Dynamic structure model of polyelectrolyte complex based controlled-release matrix tablets visualized by synchrotron radiation micro-computed tomography.

Hydrophilic matrix tablets are the most commonly used dosage forms to fabricate oral controlled-release systems. It is highly desirable to design delivery system with novel mechanism to achieve sustained drug release through a simplified preparation process. The chitosan-anionic polymers based matrix tablets is assumed to produce self-assembly in the gastrointestinal tract, then transferring into film-coated tablets from original matrix type. But its dynamic behavior during dissolution process and the on-going internal microstructural changes during drug release were still in the dark. In this study, by using synchrotron radiation X-ray micro-tomography (SR-µCT) with phase contrast imaging, the micro-structure characteristics of chitosan-λ-carrageenan (CS-λ-CG) matrix based tablets during the dissolution were successfully elucidated for the first time. The qualitative and quantitative analyses of intensity distribution distinguished a hydrated CS-λ-CG layer from a solid core. Visualization based on 3D models provided quantitative details on the micro-structural characteristics of hydration dynamics. After CS-λ-CG matrix tablets were immersed in simulated gastric fluid (SGF) pH 1.2 medium for 0.5-2.0 h, the hydrated layer transformed into a gel layer and a solid swollen layer. The erosion front, swelling front, and solvent penetration front were also defined from the distinguishable micro-structures. More importantly, once the matrix tablet was transferred from SGF to the simulated intestinal fluid (SIF) pH 6.8 medium, a new layer with the enhanced strength and compactness in comparison to common gels was formed on the surface of tablets. The temporal and spatial variation of 3D models further provided direct evidence for this cross-linking behavior, the new layer was composed of CS-λ-CG polyelectrolyte complexes (PEC) which subsequently dominated release mechanisms. In summary, the phase contrast SR-µCT technique was utilized to investigate the hydration dynamics of CS-λ-CG matrix tablets which was supposed to provide a novel drug release mechanism. Based on the structure feature obtained from the high contrast image, different hydration region was distinguished and the cross-linked film was identified and visualized directly for the first time.

Effect of Sodium Alginate Type on Drug Release from Chitosan-Sodium Alginate-Based In Situ Film-Forming Tablets.

Natural polymers are promising as the carrier of matrix-based sustained release tablets but limited by their diversity in source and structure properties. Our previous studies found that chitosan (CS)- and alginate (SA)-based tablets can form self-assembled polyelectrolyte complex (PEC) film on the surface, which controlled drug release with a novel mechanism. To elucidate whether PEC-based sustained drug delivery system could weaken the influence of single-matrix material diversity on drug release behavior, taking theophylline as a drug model, the effect of SA structure properties, including viscosity, G/M ratio, SA salt type, and degree of esterification on drug release profiles, swelling, and erosion of CS-SA composite system was investigated. The results showed that the viscosity, G content, salt type, and esterification degree of SA had a remarkable influence on drug release when SA alone was used as a matrix, but little effect of these parameters on drug release was observed in CS-SA combination system. SA of low viscosity is superior in controlling drug release from CS-SA combination system. Potassium, magnesium salt of SA, and esterified SA can help form PEC of higher thickness with different swelling and erosion extent. In conclusion, this study demonstrated that drug release diversity due to SA structure difference can be well eradicated by using CS-SA combination system, which is a promising strategy to manufacture natural polymer-based products with constant quality.

Enhanced delivery of doxorubicin to the liver through self-assembled nanoparticles formed via conjugation of glycyrrhetinic acid to the hydroxyl group of hyaluronic acid.

Liver-targeted nanoparticles is highly desired for better therapy of liver cancer. In this study, enhanced delivery of doxorubicin (DOX) to the liver cells through self-assembled nanoparticles formed via conjugation of glycyrrhetinic acid (GA) to the hydroxyl group of hyaluronic acid (HA) was investigated. The DOX loaded hyaluronic acid-glycyrrhetinic acid succinate (HSG) conjugates based nanoparticles (HSG/DOX nanoparticles) were sub-spherical in shape with particle size in the range of 180-280 nm, the drug loading was drug-to-carrier ratio and GA graft ratio dependent. In vitro release study suggested that the release of DOX from HSG nanoparticles was sustained and the release rate was pH and GA graft ratio dependent. MTT assay indicated the HSG/DOX nanoparticles presented a GA-dependent cytotoxicity to HepG2 cells. Pharmacokinetics study demonstrated the HSG/DOX nanoparticles could prolong blood circulation time of DOX and had a higher AUC value than that of DOX solution. Furthermore, tissue distribution study revealed the HSG/DOX nanoparticles significantly increased the accumulation of DOX in the liver and meanwhile decreased the cardiotoxicity and nephrotoxicity of DOX. Moreover, the liver targeting enhancing capacity was HSG conjugate structure dependent. The accumulation of HSG-20/DOX, HSG-12/DOX, and HSG-6/DOX nanoparticles in the liver was 4.0-, 3.1-, and 2.6-fold higher than that of DOX solution. In vivo imaging analysis further demonstrated HSG nanoparticles not only had better liver targeting effect, but also presented superior tumor targeting efficiency, and the tumor targeting capacity was also GA-dependent. These results indicated that HSG conjugates prepared via modifying the hydroxyl groups of HA have promising potential as a liver-targeting nanocarrier for the delivery of hydrophobic anti-tumor drugs.

