Polycarboxylic acid nanoparticles for ophthalmic drug delivery: an ex vivo evaluation with human cornea

In ophthalmic drug delivery, a major problem is retaining an adequate concentration of a therapeutic agent in the pre-corneal area. Polycarboxylic acid carriers such as polyacrylic acid and polyitaconic acid in sub-colloidal, nanoparticulate hydrogel form have a strong potential for sustained release of a drug in ocular delivery. Formulations have been prepared of brimonidine loaded in polycarboxylic (polyacrylic and polyitaconic) acid nanoparticles for potential ophthalmic delivery. These particles were prepared by a reverse micro-emulsion polymerization technique with sizes in the range of 50?nm. The loading efficiencies of the drug brimonidine in the particles were shown to be between 80–85% for polyacrylic acid nanoparticles and between 65–70% for polyitaconic nanoparticles. The loading efficiency was also found to be pH dependent. In a preliminary biocompatibility test, human corneal epithelial cells incubated with polyacrylic acid nanoparticles were found to retain their viability, whereas polyitaconic acid nanoparticles were found to be toxic. Two-photon laser scanning microscopic studies of the fluorescently labelled polyacrylic acid nanoparticles and human cornea shows that they are adhesive on the corneal surface. The polyacrylic acid nanoparticles demonstrated a controlled release of the opthalmological drug (Brimonidine) through the human cornea as compared to that of the commercial formulation, Alphagan?.     

眼用药物制剂研究进展

眼用给药系统在药学领域中有广阔的发展前景,是目前欧洲、日本、美国一些国家的研究热点之一.本文介绍了近几年来国内外眼用药物新剂型、新制剂的发展新动向、研究进展及趋势情况.     

辛芷离子敏感型鼻用原位凝胶的研制及体外释药评价

目的:开发一种新型的中药鼻腔给药系统剂型—原位凝胶。方法:采用去乙酰结冷胶为材料制备辛芷离子敏感型鼻用原位凝胶。研究不同浓度去酰基结冷胶原位凝胶的黏度特性,采用扩散池法考察其体外释药规律,并用无膜溶出法研究其释药机制。结果:辛芷离子敏感型鼻用原位凝胶的黏度随去酰基结冷胶的浓度增加而增大,其释药量随结冷胶的浓度增加而减少,其释药符合一级释药模型,其溶蚀度较小且与释放率无明显相关性(r=0.986)。结论:应用去酰基结冷胶可成功制备离子敏感型中药鼻用原位凝胶,为中药鼻腔给药提供了一种新剂型。     

Pluronic F127-g-poly(acrylic acid) copolymers as in situ gelling vehicle for ophthalmic drug delivery system

To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic F127-g-poly(acrylic acid) copolymers were studied as in situ gelling vehicle for ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. But the drug concentration had no obvious effect on drug release. The release rates of the drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount in rabbit's conjunctiveal sac increased by 5.0 and 2.6 folds for in situ gel, compared with eye drops. The decreased loss angle at body temperature and prolonged precorneal resident time also indicated that the copolymer gels had bioadhesive properties. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery system.     

Preparation and evaluation of nanoparticles loaded ophthalmic in situ gel

Context: Conventional ophthalmic solutions often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of drug in the pre-corneal area.

Objectives: Above problem can be overcome by the use of in situ gel forming systems that are instilled as drops in to the eye and undergo a sol–gel transition in the cul-de-sac.

Methods: An ion sensitive polymer gellan gum was used as gelling agent which formed immediate gel and remained for extended time period. Nanoparticles of moxifloxacin, prepared by solvent evaporation, were separated by freeze drying. The rheological properties and in vitro drug release test of in situ gel loaded with nanoparticles were evaluated and compared with marketed preparation. In vitro release study demonstrated diffusion controlled release for moxifloxacin from formulations over a period of 12?h.

Results: The developed formulation was stable and showed enhanced contact time minimizing the frequency of administration. Confocal microscopy showed clear permeation of drug loaded nanoparticles across L/S of cornea.

