Smart polymers for the controlled delivery of drugs – a concise overview

Smart polymers have enormous potential in various applications. In particular, smart polymeric drug delivery systems have been explored as “intelligent” delivery systems able to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties. The responses vary widely from swelling/contraction to disintegration. Synthesis of new polymers and crosslinkers with greater biocompatibility and better biodegradability would increase and enhance current applications. The most fascinating features of the smart polymers arise from their versatility and tunable sensitivity. The most significant weakness of all these external stimuli-sensitive polymers is slow response time. The versatility of polymer sources and their combinatorial synthesis make it possible to tune polymer sensitivity to a given stimulus within a narrow range. Development of smart polymer systems may lead to more accurate and programmable drug delivery. In this review, we discuss various mechanisms by which polymer systems are assembled in situ to form implanted devices for sustained release of therapeutic macromolecules, and we highlight various applications in the field of advanced drug delivery.KEY WORDS: Smart polymers, Temperature responsive polymers, pH responsive polymers, Field sensitive polymers, Glucose responsive polymers     

Classification of stimuli–responsive polymers as anticancer drug delivery systems

Abstract

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli–responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli–responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.     

Large molecule and particulate uptake in the nasal cavity: the effect of size on nasal absorption

One of the characteristics influencing the increased interest in the nasal cavity as a site for systemic drug delivery is the ability of large molecules to permeate through the nasal mucosa into the systemic circulation. Compilations of data regarding the absorption of large therapeutic agents, peptides and proteins in particular, along with more systematic studies using polymeric compounds have shown that for compounds larger than 1000 Da, bioavailability can be directly predicted from a knowledge of molecular weight. In general, the bioavailability of these large molecules ranges from 0.5 to 5%. Particulate uptake also occurs in the nasal mucosa, and particles up to approximately 1 μm have been shown to rapidly enter the bloodstream following intranasal administration. The unique barrier properties of this mucosal delivery site give it great promise as a route for the systemic administration of large molecules.     

Intranasal Drug Delivery of Frovatriptan Succinate–Loaded Polymeric Nanoparticles for Brain Targeting

The objective of the present study was to develop polymeric nanoparticles (PNPs) of frovatriptan succinate for brain targeting by nasal route. Double emulsion method was used to increase the entrapment efficiency of hydrophilic drug, and formulation was optimized by central composite design to achieve critical quality attributes namely particle size, zeta potential, and entrapment efficiency. Optimized batch was evaluated for surface morphology, in vitro release, permeation across nasal mucosa, stability, histopathology, and brain tissue uptake study. Prepared PNPs were found to be smooth with particle size of 264.4 ± 0.04 nm, zeta potential ?35.17 ± 0.07 mV, and 65.2 ± 0.06% entrapment efficiency. PNPs showed biphasic release pattern, initial burst release followed by sustained release up to 72 h. Ex vivo diffusion study using goat nasal mucosa at pH 6.8 revealed that PNPs permeation across nasal mucosa was about 3 times more than the pure drug solution, and quick delivery of PNPs in brain region was confirmed by fluorescence microscopic evaluation in male Wistar rats after intranasal administration. Histopathology studies further revealed integrity of nasal mucosa after treatment with PNPs. The investigation indicated that hydrophilic drug, frovatriptan succinate can be successfully entrapped in PNPs to target brain via nasal delivery, and thus it could be an effective approach for nose to brain delivery.     

Carbamazepine uptake into rat brain following intra-olfactory transport

Targeting the brain via nasal administration of drugs has been studied frequently over the last few years. In this study, a suitable gel formulation was designed to provide the absorption of a highly lipophilic drug through nasal mucosa. For this purpose, carbamazepine was chosen as the model drug. Hypromellose and Carbopol were used as mucoadhesive polymers in the formulation to increase the residence time of the gel on the mucosa. The objective of this study was to confirm the existence of a transport pathway for a drug (carbamazepine) to the brain directly from the nasal cavity, by comparing the concentration of drug in the brain after intranasal (i.n.), intravenous (i.v.), and oral (p.o.) administration. A statistically significant high level of the drug was found in the brain following intranasal administration compared with the intravenous and oral routes. These findings suggested the existence of a direct transport pathway for carbamazepine from the nasal cavity to the brain. This pathway may represent a new delivery route to the brain and central nervous system of such drugs which are needed in high and rapid concentration in the brain, especially in emergencies.     

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.     

