Model Hydrophobic Drug Research Articles

Coacervate Thermoresponsive Polysaccharide Nanoparticles as Delivery System for Piroxicam.

Low water solubility frequently compromises the therapeutic efficacy of drugs and other biologically active molecules. Here, we report on coacervate polysaccharide nanoparticles (CPNs) that can transport and release a model hydrophobic drug, piroxicam, to the cells in response to changes in temperature. The proposed, temperature-responsive drug delivery system is based on ionic derivatives of natural polysaccharides—curdlan and hydroxypropyl cellulose. Curdlan was modified with trimethylammonium groups, while the anionic derivative of hydroxypropyl cellulose was obtained by the introduction of styrenesulfonate groups. Thermally responsive nanoparticles of spherical shape and average hydrodynamic diameter in the range of 250–300 nm were spontaneously formed in water from the obtained ionic polysaccharides as a result of the coacervation process. Their morphology was visualized using SEM and AFM. The size and the surface charge of the obtained objects could be tailored by adjusting the polycation/polyanion ratio. Piroxicam (PIX) was effectively entrapped inside the nanoparticles. The release profile of the drug from the CPNs-PIX was found to be temperature-dependent in the range relevant for biomedical applications.

On-Demand Hydrophobic Drug Release Based on Microwave-Responsive Graphene Hydrogel Scaffolds.

Electromagnetically driven drug delivery systems stand out among stimulus-responsive materials due to their ability to release cargo on demand by remote stimulation, such as light, near infrared (NIR) or microwave (MW) radiation. MW-responsive soft materials, such as hydrogels, generally operate at 2.45 GHz frequencies, which usually involves rapid overheating of the scaffold and may affect tissue surrounding the target location. In contrast, 915 MHz MW penetrate deeper tissues and are less prone to induce rapid overheating. In order to circumvent these limitations, we present here for the first time a graphene-based hydrogel that is responsive to MW irradiation of ν=915 MHz. This system is a candidate soft scaffold to deliver a model hydrophobic drug. The graphene present in the hydrogel acts as a heat-sink and avoids overheating of the scaffold upon MW irradiation. In addition, the microwave trigger stimulates the in vitro delivery of the model drug, thus suggesting a remote and deep-penetrating means to deliver a drug from a delivery reservoir. Moreover, the MW-triggered release of drug was observed to be enhanced under acidic conditions, where the swelling state is maximum due to the swelling-induced pH-responsiveness of the hydrogel. The hybrid composite described here is a harmless means to deliver remotely a hydrophobic drug on demand with a MW source of 915 MHz. Potential use in biomedical applications were evaluated by cytotoxicity tests.

Antimicrobial Nanogels with Nanoinjection Capabilities for Delivery of the Hydrophobic Antibacterial Agent Triclosan.

With the ever-growing problem of antibiotic resistance, developing antimicrobial strategies is urgently needed. Herein, a hydrophobic drug delivery nanocarrier is developed for combating planktonic bacteria that enhances the efficiency of the hydrophobic antimicrobial agent, Triclosan, up to a 1000 times. The poly(N-isopropylacrylamide-co-N-[3-(dimethylamino)propyl]methacrylamide), p(NIPAM-co-DMAPMA), based nanogel is prepared via a one-pot precipitation polymerization, followed by quaternization with 1-bromododecane to form hydrophobic domains inside the nanogel network through intraparticle self-assembly of the aliphatic chains (C12). Triclosan, as the model hydrophobic antimicrobial drug, is loaded within the hydrophobic domains inside the nanogel. The nanogel can adhere to the bacterial cell wall via electrostatic interactions and induce membrane destruction via the insertion of the aliphatic chains into the cell membrane. The hydrophobic antimicrobial Triclosan can be actively injected into the cell through the destroyed membrane. This approach dramatically increases the effective concentration of Triclosan at the bacterial site. Both the minimal inhibitory concentration and minimal bactericidal concentration against the Gram-positive bacteria S. aureus and S. epidermidis decreased 3 orders of magnitude, compared to free Triclosan. The synergy of physical destruction and active nanoinjection significantly enhances the antimicrobial efficacy, and the designed nanoinjection delivery system holds great promise for combating antimicrobial resistance as well as the applications of hydrophobic drugs delivery for many other possible applications.