Conclusion: The formulation of moxifloxacin was found liquid at the formulated pH and formed gel in the presence of mono or divalent cations. The gel formed in situ showed sustained drug release over a period of 10–12?h. The formulations were less viscous before instillation and formed strong gel after instilling it into cul-de-sac. It is thus concluded that by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts to achieve desirable rheological and in vitro release property for in situ gel forming system.     

鼻用原位凝胶给药系统中药物吸收的影响因素与改进措施

药物的吸收主要是由药物的理化性质、剂型以及给药途径所决定的。原位凝胶是指在生理条件刺激下能发生分散状态或构象的可逆变化、完成溶液与凝胶间相互转变的新剂型。原位凝胶经鼻腔给药,既避免了药物的胃肠首过效应,又因其能延长药物在给药部位滞留时间,从而避免药物被鼻纤毛快速清除。本文通过系统查阅近年国内外鼻用原位凝胶给药系统的相关文献,就鼻腔的生理特点、药物理化性质与原位凝胶的制剂处方等影响其药物吸收的主要因素及改进措施,进行分析、整理和归纳,旨在为鼻用原位凝胶给药系统的设计与质量控制提供参考。     

氟比洛芬酯眼用纳米乳-离子敏型原位凝胶的研究

设计新型纳米乳-离子敏感型原位凝胶 (nanoemulsion-in situ gel, NE-ISG), 以氟比洛芬酯 (flurbiprofen axetil, FBA) 为模型药物, 研究药物在家兔眼部的房水药动学特征, 并对其流变学特征、微观形态、角膜损伤效果和角膜滞留特性等进行了评价。采用剪切均质工艺制备氟比洛芬酯纳米乳 (flurbiprofen axetil nanoemulsion, FBA/NE), 与离子敏感型凝胶材料 (结冷胶) 混合后制得氟比洛芬酯纳米乳-原位凝胶 (flurbiprofen axetil  nanoemulsion-in situ gel, FBA/NE-ISG)。流变学结果显示, FBA/NE-ISG发生胶凝后, 黏度和弹性模量分别增加2 Pa·s和5 Pa, 胶凝能力强。透射电镜结果表明, FBA/NE-ISG中乳滴粒度分布均匀, 胶凝前后无明显变化。角膜损伤评价显示, FBA/NE-ISG无角膜刺激性。角膜滞留特性评价结果显示, NE-ISG角膜滞留时间显著延长, NE-ISG和溶液组的消除速率常数分别为0.008 5 min⁻¹和0.105 2 min⁻¹。房水药动学结果显示, FBA/NE-ISG组AUC_{0→12 h} (126.8 µg·min·mL⁻¹) 和MRT (12.3 h) 分别是氟比洛芬钠滴眼液组 (flurbiprofen sodium eye drop, FB-Na) 的2.9倍和2.7倍, 眼部生物利用度显著提高。FBA/NE-ISG能够显著延长药物的眼表滞留时间, 发挥缓释作用, 提高药物的眼部生物利用度, 并有效降低原形药物氟比洛芬 (flurbiprofen, FB) 的眼部刺激性。     

原位凝胶应用于眼部给药系统的研究进展

介绍原位凝胶在眼部给药系统中的研究新方法和新进展,以及原位凝胶的不同胶凝机理,分析胶化过程和眼部应用时的影响因素。原位凝胶滴眼剂可以显著延长药物释放,提高药物生物利用度。原位凝胶滴眼剂作为一种新型眼部药物新剂型,具有良好的应用前景。     

眼部给药系统的研究进展

由于眼部特殊的生理结构与诸多屏障的存在,传统的眼用制剂存在生物利用度低、眼内保留时间短以及刺激性强等问题,常常难以达到预期治疗效果。近年来,各种新技术如纳米技术、植入技术、接触镜片的研究和应用,使得眼部给药有了长足的发展。其中纳米材料具有尺寸小、可降解、靶向性强以及对生物组织刺激性小等特点,多种纳米载体如聚合物胶束、纳米粒、纳米混悬液、脂质体与纳米乳等,已被广泛用于眼部给药系统。目前以上多种新技术在眼部给药系统中显示出良好的应用前景。笔者就近年来这方面的研究与应用作一综述,以期为眼部给药系统的研发提供参考。     

