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.     

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs.     

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.     

Electrospun Nanofibers in Oral Drug Delivery

In order to enhance the delivery of drugs with limited absorption due to poor solubility/dissolution, approaches are being developed to improve the dissolution rates and solubility of drug molecules. These approaches include identification of water-soluble salts of parent drugs, preparation of stable amorphous drug formulations, inclusion of solubility-enhancing agents in the dosage form, and particle size reduction. Technologies to reduce drug particle size to sub-micrometer range are being applied to product development more frequently. Electrospinning is being considered as one of the technologies which can produce nanosized drugs incorporated in polymeric nanofibers. In vitro and in vivo studies have demonstrated that the release rates of drugs from these nanofiber formulations are enhanced compared to those from original drug substance. This technology has the potential to be used for enhancing the oral delivery of poorly soluble drugs.     

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.     

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。     

Oral lipid based drug delivery system (LBDDS): formulation, characterization and application: a review

The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility. This may lead to high inter- and intra subject variability, lack of dose proportionality and therapeutic failure. The improvement of bio-availability of drugs with such properties presents one of the greatest challenges in drug formulations. Oral lipid based formulations are attracting considerable attention due to their capacity to increase the solubility, facilitating gastrointestinal absorption and reduce or eliminate the effect of food on the absorption of poorly water soluble, lipophilic drug and thus increasing the bioavailability. The present review outlines the recent findings on self-emulsifying drug delivery system (SEDDS), self-micro/nanoemulsifying drug delivery system (SMEDDS/SNEDDS) and evaluation of these formulations published over the past decade. The application of lipid based formulations as a promising system for the oral delivery of many therapeutic agents including traditional medicine (TM) has also been examined in the current review.     

Matrix- and reservoir-based transmucosal delivery systems

Traditionally, per-oral delivery has been the primary route of administration for therapeutic agents targeting systemic delivery. However, oral administration subjects these compounds to extensive presystemic elimination, which may include gastrointestinal degradation, metabolism, or first-pass clearance via the liver, and may ultimately result in poor bioavailability. Parenteral routes, such as intravenous or intramuscular, permit therapeutic agents to gain direct entry into the systemic circulation and, therefore, reach the intended site of action more rapidly. Unfortunately, this mode of drug administration entails numerous disadvantages, including the requirement for close medical supervision and the need for specialized equipment. Transmucosal absorption of nitroglycerin from solutions through the oral cavity was demonstrated in the mid-nineteenth century, and since that time various conventional drug delivery systems for oral mucosal delivery have been proposed and have achieved clinical application. Technologic advances in biomaterials and techniques have resulted in the formulation of novel designs more pertinent to the oral cavity, meeting the challenges of the physicochemical properties of the drug entity itself and achieving the therapeutic aims of the drug delivery system. Issues of patient compliance and convenience have recently resulted in a trend toward once-a-day administration regimens, requiring drugs with high potency and sustained effect. Such drugs usually have a short biologic half-life, exhibit poor permeability and solubility, and are susceptible to enzymatic degradation. However, because of the advantages of delivering a drug through the oral mucosa, these drugs are viable candidates for delivery via this route. Many investigators have studied the potential of transmucosal delivery through the oral cavity, and the oral mucosa is increasingly being considered as a plausible route for many drug classes. Sublingual tablets, oral lozenges, chewing gum systems, and other dosage forms represent potential drug delivery systems for the oral mucosa, but most of the literature has not discussed information on specific drug delivery systems and their challenges. This article examines the anatomy, physiology, and absorption properties of the oral mucosal environment; explores the considerations for a transmucosal system; reviews these types of systems; and evaluates and proposes matrix and reservoir transmucosal applications.     

Insoluble drug delivery strategies: review of recent advances and business prospects

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.KEY WORDS: Bioavailability, Cocrystals, Solubility, Inclusion complexation, Nanoparticles, Self-emulsifying formulations, Proliposomes     

Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol

The main objective of this study was to develop carboxylated ordered mesoporous carbon microparticles (c-MCMs) loaded with a poorly water-soluble drug, intended to be orally administered, able to enhance the drug loading capacity and improve the oral bioavailability. A model drug, carvedilol (CAR), was loaded onto c-MCMs via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The physicochemical properties of the drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and HPLC. It was found that c-MCM has a high drug loading level up to 41.6%, and higher than that of the mesoporous silica template. Incorporation of CAR in both drug carriers enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. After loading CAR into c-MCMs, its oral bioavailability was compared with the marketed product in dogs. The results showed that the bioavailability of CAR was improved 179.3% compared with that of the commercial product when c-MCM was used as the drug carrier. We believe that the present study will help in the design of oral drug delivery systems for enhanced oral bioavailability of poorly water-soluble drugs.     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

INTRODUCTION: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation. AREAS COVERED: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration. EXPERT OPINION: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk-benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

Amorphous drug delivery systems: molecular aspects, design, and performance

The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.     

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。     

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.     

Drug precipitation inhibitors in supersaturable formulations

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration.

Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

A nanosystem for water-insoluble drugs prepared by a new technology, nanoparticulation using a solid lipid and supercritical fluid

While the number and diversity of lead compounds has increased with the development of science technologies, ca. 90 % of new chemical entities under development have shown low aqueous solubility, classified as class II or IV of the biopharmaceutics classification system (BCS). The low aqueous solubility hinders their clinical translations due to low bioavailability and dissolution-limited absorption of orally-administered drugs. Several technologies have been employed to improve the solubility of poorly water-soluble drugs. In this paper, a new method of nanoparticulation using fat and a supercritical fluid (NUFS) for the formulation of hydrophobic drugs was applied to solve the low solubility problem. A typical BCS class II drug, itraconazole, was selected and formulated with hydroxypropyl methylcellulose, emulsification, and anticoagulating agents for NUFS. The non-spherical itraconazole nanoparticles prepared by NUFS were ~300–500 nm in size with a ~15-fold improved dissolution rate compared to non-nanoparticles of itraconazole (i.e., raw itraconazole). In addition, a high drug content of ~46 % by weight and a drug loading efficiency greater than 85 % were achieved. Therefore, the new technology for nano-platforms could be a promising solution for solubilization of poorly water-soluble drugs, resulting in improved bioavailability.     

Formulation approaches for orally administered poorly soluble drugs

Despite having pharmacodynamic or target activity, many drugs fail in the drug development process due to poor bioavailability, and presently marketed conventional dosage forms of poorly soluble drugs employ high doses leading to potential toxicity. The introduction of the Biopharmaceutic Classification System (BCS) has provided a basis to categorize drugs based on the two major parameters affecting absorption, solubility and permeability. Several techniques can be employed to enhance the absorption and bioavailability of poorly soluble and poorly permeable drugs based on the BCS concept. This article is an attempt to summarize the development of various formulation approaches that are currently employed to enhance bioavailability of orally administered poorly soluble drugs.