Preparation of hyaluronic acid-decorated mixed nanomicelles for targeted delivery of hydrophobic drugs to CD44-overexpressing cancer cells

Most of the employed methods for preparation of targeted nanoparticles containing hydrophobic herbal drugs have multiple surface modifications with time-consuming steps. The present research was aimed to develop a facile method for preparation of hyaluronic acid (HA)-decorated mixed nanomicelles loaded with curcumin (as a hydrophobic drug model) to provide an efficient drug delivery system for targeted therapy of breast cancer cells with high expression of CD44 receptor. To this end, curcumin was first encapsulated in the hydrophobic core of Pluronic F127/didecyldimethylammonium bromide (PD) mixed nanomicelles using thin-film hydration method. Then, negatively charged HA was coated on the positively charged surface of PD mixed nanomicelles via electrostatic interactions. The drug loading and entrapment efficiency of the targeted nanomicelles were 2.8% and 95.1%, respectively. The average hydrodynamic size of the prepared nanomicelles before and after coating with HA were 19.8 and 35.8 nm, respectively. Moreover, in vitro cytotoxicity analyses showed that, HA-coated PD (HA-PD) mixed nanomicelles can enhance the cytotoxicity of curcumin against MDA-MB-231 cancer cells compared to non-targeted ones (PD mixed nanomicelles), and free curcumin. The IC50 concentrations of free curcumin, curcumin-loaded PD mixed nanomicelles, and curcumin-loaded HA-PD mixed nanomicelles were 4.11, 3.20, and 2.83 μg/mL, respectively, after 48 h incubation with MDA-MB-231 cancer cells. Our results suggest that, curcumin-loaded HA-PD mixed nanomicelles may be considered as a promising targeted anticancer drug delivery system for breast cancer therapy and/or delivering other hydrophobic drugs to different kinds of cancer cells with CD44-receptor overexpression.

Liquid crystalline nanoparticles for drug delivery: The role of gradient and block copolymers on the morphology, internal organisation and release profile

Amphiphilic polymers represent one of the main class of stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles, being essential for their formation and stability. In the present study, poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymers were incorporated as stabilizers in liquid crystalline nanoparticles prepared from glyceryl monooleate. The polymers were chosen according to their high biocompatibility and promising stealth properties, in order to develop safe and efficient drug delivery nanosystems. The physicochemical characteristics and fractal dimension of the resultant nanosystems were obtained from light scattering techniques, while their micropolarity and microfluidity from fluorescence spectroscopy. The effect of temperature, serum proteins and ionic strength on the physicochemical behavior was monitored. Their morphology was assessed by cryo-TEM, while their thermal behavior by microcalorimetry and high-resolution ultrasound spectroscopy. Their properties were dependent on the stabilizer chemistry and topology (block/gradient copolymer) and its concentration. Subsequently, resveratrol, as model hydrophobic drug, was loaded into the nanosystems, the entrapment efficiency was calculated and in vitro release studies were carried out, highlighting how the different stabilizer can differentiate the drug release profile. In conclusion, the proposed copolymers broaden the toolbox of polymeric stabilizers for the development of liquid crystalline nanoparticles intended for drug delivery applications.

