Pluronic-g-poly(acrylic acid) copolymers as novel excipients for site specific, sustained release tablets

Potential utility of copolymers comprising Pluronic^® (PEO–PPO–PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic–PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic–PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline > hydrochlorothiazide > nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol^® 71G (C71G), and mixtures of C71G and Pluronic^® F127, with each of the above three drugs. The Pluronic–PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic–PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic–PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the pK_a > 5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic–PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24 h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic–PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic–PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the ‘stealth’ properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic^® (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the 'stealth' properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

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.     

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.     

Effects of particle size on the pharmacokinetics of puerarin nanocrystals and microcrystals after oral administration to rat

Puerarin, which is extracted from traditional Chinese medicine, is widely used in clinic in China and mainly used as a therapeutic agent to cardiovascular diseases. Owing to its poor water solubility and adverse drug reactions caused by cosolvents after intravenous administration, the development of oral formulation is urgently needed. Nowadays, nanocrystals technique has become a preferred way to develop oral dosage form. In this study, we used high pressure homogenization (HPH) to prepare puerarin nanocrystals and microcrystals with different sizes ranged from 525.8 nm to 1875.6 nm and investigated the influence of particle size on pharmacokinetics. The nanocrystals and microcrystals prepared were characterized using DLS, DSC, XRD and SEM, and we found that the crystalline state of puerarin was changed during the preparation process and the drug was dispersed into HPMC. In the pharmacokinetic study, we observed an increasing of C_max and AUC and a decreasing of CL/F with the decreasing of particle size. The AUC of the puerarin nanocrystals (525.8 nm) was 7.6-fold of that of raw puerarin suspension, with an absolute bioavailability of 21.44%. From the above results, we can conclude that nanocrystal technique is an efficient technology to improve the oral bioavailability of puerarin.     

Long-circulating, pH-sensitive liposomes sterically stabilized by copolymers bearing short blocks of lipid-mimetic units

A major hurdle towards in vivo utilization of pH-sensitive liposomes is their prompt sequestration by reticuloendothelial system and hence short circulation time. Prolonged circulation of liposomes is usually achieved by incorporation of pegylated lipids, which have been frequently reported to deteriorate the acid-triggered release. In this study we evaluate the ability of four novel nonionic copolymers, bearing short blocks of lipid-mimetic units to provide steric stabilization of DOPE:CHEMs liposomes. The vesicles were prepared using the lipid film hydration method and extrusion, yielding liposomes of 120–160 nm in size. Their pH-sensitivity was monitored via the release of encapsulated calcein. The incorporation of the block copolymers at concentration up to 10 mol% did not deteriorate the pH-sensitivity of the liposomes. A selected formulation was tested for stability in presence of 25% human plasma and proved to significantly outclass the plain DOPE:CHEMs liposomes. The ability of calcein-loaded liposomes to deliver their cargo inside EJ cells was investigated using fluorescent microscopy and the results show that the surface-modified vesicles are as effective to ensure intracellular delivery as plain liposomes. The pharmacokinetics and organ distribution of a selected formulation, containing a copolymer bearing four lipid anchors was investigated in comparison to plain liposomes and PEG (2000)–DSPE stabilized liposomes. The juxtaposition of the blood clearance curves and the calculated pharmacokinetic parameters show that the block copolymer confers superior longevity in vivo. The block copolymers utilized in this study can be consider as promising sterically stabilizing agents for pH-sensitive liposomes.     

ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins.