Tunable and sustained-release characteristics of venlafaxine hydrochloride from chitosan-carbomer matrix tablets based on in situ formed polyelectrolyte complex film coating.

The objective of this study is to design sustained-release tablets using matrix technology, which can well control the release of highly water-soluble drugs with good system robustness and simple preparation process. Taking venlafaxine hydrochloride (VH) as a drug model, the feasibility of using chitosan (CS), carbomer (CBM) combination system to achieve this goal was studied. Formulation and process variables influencing drug release from CS-CBM matrix tablets were investigated. It was found that CS-CBM combination system weakened the potential influence of CS, CBM material properties and gastric emptying time on drug release profile. Demonstrated by direct observation, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), in situ self-assembled polyelectrolyte complex (PEC) film was formed on the tablet surface during gastrointestinal tract transition, which contributed to the tunable and robust control of drug release. The sustained drug release behavior was further demonstrated in vivo in Beagle dogs, with level A in vitro and in vivo correlation (IVIVC) established successfully. In conclusion, CS-CBM matrix tablets are promising system to tune and control the release of highly water-soluble drugs with good system robustness.

Synthesis, characterization and liver targeting evaluation of self-assembled hyaluronic acid nanoparticles functionalized with glycyrrhetinic acid.

Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6-260.7nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting.

[Intranasal absorption of rivastigmine hydrogen tartrate and brain targeting evaluation].

To investigate factors influencing the intranasal absorption of rivastigmine hydrogen tartrate (RHT), we studied the pharmacokinetics of RHT after intranasal administration and evaluated its brain targeting behavior. In situ rat nasal perfusion model was used in the study and pH impact was examined on the intranasal absorption of RHT. High performance liquid chromatography (HPLC) method was established to measure RHT concentration in the plasma and brain tissue after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting index(DTI), and nose-to-brain direct transport percentage (DTP) were calculated. It was demonstrated that the intranasal absorption mechanism of RHT was passive diffusion. The absorption rate was highest at pH 6.0. The absolute bioavailability of intranasally administrated RHT was 73.58%. Compared with that of intravenous administration, RHT absorption into the brain was faster and more efficient after intranasal delivery, and the DTI value was 195.27% of intravenous injection. Moreover, 48.79% of the drug can be absorbed directly from the nose into the brain without systematic circulation. Meanwhile, drug elimination half-time in the brain was prolonged by 1.4 fold compared to that of intravenous injection. In conclusion, intranasal administration of RHT not only improves drug absorption into the system, but also enhances drug absorption rate and content in the brain remarkably, which is an advantage in the treatment of central nervous system-related diseases.

Applications of Natural Polymeric Materials in Solid Oral Modified-Release Dosage Forms.

Solid oral modified-release dosage forms provide numerous advantages for drug delivery compared to dosage forms where the drugs are released and absorbed rapidly following ingestion. Natural polymers are of particular interest as drug carriers due to their good safety profile, biocompatibility, biodegradability, and rich sources. This review described the current applications of important natural polymers, such as chitosan, alginate, pectin, guar gum, and xanthan gum, in solid oral modified-release dosage forms. It was shown that natural polymers have been widely used to fabricate solid oral modified-release dosage forms such as matrix tablets, pellets and beads, and especially oral drug delivery systems such as gastroretentive and colon drug delivery systems. Moreover, chemical modifications could overcome the shortcomings associated with the use of natural polymers, and the combination of two or more polymers presented further advantages compared with that of single polymer. In conclusion, natural polymers and modified natural polymers have promising applications in solid oral modified-release dosage forms. However, commercial products based on them are still limited. To accelerate the application of natural polymers in commercial products, in vivo behavior of natural polymers-based solid oral modified-release dosage forms should be deeply investigated, and meanwhile quality of the natural polymers should be controlled strictly, and the influence of formulation and process parameters need to be understood intensively.