肽类和蛋白质类药物肺部给药的体内外评价方法

目的介绍肽类和蛋白质类药物肺部给药的体内外评价方法。方法对肽类和蛋白质药物肺部给药研究中的给药方法、药动学评价、药效学评价、肺部沉积、体外评价及安全性评价方法进行综述。结果根据研究的不同阶段选择合适的动物给药模型,采用特异性强、灵敏度高的分析方法是肽类和蛋白质药物肺部给药系统体内评价的关键。肺内沉积是对剂型和给药装置递送效果的综合考察。具有良好体内外相关性的体外评价方法的建立与安全性评价在肺部给药制剂开发中具有十分重要的意义。结论肽类和蛋白质类药物肺部给药的体内外评价方法与其他给药途径有较大区别,在研究和开发中应根据需要选取适当的方法。     

Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery

Poor bioavailability (<1%) of drugs from conventional eye drops is mainly due to the various precorneal loss factors which include rapid tear turnover, systemic drug absorption through naso-lachrymal duct, transient residence time of the drug solution in the cul-de-sac and the relative impermeability of the drugs to corneal epithelial membrane. The present study describes the formulation and evaluation of chitosan and gellan gum based novel in-situ gel system activated by dual physiological mechanisms. Chitosan (a pH-sensitive polymer) in combination with gellan gum (an ion-activated polymer) were used as gelling agent. Timolol maleate, the drug which is frequently used for glaucoma therapy was used as model drug to check the efficacy of the formulation. The developed formulation was characterized for various in vitro parameters, for example, clarity, gelation pH, isotonicity, sterility, viscosity, transcorneal permeation profile, and ocular irritation. Ocular retention was studied by gamma scintigraphy and a significant increase in retention time was observed. The formulation was also found to be nonirritant and well tolerable. The developed system can be a viable alternative to conventional eye drops for the treatment of various ocular diseases and is suitable for clinical application.     

Research progress of in-situ gelling ophthalmic drug delivery system

 Blindness and vision impairment are the most devastating global health problems resulting in a substantial economic and social burden. Delivery of drug to particular parts of the anterior or posterior segment has been a major challenge due to various protective barriers and elimination mechanisms associated with the unique anatomical and physiological nature of the ocular system. Drug administration to the eye by conventional delivery systems results in poor ocular bioavailability (<5%). The designing of a novel approach for a safe, simple, and effective ocular drug delivery is a major concern and requires innovative strategies to combat the problem. Over the past decades, several novel approaches involving different strategies have been developed to improve the ocular delivery system. Among these, the ophthalmic in-situ gel has attained a great attention over the past few years. This review discussed and summarized the recent and the promising research progress of in-situ gelling in ocular drug delivery system.     

以黄原胶为助悬剂的Pluronic温敏原位凝胶的处方筛选与初步评价

以减少药物沉降、再分散性良好和不对原位凝胶温敏性产生不利影响为主要筛选指标,考察了难溶性药物奥硝唑的温敏原位凝胶中泊洛沙姆和助悬剂黄原胶用量等处方因素,筛选得到一种药物能稳定混悬、具有良好流变学性质和温敏性适宜的泊洛沙姆-助悬剂复配方案.所得最优处方为黄原胶0.1%,Pluronic F127 16%,Pluronic F68 1%,奥硝唑10%,氯化钠0.5%,尼泊金乙酯0.2%.制品凝胶化温度35.9℃,凝胶硬度适宜,药物沉降缓慢,再分散性和热稳定性良好.     

Dual sustained release delivery system for multiple route therapy of an antiviral drug

Abstract

Context: The first successful molecule against herpes infections was Acyclovir, which competes with new generations in the market, with its potential activity. The major physicochemical constraints and pharmacokinetics of Acyclovir such as low solubility, poor permeability, less half-life, high dose has initiated many researchers to develop diverse modified release dosage forms.

Objective: The objective of this work was to design polymeric nanoparticles of Acyclovir and then incorporate the drug-loaded nanoparticles within an in situ gelling system to provide dual sustained release effect, whereby the duration of action and bioavailability through different routes of administration could be improved.

Materials and methods: The formulation was designed through 3² factorial design, first developing the nanoparticles using Polycaprolactone and Pluronic F127 by Solvent evaporation process, followed by dispersion of the suspended nanoparticles into thermosensitive in situ gelling system of Pluronic F127 with Carbopol.

