From conventional towards new – natural surfactants in drug delivery systems design: current status and perspectives

Importance of the field: Surfactants play an important role in the development of both conventional and advanced (colloidal) drug delivery systems. There are several commercial surfactants, but a proportionally small group of them is approved as pharmaceutical excipients, recognized in various pharmacopoeias and therefore widely accepted by the pharmaceutical industry.

Areas covered in this review: The review covers some of the main categories of natural, sugar-based surfactants (alkyl polyglucosides and sugar esters) as prospective pharmaceutical excipients. It provides analysis of the physicochemical characteristics of sugar-based surfactants and their possible roles in the design of conventional or advanced drug delivery systems for different routes of administration.

What the reader will gain: Summary and analysis of recent data on functionality, applied concentrations and formulation improvements produced by alkyl polyglucosides and sugar esters in different conventional and advanced delivery systems could be of interest to researchers dealing with drug formulation.

Take home message: Recent FDA certification of an alkyl polyglucoside surfactant for topical formulation presents a significant step in the process of recognition of this relatively new group of surfactants. This could trigger further research into the potential benefits of naturally derived materials in both conventional and new drug delivery systems.     

Drug nanosuspensions: a ZIP tool between traditional and innovative pharmaceutical formulations

Introduction: A nanosuspension or nanocrystal suspension is a versatile formulation combining conventional and innovative features. It comprises 100% pure drug nanoparticles with sizes in the nano-scale range, generally stabilized by surfactants or polymers. Nanosuspensions are usually obtained in liquid media with bottom-up and top-down methods or by their combination. They have been designed to enhance the solubility, the dissolution rate and the bioavailability of drugs via various administration routes. Due to their small sizes, nanosuspensions can be also considered a drug delivery nanotechnology for the preparation of nanomedicine products.

Areas covered: This review focuses on the state of the art of the nanocrystal-based formulation. It describes theory characteristics, design parameters, preparation methods, stability issues, as well as specific in vivo applications. Innovative strategies proposed to obtain nanomedicine formulation using nanocrystals are also reported.

Expert opinion: Many drug nanodelivery systems have been developed to increase the bioavailability of drugs and to decrease adverse side effects, but few can be industrially manufactured. Nanocrystals can close this gap by combining traditional and innovative drug formulations. Indeed, they can be used in many pharmaceutical dosage forms as such, or developed as new nano-scaled products. Engineered surface nanocrystals have recently been proposed as a dual strategy for stability enhancement and targeting delivery of nanocrystals.     

Bile acids and bile acid derivatives: use in drug delivery systems and as therapeutic agents

ABSTRACT

Introduction: Bile acids are biological surfactants and signaling molecules with important paracrine and endocrine functions. The enterohepatic organotropism of bile acids turns these facial amphiphiles into attractive drug delivery systems for selective drug targeting to the liver or to enhance drug bioavailability by improving intestinal absorption and metabolic stability.

Areas covered: Bile acid-based amphiphiles, in the form of mixed micelles, bilosomes, drug conjugates and hybrid lipid-polymer nanoparticles are critically discussed as delivery systems for anticancer drugs, antimicrobial agents and therapeutic peptides/proteins, including vaccines. Therapeutic applications of bile acid derivatives as cytotoxic and neuroprotective agents are also addressed.

Expert opinion: Bile acids play an important role in modulating cancer therapy and novel derivatives with cytotoxic activity not restricted to the gastrointestinal tract can be expected. Selective toxicity targeting the bacterial membrane remains an attractive area of research for further development of bile acid-based bactericidal agents. On the other hand, the neuroprotective properties of some bile acids offer therapeutic potential in neurodegenerative disorders. Bile acid-based nanoparticles are also a growing research area due to the unique characteristics and tunable properties of these nanosystems. Therefore, multifaceted pharmaceutical and biomedical applications of bile salts are to be expected in the near future.     

Exploitation of lipid-polymeric matrices at nanoscale for drug delivery applications

ABSTRACT

Introduction: Progress in drug delivery and a better quality of life for patients, relies on the development of new and suitable drug carrier systems, with unequivocal therapeutic benefits, low systemic toxicity and reduced side effects. Lipid-polymeric nanoparticles have been explored to produce nanocarriers due to their features and applications such as high drug entrapment, physical-chemical stability and controlled release properties.

