Linseed hydrogel based floating drug delivery system for fluoroquinolone antibiotics: Design,in vitro drug release and in vivo real-time floating detection

Herein, we designed a novel gastroretentive drug delivery system as floating matrix tablets based on a polysaccharide material from linseeds (Linum usitatissimum L.) for fluoroquinolone antibiotics. A number of formulations were designed with a combination of linseed hydrogel (LSH) and different excipients to obtain a desired sustained release profile of moxifloxacin. The drug release study was performed basically at pH 1.2. However, the tablet may pass through the stomach to intestine due to certain reasons then it also offered sustained drug release at intestinal pH 4.5, 6.8 and 7.4, as well. Results indicated that sustained moxifloxacin release was directly proportional to the concentration of LSH and the release of drug followed non-Fickian diffusion. SEM of the tablets indicated porous nature of LSH with elongated channels which contributed to the swelling of the tablet and then facilitated the discharge of moxifloxacin from the core of the tablet. In vivo X-ray study was performed to assess disintegration and real-time floating of tablet that confirmed its presence for 6 h in the stomach. These findings indicated that LSH can be used to develop novel gastroretentive sustained release drug delivery systems with the double advantage of sustained drug release at all pH of GIT.     

阿霉素磁性毫微球的体内外释放研究

本文以阿霉素为模型药物,Fe3O4为磁核材料,单体乙烯吡咯烷酮为基质,通过反相乳液聚合方法制备了阿霉素磁性毫微粒,对其体内外释放性进行研究。结果发现,在体外释放研究中,毫微粒存在突释现象,72h时达到平衡,缓释效果较好;在给定同样剂量条件下,阿霉素溶液刚开始时获得较高血药浓度,但血药浓度又很快降低,在12h时血药浓度已经很低,而载药毫微粒在体内的消除较慢,在24h依然保持一定浓度,表现出一定的缓释性。     

Preparation and in vitro evaluation of enteric-coated tablets of rosiglitazone sodium

The aim of this study was to prepare the rosiglitazone sodium enteric-coated tablets and investigate its release rate. The rosiglitazone sodium enteric-coated tablet was prepared by single punch tablet press using substituted hydroxypropyl cellulose and polyvinylpyrrolidone (PVP). The release rate from the enteric-coated tablet of rosiglitazone sodium was evaluated. The release rate study showed that few rosiglitazone sodium was released from enteric coated formulation within 2 h in simulated gastric juice, while it released more than 80% of the labeled amount in 30 min in simulated intestinal juice. The preparing method of rosiglitazone sodium enteric-coated tablets was simple and had a good reproducibility. The release condition and determined methods could be used for the routine determinations of rosiglitazone sodium enteric-coated tablets.     

Self-assembled hydrogel nanoparticles responsive to tumor extracellular pH from pullulan derivative/sulfonamide conjugate: characterization,aggregation, and adriamycin release in vitro

Purpose. To investigate some physicochemical properties of self-assembled hydrogel nanoparticles of pullulan acetate (PA) and sulfonamide conjugates, as a potential tumor targeting drug carrier responsive to tumor extracellular pH. Methods. A new class of pH-responsive polymers was synthesized by conjugating a sulfonamide, sulfadimethoxine (SDM), to succinylated pullulan acetate (coohPA). The polymers formed self-assembled PA/SDM hydrogel nanoparticles in aqueous media, which was confirmed by fluorometry and field emission-scanning electron microscopy. The pH-dependent behavior of the nanoparticles was examined by measuring transmittance, particle size and zeta potential. Adriamycin (ADR) was tested for loading into and release from the nanoparticles at various pHs. Results. The mean diameters of all PA/SDM nanoparticles tested were <70 nm, with a unimodal size distribution. The critical aggregation concentrations at pH 9.0 were as low as 3.16 g/mL. The nanoparticles showed good stability at pH 7.4, but shrank and aggregated below pH 7.0. The ADR release rate from the PA/SDM nanoparticles was pH-dependent around physiological pH and significantly enhanced below a pH of 6.8. Conclusions. The pH-responsive PA/SDM nanoparticles may provide some advantages for targeted anti-cancer drug delivery due to the particle aggregation and enhanced drug release rates at tumor pH.     