Hydrogels are very attractive delivery systems for hydrophilic macromolecules such as proteins and DNA because they provide a protective environment and allow control of diffusion by adjusting cross-link densities. Physically cross-linked hydrogels generated by rapid swelling upon exposure to an aqueous environment can be obtained from ABA triblock copolymers containing hydrophobic polyester A-blocks and hydrophilic polyether B-blocks. They provide an attractive alternative to chemically cross-linked systems since they allow incorporation of macromolecular drug substances under mild process conditions. Moreover, they show controlled degradation behavior and excellent biocompatibility. In this review the synthesis and characterization of ABA triblock copolymers from polyester hard segments and poly(ethylene oxide) [PEO] soft segments as well as their biological and degradation properties will be discussed. Their use as biodegradable drug delivery devices in the form of implants, micro- and nanospheres has attracted considerable interest especially for proteins and may provide an alternative to poly(lactide-co-glycolide).     

Self assembling polymers as polymersomes for drug delivery

Polymersomes are one of the most interesting and versatile architectures among various self assembled systems for drug delivery. The stability and ability to load both hydrophilic and hydrophobic molecules make them excellent candidates to use as drug delivery systems. They demand for certain physicochemical parameters; especially hydrophilic to hydrophobic block ratio of copolymer to form vesicular morphologies. Different amphiphilic copolymers as well as their architectures show differences in the requirement of hydrophilic to hydrophobic block ratio to form polymersomes with various types of morphologies. This review focuses on basic the aspects of polymersomes along with a series of copolymers employed for preparation of polymersomes and their potential applications as drug delivery systems.     

Taste masking analysis in pharmaceutical formulation development using an electronic tongue

The purpose of this study is to assess the feasibility for taste masking and comparison of taste intensity during formulation development using a multichannel taste sensor system (e-Tongue). Seven taste sensors used in the e-Tongue were cross-selective for five basic tastes while having different sensitivity or responsibility for different tastes. Each of the individual sensors concurrently contributes to the detection of most substances in a complicated sample through the different electronic output. Taste-masking efficiency was evaluated using quinine as a bitter model compound and a sweetener, acesulfame K, as a bitterness inhibitor. In a 0.2 mM quinine solution, the group distance obtained from e-Tongue analysis was reduced with increasing concentration of acesulfame K. This result suggests that the sensors could detect the inhibition of bitterness by a sweetener and could be used for optimization of the sweetener level in a liquid formulation. In addition, the bitterness inhibition of quinine by using other known taste-masking excipients including sodium acetate, NaCl, Prosweet^® flavor, and Debittering^® powder or soft drinks could be detected by the e-Tongue. These results further suggest that the e-Tongue should be useful in a taste-masking evaluation study on selecting appropriate taste-masking excipients for a solution formulation or a reconstitution vehicle for a drug-in-bottle formulation. In another study, the intensity of the taste for several drug substances known to be bitter was compared using the e-Tongue. It was found that the group distance was 695 for prednisolone and 686 for quinine, which is much higher than that of caffeine (102). These results indicate that the taste of prednisolone and quinine is stronger or more bitter than that of caffeine as expected. Based on the group distance, the relative intensity of bitterness for these compounds could be ranked in the following order: ranitidine HCl > prednisolone Na > quinine HClphenylthiourea > paracetamol  sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor or e-Tongue may be a useful tool to evaluate taste-masking efficiency for solution formulations and to compare bitterness intensity of formulations and drug substances during pharmaceutical product development.     

Comparison of two pegylated copolymeric micelles and their potential as drug carriers

The aim of this study was to evaluate the ability of forming micelles from two types of synthesized diblock pegylated amphiphilic copolymers and their potential as a drug carrier. Two lactone monomers, ε -caprolactone (CL) and δ -valerolactone (VL), were copolymerized with methoxy poly(ethylene glycol) (MePEG), respectively. The properties of copolymers were investigated and their biocompatibility was tested through an in vitro cytotoxicity study. The influences of the type of lactone monomer (CL and VL) and the feed molar ratios of lactone/MePEG (50/1, 80/1, 160/1) on the performance and release behavior of drug-loaded micelles were investigated. The opening of CL and VL rings by MePEG was efficient, and the pegylation of poly(lactone)s allowed copolymers possessing amphiphilic property and efficiently self-assembled to form micelles with a low critical micelle concentration (CMC) in the range of 10 ^{- 7}-10^{- 8} M. The nano-sized micelles were able to incorporate hydrophobic drug and regulate drug release, and the release of drug was dominated by the hydrophobic poly(lactone) chain length. Although both amphiphilic copolymers exhibited similar controlled release character, the PCL/MePEG micelles possessed lower CMC, higher biocompatibility, and higher drug loading than PVL/MePEG micelles. These suggested that results choosing pegylated PCL as a drug carrier could be better than PVL/MePEG.     