Areas covered: In this review, we describe several hybrid nanoparticles obtained from mixing a polymer with a lipid matrix. This association can potentiate the efficacy of drug delivery systems, due to the enhancement of encapsulation efficiency and loading capacity, tailoring the drug release according to the therapeutic purpose, and improving the drug uptake by targeting it to specific receptors. Contrary to lipid nanoparticles, these hybrid nanoparticles can decrease the initial burst release and promote a more sustained and localized release of the drug.

Expert Opinion: Lipid-polymeric nanoparticles are versatile vehicles for drug delivery by different administration routes in the treatment of multiple diseases. Different solid lipids, polymers, surfactants and techniques for producing these carriers have been investigated, revealing the importance of their composition to achieve optimal characteristics to drug delivery.     

Solid lipid microparticles as an approach to drug delivery

Introduction: Solid lipid particles were introduced in the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. Although lipid nanoparticles have been the object of a substantial number of reviews, fewer are available on lipid microparticles (LMs), despite their distinct advantages, including biocompatibility, ease of production and characterisation, extended release properties and high loading.

Areas covered: This review presents an overview of the advantages and drawbacks of LMs, that is, lipid-based particles with dimensions in the micrometre range. Specific focus is on the role of the main excipients used for LM formulations, lipids and surfactants and their effects on LM properties. An update on preparation techniques and characterisation methods are also presented, with particular emphasis on more recent technologies. The interaction of LMs with biological systems and with cells in particular is reviewed. The various LM administration routes are examined, with special attention to most recent applications (i.e., pulmonary and nasal delivery).

Expert opinion: LMs represent attractive and versatile carrier systems; however, their pharmaceutical applicability has been rather limited. Investigation on the use of LMs for less-established administration routes, such as pulmonary delivery, may provide further interest within the area of LM-based systems, both in industry and in the clinic.     

Recent advances in drug delivery strategies for treatment of ovarian cancer

Introduction: Ovarian cancer is associated with the highest mortality rate of all gynecological malignancies, due in part to inadequate treatment strategies and the asymptomatic nature of the disease. Current standard of care includes surgery and systemic chemotherapy. However, this approach can result in toxicities and eventual disease relapse, due to the emergence of multidrug resistance. Drug delivery systems (DDS) have shown promise in overcoming many of the limitations facing conventional treatment regimens.

Areas covered: This review provides an overview of recent advances in DDS strategies for the treatment ovarian cancers. Nano-sized systems, including nanoparticles, micelles, liposomes and drug conjugates; microspheres; implants and injectable depots are discussed. The advantages, limitations and clinical potential of these strategies are also outlined.

Expert opinion: Nano-sized DDS enable passive targeting to tumors due to their size, and further improvements in tumor localization can be made using targeting moieties. Microspheres, implants and injectable depots have been investigated for peritoneal localized and sustained therapy. Overall, the benefits of using DDS for ovarian cancer therapy include higher drug levels at the diseased site, circumvention of drug resistance mechanisms, minimization of non-specific toxicities, improvements in solubility of poorly soluble drugs and elimination of toxicities associated with conventionally used pharmaceutical excipients.     

Methotrexate: a detailed review on drug delivery and clinical aspects

Introduction: Uses of methotrexate (MTX) are well established for the treatment of various types of malignancy, psoriasis, rheumatological diseases and the medical termination of pregnancy. Formulation and targeting approaches for MTX with controlled release carriers, multiparticulate systems, prodrug and drug conjugates have been found to improve bioavailability, reduce adverse effects and maximize clinical efficacy, compared with conventional methods.

Areas covered: This exhaustive literature survey on different electronic databases covers drug delivery and clinical trials on MTX. This review deals with the challenges and achievements of controlled release, multiparticulate, prodrug and drug conjugate systems of MTX.

Expert opinion: Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion.     

Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release

Introduction: Solid oral dosage forms are the most commonly used method for administering active pharmaceutical ingredients to patients. Understanding the mechanisms and processes of drug release is essential for improving the design of pharmaceutical tablets.

Areas covered: In this review, recent approaches where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging has been applied to study tablet dissolution and drug release have been investigated. Drug release studies of model pharmaceutical systems composed of drug/polymer mixtures in the presence of aqueous solutions have been discussed, as has the subsequent combination with UV/Vis spectroscopic detection to quantify the amount of drug dissolved as a function of time. The use of a single-reflection ATR accessory with a diamond crystal allows for in situ FTIR imaging of tablet compaction and dissolution.

