Application of freeze-drying in the development of oral drug delivery systems

ABSTRACT

Introduction: With continual focus on oral drug delivery systems (ODDS), the role of freeze-drying becomes increasingly valuable. While freeze-drying is fundamentally a desiccation process, the advantageous material properties attributed to freeze-drying extend far beyond the preparation of stable pharmaceutical products. The formulation and process variables are important considerations as they affect the final freeze-dried product characteristics. It is of interest to expound on the principles and effects of freeze-drying in the hope of introducing novel products for applications in the development of ODDS.

Areas covered: In this review, basic principles, general formulation and process variables associated with freeze-drying will be covered. The application of freeze-drying in 3 areas: modification of active ingredients, development of novel freeze-dried excipients and development of freeze-dried final dosage forms will be discussed.

Expert opinion: As a pharmaceutical unit operation, freeze-drying has created new dimensions in the area of oral drug delivery, where the properties of the drugs, excipients and characteristics of the final solid dosage form can be modified by the freeze-drying process. With the emergence of new applications, the role of freeze-drying technology in ODDS is indeed a relevant and promising one.     

Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery

Introduction: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years.

Areas covered: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach.

Expert opinion: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.     

Drug delivery devices based on mesoporous silicate

A mesoporous material based on aluminosilicate mixture was studied to investigate its ability to include drugs and then release them. Nonsteroidal anti-inflammatory agents such as diflunisal, naproxen, ibuprofen and its sodium salt have been used in this study. The preparation of the mesoporous material and its characterization by X-ray, N₂ absorption-desorption isotherm, and thermogravimetry analysis have been described. Drug loading was performed by a soaking procedure. Drug-loaded matrices were characterized for entrapped drug amount, water absorption ability, and thermogravimetric behavior. Drug release studies also were performed at pH 1.1 and 6.8 mimicking gastrointestinal fluids. Experimental results showed that this type of matrix is able to trap the bioactive agents by a soaking procedure and, then, to release them in conditions mimicking the biological fluids. Also, the high affinity of these matrices for water makes them potentially biocompatible. Release data suggest that the matrix impregnated with diflunisal offers good potential as a system for the modified drug release.     

Application of pectin in oral drug delivery

Introduction: Biopolymers have been used extensively in the pharmaceutical field. Pectin, a biopolymer, has several unique properties that enable it to be used as an excipient or carrier for oral drug delivery systems. Accordingly, several investigators have identified the benefits of pectin-based delivery systems for oral drug administration.

Areas covered: This review first describes the chemical structure, source and production, degree of esterification and gel formation properties of pectin. The application of pectin in various oral drug delivery platforms is also discussed, that is, controlled release systems, gastro-retentive systems, colon-specific delivery systems and mucoadhesive delivery systems.

Expert opinion: Pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in delivery characteristics. Scintigraphic studies and in vivo studies, in both animals and human volunteers, demonstrate the successful development of a pectin-based colon-specific drug delivery system. Pectin-based controlled release systems, gastro-retentive systems and mucoadhesive systems present promising approaches for increasing the bioavailability of drugs, but are in their infancy. A lack of direct correlation between in vitro release and in vivo absorption studies is a major concern with these systems.     

Gastrointestinal patch systems for oral drug delivery

Gastrointestinal patch systems with integrated multifunctions could surmount the challenges associated with conventional drug delivery. Several gastrointestinal patch systems provide bioadhesion, drug protection and unidirectional release. This combination of function could improve the overall oral bioavailability of large molecules that can currently be delivered only by injection, for example, epoetin-alpha and granulocyte-colony-stimulating factor, which are commonly used to treat chemotherapy-associated anemia and leukopenia, respectively. Furthermore, self-regulated release and cell-specific targeting provide additional 'smart' characteristics to this innovative therapeutic platform.     