Self-healing multilayer films for simultaneous release of hydrophilic and hydrophobic drugs

ABSTRACT Coloading and codelivery of hydrophilic and hydrophobic drugs as techniques for effective therapy have drawn attention but still present a challenge owing to the opposite nature of both drugs. Therefore, determining a convenient method for coloading and coreleasing hydrophilic and hydrophobic drugs in the development of biomedical devices is important. We constructed multilayer films with a microporous structure for the successful coloading of hydrophilic and hydrophobic drugs. The multilayer films were fabricated using chitosan (CS) and polyacrylic acid (PAA) via layer-by-layer self-assembly. A quartz crystal microbalance (QCM) was used to investigate the self-assembly of (CS/PAA) in films. With a low pH to change the inner structure of the multilayer films, these microporous structures exhibit humidity responsiveness and can return to the original compact structures by treatment with 100% relative humidity. The microporous films can simultaneously load a large number of hydrophobic drugs (tetracycline) and hydrophilic model drugs (Rhodamine B) by wicking and subsequent micropore self-healing. The loading and release ratio of the two drugs in the microporous films is consistent with the initial loading ratio in the solution, providing a good platform for coloading and codelivery of hydrophobic and hydrophilic drugs in biomedical applications.

Spontaneous foaming during vacuum drying of polyvinylpyrrolidone- and sugar-alcohol mixtures and enhancement of water-dissolution of water insoluble drug

We experimentally investigate the foamability of PVP 2.5k/ethanol and amorphous α-maltose/methanol solution under moderate vacuum. We investigate the influence of the solution concentration and the impact of the container shape on the foamability. We show that spontaneous foaming is strongly influenced by the container’s shape. The concentration of the solution is another important parameter, and our results suggest that, for a given solution, there seems to be only a narrow concentration window that enables the formation of a stable foam. When loaded with a model hydrophobic drug (ibuprofen), the spontaneous foaming enhances the dispersion of the drug molecules, by acting as an additional mixing force through extensive shear of the solution.

Light-tuning amphiphility of host-guest Alginate-based supramolecular assemblies for photo-responsive Pickering emulsions

Various Pickering emulsions-based system have been increasing demand for potential applications in a wide variety of fields. However, tunable emulsifiers and controllable Pickering emulsions with the ability to respond to external triggers remains an outstanding challenge. Here, we demonstrate the photo-tuning amphiphilicity in Pickering emulsions using β-cyclodextrin-grafted alginate and azobenzene derivative supramolecular self-assemblies as photoactivatable emulsifiers. Specifically, the photoisomerization of a host-guest system between β-cyclodextrin and azobenzene derivative was employed to tailor the polarity of the microenvironment, resulting in the reversible variation of hydrophilic/hydrophobic balance. The photoactivatable emulsifier based on supramolecular self-assemblies could effectively destabilize o/w emulsions by tailoring the amphiphilic balance at oil-water interface under an external UV irradiation, leading to the oil-water separation from Pickering emulsion. The light regulating demulsification is further showcased here by the photodelivery of hydrophobic model drug. Finally, this study provides a sustainable yet eco-friendly formulation for the fabrication of stimuli-responsive Pickering emulsions.

Cell‐Membrane‐Targeted Drug Delivery System Based on Choline‐Phosphate‐Functionalized β‐Cyclodextrin

In this study, a novel cyclodextrin derivative, i.e., zwitterionic choline phosphate (CP)-functionalized β-cyclodextrin (CP-β-CD) is successfully synthesized by click chemistry reaction. CP-β-CD has excellent cell-membrane-targeted ability because of the CP group can bind to phosphate choline (PC) in the cell membrane and promote the cellular uptake. Due to the introduction of CP group on β-CD, it disrupts the hydrogen network between natural β-CD molecules. Meanwhile, the water solubility of CP-β-CD is improved dramatically to 816mg mL-1 , which is 440 times as that of unmodified β-CD. Apatinib, a small molecular inhibitor, is used as a model of hydrophobic drug and loaded into CP-β-CD to study the solubilization effect and the anti-angiogenisis activity. In addition, the cytotoxicity of CP-β-CD is also studied, and it is demonstrated that CP-β-CD is nontoxic. These results indicate that the apatinib can be transported into cell interior and play an excellent anti-angiogenisis activity after being loaded into CP-β-CD drug delivery system. This work suggests that the water soluble CP-β-CD with excellent cell internalization efficiency has a potential application prospect in the field of drug delivery.

