Linear cyclodextrin-containing polymers and their use as delivery agents

Cyclodextrins, cyclic oligomers of glucose, have been used in pharmaceutical formulations for decades as a result to their biocompatibilities, low toxicities and their abilities to solubilise organic small molecules via inclusion complex formation. The incorporation of cyclodextrins within polymers of numerous types, for use as drug delivery agents, has been explored. Illustrative of the flexibility in polymer chemistry and delivery application that is possible with these materials, two linear cyclodextrin-containing polymers are in preclinical and clinical development for the non-covalent delivery of nucleic acid therapeutics and covalent delivery of a small-molecule drug, respectively. This document provides an overview of the background and progress that has been made with these materials thus far, as well as suggestions for their future development and characterisation.     

Linear cyclodextrin-containing polymers and their use as delivery agents

Cyclodextrins, cyclic oligomers of glucose, have been used in pharmaceutical formulations for decades as a result to their biocompatibilities, low toxicities and their abilities to solubilise organic small molecules via inclusion complex formation. The incorporation of cyclodextrins within polymers of numerous types, for use as drug delivery agents, has been explored. Illustrative of the flexibility in polymer chemistry and delivery application that is possible with these materials, two linear cyclodextrin-containing polymers are in preclinical and clinical development for the non-covalent delivery of nucleic acid therapeutics and covalent delivery of a small-molecule drug, respectively. This document provides an overview of the background and progress that has been made with these materials thus far, as well as suggestions for their future development and characterisation.     

Cyclodextrins in topical drug formulations: theory and practice

Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs. In aqueous solutions drug molecules located in the central cavity are in a dynamic equilibrium with free drug molecules. Furthermore, lipophilic molecules in the aqueous complexation media will compete with each other for a space in the cavity. Due to their size and hydrophilicity only insignificant amounts of cyclodextrins and drug/cyclodextrin complexes are able to penetrate into lipophilic biological barriers, such as intact skin. In general, cyclodextrins enhance topical drug delivery by increasing the drug availability at the barrier surface. At the surface the drug molecules partition from the cyclodextrin cavity into the lipophilic barrier. Thus, drug delivery from aqueous cyclodextrin solutions is both diffusion controlled and membrane controlled. It appears that cyclodextrins can only enhance topical drug delivery in the presence of water.     

Applications of polymeric nanocapsules in field of drug delivery systems

Drug-loaded polymeric nanocapsules have exhibited potential applications in the field of drug delivery systems in recent years. This article entails the biodegradable polymers generally used for preparing nanocapsules, which include both natural polymers and synthetic polymers. Furthermore, the article presents a general review of the different preparation methods: nanoprecipitation method, emulsion-diffusion method, double emulsification method, emulsion-coacervation method, layer-by-layer assembly method. In addition, the analysis methods of nanocapsule characteristics, such as mean size, morphology, surface characteristics, shell thickness, encapsulation efficiency, active substance release, dispersion stability, are mentioned. Also, the applications of nanocapsules as carriers for use in drug delivery systems are reviewed, which primarily involve targeting drug delivery, controlled/sustained release drug delivery systems, transdermal drug delivery systems and improving stability and bioavailability of drugs. Nanocapsules, prepared with different biodegradable polymers, have received more and more attention and have been regarded as one of the most promising drug delivery systems.     

Role of Cyclodextrins in Nanoparticle-Based Drug Delivery Systems

Cyclodextrins (CDs) are cyclic oligosaccharides with unique hydrophobic interior surfaces. Three parent CDs, α-CD, β-CD, and γ-CD, are further chemically modified primarily to make them suitable for parenteral administration, and these are used for many pharmaceutical applications. CDs offer distinctive advantages due to their unique ability to form inclusion complexes with a variety of organic and inorganic lipophilic molecules. This attribute is promising for a wide range of fields such as drug delivery, cancer therapy, gene delivery, and biosensing. In recent years, CDs have become more commonly used functional materials in nanoparticle (NP)-based drug delivery. The properties of NPs can be advantageously modified by the inclusion of CDs or their derivatives. CD-conjugated NPs (CD-NPs) have many benefits such as improved drug solubility and serve as drug carriers to specific locations such as cancer cells, which reduces toxicity to normal cells. In addition, CDs can overcome the limitations of NPs such as low encapsulation efficiency and drug loading. This review will discuss the various uses of CDs as it applies to NP-based drug carriers. Specifically, how CDs enhance the characteristics of polymeric, magnetic, lipid, metallic, and mesoporous NPs are discussed.     

Recent Developments in Cyclic Acetal Biomaterials for Tissue Engineering Applications

At an ever increasing pace, synthetic biomaterials are being developed with specific functionalities for tissue engineering applications. These biomaterials possess properties including biocompatibility, mechanical strength, and degradation as well as functionalities such as specific cell adhesion and directed cell migration. However, synthetic polymers are often not completely biologically inert and may non-specifically react with the surrounding in vivo environment. An example of this reactivity is the release of acidic degradation products from hydrolytically degradable polymers based upon an ester moiety. In order to address this concern, a novel class of biomaterials based upon a cyclic acetal unit has been developed. Scaffolds suitable for the replacement of both hard and soft tissues have been successfully fabricated from cyclic acetals and a detailed characterization of scaffold properties has been performed. Cyclic acetal based biomaterials have also been used to repair bone defects and promote bone growth, displaying a minimal inflammatory response. This review will discuss the most recent research of current biomaterials and cyclic acetals, and particularly focus on the tissue engineering applications of these materials. Finally, this review will also briefly discuss polyacetals and polyketals for drug delivery applications.     

