Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

可生物降解高分子微针的制作及透皮应用

透皮给药相比于传统的给药方式,具有更多的优势．但是,皮肤的角质层能够阻止外源性物质的侵犯,限制了透皮给药系统的应用．为此,基于微针的透皮给药系统的提出增大了透皮给药系统的应用范围．首先,采用MEM技术制作单晶硅微针．接下来,提出一种新颖、简单而且经济的方法快速制作聚乳酸微针．通过理论分析及有限元分析微针的力学性能,表明微针有足够的强度．体外透皮实验表明,未经微针处理的皮肤,钙黄绿素10h的累计渗透量只有0．17±0．07 μg／cm2;手动进针处理的皮肤只达到4．54±1．17 μg／cm2,比未用微针处理的皮肤增加了30倍;经过进针器处理的皮肤,各个时间点的渗透量均有显著性提高（P〈0．05）,渗透量达到45．37±5．80 μg／cm2,比未用微针处理的皮肤增加了300倍．所有的结果都表明,本实验室制备可降解的聚乳酸微针的方法新颖、快速且经济,而且对于透皮给药系统来说具有很大的潜在价值．     

Biodegradable Progesterone Microsphere Delivery System for Osteoporosis Therapy

The purpose of this study was to formulate and characterize a controlled-release biodegradable delivery system of progesterone for the treatment or prevention of osteoporosis. Microspheres of progesterone were formulated using copolymers of poly(glycolic acid-co-dl-lactic acid)(PGLA 50/50 and PGLA 15/85) and poly(L-lactic acid)(L-PLA) of similar molecular weight by the emulsion solvent evaporation technique. The effects of process variables, such as volume fraction, polyvinyl alcohol (PVA) concentration, polymer composition, and stir speed during preparation, on the yield, encapsulation efficiency (EEF), particle size distribution, in vitro release profiles of progesterone, and surface morphology of progesterone microspheres were investigated. Increasing the volume fraction from 9% to 22% increased the EEF without significantly increasing the yield; however, the rate of progesterone release from the microspheres decreased. Increasing the PVA concentration from 1% to 5% had no significant influence on the EEF, but the rate of progesterone release from microspheres increased. Polymer composition had no significant effect on the EEF, but had a significant effect on the particle size distribution, surface morphology, and release rate of progesterone from the microspheres. Stir speed did not have a significant influence on the EEF; however, stir speed influenced particle size distribution and the rate of progesterone release from microspheres of the same sieve-size range. The results suggest that controlled release of progesterone is possible by varying the different process variables, and that PGLA 50/50 provided the slowest release of progesterone. This should provide a means of delivering progesterone for months for the treatment or prevention of osteoporosis in postmenopausal women.     

Development and Characterization of Self-Microemulsifying Drug Delivery System of Tacrolimus for Intravenous Administration

Tacrolimus (FK 506), a poorly soluble immunosuppressant is currently formulated in nonaqueous vehicle containing hydrogenated castor oil derivative for intravenous administration. Hydrogenated castor oil derivatives are associated with acute anaphylactic reactions. This proposes to overcome the problems of poor aqueous solubility of the drug and the toxicity associated with currently used excipients by the development of a new parenterally acceptable formulation using self-microemulsifying drug delivery system (SMEDDS). Solubility of FK 506 in various oils, surfactants, and cosurfactants was determined to identify SMEDDS components. Phase diagrams were constructed at different ratios of surfactants: cosurfactant (K_m) to determine microemulsion existence area. Influence of oily phase content, K_m, aqueous phase composition, dilution, and incorporation of drug on mean globule size of microemulsions was studied. SMEDDSs were developed using ethyl oleate as oily phase and Solutol HS 15 as surfactant. Glycofurol was used successfully as a cosurfactant. Developed SMEDDS could solubilize 0.8% (wt/wt) FK 506 and on addition to aqueous phase could form spontaneous microemulsion with mean globule size < 30 nm. The resulting microemulsion was iso-osmotic, did not show any phase separation or drug precipitation even after 24 h, and exhibited negligible hemolytic potential to red blood cells.     

Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.     

Controlled Drug Delivery by Biodegradable Poly(Ester) Devices: Different Preparative Approaches

Abstract

There has been extensive research on drug delivery by biodegradable polymeric devices since bioresorbable surgical sutures entered the market two decades ago. Among the different classes of biodegradable polymers, the thermoplastic aliphatic poly (esters) such as poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer oflactide and glycolide referred to as poly(lactide-co-glycolide) (PLGA) have generated tremendous interest because of their excellent biocompatibility, biodegradability, and mechanical strength. They are easy to formulate into various devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Most importantly, they have been approved by the United States Food and Drug Administration (FDA) for drug delivery. This review presents different preparation techniques of various drug-loaded PLGA devices, with special emphasis on preparing microparticles. Certain issues about other related biodegradable polyesters are discussed.     

