Drug delivery vehicles with improved encapsulation efficiency: taking advantage of specific drug–carrier interactions

Introduction: Drug encapsulation strategies are vital for the delivery of poorly soluble, fragile or toxic compounds. Increasing a drug's encapsulation efficiency in drug carrier particles can achieve a stronger therapeutic effect along with minimized side effects. For these reasons, new encapsulation methods are developed by using new materials and various types of drug–carrier interaction.

Areas covered: Strategies used for drug encapsulation are discussed in this review, focusing particularly on approaches leading to high encapsulation ratios resulting from specific interactions between the drug and the carrier. In the first part, classical encapsulation by hydrophobic self-assembly, its limitations and improvements are briefly discussed. Following this, encapsulation strategies for specific drugs are reviewed, where particular kinds of interaction play a role between the drug and the encapsulating material, which can lead to dramatically increased entrapment. Such specific approaches can be utilized more generically for various classes of molecules with similar properties, with regard to their ability to participate in a given kind of interaction.

Expert opinion: With the focus on delivering a high drug dose precisely to the site of action, high encapsulation efficiency is the first thing to consider in drug development. Academic research shows considerable interest in specific encapsulation, and it seems to be an established trend now to design drug delivery particles to achieve the most favorable properties. The authors believe the research in this area will focus on material properties and interactions between the drug and the carrier to ensure high drug loading into particles.     

Nanocapsules with specific targeting and release properties using miniemulsion polymerization

Introduction: The field of application for nanosized materials ranges from mere technical purposes to a growing field of applications in biomedicine. Among the different techniques and processes to produce these materials for encapsulation of reporter molecules and drugs, the miniemulsion process has been proven to be highly adaptable to these specific needs.

Areas covered: The review covers the recent developments in the field of miniemulsion as a very powerful technique for the formation of complex carriers for the encapsulation of different kinds of reporter molecule and drugs. The use of a wide variety of polymerization techniques in the miniemulsion process and possible utilization of a wide range of monomers as requested by the biomedical applications is demonstrated. Hereby important factors, such as size, shape, degradation, release kinetics and surface functionalization can be tuned as requested. Furthermore, the inclusion of many payloads, for example, magnetic resonance imaging markers and chemotherapeutic drugs, in a highly controlled manner is discussed. Not only hydrophobic but also hydrophilic substances can be elegantly incorporated.

Expert opinion: Further investigations should be focused on the body distribution and intracellular degradation of nanoparticles and nanocapsules. For the former, a better understanding of the interaction with proteins from blood plasma and other body fluids is required. While understanding the uptake mechanisms of nanomaterials into cells has been improved during the last decade, there is still no good methodology to determine the intracellular degradation mechanisms.     

Recent advances in cyclodextrin delivery techniques

Introduction: Active pharmaceutical ingredients (APIs) are evolving from low-molecular-weight drugs to peptide-, protein-, gene-, oligonucleotide- and cell-based drugs. Therefore, advanced pharmaceutical technologies are required to achieve manifestation of the drug efficacy, side effect reduction and the adequate dosage form design.

Areas covered: In this review, the authors highlight the recent advances in drug delivery techniques utilizing cyclodextrins (CyDs), and cyclic oligosaccharides consisting of α-1,4-linked α-D-glucopyranose units, for various drugs described above. Especially, drug delivery system consisting of combination systems of CyDs and functional materials such as dendrimer, liposome and PEG are introduced. Furthermore, the utilities of CyDs as APIs have been also described.

Expert opinion: To achieve the controlled release and/or targeting of low-molecular-weight drugs in systemic administration, the construction of novel CyDs and CyD the supramolecular system should be a useful approach because of the stable complexation of drugs with CyDs. In addition, the combination systems of CyDs and various carriers have the potential as advanced drug delivery systems for proteins and nucleic acids. Furthermore, CyDs have great potential as APIs for various diseases with few side effects, although the detailed mechanism, especially cellular uptake of CyDs, should be clarified.     

