Absorption of diltiazem in beagle dog from pulsatile release tablet.

An orally applicable pulsatile drug delivery system in dry-coated tablet form was prepared using diltiazem hydrochloride as the model drug, and a polyvinyl chloride-hydrogenated castor oil-polyethyleneglycol mixture as the outer shell of the tablet. In vitro drug release from the prepared tablet exhibited a typical pulsatile pattern with a 7 h lag phase (non-drug release period). This dosage form was orally administered to three beagle dogs under non-fasting and fasting conditions, and the plasma concentration level of diltiazem was determined according to time after administration. The result of the in vivo study in non-fasting dogs suggested that the drug could be released in the gastrointestinal tract as in the in vitro test. However, under the fasting condition, a large difference in the plasma concentration profile was found, suggesting that the disintegration time of the tablet tended to be influenced by the feeding condition of subject.     

Design and preparation of pulsatile release tablet as a new oral drug delivery system.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.     

Development and evaluation of a monolithic floating drug delivery system for acyclovir

Acyclovir (ACV), a model drug for this study, is one of the most effective drugs against viruses of the herpes group. Absorption of orally administered ACV is variable and incomplete, with a bioavailability of ca. 15-30%. The drug is absorbed in the duodenum after oral administration and hence, preparation of a floating drug delivery system (FDDS) for ACV may increase oral absorption of the drug. ACV matrix tablets (200?mg) containing an effervescent base (sodium bicarbonate and citric acid) and a binary combination of hydroxypropyl methylcellulose (HPMC) K4M with carbopol or sodium carboxymethyl cellulose (Na CMC) or polyvinylpyrrolidone (PVP) and/or sodium alginate were prepared by the direct compression method. The tablets were evaluated for physicochemical properties and in vitro floating ability (floating lag-time and duration), bioadhesiveness and drug release. The drug release studies were carried out in 0.1?N HCl (pH 1.2) at 37±0.5°C. At appropriate time intervals, samples were withdrawn and assayed spectrophotometrically at λ(max)=259?nm. The floating test showed tablets containing 15% effervescent base had a floating lag time of 10-30?s and a duration of floating time of 24?h. The formulations containing HPMC-PVP, HPMC-Na CMC, HPMC-carbopol, and HPMC-sodium alginate released about 60-90% of their drug content during a 12-h period. Increasing carbopol caused slower drug release. We concluded that the proposed tablets with 15% effervescent base, 20-30% HPMC, 30% Na CMC (and/or 20% PVP or 20% sodium alginate) showed good floating and drug release properties in vitro, and should be considered as FDDS for ACV.     

pH-enzyme di-dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(?) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release.     

Formulation approach for nicorandil pulsatile release tablet

The purpose of this study was to obtain a nicorandil pulsatile release tablet that has a well-regulated release lag time. When nicorandil is used as an antiangina drug, administration time control is important. A pulsatile release tablet is one of the effective approaches to modified release to reduce daily administration frequency. In this study, a pulsatile release tablet of nicorandil was formulated by fumaric acid dry coating around the core tablet including nicorandil. The model tablets, which had different content ratios of excipients in the dry-coating layer, were characterized by a dissolution test. The results showed that the release lag time was generated with fast release profiles. Various lag time controls of tablets were achieved, from 60 to 310 min on average, by variation of outer layer composition. From an analysis of the relation between lag times and outer layer composition, the key ingredient for prolongation of lag time was found to be fumaric acid. To analyze the lag time generation mechanism, water penetration for tablet was measured. The results indicated that the penetration depth was proportionate to the square root of time and the lag time formation mechanism was simple water penetration through the matrix of fumaric acid to the tablet core. The results also showed that the Washburn equation could be used to design the lag time of the pulsatile release tablet in this study. In conclusion, novel release control technology using fumaric acid was appropriate to obtain a nicorandil pulsatile release tablet that has well regulated lag time.     

Preparation and evaluation of berberine alginate beads for stomach-specific delivery

The purpose of this research was to prepare floating calcium alginate beads of berberine for targeting the gastric mucosa and prolonging their gastric residence time. The floating beads were prepared by suspending octodecanol and berberine in sodium alginate (SA) solution. The suspension was then dripped into a solution of calcium chloride. The hydrophobic and low-density octodecanol enhanced the sustained-release properties and floating ability of the beads. The bead formulation was optimized for different weight ratios of octodecanol and SA and evaluated in terms of diameter, floating ability and drug loading, entrapment and release. In vitro release studies showed that the floating and sustained release time were effectively increased in gastric media by addition of octodecanol. In vivo studies with rats showed that a significant increase in gastric residence time of beads had been achieved.     