Dynamic Behavior of the Structural Phase Transition of Hydrogel Formation Induced by Temperature Ramp and Addition of Ibuprofen.

Understanding the dynamic behavior of hydrogel formation induced by a temperature ramp is essential for the design of gel-based injectable formulation as drug-delivery vehicles. In this study, the dynamic behavior of the hydrogel formation of Pluronic F108 aqueous solutions within different heating rates was explored in both macroscopic and microscopic views. It was discovered that when the heating rate is increased, the gelation temperature window (hard gel region) shrinks and the mechanical strength of the hydrogel decreases. A given system at different heating rates would lead to different crystalline structural evolutions. The time-resolved small-angle X-ray scattering (SAXS) experiments at a heating rate of 10 °C/min disclose that the crystalline structure of micelle packing in the hydrogel exhibits a series of transitions: hexagonal close-packed (HCP) to face-centered cubic (FCC) and body-centered cubic (BCC) structures coexisting and then to the BCC structure along with the increasing temperature. For the system at equilibrium, the BCC structure exclusively dominates the system. Furthermore, the addition of a hydrophobic model drug (ibuprofen) to the F108 aqueous solution promotes hard gel formation at even lower temperatures and concentrations of F108. The SAXS results for the system with ibuprofen at a heating rate of 10 °C/min demonstrate a mixture of FCC and BCC structures coexisting over the whole gelation window compared to the BCC structure that exclusively dominates the system at equilibrium. The addition of ibuprofen would alter the structural evolution to change the delivery path of the encapsulated drug, which is significantly related to the performance of drug release.

Targeting folate receptors (α1) to internalize the bleomycin loaded DNA-nanotubes into prostate cancer xenograft CWR22R cells

DNA-nanotechnology based on DNA scaffolding technique is an established approach to formulate water-miscible nano-structural frameworks. We have designed the hydrophilic DNA-nanotubes (D-NTs) as a (water-soluble) vehicle to encapsulate a water-insoluble DNA-intercalating anticancer drug. Bleomycin (BM) is a model hydrophobic anticancer drug used in this study capable to bind with the D-NTs to formulate BM loaded D-NTs. This BM@D-NTs system was evaluated for the improvement of the in vitro anti-cancer effects on the resistant prostate cancer xenograft CWR22R cells, over-expressed with the folate receptors/alpha (FRα). D-NTs were functionalized with the FRα-targeting antibodies to interact with the FRα (receptors) highly expressed on the resistant prostate cancer xenograft CWR22R cells. D-NTs not only increased the aqueous miscibility/dispersibility of BM but also enhanced the therapeutic efficiency as a targeted (site-specific) drug delivery system. D-NTs synthesis was achieved by sticky ends cohesions of DNA triangular tiles. DNA triangles were self-assembled from a freshly circularized short scaffold chain (84-NT) by annealing with the various staple strands. The polymerization of the triangular tiles gave rise to DNA-nanosheet lattices which underwent morphological transition guided by the twists in the DNA duplexes. This DNA double helix curvature caused self-coiling of the DNA 2D nano-sheets to condense into D-NTs morphology. Native-Page gel experiment showed decreased electrophoretic mobility down the gel confirming the successful execution of the polymerized lattices via sticky ends cohesion of the DNA-triangles. The final morphology and self-coiling of 2D DNA nano-sheets were confirmed through atomic force microscopy (AFM) showed the successful synthesis of D-NTs having diameter 3 to 5 μm and length 200 to 600 nm. BM was loaded onto D-NTs via incubation of hydro-alcoholic solution of the BM with the aqueous solution of D-NTs followed by the evaporation of alcohol and intercalation of the BM onto D-NTs. The intercalation of BM onto D-NTs was confirmed by UV-shift analysis. The targeted cytotoxicity of the BM@D-NTs for the CWR22R (resistant prostate cancer xenograft) cells was confirmed through MTT assay and the flow cytometry compared to the highly compatible empty D-NTs. Confocal microscopy revealed the time-dependent transfection of BM@D-NTs into CWR22R cells compared to the control cell line.