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.     

Targeted Cancer Therapy With Novel High Drug-Loading Nanocrystals

A novel nanocrystal formulation of hydrophobic drugs has been developed for cancer therapy. The new method, called a three-phase nanoparticle engineering technology (3PNET), includes three phases: phase 1, amorphous precipitate; phase 2, hydrated amorphous aggregate; and phase 3, stabilized nanocrystal. The 3PNET has been applied to two anticancer drugs, paclitaxel (PTX) and camptothecin (CPT), using Pluronic F127 (F127) polymer as a single excipient. The nanocrystals encapsulated over 99% of the drug with a high ratio of drug to excipient. The nanocrystal formulation of PTX did not induce hemolysis at pharmacologically relevant concentrations. Antitumor activity in two tumor models, human lung cancer and murine breast cancer, demonstrated that intravenously injected nanocrystals significantly inhibited the tumor growth. The nanocrystals also showed significant therapeutic effects via oral administration. In addition, the nanocrystals could be further modified for targeted delivery of PTX by conjugating a folate ligand to F127. The new nanomedicine formulations show clear potential for clinical development because of the excellent antitumor activity, low toxicity, and the ease of scale-up manufacture. The formulation method may apply to other hydrophobic drugs.     

New method for delivering a hydrophobic drug for photodynamic therapy using pure nanocrystal form of the drug

A carrier-free method for delivery of a hydrophobic drug in its pure form, using nanocrystals (nanosized crystals), is proposed. To demonstrate this technique, nanocrystals of a hydrophobic photosensitizing anticancer drug, 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide (HPPH), have been synthesized using the reprecipitation method. The resulting drug nanocrystals were monodispersed and stable in aqueous dispersion, without the necessity of an additional stabilizer (surfactant). As shown by confocal microscopy, these pure drug nanocrystals were taken up by the cancer cells with high avidity. Though the fluorescence and photodynamic activity of the drug were substantially quenched in the form of nanocrystals in aqueous suspension, both these characteristics were recovered under in vitro and in vivo conditions. This recovery of drug activity and fluorescence is possibly due to the interaction of nanocrystals with serum albumin, resulting in conversion of the drug nanocrystals into the molecular form. This was confirmed by demonstrating similar recovery in presence of fetal bovine serum (FBS) or bovine serum albumin (BSA). Under similar treatment conditions, the HPPH in nanocrystal form or in 1% Tween-80/water formulation showed comparable in vitro and in vivo efficacy.     

Copolymer micelles and nanospheres with different in vitro stability demonstrate similar paclitaxel pharmacokinetics

Paclitaxel loaded amphiphilic block copolymer nanoparticles have been demonstrated to enhance the aqueous solubility and improve the toxicity profile as compared to the commercially available product Taxol; however, in many cases long circulation of the drug is not achieved due to rapid partitioning of the drug from the carrier and/or carrier instability upon injection. In this work we investigated the effect of increasing the hydrophobic block length of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) copolymers on the physicochemical properties and in vitro stability of the formed nanoparticles as well as the pharmacokinetics and biodistribution of both the copolymer and solubilized drug. We hypothesized that copolymers composed of high molecular weight hydrophobic blocks (MePEG???-b-PCL???) that form nanoparticles with a kinetically "frozen core" (which we term nanospheres) would better retain their PTX payload as compared to micelles composed of shorter hydrophobic blocks (MePEG???-b-PCL??), thus leading to prolonged drug circulation. Nanospheres solubilized PTX more efficiently, released the drug in a more sustained fashion and were characterized by enhanced stability and drug retention in the presence of plasma proteins as compared to micelles. Using radiolabeled copolymers and PTX, it was found that, upon injection, MePEG???-b-PCL??? circulated for longer than MePEG???-b-PCL??; however, the drug was rapidly eliminated from the blood regardless of the formulation. These results suggest that, despite formulation in more stable nanospheres, PTX was still rapidly extracted from these nanoparticles.     