Controlled release effervescent buccal discs of buspirone hydrochloride: in vitro and in vivo evaluation studies

Abstract

In the present study controlled release effervescent buccal discs of buspirone hydrochloride (BS) were designed using HPMC as rate controlling and bioadhesive polymer by direct compression method. Sodium bicarbonate and citric acid were used in varying amounts as effervescence forming agents. Carbon dioxide evolved due to reaction of sodium bicarbonate and citric acid was explored for its potential as buccal permeation enhancer. The designed buccal discs were evaluated for physical characteristics and in vitro drug release studies. Bioadhesive behavior of designed buccal discs was assessed using texture analyzer. In vivo animal studies were performed in rabbits to study bioavailability of BS in the designed buccal discs and to establish permeation enhancement ability of carbon dioxide. It was observed that effervescent buccal discs have faster drug release compared to non-effervescent buccal discs in vitro and effervescent buccal discs demonstrated significant increase in bioavailability of drug when compared to non-effervescent formulation. Hence, effervescent buccal discs can be used as an alternative to improve the drug permeation resulting in better bioavailability. However, the amount of acid and base used for generation of carbon dioxide should be selected with care as this may damage the integrity of bioadhesive dosage form.     

Injectable nanospheres from a novel multiblock copolymer: Cytocompatibility,degradation and in vitro release studies

The aim was to develop and characterize nanospheres made from a newly synthesized poly (D, L-lactide-co-ethyleneglycol) (-PLA-PEG-PLA-)_n multi-block copolymer. Nanospheres were prepared under optimized conditions of modified emulsion-solvent evaporation technique in a continuous flow process using rhodamine B as a drug model. They were characterized for size distribution, zeta (ζ) potential, porosity and morphology. Drug loading and yield were also determined. In vitro degradation studies of the copolymer were conducted in phosphate buffer (pH 7.4) at 37°C. The cytotoxic properties of the polymer and vector were analysed by dimethylthiazoldiphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays on the B16 mouse cell line. Release of rhodamine B from the nanospheres was assayed in vitro using a dialysis bag in isotonic phosphate buffer (pH 7.4) at 37°C. Spherical and non-porous nanospheres with mean size less than 800nm could be prepared. The (ζ) potential was neutral. The average yield was approximately 70% with 7% rhodamine loading. A total of 50% of the multiblock underwent initial degradation after 4 weeks, while degradation was complete after 16 weeks. Cellular proliferation was not inhibited as no cytotoxicity was observed with the copolymers and nanospheres. Rhodamine B was released in a stepwise pattern. The initial burst was 20%, and release was prolonged thereafter for 29 days. Thus, injectable nanospheres with prolonged rhodamine B release have been designed and characterized as a potential drug-delivery system.     

Enteric delivery of ketoprofen through functionally modified poly(acrylamide-grafted-xanthan)-based pH-sensitive hydrogel beads: Preparation,in vitro and in vivo evaluation

Novel pH-sensitive hydrogel beads were prepared using a hydrolyzed poly(acrylamide-g-xanthan) (PAAm-g-XG) copolymer from a complete aqueous environment and evaluated for targeting ketoprofen to the intestine. The PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The copolymer was characterized by FTIR spectroscopy, ¹H NMR spectroscopy, elemental analysis and thermogravimetric analysis. Pulsatile swelling study indicated that the copolymer exhibits considerable pH-sensitive behavior unlike pristine xanthan gum. Ketoprofen-loaded pH-sensitive beads were prepared by ionotropic gelation with Al^{3 +} ions. Release of drug from all the copolymeric beads was much lesser than that from pristine xanthan beads. Moreover, a maximum of 20% ketoprofen was released from the copolymeric beads in pH 1.2–5.5 during a period of 3 h, while a major portion of the drug was released in pH 6.8–7.4 gradually over a longer period. Pharmacodynamic activity and stomach histopathology of albino rats indicated that the beads were able to retard the drug release in stomach, and gastric side effects such as ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-XG-based pH-sensitive beads.     

N-(2-羟丙基)甲基丙烯酰胺聚合物-5-氟尿嘧啶接合物的体外释药规律、体内分布及抗肿瘤活性研究

考察本实验室合成的N-(2-羟丙基)甲基丙烯酰胺[N-(2-hydroxypropyl)methacrylamide,HPMA]聚合物-5-氟尿嘧啶(5-flurouracil,5-FU)接合物(P-FU)的体外释药、体内分布及抗肿瘤活性。以小鼠血浆为介质,考察P-FU中5-FU的释放规律;以小鼠H22肝癌实体瘤模型(皮下型)为肿瘤模型,考察接合物在荷瘤小鼠体内的分布情况、药代动力学规律及抑瘤活性。结果表明,37℃时P-FU在小鼠血浆中具有一定的稳定性,半衰期(t1/2)为32.4 h。与5-FU相比,P-FU在荷瘤小鼠体内的循环时间明显延长(血浆中t1/2为原药的166倍),在肿瘤中的沉积量(AUC为5-FU的3.3倍)及滞留时间(t1/2为5-FU的2.3倍)均有明显增加。体内药效学研究表明,P-FU组对荷瘤小鼠的肿瘤生长抑制率(69.09%)显著高于5-FU组(56.49%,P<0.05),瘤块组织病理学观察结果也显示P-FU组小鼠肿瘤组织中细胞凋亡程度大于5-FU组。HPMA聚合物可被用于为5-FU构建一种新型实体瘤高分子给药系统。     