Expert opinion: ATR-FTIR imaging can address the challenges of investigating the mechanisms of drug release from a range of innovative new delivery systems. Unlike standard dissolution tests, this spectroscopic imaging method obtains insight and information about changes within the tablet during dissolution. Areas where ATR-FTIR imaging has shown further potential to be particularly useful are for the study of multi-layered solid tablets, high-throughput analysis, use of microfluidic devices and for surface-enhanced ATR-FTIR spectroscopy.     

Calcium carbonate nanoparticles as cancer drug delivery system

Introduction: Calcium carbonate (CaCO₃) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO₃ nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO₃ matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration.

Areas covered: Development of drug delivery carriers using CaCO₃ nanoparticles has been reviewed. The current state of CaCO₃ nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated.

Expert opinion: According to our review, CaCO₃ nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.     

Niosomes as a propitious carrier for topical drug delivery

Introduction: Topical delivery is defined as drug targeting to the pathologic sites of skin with the least systemic absorption. Drug localization in this case is a crucial issue. For these purposes vesicular drug delivery systems including niosomes, proniosomes, liposomes and transferosomes have been developed.

Areas covered: This review first highlights the role of niosome in dermatology focusing on localized skin delivery and then reviews the most recent literatures regarding specific applications of niosomal drug delivery systems in clinics.

Expert opinion: Niosomes are becoming popular in the field of topical drug delivery due to their outstanding characteristics like enhancing the penetration of drugs, providing a sustained pattern of drug release, increasing drug stability and ability to carry both hydrophilic and lipophilic drugs.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

Introduction: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems.

Areas covered: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems.

Expert opinion: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Nanostructured porous silicon-mediated drug delivery

Introduction: The particular properties of nanostructured porous silicon (nanoPS) make it an attractive material for controlled and localized release of therapeutics within the body, aiming at increased efficacy and reduced risks of potential side effects. Since this is a rapidly evolving field as a consequence of the number of research groups involved, a critical review of the state of the art is necessary.

Areas covered: In this work, the most promising and successful applications of nanoPS in the field of drug delivery are reviewed and discussed. Two key issues such as drug loading and release are also analyzed in detail. The development of multifunctional (hybrid) systems, aiming at imparting additional functionalities to the nanoPS particles such as luminescence, magnetic response and/or plasmonic effects (allowing simultaneous tracking and guiding), is also examined.

Expert opinion: Nanostructured materials based on silicon are promising platforms for pharmaceutical applications given their ability to degrade and low toxicity. However, a very limited number of clinical applications have been demonstrated so far.     

Polysaccharides: a targeting strategy for colonic drug delivery

Introduction: Colon targeting has gained increasing importance for the topical treatment of diseases of the colon, such as Crohn's disease, ulcerative colitis, colorectal cancer and amebiasis. Various strategies used for targeting drugs to the colon include formation of a prodrug, coating with time or pH-dependent polymers, use of colon-specific biodegradable polymers, osmotic systems and pressure-controlled drug delivery systems. Among the different approaches used, polysaccharides that are precisely activated by the physiological conditions of the colon hold great promise, as they provide improved site specificity and meet the desired therapeutic needs.

Areas covered: This review aims to summarize the natural and modified properties of polysaccharides that are responsible for their colon targeting abilities. Emphasis is placed on describing formulation approaches that use polysaccharides as a strategy for targeting drugs to the colon.

Expert opinion: Polysaccharide-based colon-targeted drug delivery systems are effective when they are precisely activated by the physiological conditions of the colon. Absence of enzymes during colonic disorders might hinder the activation of the delivery system. To guarantee delivery of the drug to the colon, it is preferable to combine polysaccharides with enteric or cellulose polymers.     

Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates

Introduction: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs.

Areas covered: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize^?, closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug–carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer^TM used to prepare stable amorphous SD.

Expert opinion: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.     

Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals

Introduction: Compritol® 888 ATO is a lipid excipient that is generally used in cosmetic industry as a surfactant, emulsifying agent and viscosity-inducing agent in emulsions or creams. Based on its chemical composition, Compritol 888 ATO is a blend of different esters of behenic acid with glycerol.