Transdermal Drug Delivery System of Haloperidol to Overcome Self-Induced Extrapyramidal Syndrome

Abstract

Haloperidol (HAL), an antipsychotic, is associated with side effects of drug-induced extrapyramidal syndrome (EPS) in conventional monotherapy. Controlled released transdermal dosage form (TDDS) of the drug was designed for maintenance therapy. Matrix-diffusion type transdermal film of HAL was designed with Eudragit NE 30D copolymer without permeation enhancer in different combinations. For the feasibility studies, all standard evaluations were performed, and their results pointed toward the suitability of TDDS. The drug release and permeation studies in Franz diffusion cell in 20% PEG-normal saline followed the Higuchi equation with optimum correlation coefficient. The neuroleptic efficacy was confirmed by maximum graded response in a rotarod apparatus. The neuroleptic-induced catatonia (EPS) in albino rats was minimum with a score of zero over a 72-hr study. The pharmacokinetic parameters in rabbit model showed a very significant prolongation of action up to 72 hr with steady-state plasma concentration (cp_ss) of 11.58 ng/mL. Thus, the HAL-loaded TDDS improved the therapeutic profile by preventing the neuroleptic-induced EPS and might be a better alternative during its long period of psychiatric treatment over conventional dosage form.     

黏土矿物基载药体系的研究进展

我国黏土矿物储量丰富,应用广泛.为满足经济建设发展要求和人民日益增长的需要,近年来,我国大力发展黏土矿物相关产业.在经济战略发展的重要时期,黏土矿物将是未来我国重点优势矿种,其相关研究成为我国矿物功能材料发展的重大突破口,可满足未来国家重大战略和发展需求.黏土矿物具有特殊的形貌结构、优异的理化特性、较好的生物相容性,在新兴生物医学领域展现出极大的应用潜力.一直以来,多种给药方式都受到药物泄露、突释、剂量依赖毒性等多方面限制,大大降低了药物的生物利用度与治疗效果,这便对药物载体提出了新的要求.目前应用于药物载体的材料主要为有机、无机、有机?无机复合材料,其药物释放系统的研究方向主要为靶向给药和药物的缓、控释.大多数载药体系存在着制备过程繁琐、生产成本高、性质不稳定的问题,而黏土矿物有层状、管状、纤维状等特殊结构,表面存在丰富的羟基基团,具有良好的吸附能力、稳定的物理化学性质,因此被广泛应用于药物载体材料.大多数学者使用黏土矿物本身作为载体,制备黏土矿物基载药体系,并研究其载药性能及生物安全性.随着科学技术的发展以及矿物学、化学、医学等多学科的交叉融合,研究者对黏土矿物进行进一步的改性.利用黏土矿物独特的理化性质,可对其进行表面改性和结构改型,并结合理论计算、高技术表征等对矿物结构与性质进行剖析,从而设计功能性矿物基载药体系.本文综述了黏土矿物基载药体系的研究进展,从黏土矿物理化性质和研究现状等方面对当前黏土矿物作为药物载体的优越性和所面临的挑战进行分析,介绍了常见黏土矿物基载药体系,如蒙脱石基载药体系、埃洛石基载药体系、高岭石基载药体系.另外,本文还介绍了未来黏土矿物基载药体系的主要研究方向,可以为开发载药率高、缓释性能好、靶向性强的新型高效载药体系的相关研究提供参考.     

快速响应水凝胶在给药系统中的应用进展

传统智能水凝胶作为药物载体可控制药物的定点、定时、定量释放,具有提高药效、靶向,减少给药频率,增加安全性等优点。但由于存在响应速率慢的缺点而大大限制其应用。因此,近年来围绕提高智能水凝胶给药的响应速率的研究非常活跃,展示了广阔的应用前景。文中综述了快速响应水凝胶的类型、制备原理与给药系统中的应用进展,并指出其缺点及发展方向。     

A Diffusion Controlled Drug Delivery System for Theophylline

Abstract

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.     

A Diffusion Controlled Drug Delivery System for Theophylline

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.     

Interactive Mixture as a Rapid Drug Delivery System

The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.     

Biodegradable Poly(Lactic Acid) and Poly (Lactide-Co-Glycolide) Polymers in Sustained Drug Delivery

Abstract

Poly(lactic acid) [PLA] and its co-polymers with glycolic acid [PLCG] have been known for the past 20 years of its biodegradability and histocompatibility. Their physico-chemical and biological properties have been found suitable, in many instances, for sustaining drug release in vivo and in vitro from days to months. A wide variety of drugs ranging from small molecular weight therapeutic agents to peptide hormones, antibiotics, chemotherapeutic drugs have been studied using these biodegradable polymers. Several parenteral and oral dosage forms have been investigated, which includes microcapsules, implants, pseudolatices, nanoparticles, tablets, films as well as occular devices for local delivery of drug into the eye. An attempt have been taken in this paper to review the prospect of using these biodegradable polymers for long term parenteral drug delivery of different classes of drugs.