温敏性壳聚糖凝胶的阿霉素药物体外缓释研究

目的 壳聚糖辅以甘油磷酸钠制成温敏性凝胶，将该温敏性凝胶用作阿霉素药物栽体并观察其缓释特性。方法 制备负载阿霉素的温敏性壳聚糖凝胶，建立体外持续流动释放系统，应用紫外分光光度法测定阿霉素的含量，对该栽药凝胶进行体外的缓释实验。结果 制备了负载阿霉素的温敏性壳聚糖凝胶，并得到了其缓释曲线。结论 该温敏性凝胶能够用于负载并释放阿霉素，这为改善阿霉素使用途径提供了实验基础。     

Nasal administration of metoclopramide from different dosage forms: in vitro,ex vivo,and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p?<?0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p?<?0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.     

Methylprednisolone esters of hyaluronic acid in ophthalmic drug delivery: in vitro and in vivo release studies

Films and microspheres were prepared from various esters of hyaluronic acid. A model drug, methylprednisolone, was either physically incorporated into the polymer matrix or chemically bound to the polymer backbone through an ester linkage. In vitro release from films with covalently bound drug was much slower (t_50% = 71 h) than that for physically dispersed drug (t_50% = 2.5−17 h). Methylprednisolone concentrations in the tear fluid of New Zealand rabbits were measured after ocular application of drug (approx. 420 μg) in different dosage forms. When methylprenisolone was physically dispersed in the polymer matrix, in vivo drug release from matrices was slower than that observed in vitro. Compared with a suspension control, peak methylprednisolone concentrations in tear fluid were 9–14 times lower after administration of drug in polymer films and AUC_{0–8 h} values were 4–7 times higher. These results imply that hyaluronic acid ester preparations can increase the residence time of methylprednisolone in the tear fluid of rabbits.     

Magnetic iron oxide nanoparticles for drug delivery: applications and characteristics

Introduction: For many years, the controlled delivery of therapeutic compounds has been a matter of great interest in the field of nanomedicine. Among the wide amount of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) stand out from the crowd and constitute robust nanoplatforms since they can achieve high drug loading as well as targeting abilities stemming from their remarkable properties (magnetic and biological properties). These applications require precise design of the nanoparticles regarding several parameters which must be considered together in order to attain highest therapeutic efficacy.

Areas covered: This short review presents recent developments in the field of cancer targeted drug delivery using magnetic nanocarriers as drug delivery systems.

Expert opinion: The design of nanocarriers enabling efficient delivery of therapeutic compounds toward targeted locations is one of the major area of research in the targeted drug delivery field. By precisely shaping the structural properties of the iron oxide nanoparticles, drugs loaded onto the nanoparticles can be efficiently guided and selectively delivered toward targeted locations. With these goals in mind, special attention should be given to the pharmacokinetics and in vivo behavior of the developed nanocarriers.     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

Paediatric drug development of ramipril: reformulation,in vitro and in vivo evaluation

Ramipril is used mainly for the treatment of hypertension and to reduce incidence of fatality following heart attacks in patients who develop indications of congestive heart failure. In the paediatric population, it is used most commonly for the treatment of heart failure, hypertension in type 1 diabetes and diabetic nephropathy. Due to the lack of a suitable liquid formulation, the current study evaluates the development of a range of oral liquid formulations of ramipril along with their in vitro and in vivo absorption studies. Three different formulation development approaches were studied: solubilisation using acetic acid as a co-solvent, complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and suspension development using xanthan gum. Systematic optimisation of formulation parameters for the different strategies resulted in the development of products stable for 12 months at long-term stability conditions. In vivo evaluation showed C_max of 10.48?µg/ml for co-solvent, 13.04?µg/ml for the suspension and 29.58?µg/ml for the cyclodextrin-based ramipril solution. Interestingly, both ramipril solution (co-solvent) and the suspension showed a T_max of 2.5?h, however, cyclodextrin-based ramipril produced T_max at 0.75?h following administration. The results presented in this study provide translatable products for oral liquid ramipril which offer preferential paediatric use over existing alternatives.     

卡莫氟-聚乳酸纳米纤维缓释体系的制备及体外缓释性能

目的：以聚乳酸纳米纤维为载体,制备卡莫氟-聚乳酸纳米纤维药物缓释体系,研究其体外药物释放性能.方法：用静电纺丝制备卡莫氟-聚乳酸纳米纤维药物缓释体系,用紫外分光光度法研究药物的在37℃模拟体液中的释放性能.结果：溶剂不同,纤维的形貌有很大差别;纳米纤维体外药物释放速度也大不相同,缓释曲线符合Higuchi方程.结论：随着溶液的导电性和介电常数的增加,静电纺丝纤维的直径明显变小,纤维表面也逐渐光滑;纳米纤维的形貌对体外药物释放速度有较大影响.     