脑靶向鼻腔给药的研究进展

目的阐述鼻腔的生理特点和药物由鼻黏膜转运入脑的机制及其影响因素。方法依据近年来的29篇中外文文献,对药物的鼻腔脑靶向实验手段、离体在体模型、鼻黏膜的毒性等方面的研究进展进行阐述。结果鼻黏膜给药途径在脑内递药领域具有独特优势,其在脑部疾病治疗方面具有独到之处,值得进一步深入研究。结论药物的鼻腔脑靶向给药将受到越来越多的关注。     

From nose to brain: understanding transport capacity and transport rate of drugs

The unique relationship between nasal cavity and cranial cavity tissues in anatomy and physiology makes intranasal delivery to the brain feasible. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. In the past two decades, a good number of encouraging outcomes have been reported in the treatment of diseases of the brain or central nervous system (CNS) through nasal administration. In spite of the significant merit of bypassing the BBB, direct nose-to-brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption. It is crucial that selective distribution and retention time of drugs or preparations on olfactory mucosa should be enhanced so as to increase the direct delivery efficiency. In this article, we first briefly review the nose-to-brain transport pathways, before detailing the impacts on them, followed by a comprehensive summary of effective methods, including formulation modification, agglutinant-mediated transport and a brain-homing, peptide-mediated delivery based on phage display screening technique, with a view to providing a theoretic reference for elevating the therapeutic effects on brain diseases.     

Engineered polymers for advanced drug delivery

Engineered polymers have been utilized for developing advanced drug delivery systems. The development of such polymers has caused advances in polymer chemistry, which, in turn, has resulted in smart polymers that can respond to changes in environmental condition such as temperature, pH, and biomolecules. The responses vary widely from swelling/deswelling to degradation. Drug-polymer conjugates and drug-containing nano/micro-particles have been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such as molecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used as traditional drug delivery systems and as more recent applications in nanotechnology.     

Noninvasive delivery technologies: respiratory delivery of vaccines

This paper reviews the developments in noninvasive methods of drug delivery, with a focus on the delivery of vaccines via the respiratory tract. Recent results indicate that the respiratory system, and the nasal mucosa in particular, provide a valuable target site for immunisation against respiratory and mucosal pathogens. Vaccine delivery via the nasal and pulmonary routes each present distinct sets of performance requirements. Current delivery systems in development for both routes are reviewed herein. The storage and respiratory delivery of drugs and vaccines in powder form has been shown to provide improved stability and extended retention time in the respiratory mucosa. These features, in addition to the noninvasive nature of respiratory delivery, can provide benefits to public health vaccination campaigns, facilitating mass vaccination without the high cost of maintaining cold-chain storage.     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives

Nasal drug delivery has now been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. It has been demonstrated that low absorption of drugs can be countered by using absorption enhancers or increasing the drug residence time in the nasal cavity, and that some mucoadhesive polymers can serve both functions. This article reviews the background of nasal mucoadhesive drug delivery with special references to the biological and pharmaceutical considerations for nasal mucoadhesive drug administration. Applications of nasal mucoadhesives for the delivery of small organic molecules, antibiotics, proteins, vaccines and DNA are also discussed. Furthermore, new classes of functionalized mucoadhesive polymers, the characterization and safety aspects of nasal drug products as well as the opportunities presented by nasal drug delivery are extensively discussed.     

Recent advances in mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymeric carriers

Importance of the field: The mucosal delivery of vaccines provides the basis for induction of humoral, cellular and mucosal immune responses against infectious diseases. The delivery of antigens to and through mucosal barriers always remains challenging due to adverse physiological conditions (pH and enzymes) and biological barriers created by tight epithelial junctions restricting transportation of macromolecules. Mucoadhesive and biodegradable polymers offer numerous advantages in therapeutic delivery of proteins/antigens particularly through the mucosal route by protecting antigens from degradation, increasing concentration of antigen in the vicinity of mucosal tissue for better absorption, extending their residence time in the body and/or targeting them to sites of antigen uptake. Furthermore, antigen can be delivered more effectively to the antigen presenting cells by anchoring the ligand having affinity on the surface of carrier for the receptors present on the mucosal epithelial cells.

Areas covered in this review: The present review covers various polymeric carriers, which allow the possibility of modification and manipulation of their properties, thereby, enhancing the effectiveness of mucosal vaccines. This article reviews the recent literature and patents in the field of vaccine delivery using mucoadhesive polymeric carriers.

What the reader will gain: The reader will gain insights into various natural polymers, synthetic polymers and ligand derived polymeric carrier systems studied to enhance mucosal immunization.

Take home message: Biodegradable polymeric carriers represent a promising approach for mucosal delivery of vaccine.     