Cyclodextrin complexes: Perspective from drug delivery and formulation

Cyclodextrins (CDs) have been widely investigated as a unique pharmaceutical excipient for past few decades and is still explored for new applications. They are highly versatile oligosaccharides which possess multifunctional characteristics, and are mainly used to improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs. Stability constant, factors affecting complexation, techniques to enhance complexation efficiency, the preparation methods for molecular inclusion complexes and release of guest molecules are discussed in brief. In addition, different CD derivatives and their pharmacokinetics are elaborated. Further, the significance of CD complex in aqueous solubility, dissolution and bioavailability, stability, and taste masking is explained. The recent advancement of CDs in developing various drug delivery systems is enlightened. Indeed, the potential of CDs by means of inclusion complex formation have widen the applicability of these materials in various drug delivery systems including ocular, osmotic, mucoadhesive, transdermal, nasal, and targeted delivery systems. Feasibility studies have been performed on the benefit of these cyclic oligomers as nanocarriers, a strategy that can modify the drugs with improved physicochemical properties. Studies also demonstrated the feasibility of CDs to self‐assemble in the form of stable nanoaggregates, which may extend the scope of CDs in drug delivery to the continually expanding list of new drug entities.     

Using drug-excipient interactions for siRNA delivery

SiRNA is the trigger of RNA interference, a mechanism discovered in the late 1990s. To release the therapeutic potential of this versatile but large and fragile molecule, excipients are used which either interact by electrostatic interaction, passively encapsulate siRNA or are covalently attached to enable specific and safe delivery of the drug substance. Controlling the delicate balance between protective complexation and release of siRNA at the right point and time is done by understanding excipients-siRNA interactions. These can be lipids, polymers such as PEI, PLGA, Chitosans, Cyclodextrins, as well as aptamers and peptides. This review describes the mechanisms of interaction of the most commonly used siRNA delivery vehicles, and looks at the results of their clinical and preclinical studies.     

Therapeutic applications of viscous and injectable poly(ortho esters).

Poly(ortho esters) (POE) are hydrophobic and bioerodible polymers that have been investigated for pharmaceutical use since the early 1970s. Among the four described generations of POE, the third (POE III) and fourth (POE IV) are promising viscous and injectable materials which have been investigated in numerous biomedical applications. POE III has been extensively studied for ophthalmic drug delivery, it presents an excellent biocompatibility and is currently being investigated as a vehicle for sustained drug delivery to treat diseases of the posterior segment of the eye. POE IV is distinguishable by a highly reproducible and controlled synthesis, a higher hydrophobicity, and an excellent biocompatibility. It is currently under development for a variety of applications, such as ocular delivery, periodontal disease treatment and applications in veterinary medicine. This review will also focus on new perspectives for this promising family of polymers, such as guided tissue regeneration, treatment of osteoarthritis, as well as peptide and protein delivery.     

Approaches for the preparation of non-linear amphiphilic polymers and their applications to drug delivery

Amphiphilic polymers are particularly useful for drug delivery because of their ability to self-assemble into discrete aggregates. While this behavior has been studied in depth for simple linear block copolymer amphiphiles, recent advances in synthetic methodologies have provided efficient routes to amphiphilic polymers with more complex architecture, including dendrimers, hyperbranched polymers, star polymers, and cyclic polymers. These architectures can impart unique advantages, such as increased stability, on their micellar aggregates. Herein the different strategies for preparing these complex amphiphiles are described, and the application of their assemblies towards drug delivery are summarized.     

Studies on thermoresponsive polymers: Phase behaviour,drug delivery and biomedical applications

The present review aims to highlight the applications of thermoresponsive polymers. Thermo-responsive polymers show a sharp change in properties upon a small or modest change in temperature. This behaviour can be utilized for the preparation of so-called ‘smart’ drug delivery systems, which mimic biological response behaviour to a certain extent. Such materials are used in the development of several applications, such as drug delivery systems, tissue engineering scaffolds and gene delivery. Advances in this field are particularly relevant to applications in the areas of regenerative medicine and drug delivery. This review addresses summary of the main applications of thermoresponsive polymers which are categorized based on their 3-dimensional structure; hydrogels, interpenetrating networks, micelles, films and particles. The physico-chemical behaviour underlying the phase transition is also discussed in brief.     

pH-sensitive polymers for cytoplasmic drug delivery

The pH-sensitive drug delivery systems could be triggered by a mild acidic environment, such as that occurring in solid tumors, inflammatory tissues and intracellular endosomal compartments. Moreover, the cytoplasmic delivery of internalized macromolecules (such as oligonucleic acid, siRNA, DNA, proteins and polymer–antibody complex) will be possible. Synthetic polymers – such as polyanions (acrylic acid derivatives) and polycations (poly ethylenimine and chitosan complexes) – are among the most popular compounds studied for intracellular trafficking of drugs. As research is progressing in the area of cytoplasmic delivery, many novel and innovative applications making use of the unique properties of pH-sensitive polymers are expected in the future.     