Dissolution of amorphous nifedipine from micelle-forming carboxymethylcellulose derivatives

We show that a novel amphiphilic graft copolymer combining the biodegradability and biocompatibility of oxidized carboxymethylcellulose (CMC) with that of hydrophilic poly(ethylene glycol) (PEG), and hydrophobic dodecylamine (DDA), improves the solubility and dissolution performance of nifedipine (NIF), considered as a model hydrophobic drug. The hydrophobic components of the graft copolymer have the multiple effect of favouring micelle formation and loading. At the same time, the interaction between the hydrophobic core and NIF has the secondary effect to suppress drug crystallization, favouring its dissolution, and to increase photostability. Oxidized CMC-g-PEG-DDA micelles reached values of drug concentration, loading capacity and encapsulation efficiency as high as 340 μg mL−1, 6.4 % and 34.1 %, respectively. Loaded micelles showed a good stability with a limited release profile at pH 1.2, whereas at pH 7.4 the swollen cores enable much higher and progressive release, that reaches 3.4 and 6.6 % after 3 and 5 h, respectively, corresponding to very competitive concentration of 34 and 66 μg mL−1.

Production of lipophilic nanogels by spontaneous emulsification.

Nanosized gel particles, so-called nanogels, have attracted substantial interest in different application fields, thanks to their controllable and three-dimensional physical structure, good mechanical properties and potential biocompatibility. Literature reports many technologies for their preparation and design, however a recurrent limitation remains in their broad size distributions as well as in the poor size control. Therefore, the monodisperse and size-controlled nanogels preparation by simple process -like emulsification- is a real challenge still in abeyance to date. In this study we propose an original low energy emulsification approach for the production of monodisperse nanogels, for which the size can be finely controlled in the range 30 to 200nm. The principle lies in the fabrication of a direct nano-emulsion containing both oil (medium chain triglycerides) and a bi-functional acrylate monomer. The nanogels are thus formed in situ upon UV irradiation of the droplet suspension. Advantage of such modification of the oil nano-carriers are the potential modulation of the release of encapsulated drugs, as a function of the density and/or properties of the polymer chain network entrapped in the oil nano-droplets. This hypothesis was confirmed using a model of hydrophobic drug -ketoprofen- entrapped into the nanogels particles, along with the study of the release profile, carried out in function of the nature of the monomers, density of polymer chains, and different formulation parameters.

Meloxicam Carrier Systems Having Enhanced Release and Aqueous Wettability Prepared Using Micro-suspensions in Different Liquid Media.

One of the conventional methods of alleviating the problem of poor drug solubility is the particle size reduction. The efficiency of this approach depends on successful formulation suppressing the drug agglomeration. The aim of this study was to circumvent the dissolution problems of model hydrophobic meloxicam drug (MLX) by using liquid media of different wetting capacity to comminute and formulate a rapidly dissolving carrier system without the use of surfactants. Micro-suspensions of MLX were prepared by ball milling, using water or n-Heptane as a liquid medium. The suspensions were used as granulation liquids to formulate granulate from microcrystalline cellulose and lactose mixture. The release kinetics from prepared granulates were studied using the USP-4 dissolution apparatus. Micro-suspensions prepared via wet milling in non-water liquid media exhibited a massive improvement of release rate compared with source meloxicam and they outperformed their water-milled counterparts. The release rates from those formulations, despite not comprising any surfactant, were comparable to those obtained by different authors using surfactant stabilized nanosuspension formulations. Thus, they can present an interesting formulation alternative for hydrophobic drugs that are dissolution limited.