Preparation of hydroxypropylmethyl cellulose-based porous matrix for gastroretentive delivery of gabapentin using the freeze-drying method

The aims of the present study were to prepare hydroxypropylmethyl cellulose (HPMC)-based porous matrix tablets for gastroretentive drug delivery and to characterize their physicochemical properties. Gabapentin (GBP) was used as a model drug. Paste containing GBP, HPMC and water was molded and freeze-dried to prepare freeze-dried gastroretentive matrix tablet (FD-GRT). In vitro drug release and erosion studies were also performed. Although FD-GRT exhibited porous structure, they had good tablet strength and friability. Density of FD-GRT ranged from 0.402 to 0.509 g/cm³ and thus they could float on the medium surface without any lag time. FD-GRT was remained floated until the entire matrix erosion or end of drug release during in vitro release test. Release behavior of GBP could be modulated by the amount and the viscosity grade of HPMC. However, large amount and high viscosity of HPMC caused trouble in molding prior to freeze-drying. Addition of ethylcellulose could retard the release rate of GBP, with relatively low increase in viscosity of paste. Since pores generated by freeze drying imparted buoyancy for gastric retention to FD-GRT, additional materials for buoyancy was not necessary and FD-GRT had no lag time for buoyancy due to low density. Therefore it could be a promising tool for gastroretentive drug delivery.     

A Free‐Blockage Controlled Release System Based on the Hydrophobic/Hydrophilic Conversion of Mesoporous Silica Nanopores

A pH‐responsive free‐blockage release system was achieved through controlling the hydrophobic/hydrophilic conversion of mesoporous silica nanopores. This system further presented pulsatile release with changing pH values between 4.0 and 7.0 for several cycles. This free‐blockage release system could also release antitumor agents to induce cell death after infecting tumor cells and could have the ability of continuous infection to tumor cells with high drug‐delivery efficiency and few side effects.     

Biodegradable PLGA microspheres as a sustained release system for a new luteinizing hormone-releasing hormone (LHRH) antagonist

A sustained release poly(DL-lactide-co-glycolide) (PLGA) microsphere delivery system to treat prostate cancer for a luteinizing hormone-releasing hormone (LHRH) antagonists, LXT-101 was prepared and evaluated in the paper. LXT-101 microspheres were prepared from PLGA by three methods: (1) double-emulsion solvent extraction/evaporation technique, (2) single-emulsion solvent extraction/evaporation technique, and (3) S/O/O (solid-in-oil-in-oil) method. The microspheres were investigated on drug loading, particle size, surface morphology and in vitro release profiles. An accelerated release approach was also established in order to expedite the evaluation periods. The in vivo evaluation of the microspheres was made by monitoring testosterone levels after subcutaneous administration to rats. The LXT-101 PLGA microspheres showed smooth and round surfaces according to a scanning electron microscopic investigation, and average particle size of ca. 30 mum according to laser diffractometry. The drug encapsulation efficiency of microspheres was influenced by LA/GA ratio of PLGA, salt concentrations, solvent mixture and preparation methods. Moreover, LA/GA ratio of PLGA, different preparation methods and different peptide stabilizers affected in vitro release of drugs. In vivo study, the testosterone levels were suppressed to castration up to 42 d as for the 7.5 mg/kg dose. And in vivo performance of LXT-101 microspheres was dose-dependent. The weights of rat sexual organs decreased and histopathological appearance of testes had little changes after 4-month microspheres therapy. This also testified that LXT-101 sustained release microspheres could exert the efficacy to suppress the testosterone level to castration with little toxicity. In conclusion, the PLGA microspheres could be a well sustained release system for LXT-101.     

羟基喜树碱-类水滑石纳米杂化的共组装制备及表征

采用共组装法在水溶液中制备羟基喜树碱(HCPT)-层状双金属氢氧化物(LDH)纳米杂化物.先利用微通道反应器通过共沉淀法制备了Zn₂Al-NO₃ LDH纳米片,然后与羧酸盐型HCPT在水介质中共组装,制备了HCPT插层LDH的纳米杂化物.利用酸处理,可将层间HCPT由非生物活性的羧酸盐型转化为生物活性的内酯型,这对高生物活性HCPT-LDH纳米杂化物的绿色制备具有重要意义.共组装法制备HCPT-LDH纳米杂化物,耗时短、载药量高、分散性好,且利用原料配比可方便地调控载药量. HCPT分子在LDH层间以其长轴倾斜于层板呈双层排列.所制备的HCPT-LDH纳米杂化物具有良好的药物缓释性能,颗粒内部扩散是药物释放过程的控速步骤.药物释放过程可用准二级动力学模型描述.可以用于构筑LDH基药物输送-控释体系.     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

