Potentials and challenges in self-nanoemulsifying drug delivery systems

Introduction: A significant number of new chemical entities (almost 40%), that are outcome of contemporary drug discovery programs, have a potential therapeutic promise for patient, as they are highly potent but poorly water soluble resulting in reduced oral bioavailability. Self-nanoemulsifying drug delivery systems (SNEDDS) have emerged as a vital strategy to formulate these poorly soluble compounds for bioavailability enhancement.

Areas covered: The review gives an insight about potential of SNEDDS with regards to oral drug delivery. The effect of various key constituents on formulation of SNEDDS and their applications in oral drug delivery is also discussed. Various aspects of formulation, characterization and biopharmaceutical aspects of SNEDDS are also been explored. The choice and selection of excipients for development of SNEDDS is also discussed.

Expert opinion: The ability of SNEDDS to present the drug in single unit dosage form either as soft or hard gelatin capsule with enhanced solubility maintaining the uniformity of dose is unique. With the ease of large-scale production, high drug-loading capacity, improvement in release behavior of poorly water-soluble drugs and improvement of oral bioavailability, SNEDDS have emerged as preferable system for the formulation of drug compounds with bioavailability problems due to poor aqueous solubility.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.     

Lipid-based formulations for oral administration of poorly water-soluble drugs

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. The aim of this review is to provide an overview of the different lipid-based dosage forms from a biopharmaceutical point of view and to describe effects of lipid dosage forms and lipid excipients on drug solubility, absorption and distribution.     

Solubility enhancers for oral drug delivery

With recent progress in high throughput screening of potential therapeutic agents, the number of poorly water-soluble drug candidates has risen sharply and formulating for poorly water-soluble compounds for oral delivery now presents one of the most frequent and greatest challenges to scientists in the pharmaceutical industry. Many new drugs and potential therapeutic compounds under investigation possess high lipophilicity, poor water solubility, and low oral bioavailability. Furthermore, development of improved oral dosage forms for currently marketed drugs can also enhance their therapeutic value. Oral delivery systems designed for poorly water-soluble drugs include micelles with surfactants, microemulsions, self-emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS), solid dispersions, microspheres and cyclodextrin inclusion complexes. These delivery systems have been shown to enhance oral bioavailability and therapeutic effects of poorly water-soluble drugs mainly by improving the poor solubility. As a consequence of extensive research, various oral delivery systems for poorly water-soluble agents are being developed in clinical phases worldwide. New formulation technologies and multidisciplinary expertise may lead to development of advanced and effective oral drug delivery systems applicable to a wide range of poorly water-soluble drugs in the near future.     

Emerging trends in the stabilization of amorphous drugs

The number of active pharmaceutical substances having high therapeutic potential but low water solubility is constantly increasing, making it difficult to formulate these compounds as oral dosage forms. The solubility and dissolution rate, and thus potentially the bioavailability, of these poorly water-soluble drugs can be increased by the formation of stabilized amorphous forms. Currently, formulation as solid polymer dispersions is the preferred method to enhance drug dissolution and to stabilize the amorphous form of a drug.     

共无定形给药系统研究进展

共无定形药物是将活性药物成分和其他药物或辅料等小分子固体组分混合形成的一种二元单相无定形固体分散体给药系统。作为一种新颖的药物传递系统，共无定形药物可能改善水难溶性药物的溶解度和口服生物利用度问题，为仿制药物和复方药物的开发提供了新的策略和思路。近年来，共无定形药物在学术和制药工业领域受到广泛关注。本文综述了共无定形药物的载体材料的筛选、制备方法、物理稳定机制，以及体外溶出性能和体内吸收情况，并对共无定形药物的未来发展前景进行了展望。     

应用纳米技术增加难溶性药物吸收的研究进展

随着高通量筛选等新技术的出现,涌现出许多难溶性的候选药物。利用纳米技术能减小难溶性药物的粒径,增加其溶解度、溶出度和口服生物利用度,减少食物效应的影响。本文介绍了纳米粒的制备方法,商用的专利纳米技术以及应用纳米技术成功上市的药品。纳米技术对改善生物药剂学分类体系（BCS）Ⅱ类药物的吸收具有广阔的前景。     

Recent advances in intravenous delivery of poorly water-soluble compounds

In recent years, with the widespread application of high-throughput screening technologies in drug discovery, an increasing number of new chemical entities with extremely poor aqueous solubility have been generated. Their poor solubility represents a major challenge for formulation of these compounds for both oral and parenteral administration. Formulations for intravenous (i.v.) application are of significant importance because they are frequently used in several key therapeutic areas, such as oncology and anesthesia. Furthermore, i.v. formulations of new compounds are often needed to determine basic biopharmaceutical parameters and to obtain proof of concept results in the early phase of product development. This review provides an overview of the recent advances in formulation approaches and drug delivery technologies for poorly water-soluble compounds applicable to i.v. administration. The advantages and disadvantages of different strategies are highlighted and an expert opinion on each technical field is presented.     