The use of multifunctional polymers for non-invasive peptide and protein application

For the efficient delivery of peptide and protein drugs by non-invasive routes various strategies have been pursued to overcome enzymatic and mucosal barriers to gain sufficient bioavailability. Among such delivery systems multifunctional polymers have received considerable attention, which is reflected by numerous publications and patents. They are able to provide a controlled release for therapeutic peptides and proteins being embedded in the polymeric network either based on a simple diffusion process or on the biodegradation of the carrier matrix. Additionally, polymers such as polyacrylates display an inhibitory effect towards various proteases located on the absorption membrane. In combination with enzyme inhibitors, this protective effect towards enzymatic attack may further be improved. Moreover, polyacrylates and chitosan display a permeation enhancing effect, in particular for the paracellular uptake of peptide drugs from mucosal tissues. If these polymers also exhibit mucoadhesive properties, the concentration gradient of the drug on the mucosa can be increased and in the case of oral delivery the presystemic enzymatic degradation of the (poly)peptide drug in the intestine between the delivery system and the absorption membrane can be reduced. Delivery systems utilising multifunctional polymers include formulations such as nano- and microspheres, pellets and matrix-tablets.     

Site-specific delivery of polymeric encapsulated microorganisms: a patent evaluation of US20170165201A1

Introduction: Probiotics inculde live microorganisms therapeutically effective in the treatment of wide range of diseases. Probiotics possibly stimulates the growth of preferred microorganisms, crowds out potentially harmful microorganisms, and reinforces the body’s natural defense mechanisms. Microencapsulation of probiotic microorganisms protects them from the destructive environment and prolongs their survival. Use of mucoadhesive and pH responsive polymers could impart extended retention, pH sensitive release and mucoadhesive properties to the system. The probiotic formulations could be used for therapeutic, diagnostic, and prophylactic purposes.

Areas covered: Layer-by-layer techology was developed for encapsulating Bacillus coagulans employing chitosan and alginate as mucoadhesive polymers (for attachment to the gastrointestinal mucosa) and Eudragit EPO and Eudragit L100 as pH responsive polymers (for site-specific delivery). The formulation was evaluated for layer stability, mucoadhesion capability, protection of microorganisms from biological insults, pH responsive layer removal, in vitro evaluation in three-dimensional intestinal tissue model, probiotic bacterial delivery.

Expert opinion: In this patent, a unique layer-by-layer assembly of two differently charged polymers (mucoadhesive and pH repsonsive) was achieved for encapsulating the probiotic microorganism. For assessing the clinical applicability of the invention, further studies may be needed since the conclusions are drawn solely based on in vitro data.     

Recovery of the nasal mucosa following laureth-9 induced damage

Polyoxyethylene-9-lauryl ether (laureth-9) has been used in drug formulations for nasal delivery to promote drug absorption and increase bioavailability, especially for compounds with high molecular weights. However, it has also been reported that laureth-9 causes morphological damage to the nasal membranes when it is administered. This morphological change/damage can affect the normal functioning of the nasal epithelium, and readily increases the potential for infection and the absorption of substances through the disrupted epithelial barrier. While previous investigators have studied the mucosal repair rate from various other respiratory tissues, few reports are available regarding the repair rate of the nasal mucosa itself. Laureth-9 was used to chemically induce damage to the nasal mucosa of anesthetized rats. Individual animals were then sacrificed at various times over the following 10 days for morphological examination of the nasal mucosa. Following euthanasia, the tissues of the nasal cavity were decalcified, fixed, sectioned, and stained with hematoxylin and eosin for light microscopic examination. Histological examination of mucosal samples taken 4 h after exposure showed no apparent morphological changes, whereas samples taken 24 and 48 h after administration showed signs of severe damage to the epithelium. Regrowth of the epithelium could be observed beginning on the third day following laureth-9 exposure; there was evidence of basal cell regrowth and differentiation by the fourth day. A completely regenerated epithelium could be observed between the seventh and the tenth days following exposure to the surfactant.     

An in vitro model for investigating the gastric mucosal retention of 14C-labelled poly(acrylic acid) dispersions

Polymers that bind from solution onto gastric mucosae can be used as a means of facilitating localised drug delivery, or act as therapeutic agents in their own right (e.g. by forming a protective layer or by inhibiting enzymes). Previous workers have used semi-quantitative methods to identify the ability of commercially available poly(acrylic acid)s to bind to gastric mucosa. In this study, the binding and retention of labelled poly(acrylic acid)s to sections of gastric mucosa from the pyloric region of pigs stomach were evaluated using 'static' and 'dynamic flow' test systems. Dispersions (3%) of 'low', 'high' and 'ultra high' (cross-linked) polymers were seen to adhere to porcine pyloric mucosa after exposure and rinsing in the 'static' system. The high molecular weight polymer showed the greatest retention in the 'dynamic' test system when washing continuously with simulated gastric acid. Changing the pH of the dispersions from 4.3 to 6.2 had little effect on polymer retention. It was concluded that polymers that were sufficiently mobile in solution to spread on, and interact with, the mucosal surface, but had a sufficiently high molecular weight to form viscous solutions and/or bioadhere to the mucosa, may be retained on the mucosal surface for the longest periods.     