New solid mucoadhesive systems for benzydamine vaginal administration

The aim of this work was the realization of new formulations for vaginal application to improve the pharmacological effect of benzydamine, displaying both anti-inflammatory and antiseptic activities. For this reasons, this drug was formulated in solid dispersions, by using the mucoadhesive polymers HPMC and/or Carbopol(?), then compressed. Tablets were characterized by studies of friability, hardness, hydration, DSC, mucoadhesion and in vitro release. Kinetics, responsible for drug delivery, was investigated as well. Tablets prepared by using only HPMC showed the best results in terms of swelling and mucoadhesion (time and force) together with prolonged and complete drug release, by diffusive mechanism, through gelled layer. Despite the good mucoadhesive properties, Carbopol(?) does not represent a good excipient because, after the contact with water, it generates a spongy gel layer, not homogeneous, stiff, brittle and with breaking tendency when highly swelled. This kind of gel does not guarantee a linear drug release and could provoke discomfort because of fragment release. HPMC mucoadhesive tablets could be a proper delivery system for benzydamine administration representing a good alternative to traditional dosage forms for vaginal topical therapy.     

Design and In Vitro Evaluation of Solid-Lipid Nanoparticle Drug Delivery for Aceclofenac

Solid-lipid nanoparticles (SLNs) are an interesting nanoparticulate delivery system. The present work was carried out with the aim to develop a prolonged release solid-lipid nanoparticulate system for the drug using aceclofenac. Aceclofenac-loaded solid-lipid nanoparticles (ACSLNs) was prepared by hot high pressure homogenization technique. Tripalmitin was used as the lipid core. Surfactants (Poloxamer 188, Tween 80, and soya lecithin) and co-surfactant (sodium tauro glycholate) were used in the formulations. The prepared ACSLN formulations were characterized for encapsulation efficiency (EE), photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and x-ray diffraction (XRD). From these studies, mean particle diameter of the formulation prepared with combination of surfactants (Poloxmer 188 and Tween 80) was about 200 nm with spherical morphology and amorphous nature. Higher EE was obtained with SLNs prepared using combination of soya lecithin and poloxmer 188. The organization and distribution of the ingredients in the nanoparticulate system were studied by differential scanning calorimetry (DSC) and the results showed that the drug is incorporated into the solid matrix. The prepared formulations demonstrated favorable in vitro prolonged release characteristics. Experimental in vitro release data were substituted in available mathematical models to establish the release kinetics of ACSLNs and it was found to follow first-order kinetics and Higuchi diffusion mechanism. Our results suggest that these SLN formulations could constitute a promising approach for the drug delivery of aceclofenac.     

A bioinspired 4D printed hydrogel capsule for smart controlled drug release

With the ever-increasing demands for personalized drugs, disease-specific and condition-dependent drug delivery systems, four-dimensional (4D) printing can be used as a new approach to develop drug capsules that display unique advantages of self-changing drug release behavior according to the actual physiological circumstances. Herein, a plant stomata-inspired smart hydrogel capsule was developed using an extrusion-based 4D printing method, which featured with UV cross-linked poly(N-isopropylacrylamide) (PNIPAM) hydrogel as the capsule shell. The lower critical solution temperature (LCST) of the PNIPAM hydrogels was approximately 34.9 °C and macroporous PNIPAM hydrogels were prepared with higher molecular weight polyethylene glycols (PEGs) as the pore-forming agents. Owing to the LCST-induced shrinking/swelling properties, the prepared PNIPAM hydrogel capsules exhibited temperature-responsive drug release along with the microstructure changes in the PNIPAM hydrogels. The in vitro drug release test confirmed that the PNIPAM hydrogel capsules can autonomously control their drug release behaviors on the basis of ambient temperature changes. Moreover, the increased PEG molecular weights in the macroporous PNIPAM hydrogel capsules caused an obvious improvement of drug release rate, distinctly indicating that the drug release profiles can be well programmed by adjusting the internal pore size of the hydrogel capsules. In vitro biocompatibility studies confirmed that the PNIPAM hydrogel capsules have great potential for biomedical applications. The bioinspired 4D printed hydrogel capsules pioneer the paradigm of smart controlled drug release.     