Areas covered: Recently, there has been great interest in the multiple roles that Compritol 888 ATO plays in various pharmaceutical delivery systems. Accordingly, this review aimed at summarizing the current and potential applications of Compritol 888 ATO in various drug delivery areas.

Expert opinion: Different researches have highlighted the feasibility of using Compritol 888 ATO as a lubricant or coating agent for oral solid dosage formulations. It has also been explored as a matrix-forming agent for controlling drug release. At present, the most common pharmaceutical application of Compritol 888 ATO is in lipid-based colloidal drug delivery system such as solid lipid microparticles, solid lipid nanoparticles and nanostructured lipid carriers. Although, Compritol 888 ATO has acceptable regulatory and safety profiles and although the number of articles that emphasize on its applicability as an innovative excipient in pharmaceutical technology is continuously increasing, it is not widely used in the pharmaceutical market products and its use is limited to its sustain release ability in extended release tablets.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

Integrin targeted drug and gene delivery

Importance of the field: Recently, there has been substantial progress in the development of integrin targeted pharmaceuticals and drug delivery systems. Integrin is an important member in the cell adhesion molecule family, which is involved in regulation of complex biological conditions, from keeping normal physiological activities to causing cellular dysfunction in diseased cells. Hence, it is timely to summarize the recent developments in integrin targeted drug and gene delivery systems to understand better their advantages and limitations.

Areas covered in this review: In this review, advances in the discovery and clinical trials of these integrin antagonists against different integrin subunits are summarized and discussed. Besides using integrin inhibitor as a single therapeutic agent, integrin antagonists that were conjugated to cytotoxic drugs by synthetic chemistry or coupled to biomacromolecules by either DNA recombination technology or fusion protein technology for integrin targeted therapy have been explored. Furthermore, nanoparticles with integrin targeting ligands for both drug and gene delivery, typically for antiangiogenesis and anticancer therapy, are highlighted and evaluated.

What the reader will gain: This review sheds light on the future development of integrin targeted drug and/or gene delivery systems.

Take home message: Although thus far there are still limitations, integrin targeted delivery systems have already shown their potential as important pharmaceuticals in the near future.     

Chitosan nanoparticles in drug therapy of infectious and inflammatory diseases

ABSTRACT

Introduction: Chitosan, a polymer from the chitin family has diverse pharmaceutical and bio-medical utility because of its easy widespread availability, non-toxicity, biocompatibility, biodegradability, rich functionalities and high drug-loading capacity. Recent pharmaceutical research has examined the use of chitosan-based systems for drug delivery applications in various diseases. The availability of functional groups permits the conjugation of specific ligands and thus helps to target loaded drugs to the site of infection/inflammation. Slow biodegradation of chitosan permits controlled and sustained release of loaded moieties; reduces the dosing frequency and is useful for improving patient compliance in infectious drug therapy. The muco-adhesion offered by chitosan makes it an attractive candidate for anti-inflammatory drug delivery, where rapid clearance of the active moiety due to the increased tissue permeability is the major problem. The pH-dependent swelling and drug release properties of chitosan present a means of passive targeting of active drug moieties to inflammatory sites.

Areas covered: Development of chitosan-based nanoparticulate systems for drug delivery applications is reviewed. The current state of chitosan-based nanosystems; with particular emphasis on drug therapy in inflammatory and infectious diseases is also covered.

Expert opinion: The authors believe that chitosan-based nanosystems, due to the special and specific advantages, will have a promising role in the management of infectious and inflammatory diseases.     

Opportunities and limits of cell-based assay miniaturization in drug discovery

Importance of the field: Miniaturization is a significant driver for many life-science applications and a key technology for personalized medicine. Innovations in microfluidics will make ex vivo testing in in vivo-like environment possible, thus, allowing novel pathways for drug discovery.

Areas covered in this review: This review covers the application of miniaturization technologies, namely microfluidics for cell-based assay development. We highlight the use of microfluidics in sample preparation and clinical trials, review the progress towards in vivo-like test environments and point out practical challenges in the work with microfluidic systems.

What the reader will gain: The reader will gain an overview of the different application areas of miniaturized systems for cell-based assay-methods and the technologies involved in how they can be applied in the drug discovery process is given. Examples of clinical applications are pointed out.

Take home message: Miniaturization is a key technology driver for methodological progress in drug discovery. The enabling nature of this technology is reflected in the multitude of applications covering all aspects of the drug discovery process.