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.     

Mucoadhesive drug carrier based on functional-modified cellulose as poorly water-soluble drug delivery system

Abstract

The purpose of this study was to design and characterise an oral mucoadhesive micellar drug carrier. In this regard, a mucoadhesive hydrophobic cationic aminocellulose was easily synthesised under mild homogeneous conditions with high yield. The cellulose derivative resulted in strongly improved mucoadhesive properties but was pH dependent. Furthermore, the hydrophobic anticancer drug camptothecin was successfully encapsulated into the mucoadhesive cellulose derivative micelles with spherical shape stability of 233?nm in diameter and low particle size distribution. The CPT-loaded nanocarriers provided high encapsulation efficiency about 86.4%. In vitro release, CPT-loaded cellulose derivative micelles showed a reduction in release rate compared with physically pure CPT solution. The release results also indicated that a sustained release of CPT to >80% over 4?d for pH 6.8 and 7.4. Therefore, mucoadhesive hydrophobic cationic aminocellulose micelles seem to be a promising carrier for various pharmaceutical applications especially for poorly water-soluble drug delivery system.     

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs

Introduction: Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo.

Areas covered: In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed.

Expert opinion: During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.     

Overcoming formulation challenges for the next generation of vaccines

Introduction: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems.

Areas covered: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes–Whitney equation, while the wetting properties of the used polymer may also play an important role.

Expert opinion: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

Extended release formulations using silk proteins for controlled delivery of therapeutics

ABSTRACT

Introduction: Silk is a promising biomaterial for controlled delivery of therapeutics and has a unique protein chemistry that can be tuned to form different carrier formats. The protein has been studied for sustained release depot systems for the targeted or localized delivery of drugs.

Areas covered: An overview of natural silk proteins for controlled delivery of therapeutics is provided, with a focus on the features of silk proteins that allow them to be useful tools for controlled delivery. Recent applications of natural silk proteins as controlled delivery systems are also summarized.

Expert opinion: The versatility of silk proteins makes them desirable biomaterials for a broad range of applications for controlled delivery of both small and large molecules. Further, the degradation profile leading to peptides and amino acids provides compatibility with pH-sensitive therapeutics. While silk sericin and spider silks are under study, silk fibroin extracted from silkworms (e.g. Bombyx mori) dominates pharmaceutical studies with silk. Silk fibroin can be formed into drug delivery tools for systemic or local injections, topical and transdermal applications, and implantation; depending on the target disease and therapeutic molecule. In vitro to in vivo correlations and scale-up needs are the next steps towards clinical applications.     

Hydrogels with smart systems for delivery of hydrophobic drugs

Introduction: Smart hydrogel systems present opportunities to not only provide hydrophobic molecule encapsulation capability but to also respond to specific delivery routes.

Areas covered: An overview of the design principles, preparation methods and applications of hydrogel systems for delivery of hydrophobic drugs is given. It begins with a summary of the advantages of hydrogels as delivery vehicles over other approaches, particularly macromolecular nanocarriers, before proceeding to address the design and preparation strategies and chemistry involved, with a particular focus on the introduction of hydrophobic domains into (naturally) hydrophilic hydrogels. Finally, the applications in different delivery routes are discussed.

Expert opinion: Modifications to conventional hydrogels can endow them with the capability to carry hydrophobic drugs but other functions as well, such as the improved mechanical stability, which is important for long-term in vivo residence and/or self-healing properties useful for injectable delivery pathways. These modifications harness hydrophobic-hydrophobic forces, physical interactions and inclusion complexes. The lack of in-depth understanding of these interactions, currently limits more delicate and application-oriented designs. Increased efforts are needed in (i) understanding the interplay of gel formation and simultaneous drug loading; (ii) improving hydrogel systems with respect to their biosafety; and (iii) control over release mechanism and profile.     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Driving forces for drug loading in drug carriers