Application of pectin in oral drug delivery

INTRODUCTION: Biopolymers have been used extensively in the pharmaceutical field. Pectin, a biopolymer, has several unique properties that enable it to be used as an excipient or carrier for oral drug delivery systems. Accordingly, several investigators have identified the benefits of pectin-based delivery systems for oral drug administration. AREAS COVERED: This review first describes the chemical structure, source and production, degree of esterification and gel formation properties of pectin. The application of pectin in various oral drug delivery platforms is also discussed, that is, controlled release systems, gastro-retentive systems, colon-specific delivery systems and mucoadhesive delivery systems. EXPERT OPINION: Pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in delivery characteristics. Scintigraphic studies and in vivo studies, in both animals and human volunteers, demonstrate the successful development of a pectin-based colon-specific drug delivery system. Pectin-based controlled release systems, gastro-retentive systems and mucoadhesive systems present promising approaches for increasing the bioavailability of drugs, but are in their infancy. A lack of direct correlation between in vitro release and in vivo absorption studies is a major concern with these systems.     

Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges

Oral drug delivery systems (ODDSs) have various advantages of simple operation and few side effects. ODDSs are highly desirable for colon-targeted therapy (e.g. ulcerative colitis and colorectal cancer), as they improve therapeutic efficiency and reduce systemic toxicity. Chitosan/alginate nanoparticles (CANPs) show strong electrostatic interaction between the carboxyl group of alginates and the amino group of chitosan which leads to shrinkage and gel formation at low pH, thereby protecting the drugs from the gastrointestinal tract (GIT) and aggressive gastric environment. Meanwhile, CANPs as biocompatible polymer, show intestinal mucosal adhesion, which could extend the retention time of drugs on inflammatory sites. Recently, CANPs have attracted increasing interest as colon-targeted oral drug delivery system for intestinal diseases. The purpose of this review is to summarize the application and treatment of CANPs in intestinal diseases and insulin delivery. And then provide a future perspective of the potential and development direction of CANPs as colon-targeted ODDSs.     

口服结肠靶向给药系统的研究概况

口服结肠靶向给药系统具有很多优点,尤其对肠病的治疗。本文综述了口服结肠靶向蛤药系统的机制、类型的研究概况。     

Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery

Introduction: Amorphous solid dispersions (ASDs) are one of the key formulation technologies that aid the development of poorly soluble candidates. However, their dynamic behaviors, including dissolution and crystallization processes, are still full of mystery. Further understanding of these processes should enhance their wider use.

Areas covered: The first part of this review describes the current understanding of the dissolution of ASDs, where phase separation behavior is frequently involved and attempts to develop appropriate dissolution tests to achieve an in vitro–in vivo correlation are examined. The second part of this review discusses crystallization of the drug molecule with the eventual aim of establishing an accelerated testing protocol for predicting its physical stability.

Expert opinion: The phase separation behavior from the supersaturated state during the dissolution test must be understood, and its relevance to the oral absorption behavior needs to be clarified. Research efforts should focus on the differences between the phase behavior in in vitro and in vivo situations. Initiation time of the crystallization was shown to be predicted only from storage and glass transition temperatures. This finding should encourage the establishment of testing protocol of the physical stability of ASDs.     

Cell-penetrating self-nanoemulsifying drug delivery systems (SNEDDS) for oral gene delivery

ABSTRACT

Objective: The aim of study was to investigate whether cell-penetrating peptides could amplify cellular uptake of plasmid DNA (pDNA) loaded self-nanoemulsifying drug delivery systems (SNEDDS) by mucosal epithelial cells, thereby enhancing transfection efficiency.

Methods: HIV-1 Tat peptide-oleoyl conjugate (TAT-OL) was synthesized through amide bond formation between HIV-1 Tat-protein 49–57 (TAT) and oleoyl-chloride (OL). SNEDDS formulation contained 29.7% each of Cremophor EL, Capmul MCM and Crodamol, 9.9% propylene glycol and 1% TAT-OL. SNEDDS with OL instead of TAT-OL served as control.

Results: Fluorescent-microscopy demonstrated 0.5% (m/v) nanoemulsions were suitable for subsequent studies. Mucus diffusion of nanoemulsion loaded with fluorescein diacetate (FDA) was 1.5-fold increased by incorporation of TAT-OL. Confocal microscopy confirmed that droplets of nanoemulsions were successfully internalized. Furthermore, quantitative analysis showed that addition of TAT-OL increases uptake of nanoemulsions by 2.3- and 2.6-folds after 2 and 4 hours of incubation, respectively. Cellular internalization pathways were found with substantial decrease in uptake in presence of indomethacin and chlorpromazine. Transfection efficiency investigated on HEK-293-cells was found to be 1.7- and 1.8-fold higher for SNEDDS loaded with TAT-OL compared to Lipofectin and control, respectively.

