stability). Nanosized spherical particles were prepared and demonstrated high stability over three months either in a powdered form or as suspensions. Sustained release of albumin over time and high enzymatic stability as compared to the free albumin were observed. In vivo, higher serum concentrations of albumin in normal rabbits and cirrhotic rats were attained following oral and intraperitoneal administrations of the albumin-loaded nanoparticles as compared to the free albumin. The nanoparticles developed in the current study might provide efficient nanovehicles for oral administration of therapeutic albumin.     

Magnetic chitosan oligomer-sulfonate-stearic acid triple combination as cisplatin carrier for site-specific targeted on MCF-7 cancer cells: Preparation,characterization and in vitro experiments

In this study, a new amphiphilic target-specific adsorbent, chitosan oligomer-sulfonate-stearic acid triple combination (S-Cho-SA), and magnetic chitosan oligomer-sulfonate-stearic acid triple combination (M-S-Cho-SA) by oleic acid (OA)-modified Fe₃O₄ via hydrophobic interaction are fabricated. By modifying the nanoparticle surfaces and having the ability to magnetically allow the target region, these particles attract attention as important particles used in targeting mechanisms in cancer therapy. With magnetic nanoparticles and an external magnetic field, it is possible to transport therapeutic agents to the target site and keep them in the desired effect zone for a longer period of time. These new adsorbents are characterized by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy, nuclear magnetic resonance (NMR), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), and thermogravimetric analysis (TG/DTA). After chemical characterization, it is complexed with cisplatin (CDDP). The magnetic adsorbents were loaded with high efficiency (>50%), and the release experiments exhibited that cisplatin is released more at pH 4.5 compared with pH 7.4 at 37°C. It showed better drug release results under a magnetic field for magnetic adsorbents (36% for pH 4.5 and 3.6% for pH 7.4). The biocompatibility of the prepared adsorbents was demonstrated via the XTT assay in MCF-7 cell lines. The results also exhibited that S-Cho-SA and M-S-Cho-SA were biocompatible, and free cisplatin and cisplatin-complexed adsorbents showed an antiproliferative effect. The results showed that these new cisplatin-loaded (M-S-Cho-SA) nanoparticles are good candidates for thermotherapy in cancer treatment in the future, as they can provide selectivity by site-specific targeting and hold onto an alternative magnetic field due to the magnetic nature of the nanoparticles.     

Preparation and characterization of chitosan microparticles for oral sustained delivery of gliclazide: in vitro/in vivo evaluation

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic cross‐linking with gliclazide (GLZ) as a model drug. The particle sizes of TPP‐chitosan microparticles ranged from 675–887 µm with loading efficiencies of greater than 94%. Chitosan concentration, TPP solution pH, and glutaraldehyde volume solution added to the TPP cross‐linking solution affected drug release characteristics. Pectin interactions with cationic chitosan on the surface of TPP/chitosan microparticles led to the formation of polyelectrolyte complex films that improved drug sustained release performance. In vivo testing of the GLZ‐chitosan microparticles in diabetic albino rabbits demonstrated a significant antidiabetic effect of GLZ/chitosan microparticles after 8 h that lasts for 18 h compared with GLZ powder that produced a maximal hypoglycemic effect at 4 h, suggesting that GLZ/chitosan microparticles represent an improved system for the long‐term delivery of GLZ. Drug Dev Res 72: 235–246, 2011. © 2010 Wiley‐Liss, Inc.     

Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.     

Gastroscopic and pharmacokinetic evaluation of a new pivmecillinam tablet

Summary Three different pivmecillinam preparations, a conventional 200 mg tablet (P tablet) and two new formulations containing respectively pivmecillinam 200 mg and 400 mg plus Avicel^? (microcrystalline cellulose) as a disintegrator (PA tablet), were compared in vitro and in a gastroscopic study in 8 healthy volunteers. Disintegration of the PA tablet was significantly more rapid both in vitro and in the stomach. Following disintegration, the content of the PA tablet was spread over a larger area of the gastric mucosa (1088 mm²) than was observed with the P tablets (408 mm²). Three of the 8 volunteers taking the P tablet developed hyperaemia, interstitial bleeding or erosions of the mucosa of the stomach. No such reactions were seen with the PA tablets. Serum concentrations of mecillinam following ingestion of pivmecillinam tablets were determined in three groups of subjects; fasting volunteers, both supine and ambulant, and in ambulant subjects who took the preparation with a light meal. There was a tendency for the new PA tablets to produce a higher peak serum level as well as greater bioavailability of mecillinam. Administration of the PA tablets with a meal significantly increased the peak serum level and total bioavailability of the drug. On the basis of our observations we recommend adoption of the new PA tablet, because of its quick passage through the oesophagus and its more rapid and complete disintegration in the stomach.     

Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development,characterization, and evaluation

In clinical practices, solution of dorzolamide hydrochloride (DH) and timolol maléate (TM) is recommended for the treatment of glaucoma. However, low drug-contact time and poor ocular bioavailability of drugs due to drainage of solution, tear turnover and its dilution or lacrimation limits its uses. In addition, systemic absorption of TM may induce undesirable cardiovascular side effects. Chitosan (CS) is a polycationic biodegradable polymer which provides sustained and local delivery of drugs to the ocular sites. Hyaluronic acid (HA) also provides synergistic effect for mucoadhesion in association with chitosan. In the present study, hyaluronic acid modified chitosan nanoparticles (CS-HA-NPs) loaded with TM and DH were developed and characterized. The CS-HA-NPs were evaluated for size, shape, zeta potential, entrapment efficiency, and mucoadhesive strength. The in vitro release study was also performed in PBS pH 7.4. The ocular irritation potential of CS-HA-NPs was estimated using draize test on albino rabbits. A significant reduction in IOP level was obtained using CS-HA-NPs as compared to plain solution of drug and a comparable higher reduction in IOP level was observed as to CS-NPs. These results suggest that HA potentialy enhance the mucoadhesiveness and efficiency of CS-NPs and may be promising carrier for ocular drug delivery.     

pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation

The aim of present study was to investigate a pH-responsive and mucoadhesive nanoparticle system for oral bioavailability enhancement of low-molecular weight heparin (LMWH). The thioglycolic acid (TGA) was first covalently attached to chitosan (CS) with 396.97?±?54.54?μmol thiol groups per gram of polymer and then the nanoparticles were prepared with thiolated chitosan (TCS) and pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by ionic cross-linking method. The obtained nanoparticles were characterized for the shape, particle size, zeta potential, drug entrapment efficiency and loading capacity. In vitro results revealed the acid stability of pH-responsive nanoparticles, which had a significant control over LMWH release and could effectively protect entrapped drugs in simulated gastric conditions. By the attachment of the thiol ligand, an improvement of permeation-enhancing effect on freshly excised carp intestine (1.86-fold improvement) could be found. The mucoadhesive properties were evaluated using fluorescently labeled TCS or CS nanoparticles. As compared with the controls, a significant improvement of mucoadhesion on rat intestinal mucosa was observed in TCS/HPMCP nanoparticles via confocal laser scanning microscopy. The activated partial thromboplastin time (APTT) was significantly prolonged and an increase in the oral bioavailability of LMWH was turned out to be pronounced after oral delivered LMWH-loaded TCS/HPMCP nanoparticles in rats, which suggested enhanced anticoagulant effects and improved absorption of LMWH. In conclusion, pH-responsive TCS/HPMCP nanoparticles hold promise for oral delivery of LMWH.