In vitro and in vivo evaluation of targeting efficiency of Adriamycin hydrochloride magnetic microspheres

The objective of this study was to prepare magnetic microspheres as a targeting drug delivery system and to specifically evaluate its targeting efficiency. The magnetic microspheres were prepared by emulsion cross-linking techniques. Targeting efficiency was specifically investigated by experiments of biodistribution on rats and histological study. Adriamycin hydrochloride (ADR)-loaded magnetic microspheres were successfully prepared with the mean diameter of 3.853 μm (± 1.484 μm), and had its speciality of superparamagnetism. The results of the targeting efficiency study showed that application of the external magnetic field significantly increased the ADR concentration from 40.28 μg/ml to 100.70 μg/ml at 10?min, 36.99 μg/ml to 91.16 μg/ml at 60?min, and 13.71 μg/ml to 28.30 μg/ml at 180?min in liver as the targeting tissue. The relative uptake efficiencies in liver by injection treatment of ADR magnetic microspheres with external magnetic field were 3.87, 5.59, and 3.34 at 10?min, 60?min, and 180?min after administration, respectively. In conclusion, distinguished targeting efficiency was displayed, which indicated that the magnetic microspheres could be applied as a novel targeting drug delivery system.     

盐酸维拉帕米脉冲胶囊的制备及其体外释药考察

目的:制备一种新型脉冲式胶囊给药系统,探索影响药物在一定的时滞后脉冲释放的因素。方法:以蘸胶工艺制备不溶性半透膜囊体,灌装药物粉末或药物与渗透促进剂混合物,以果胶直接压片制备胶塞,塞入囊体后,套上胃溶性囊帽和囊体后外包肠溶衣,进行体外释放试验。结果:该给药系统在人工胃液中不变形,药物不释放,在pH7.4人工肠液中药物的脉冲释放受肠溶包衣厚度、不溶性囊体中致孔剂含量和填充物渗透促进剂比例的影响。结论:胶囊系统设计原理简单,各组成部分可单独制备,药物释放可根据要求来设计调节,可应用于多种药物,有望开发成一种新型药物脉冲释放系统。     

Preparation,characterization, and evaluation of amino acid modified magnetic nanoparticles: drug delivery and MRI contrast agent applications

Abstract

This study is a report about the synthesis iron oxide magnetic nanoparticles (IONPs) which modified with positive and negative charged amino acids (AAs). l-Arginine (Arg) and l-aspartic acid (Asp) which have of guanidinium and carboxylic acid groups, respectively, were selected for this study. After loading chrysin in amino acids modified iron oxide magnetic nanoparticles (F@AAs@Chrysin NPs), it was characterized by XRD, TGA, FTIR, VSM, and TEM techniques. Finally, MTT assays on HFF-2 and HEK-293 cell lines were performed for determination of biocompatibility of AA coated IONPs. The results show that, the ζ-potential and average size of F@Arg@chrysin NPs and F@Asp@chrysin NPs were to ?3.87, ?2.12?mV, 18.75?±?2.40 (mean?±?SD (n?=?50)) nm, and 19.86?±?2.22 (mean?±?SD (n?=?48)) nm, respectively. Also, the results indicated that these F@AAs@Chrysin NPs were appropriate for delivery of chrysin. Furthermore, the phantom MRI studies showed the IONPs can be used as contrast agent for the revealing of tumor.     

Basal level insulin delivery: in vitro release, stability, biocompatibility, and in vivo absorption from thermosensitive triblock copolymers

The major goal of this study was to develop the biodegradable and biocompatible thermosensitive polylactic acid-polyethylene glycol-polylactic acid triblock copolymer-based delivery systems for controlled release of basal level insulin for a longer duration after single subcutaneous injection. Insulin was dispersed into aqueous copolymer solutions to prepare the delivery system. The in vitro release profile of insulin from delivery systems was studied at 37°C in phosphate-buffered saline. Stability of released insulin was investigated using circular dichroism, differential scanning calorimetry, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and skin histology were used to determine the in vitro and in vivo biocompatibility of the delivery systems, respectively. Streptozotocin-induced diabetic rat model was used to study the in vivo absorption and bioactivity of insulin. In vitro release studies indicated that the delivery systems released insulin over 3 months in structurally stable form. The delivery systems were biocompatible in vitro and in vivo. In vivo absorption and bioactivity studies demonstrated elevated insulin level and corresponding decreased blood glucose level in diabetic rats. Thus, the delivery systems released insulin at a controlled rate in vitro in conformationally and chemically stable form and in vivo in biologically active form up to 3 months.