Carrier mediated transport of chlorpheniramine and chlorcyclizine across bovine olfactory mucosa: implications on nose-to-brain transport

Delivery to the CNS via the nasal cavity has been pursued as a means to circumvent the blood-brain barrier (BBB), yet the mechanism of drug transport across this novel route is not well understood. Hydroxyzine and triprolidine have been reported to readily reach the CNS following nasal administration, whereas no measurable amounts of chlorcyclizine or chlorpheniramine, structurally similar antihistamines, were observed in the CSF. The permeation of chlorpheniramine and chlorcyclizine in vitro across the bovine olfactory mucosa was studied to investigate the biological and physicochemical characteristics that contribute to the limited CNS disposition of these compounds following nasal administration. The submucosal to mucosal fluxes (J(s-m)) of chlorcyclizine and chlorpheniramine across the olfactory mucosa were significantly greater than the mucosal to submucosal fluxes (J(m-s)). Moreover, the submucosal-mucosal permeability of both compounds was temperature dependent and saturable. In the presence of metabolic inhibitors (ouabain and 2,4-dinitrophenol) and P-glycoprotein (P-gp)/multidrug resistance protein 1 (MRP1) inhibitors (quinidine and verapamil), the J(m-s) increased and J(s-m) decreased significantly. These results indicate that chlorpheniramine and chlorcyclizine are effluxed from the olfactory mucosa by efflux transporters such as P-gp and MRP1. Transport studies across inert polymeric membranes demonstrated that the permeability of chlorpheniramine and chlorcyclizine decreased at donor concentrations higher than 3 mM suggesting that physicochemical properties such as self-aggregation also play a role in the reduced olfactory mucosal permeability of these compounds at higher concentrations.     

Cyclodextrins in nasal drug delivery

Nasal drug delivery is an attractive approach for the systemic delivery of high potency drugs with a low oral bioavailability due to extensive gastrointestinal breakdown and high hepatic first-pass effect. For lipophilic drugs nasal delivery is possible if they can be dissolved in the dosage form. Peptide and protein drugs often have a low nasal bioavailability because of their large size and hydrophilicity, resulting in poor transport properties across the nasal mucosa. Cyclodextrins are used to improve the nasal absorption of these drugs by increasing their aqueous solubility and/or by enhancing their nasal absorption. With several cyclodextrins very efficient nasal drug absorption has been reported, but also large interspecies differences have been found. Studies concerning the safety of cyclodextrins in nasal drug formulations demonstrate the non-toxicity of the cyclodextrins and also clinical data show no adverse effects. Therefore, some cyclodextrins can be expected to become effective and safe excipients in nasal drug delivery.     

Temperature and pH-responsive PNIPAM@PAA Nanospheres with a Core-Shell Structure for Controlled Release of Doxorubicin in Breast Cancer Treatment

Stimuli-responsive polymers have been of great interest in the fabrication of advanced drug delivery systems. In this study, a facile approach was developed to synthesize a dually temperature/pH-responsive drug delivery system with a core-shell structure to control the release of doxorubicin (DOX) at the target site. For this purpose, poly(acrylic acid) (PAA) nanospheres were first synthesized using the precipitation polymerization technique and were used as pH-responsive polymeric cores. Then, poly(N-isopropylacrylamide) (PNIPAM) with thermo-responsivity properties was coated on the outer surface of PAA cores via seed emulsion polymerization technique to render monodisperse PNIPAM-coated PAA (PNIPAM@PAA) nanospheres. The optimized PNIPAM@PAA nanospheres with an average particle size of 116.8 nm (PDI= 0.243), had a high negative surface charge (zeta potential= -47.6 mV). Then, DOX was loaded on PNIPAM@PAA nanospheres and the entrapment efficiency (EE) and drug loading (DL) capacity were measured to be 92.7% and 18.5%, respectively. The drug-loaded nanospheres exhibited a low leakage at neutral pH and physiological temperature, but drug release significantly enhanced at acidic pH (pH= 5.5), indicating the tumor-environment responsive drug release behavior of the prepared nanospheres. Also, kinetics studies showed that, the sustained release of DOX from PNIPAM@PAA nanospheres was consistent with the Fickian diffusion mechanism. Moreover, the anticancer efficacy of DOX-loaded nanospheres was evaluated in vitro against MCF-7 breast cancer cells. The obtained results revealed that, the incorporation of DOX into PNIPAM@PAA nanospheres increases its cytotoxicity against cancer cells compared to the free DOX. Our results suggest that, PNIPAM@PAA nanospheres can be considered as a promising vector to release anticancer drugs with dual-stimuli responsivity to pH and temperature.