Abstract

The loading capacity of a drug carrier is determined essentially by intermolecular interactions between drugs and carrier materials. In this review, the process of drug loading is described in detail based on the differences in the driving force for drug incorporation, including hydrophobic interaction, electrostatic interaction, hydrogen bonding, Pi–Pi stacking and van der Waals force. Modifying drug-loading sites of carrier materials with interacting groups aiming at tailoring drug–carrier interactions is reviewed by highlighting its importance for improving in vitro properties such as the loading capacity, release behaviour and stability. Other factors affecting drug loading, methods employed to predict the encapsulation capacity and the techniques to verify intermolecular interactions are also discussed to inform the readers of all-sided information on drug-loading processes and theories. The drug carriers can be designed more reasonably with the better understanding of the nature and interacting mechanism of intermolecular interactions.     

Technology evaluation: Kollicoat IR

Introduction: Developments in industrial pharmacy are often linked to the discovery of pharmaceutical excipients. Although recently introduced as a material for immediate release coatings, Kollicoat IR already has other applications.

Areas covered: In this review, the different properties and pharmaceutical applications of Kollicoat IR as an excipient are discussed. In the first part, the chemical structure and the physicochemical characteristics are examined. The second part is a presentation of the available Kollicoat IR products followed by a brief overview of the preclinical studies completed for its use as an instant release coating material.

Expert opinion: Although the polymer was intended as an immediate release coating material for tablets, grafting PEG with polyvinyl alcohol to form this polymer provides physicochemical properties that lead to ever-broadening applications. Understanding its properties can lead to the development of a new use for Kollicoat IR. The addition of Kollicoat IR to an ethylcellulose or polyvinyl acetate tablet coat was successful at modifying the drug release rate. Designing a successful controlled release coat simply requires acknowledgment of the drug release mechanism from the mixture of polymers that includes Kollicoat IR. Moreover, the interaction between Kollicoat IR and poorly soluble drugs produces fast-dissolving solid dispersions prepared using hot stage extrusion, spray drying, or freeze drying.     

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.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

One-step solid-oil-water emulsion for sustained bioactive ranibizumab release

ABSTRACT

Background: The advent of therapeutic proteins highlights the need for delivery systems that protect and extend the duration of its action. Ranibizumab-VEGF is one such drug used for treating wet AMD. This paper describes a facile method to sustain bioactive ranibizumab release from PLGA-based particles.

Methods: Two emulsion techniques were explored namely: water-in-oil-in-water (WOW) and solid-in-oil-in-water (SOW) emulsion. The bioactivity of ranibizumab was evaluated by comparing its binding capability to VEGF, measured with ELISA to total protein measured by microBCA.

Results: During the emulsion process, contact of ranibizumab with the water-oil interface is the main destabilizing factor and this can be prevented with the use of amphiphilic PVA and solid-state protein in WOW and SOW emulsion respectively. In vitro release of the ranibizumab-loaded particles indicated that a 15-day release could be achieved with SOW particles while the WOW particles generally suffered from a burst release. Released ranibizumab was capable of inhibiting endothelial cell growth indicating its retention of bioactivity. The suppression of burst release from the SOW particles was attributed to the relatively smooth surface morphology of the SOW microparticles.

Conclusions: The use of SOW encapsulation in modulating ranibizumab release while maintaining their bioactivity has been highlighted.     

Recent developments in novel drug delivery systems for wound healing

Introduction: Complete regeneration and restoration of the skin’s structure and function with no or minimal scarring remains the goal of wound healing research. Novel pharmaceutical carriers have the potential to deliver wound healing drugs such as antibiotics, antimicrobials, human EGFs, and so on. Thus, offering a potential platform to overcome the limitations of conventional wound dressings.