Natural polymers for gene delivery and tissue engineering

Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.     

Role of cyclodextrins in ophthalmics

Cyclodextrins are oligosaccharides having outer hydrophilic surface and central hydrophobic cavity. These agents form inclusion complexes with poorly water-soluble drugs; hence they show an important implication for use in ophthalmics because of their applications in solubilising and stabilising the ocular drugs. Most of the drugs being used in ophthalmics were not tailor-made for the eye and considering the poor bioavailability of <1% from the corneal surface, presentation of the drug in a soluble form and at high concentration is important. Provision of a high drug concentration at the corneal surface increases the percent drug permeation indicating the usefulness of cyclodextrins as penetration enhancers. A decrease in irritation potential of some drugs upon incorporation of cyclodextrins is also reported. Polymer-cyclodextrin multicomponent systems further extend the role of cyclodextrins in improving the solubility and bioavilability of ocular drugs. Large hydrophilic cyclodextrins like hydroxypropyl-beta-cyclodextrin and sulphobutylether-beta-cyclodextrin are safe for the use in aqueous eye drop solutions especially since they do not cross the lipophilic cornea. Various aspects about the applications of cyclodextrins in ophthalmics, the formulation considerations and expected toxicity of cyclodextrins (especially if high concentration is used) is discussed in this review. Strategies like use of polymers to reduce the effective concentration of cyclodextrin required without compromising solubility are also included. Further the concept of incorporating the drug-cyclodextrin complexes into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is discussed as a possible future option.     

Polyphosphates and other phosphorus-containing polymers for drug delivery applications

Poly(phosphate ester)s, polyphosphonates, and polyphosphazenes are three classes of phosphorus-containing polymers that have received wide attention over the past decade for their utility in biomedicine and tissue engineering. These three families of polymers can lead to a number of subclasses of polymers with varied properties. Significant research in this area has led to niche polymers with morphologies ranging from viscous gels to amorphous microparticles for utility in drug delivery. Furthermore, the pentavalency of phosphorus offers the potential for covalent linking of the drug. The classes of polymers discussed in this review are being explored in human clinical trials for vaccine delivery as well as delivery of oncolytic and CNS therapeutics. More applications in the areas of DNA delivery and tissue engineering are also being explored.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are ~ 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications

The present paper intends to overview a wide range of natural-origin polymers with special focus on proteins and polysaccharides (the systems more inspired on the extracellular matrix) that are being used in research, or might be potentially useful as carriers systems for active biomolecules or as cell carriers with application in the tissue engineering field targeting several biological tissues. The combination of both applications into a single material has proven to be very challenging though. The paper presents also some examples of commercially available natural-origin polymers with applications in research or in clinical use in several applications. As it is recognized, this class of polymers is being widely used due to their similarities with the extracellular matrix, high chemical versatility, typically good biological performance and inherent cellular interaction and, also very significant, the cell or enzyme-controlled degradability. These biocharacteristics classify the natural-origin polymers as one of the most attractive options to be used in the tissue engineering field and drug delivery applications.     

Synthetic polymer systems in drug delivery

The development of synthetic polymers for applications in drug delivery is reviewed, with particular reference to polymers that can be activated to release a medicinal agent in vivo or that can respond to changes in environment to enhance the effectiveness of therapy. The mechanisms by which these polymers are designed to deliver drugs are highlighted, along with the challenges facing synthetic chemists and pharmaceutical scientists in designing new and more active therapeutic vehicles. Currently, synthetic materials with biomimetic properties are attracting growing attention as possible new dosage formulations and the potential applications of these increasingly sophisticated polymers in cell-specific drug targeting and in the emerging field of gene therapy are also considered. Finally, the potential development issues for delivery of therapeutics using active or 'smart' polymers are discussed with an analysis of the future trends in this rapidly expanding area of research.     

Biodegradable polymeric drug delivery systems

The use of biodegradable polymeric materials as drug carriers is a relatively new dimension in polymeric drug delivery systems. A number of biodegradable or bioerodible polymers, such as poly (lactic/glycolic acid) copolymer, poly(α-amino acid), polyanhydride, and poly (ortho ester) are currently being investigated for this purpose. These polymers are useful for matrix and reservoir-type delivery devices. In addition, when chemical functional groups are introduced to the biodegradable polymer backbone, such as poly (N-(2-hydroxypropy) methacrylamide), the therapeutic agent can be covalently bound directly orvia spacer to the backbone polymer. These polymer/drug conjugates represent another new dimension in biodegradable polymeric drug delivery systems. In this paper, major emphasis is placed on clinical applications of biodegradable polymeric delivery systems. In addition, examples of biodegradable polymeric durg delivery systems currently being investigated will be discussed for the purpose of demonstrating the potential importance of this new field.