Preparation, characterization, and pharmacodynamics of exenatide-loaded poly(DL-lactic-co-glycolic acid) microspheres

Exenatide (synthetic exendin-4), a 39-amino acid peptide, was encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) microspheres as a sustained release delivery system for the therapy of type 2 diabetes mellitus. The microspheres were prepared by a double-emulsion solvent evaporation method and the particle size, surface morphology, drug encapsulation efficiency, in vitro release profiles and in vivo hypoglycemic activity were evaluated. The results indicated that the morphology of the exenatide PLGA microspheres presented as a spherical shape with smooth surface, and the particle sizes distributed from 5.8 to 13.6 μm. The drug encapsulation efficiency tested by micro-bicinchoninic acid (BCA) assay was influenced by certain parameters such as inner and outer aqueous phase volume, PLGA concentration in oil phase, polyvinyl alcohol (PVA) concentrations in outer aqueous phase. Moreover, in vitro release behaviors were also affected by some parameters such as polymer type, PLGA molecular, internal aqueous phase volume, PLGA concentration. The pharmacodynamics in streptozotocin (STZ)-induced diabetic mice suggested that, exenatide microspheres have a significant hypoglycemic activity within one month, and its controlling of plasma glucose was similar to that of exenatide solution injected twice daily with identical exenatide amount. In conclusion, this microsphere could be a well sustained delivery system for exenatide to treat type 2 diabetes mellitus.     

生物降解多功能缓释微球的制备与表征

通过羧甲基壳聚糖接枝二甲基十八烷基环氧丙基氯化铵, 合成水油两溶性的羧甲基壳聚糖十八烷基季铵盐(OQCMC); 并将其作为乳化剂与乳酸-羟基乙酸(PLGA)和羟乙基纤维素(HEC)复合, 利用溶剂挥发法, 构建一种多功能的药物载体缓释系统, 并尝试包裹脂溶性药物盐酸米诺环素. 利用Transmission electron microscopy, Quasielastic laser light scattering, Zeta电位仪, FTIR, 1H NMR等对OQCMC及载药微球进行表征, 并进行药物的体外释放实验. 结果表明: OQCMC可作为一种优良的乳化剂对PLGA微球进行修饰; 并可使复合微球体系带正电, 在提高微球载药率(9.4%)的同时减小微球粒径[(166.4±0.8) nm]; 复合微球体系对盐酸米诺环素具有较好的物理包裹能力, 并有长效缓释作用(PBS, pH＝7.9).     

Highly efficient drug delivery with gold nanoparticle vectors for in vivo photodynamic therapy of cancer

A highly efficient drug vector for photodynamic therapy (PDT) drug delivery was developed by synthesizing PEGylated gold nanoparticle conjugates, which act as a water-soluble and biocompatible "cage" that allows delivery of a hydrophobic drug to its site of PDT action. The dynamics of drug release in vitro in a two-phase solution system and in vivo in cancer-bearing mice indicates that the process of drug delivery is highly efficient, and passive targeting prefers the tumor site. With the Au NP-Pc 4 conjugates, the drug delivery time required for PDT has been greatly reduced to less than 2 h, compared to 2 days for the free drug.     

Sustained release drug delivery using supramolecular hydrogels of the triblock copolymer PCL–PEG–PCL and α-cyclodextrin

Supramolecular hydrogels (SMGel) have attracted much attention as a drug and gene delivery system in recent years. In this study, SMGels based on the tri-block copolymer of poly-ε-caprolactone–polyethylene glycol–poly-ε-caprolactone (PCL–PEG–PCL) and α-cyclodextrin (α-CD) were prepared and evaluated for the delivery of two model drugs, naltrexone hydrochloride and vitamin B₁₂. Tri-block copolymers were synthesized easily in 15 min by ring-opening polymerization using the microwave irradiation technique, and their structures were determined by gel permeation chromatography and nuclear magnetic resonance methods. SMGels composed of various concentrations of the copolymer and α-CD were prepared and characterized for their rheological behaviour, their gel formation time and in vitro drug release profile. The results indicated that copolymers with a PCL to PEG ratio of 1:4 are suitable for SMGel preparation. The most viscose system with good syringeability was prepared by mixing 12 % wt α-CD and 10 % wt of copolymer. The gelation was found to occur within a minute after mixing. The viscosity of the hydrogel systems was determined as a function of shear rate. Finally, in vitro B₁₂ release through the hydrogel systems was studied. Up to 80 % of Vitamin B₁₂ was released through this system during a period of 20 days. Rheological evaluation revealed that the hydrogel has shear thinning properties, and the system regained its ground rheological state in a time dependent manner. Polymer concentration did not affect the drug release profiles. Finally, it was concluded that such systems are appropriate drug delivery systems due to their ability to provide a controlled drug release profile and their shear thinning thixotropic behaviour, which makes them syringeable and injectable.     

Properties of gastroretentive sustained release tablets prepared by combination of melt/sublimation actions of L-menthol and penetration of molten polymers into tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax? was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.