Results and discussion: The characterization of the nanoparticles and its sol-gel system performed through zeta sizer, SEM, XRD, TG-DSC, FTIR and rheology helped to optimize the formulation. The drug release could be sustained to 60% and 30% at eight hours, for the nanoparticles and their in situ gel systems, respectively, with non-Fickian diffusion mechanism of drug release. The test for % cell viability with NIH3T3 cell line revealed low level of toxicity for the nanoparticles.

Conclusion: The statistical significance obtained for the trail formulations experimentally proved its suitability for this dosage form design to achieve desired level of drug release.     

Thermosensitive in situ nanogel as ophthalmic delivery system of curcumin: development,characterization, in vitro permeation and in vivo pharmacokinetic studies

Context: The nanogel combining cationic nanostructured lipid carriers (CNLC) and thermosensitive gelling agent could enhance preocular retention and ocular permeation capacity of curcumin (CUR).

Objective: The purpose of the study was to develop and characterize a thermosensitive ophthalmic in situ nanogel of CUR-CNLC (CUR-CNLC-GEL) and evaluate in vitro and in vivo properties of the formulations.

Materials and methods: The physicochemical properties, in vitro release and corneal permeation, were evaluated. Ocular irritation and preocular retention capacity were also conducted. Finally, pharmacokinetic study in the aqueous humor was investigated by microdialysis technique.

Results: The solution–gel transition temperature of the optimized formulation diluted by simulated tear fluid was 34?±?1.0?°C. The CUR-CNLC-GEL displayed zero-order release kinetics. The apparent permeability coefficient (P_app) and the area under the curve (AUC_0→∞) of CUR-CNLC-GEL were 1.56-fold and 9.24-fold, respectively, than those of curcumin solution (CUR-SOL, p?<?0.01). The maximal concentration (C_max) was significantly improved (p?<?0.01). The prolonged mean residence time (p?<?0.01) indicated that CUR-CNLC-GEL is a controlled release formulation.

Discussion and conclusion: Those results demonstrated that CUR-CNLC-GEL could become a potential formulation for increasing the bioavailability of CUR in the aqueous humor by enhancing corneal permeation and retention capacity.     

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.     

In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 ± 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 ± 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T_max of 8 h comparing to that of theophylline solution with T_max of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2626–2635, 2009     

盐酸多西环素注射用缓释凝胶的体内释药研究

目的考察盐酸多西环素注射用缓释凝胶的体内释放特性及体内外相关性。方法将含药凝胶注射到家兔牙龈内 ,用HPLC法测定不同时间凝胶中的残余药量 ,从而计算药物的释放量。结果 7d盐酸多西环素的释放度达 99 7%。结论药物可缓释 7d ,体内外相关。     

Brimonidine formulation in polyacrylic acid nanoparticles for ophthalmic delivery

In ocular drug delivery, a major problem is providing an adequate concentration of a therapeutic agent in the precorneal area. Mucoadhesive carriers such as polyacrylic acid in sub-colloidal, nanoparticulate form, have a strong potential for ophthalmic drug delivery. A formulation of brimonidine loaded in polyacrylic acid nanoparticles has been prepared for potential delivery in ophthalmic therapy. The particles were prepared by a reverse microemulsion polymerization technique and their sizes were in the range of 50 nm. In a preliminary biocompatibility test, Caco-2 cells (human primary colonic tumour adenocarcinoma) and human corneal epithelial cells incubated with polyacrylic acid nanoparticles were found to retain their viability over varying times. The loading efficiency of the drug brimonidine in the particles was shown to be between 80–85% and pH dependent. The bioadhesive polyacrylic hydrogel nanoparticles, used in the present study, exhibited superior loading properties for brimonidine, and the formulation was stable for more than 5 weeks. When the drug-loaded nanoparticles were dispersed in a phosphate buffer saline (pH = 7.4), the drug was slowly released over several hours. Two-photon laser scanning microscopic studies of dye-conjugated polyacrylic acid nanoparticles demonstrated the accumulation of the particles on the surface and intercellular spaces of Caco-2 cells.