Cyclodextrins as stabilizers for the preparation of drug nanocrystals by the emulsion solvent diffusion method

Cyclodextrins (CyDs) were employed as protective stabilizers for the preparation of surfactant-free nanocrystals of indomethacin (IMC) by using the emulsion solvent diffusion method. The effect of changing the type and concentration of CyDs on the formation of IMC nanocrystals was investigated. Dispersions were freeze-dried to characterize the size, shape, nanoparticle yield, crystallinity, and dissolution behavior of the obtained particles. Submicron-sized particles of IMC with average diameters in the range of 300–500 nm were obtained by incorporating -, β-, or γ-CyD in the outer phase of the primary emulsions. Quantitative determination demonstrated that more than 80% of IMC was recovered as fine particles smaller than 0.8 μm. The powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses of the freeze-dried samples confirmed the polymorphic change of IMC to the meta-stable form. A significant enhancement in the dissolution rate of IMC nanocrystals was observed when compared to the commercial powder.     

A polymeric micellar carrier for the solubilization of biphenyl dimethyl dicarboxylate

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1 K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialy-sis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1 K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (>5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.     

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery

pH-sensitive drug delivery systems can be engineered to release their contents or change their physicochemical properties in response to variations in the acidity of the surroundings. The present work describes the preparation and characterization of novel polymeric micelles (PM) composed of amphiphilic pH-responsive poly(N-isopropylacrylamide) (PNIPAM) or poly(alkyl(meth)acrylate) derivatives. On one hand, acidification of the PNIPAM copolymers induces a coil-to-globule transition that can be exploited to destabilize the intracellular vesicle membranes. In this work, PNIPAM-based PM were loaded with either doxorubicin or aluminium chloride phthalocyanine and their cytotoxicity was assessed in murine tumoral models. On the other hand, poly(alkyl(meth)acrylate) copolymers can be designed to interact with either hydrophobic drugs or polyions and release their cargo upon an increase in pH.     

Amphiphilic block copolymers in drug delivery: advances in formulation structure and performance

ABSTRACT

Introduction: Nanostructured delivery vehicles can address key challenges facing drug delivery, including the lipophilic nature of therapeutic compounds and their effective transport through the body. Amphiphilic block copolymers that self-assemble offer advantages compared with homopolymer-, lipid-, and protein-based delivery vehicles. Poly(ethylene oxide)-poly(propylene oxide) amphiphilic block copolymers (Poloxamers) serve well as pharmaceutical excipients because of their highly tunable association properties, low toxicity, and ability to functionalize. The formulation nanostructure underpins performance across various administration routes and diseases, but is strongly dependent on the amphiphile, drug, and environment (temperature, concentration, and types of additives), thus demanding further elucidation.

Areas covered: The phase behavior of Poloxamers in aqueous solution is presented first, to inform an overview of drug encapsulation processes. The formulation composition and preparation method are centrally important to the nanostructure obtained. Several self-assembled structures are discussed which present advantages for particular administration routes: transdermal, ophthalmic, oral, nasal, and subcutaneous. Many diseases are treatable through these routes, e.g., inflammation, diabetes, hypertension, and cancer.

Expert opinion: The exceptional ability to tune amphiphilic block copolymer nanostructure (micelles, hydrogels, lyotropic liquid crystals, etc.) renders them a powerful tool in the formulation of drug delivery systems, offering multiple processing options and physical states to accommodate diverse drugs and administration pathways.