Conclusion: In comparison to prevailing lipid and polymer-based delivery systems, these novel cell-penetrating SNEDDS likely represent most effective, simplistic and expedite dosage form for mucosal gene delivery.     

黄芩素自微乳的制备及大鼠体内生物利用度研究

目的:制备黄芩素自微乳化制剂(SMEDDS),考察其大鼠体内生物利用度。方法:采用伪三元相图法筛选自微乳的油相、表面活性剂及助表面活性剂;采用HPLC法测定大鼠血浆中药物浓度,与原料比较,对黄芩素自微乳进行大鼠体内生物利用度评价。结果:通过使用混合油相、混合表面活性剂及助表面活性剂,可获得较为理想的黄芩素自微乳。大鼠体内血药浓度-时间曲线结果表明,黄芩素自微乳的AUC是原料的3.77倍,且药时曲线的形状发生一定的改变。结论:自微乳系统可显著增加黄芩素的溶解度,有利于提高口服生物利用度,且自微乳可能改变其胃肠道吸收行为。     

口服结肠靶向释药系统的制备及应用

目的由于在治疗肠道或某些全身性疾病中具有特殊的优点,口服结肠靶向给药系统受到更多的关注。但消化道的复杂性导致影响药物在结肠靶向释药的因素较多,重现性不好。本文对经口服药物结肠靶向释药的生理因素、目前已有的制备技术及应用进行综述。     

Mesoporous silicon in drug delivery applications

During the last few years, a number of interesting drug delivery applications of mesoporous materials have been demonstrated. Mesoporous silicon has many important properties advantageous to drug delivery applications. The small size of the pores confines the space of a drug and engages the effects of surface interactions of the drug molecules and the pore wall. The size of the pores and the surface chemistry of the pore walls may be easily changed and controlled. Depending on the size and the surface chemistry of the pores, increased or sustained release of the loaded drug can be obtained. Drug loading from a solution at room temperature enables the use of porous silicon (PSi) also with sensitive therapeutic compounds susceptible to degradation, like peptides and proteins. This article reviews the fabrication and chemical modifications of PSi for biomedical applications, and also the potential advantages of PSi in drug delivery.     

Novel engineered systems for oral,mucosal and transdermal drug delivery

Abstract

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.     

辅料在结肠靶向制剂中的应用

结肠靶向制剂是根据结肠部位血流量少、体液分布特殊（多种酶存在）的生理特性而发展起来的使药物在结肠部位集中释放药物,从而达到治疗目的的一种给药形式.这种制剂主要分为时滞型、pH依顿型、细菌触发型三类释药系统.本文根据不同释药系统的制备工艺及不同性质药物所用的辅料进行综述.     

智能药物释放体系的应用及研究进展

智能药物释放体系能按病灶信号实现药物释放的开-关控制,由高分子包囊药物所构筑。智能型聚合物在环境发生变化时,其微结构发生可逆变化,即从亲水状态转变成疏水状态,据此可构筑响应不同刺激信号的药物释放体系。本文概述了智能药物释放体系的应用现状及研究进展。     

基于介孔碳纳米粒包载胰岛素实现口服递药的研究

目的 利用介孔碳纳米粒(MCN)包载胰岛素从而实现口服缓释递药.方法 (1)制备与表征:制备包载胰岛素的介孔碳纳米粒(MCN-I),通过扫描电镜和透射电镜进行表征,高效液相色谱测定包封率和载药量,激光粒度仪测定粒径、多分散系数及Zeta电位,考察MCN-I的体外释放性能.(2)体内分布实验:按照体重将SD大鼠随机分为4...     

盐酸小檗碱纳米乳口服给药系统的制备及体外评价

目的 制备盐酸小檗碱纳米乳,优选其处方组成和制备工艺,并对其外观、粒径及体外释放行为等进行评价.方法 采用水滴加法制备盐酸小檗碱纳米乳,绘制纳米乳伪三元相图.选择星点设计-效应面法对纳米乳处方进行优化,确定最优处方组成比例.对制备的盐酸小檗碱纳米乳的粒径、电位、外观形态、体外释药行为等进行表征.结果 确定了盐酸小檗碱纳...