PEG–lipid micelles as drug carriers: physiochemical attributes,formulation principles and biological implication

PEG–lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG–DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG–DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG–lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG–lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG–lipid micelles and their relevance to the inherent advantages and applications of PEG–lipid micelles for drug delivery.     

Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system.

Poorly water-soluble drug candidates often emerge from contemporary drug discovery programs, and present formulators with considerable technical challenges. The absorption of such compounds when presented in the crystalline state to the gastrointestinal tract is typically dissolution rate-limited, and the drugs are typically BCS class II or class IV compounds. Class IV compounds, which have low membrane permeability as well as poor aqueous solubility, are often poor candidates for development, unless the dose is expected to be low. The rate and extent of absorption of class II compounds is highly dependent on the performance of the formulated product. These drugs can be successfully formulated for oral administration, but care needs to be taken with formulation design to ensure consistent bioavailability. Essentially the options available involve either reduction of particle size (of crystalline drug) or formulation of the drug in solution, as an amorphous system or lipid formulation. The performance of amorphous or lipid formulations is dependent on their interaction with the contents of the gastrointestinal tract, therefore, a formulation exercise should involve the use of techniques which can predict the influence of gut physiology. A major consideration is the fate of metastable supersaturated solutions of drug, which are formed typically after dispersion of the formulation and its exposure to gastrointestinal digestion. A better understanding of the factors which affect drug crystallization is required, and the introduction of standardised predictive in vitro tests would be valuable. Although many bioavailability studies have been performed with poorly water-soluble drugs, thus far this research field has lacked a systematic approach. The use of a lipid formulation classification system combined with appropriate in vitro tests will help to establish a database for in vitro-in vivo correlation studies.     

Rational formulation strategy from drug discovery profiling to human proof of concept

Abstract

The objective of this paper is to introduce some strategic guidance to a rational formulation strategy of new molecules as oral dosage forms, based on a sound scientific understanding of factors determining the oral bioavailability. The critical implication of permeability and solubility is discussed along with the efficient dose of the drug. The concept of dose-solubility number is introduced as a tool for chemists to assess the develop-ability of different molecules very early during discovery stage. Based on this understanding, a rational formulation strategy for preclinical and early clinical phases is provided. The technical considerations and limitations of different formulation technologies are discussed and illustrated via concrete examples. This approach has the advantage of streamlining the formulation process in order to avoid delaying the development of new drugs due to formulation related issues.     

Development of solid dispersion lipid nanoparticles for improving skin delivery

Applications of poorly water-soluble drugs in skin delivery pose several challenges to pharmaceutical formulation. This research originally developed solid lipid nanoparticles (SLNs) packaging a modified core of a solid dispersion (SD) in the lipid matrix to modulate the skin release patterns. Curcumin (CUR) was selected as the poorly water-soluble drug applied in the formulation. The designed system, so-called solid dispersion lipid nanoparticles (SD-SLNs), was fabricated by incorporating a solidifying SD or a non-solidifying SD into the core of the SLNs by ultrasonication. Release studies illustrated an important enhancement in the drug release of the proposed system compared to pure CUR and SLN formulations without the presence of SD as the modified core, which indicated the positive effect of the combined colloidal method of SD and SLNs. The physicochemical properties of the SD-SLN systems were also elucidated using powder X-ray diffraction, Fourier transform infrared spectroscopy, and particle size analysis. The drug was found to change to an amorphous state without any molecular interactions along with a marked particle size reduction. This work demonstrated the strong potential of applying a novel SD-SLN system for the skin delivery of a drug with poor water solubility.     

Statistical modeling,optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment

Objective: Lopinavir (LPV), an antiretroviral protease inhibitor shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism. The aim of the present work was to investigate the potential of the solid self-nanoemulsifying drug delivery system (S-SNEDDS) in improving dissolution rate and oral bioavailability of LPV.

Materials and methods: Liquid SNEDDS (L-SNEDDS) of LPV were prepared using Capmul MCM C8, Cremophor RH 40 and propylene glycol and their amounts were optimized by Scheffe’s mixture design. L-SNEDDS formulations were evaluated for different physicochemical and in vitro drug release parameters. S-SNEDDS were prepared by adsorbing L-SNEDDS on Neusilin US2 and characterized for solid-state properties. In vivo bioavailability of S-SNEDDS, marketed Lopinavir?+?Ritonavir (LPV/RTV) formulation and pure LPV was studied in Wistar rats. Stability study of S-SNEDDS was performed as per ICH guidelines.