Areas covered: This review will describe various techniques such as microspheres, nanoparticles, liposomes, solid lipid nanoparticles, nano and microemulsions, sponges and wafers, and so on, that are successfully applied as carriers for wound healing drugs. Results of various studies including in vitro and in vivo experiments are also discussed.

Expert opinion: Controlled and localized delivery of wound healing drugs to the wounds is more convenient than systemic administration as higher concentrations of the medication are delivered directly to the desired area in a sustained manner. They are also capable of providing optimum environmental conditions to facilitate wound healing while eliminating the need for frequent changes of dressings. As the number of people suffering from chronic wounds is increasing around the world, controlled delivery of wound healing agents have enormous potential for patient-friendly wound management.     

Controlled release of therapeutics using interpenetrating polymeric networks

Introduction: The ever-increasing developments in pharmaceutical formulations have led to the widespread use of biodegradable polymers in various forms and configurations. In particular, interpenetrating network (IPN) and semi-IPN polymer structures that are capable of releasing drugs in a controlled manner have gained much wider importance in recent years.

Areas covered: Recently, IPNs and semi-IPNs have emerged as innovative materials of choice in controlled release (CR) of drugs as the release from these systems depends on pH of the media and temperature in addition to the nature of the system. These networks can be prepared as smart hydrogels following chemical or physical crosslinking methods to show remarkable drug release patterns compared to single polymer systems.

Expert opinion: A large number of IPNs and semi-IPNs have been reported in the literature. The present review is focused on the preparation methods and their CR properties with reference to anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority of these drugs have been reported to be the ideal choices for using IPNs and semi-IPNs.     

Formulation parameters and release mechanism of theophylline loaded ethyl cellulose microspheres: effect of different dual surfactant ratios

Altering the combined hydrophilic-lipophilic balance (CHLB), by varying the ratio of dual surfactants, on formulation parameters and in vitro drug release of ethyl cellulose microspheres was examined.

Theophylline, a xanthine bronchodilator was used to model controlled release owing to its narrow therapeutic index. Microspheres were prepared using different ratios of dual surfactant in an emulsion-solvent evaporation process. Drug loading, encapsulation efficiency, particle size distribution, and geometric mean diameters were evaluated. Drug release was evaluated using several kinetic models including zero and first order, Higuchi square root, and Hixson-Crowell.

Microspheres presented as mostly spherical particles and diffusional drug release was affected by microsphere construction. For this novel, dual surfactant system the microsphere matrix is a hydrophobic polymer and the release rate may be modulated with variation in ratio of dual surfactants. Dissolution data followed the Higuchi model and supports the formation of a monolithic microsphere matrix that releases theophylline by Fickian diffusion.

Dual surfactants for preparation of microspheres are an inadequately studied research area that offers another means to modulate particle size and drug release. For the current study microspheres prepared with surfactant ratios of Span 65: Tween 40 between 3:1 and 2:1 provided the best control of size and drug release.     

Microsponges: a futuristic approach for oral drug delivery

Introduction: Microparticulate drug delivery systems have, due to their advantages, guided researchers across the globe to explore them as drug carriers. This has, sequentially, led to the development of microsponges in 1988. These porous microspheres were exclusively designed for chronotherapeutic topical drug delivery but attempts to utilize them for oral, pulmonary and parenteral drug delivery were also made. Researchers have extensively studied their properties and characteristics affecting the drug release and loading. Various advances were made with this carrier particle resulting in the development of various novel development techniques and carrier particles.

Areas covered: This review deals with the considerations of the drug material to be entrapped in microsponges, pharmaceutical considerations for fabrication of microsponges, their potential for oral drug delivery, clinical perspectives and also provides an insight on the recent advances made in this field and future prospect.

Expert opinion: Clinical studies show that these carriers can increase drug efficacy. Due to their potential advantages over other carrier particles, microsponges form a prospective platform for the oral delivery of pharmaceuticals and biopharmaceuticals. Although these carriers have several advantages, they too possess some drawbacks which limit their commercialization for oral application.     

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.