Results and discussion: Optimized L-SNEDDS obtained by Scheffe design had drug loading 160?±?1.15?mg, globule size 32.9?±?1.45?nm and drug release?>95% within 15?min. Solid state studies suggested the transformation of the crystalline drug to amorphous drug. The size and zeta potential of globules obtained on dilution S-SNEDDS remained similar to L-SNEEDS. In vivo bioavailability study revealed that S-SNEDDS has 2.97 and 1.54-folds higher bioavailability than pure LPV and LPV/RTV formulation, respectively. The optimized S-SNEDDS was found to be stable and had a shelf life of 2.85 years.

Conclusion: The significant increase in drug dissolution and bioavailability by prepared SNEDDS suggest that the developed S-SNEDDS is a useful solid platform for improving oral bioavailability of poorly soluble LPV.     

口服药物吸收中的生物药剂学性质

目的综述药物的生物药剂学性质对药物口服吸收的影响。方法依据本课题组在该领域的工作,查阅国内外30篇相关文献,并结合最新进展进行归纳总结。结果药物的溶解性、稳定性、膜通透性和首过作用等生物药剂学性质是影响药物口服后经胃肠道吸收的主要因素。结论药物的生物药剂学性质显著影响口服药物的吸收,在药物结构设计、制剂处方设计、临床合理用药及口服给药系统开发中应重视评价药物的生物药剂学性质。     

Recent advances in oral delivery of drugs and bioactive natural products using solid lipid nanoparticles as the carriers

Chemical and enzymatic barriers in the gastrointestinal (GI) tract hamper the oral delivery of many labile drugs. The GI epithelium also contributes to poor permeability for numerous drugs. Drugs with poor aqueous solubility have difficulty dissolving in the GI tract, resulting in low bioavailability. Nanomedicine provides an opportunity to improve the delivery efficiency of orally administered drugs. Solid lipid nanoparticles (SLNs) are categorized as a new generation of lipid nanoparticles consisting of a complete solid lipid matrix. SLNs used for oral administration offer several benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. The nontoxic excipients and sophisticated material engineering of SLNs tailor the controllable physicochemical properties of the nanoparticles for GI penetration via mucosal or lymphatic transport. In this review, we highlight the recent progress in the development of SLNs for disease treatment. Recent application of oral SLNs includes therapies for cancers, central nervous system-related disorders, cardiovascular-related diseases, infection, diabetes, and osteoporosis. In addition to drugs that may be active cargos in SLNs, some natural compounds with pharmacological activity are also suitable for SLN encapsulation to enhance oral bioavailability. In this article, we systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for drug- and natural compound-loaded SLNs.     

纳米载体提高难溶性药物口服生物利用度的研究进展

纳米载体是药剂学备受关注的研究领域,作为一类新型给药系统,它能显著提高难溶性药物的溶解度、生物利用度和稳定性,且具有明显的缓释作用,因此得到了广泛的应用。目前常用于提高难溶性药物口服生物利用度的纳米载体有纳米脂质体、固体脂质纳米粒、纳米胶束、和纳米结晶等,它们的粒径、表面性质及其释药环境等是影响纳米载体药物口服吸收的主要因素。本文对纳米载体提高难溶性药物口服生物利用度的研究进展作一综述。     

Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation

PURPOSE: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. METHODS: Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. RESULTS: The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. CONCLUSIONS: Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.     

非晶固体分散体技术的研究现状

提高药物的溶解度和生物利用度是制剂研究的重要挑战.非晶固体分散体(ASD)能极大增加药物的溶解度和溶出速度,从而改善其生物利用度,被广泛用于难溶性药物的递送.ASD的成功必须满足两点要求:良好的物理稳定性以及良好的溶出以获得较高的生物利用度.本文主要综述ASD的制备方法,表征技术,物理稳定性以及制剂设计理论,以期为AS...     

Lipid - An emerging platform for oral delivery of drugs with poor bioavailability

The sole objective of pharmaceutical science is to design successful dosage forms which fulfill the therapeutic needs of the patients effectively. Development of new drug entities is posing real challenge to formulators, particularly due to their poor aqueous solubility which in turn is also a major factor responsible for their poor oral bioavailability. Lipids as carriers, in their various forms, have the potential of providing endless opportunities in the area of drug delivery due to their ability to enhance gastrointestinal solubilization and absorption via selective lymphatic uptake of poorly bioavailable drugs. These properties can be harvested to improve the therapeutic efficacy of the drugs with low bioavailability, as well as to reduce their effective dose requirement. The present communication embodies an in-depth discussion on the role of lipids (both endogenous and exogenous) in bioavailability enhancement of poorly soluble drugs, mechanisms involved therein, approaches in the design of lipid-based oral drug delivery systems with particular emphasis on solid dosage forms, understanding of morphological characteristics of lipids upon digestion, in vitro lipid digestion models, in vivo studies and in vitro-in vivo correlation.