Design of polyester structure in amphiphilic copolymer coated on magnetite nanoparticle: Effect on loading and sustaining release of indomethacin

This works presented the surface modification of magnetite nanoparticles (MNPs) with the copolymers containing hydrophilic mPEG and hydrophobic polyester for use in drug controlled release applications. Polyester moieties in the copolymers were adsorbed on MNPs to form hydrophobic layer for entrapment of a hydrophobic indomethacin model drug, while hydrophilic mPEG provided their good water dispersibity. Three different polyester structures in the copolymer for MNP coating were; 1) saturated, 2) unsaturated and 3) crosslinked polyesters. The copolymer structures were characterized via1H NMR and their coatings were confirmed by FTIR. These water dispersible MNPs contained 53–61% copolymer in the complexes with the size ranging between 8 and 14 nm. The MNPs containing saturated polyester showed higher drug entrapment and loading efficiencies than the other two samples. Interestingly, those containing crosslinked polyester exhibited a potential to sustain the release of the entrapped drug. These complexes might be suitable for use as vehicles for entrapment of hydrophobic drugs with tunable and controllable release rate.

Chitosan/carboxymethylcellulose-stabilized poly(lactide-co-glycolide) particles as bio-based drug delivery carriers

Poly(lactide-co-glycolide) (PLGA) colloidal particles stabilized by complexes of two oppositely charged polysaccharides, chitosan (cationic, CS) and sodium carboxymethylcellulose (anionic, NaCMC), were fabricated. Dichloromethane containing dissolved PLGA was first emulsified in an aqueous phase containing mixtures of CS and NaCMC. Evaporation of dichloromethane from the resulting emulsion led to CS/NaCMC-covered-PLGA particles. CS and NaCMC contents affected the short-term stability of PLGA particles and also their intrinsic characteristics. The particles displayed pH-dependent characteristic. Zeta potential varied from +54 to −50 mV when pH was varied from 3 to 10. CS/NaCMC-covered-PLGA particles showed colloidal stability, over a wider pH range as compared to CS-covered-PLGA particles. Curcumin, a model hydrophobic drug, was encapsulated into the particles up to 10 wt% of PLGA. The CS/NaCMC-covered-PLGA particles loaded with curcumin showed delayed release in mildly acidic conditions and faster release in neutral and basic conditions. Cytotoxicity experiments were carried out with human colorectal carcinoma cells.

Synthesis and Characterization of Sulfanilamide‐Based Nonionic Surfactants and Evaluation of Their Nano‐Vesicular Drug Loading Application

AbstractNonionic surfactants are highly stable and cost‐effective and receiving acceptance for applications in many diverse fields including drug delivery, due to their distinctive properties. Here, we report on the synthesis and characterization of sulfanilamide‐based nonionic surfactants for nanoscale vesicular drug loading applications. Nonionic surfactants were synthesized through alkylation of sulfanilamide with alkyl halides that possessed diverse degrees of lipophilicity. They were explored for their nanovesicular drug loading with Cefixime as a hydrophobic model drug. Drug‐loaded nanovesicles were characterized for surface morphologies, size, size distribution, surface charge, and drug loading efficiency using atomic force microscopy (AFM), dynamic light scattering (DLS), and UV–visible spectrophotometry. All of the synthesized nonionic surfactants revealed their CMC values in 0.055–0.035 mM range depending upon the lipophilic chain length of surfactants. They caused a decreased hemoglobin release and low toxicity against cell culture. They self‐assembled and loaded an increased amount of drug in the form of nanorange spherical shape niosomal vesicles. Results of the current study verify these synthesized nonionic surfactants are hemocompatible, nontoxic, and capable of self‐assembling into nanorange niosomal vesicles. These niosomal vesicles can be suggested as safe and highly efficient nanocarriers for hydrophobic drug loading and delivery.

Location of stimuli-responsive peptide sequences within silk-elastinlike protein-based polymers affects nanostructure assembly and drug–polymer interactions

Silk-elastinlike protein polymers (SELPs) self-assemble into nanostructures when designed with appropriate silk-to-elastin ratios. Here, we investigate the effect of insertion of a matrix metalloproteinase-responsive peptide sequence, GPQGIFGQ, into various locations within the SELP backbone on supramolecular self-assembly. Insertion of the hydrophilic, enzyme-degradable sequence into the elastin repeats allows the formation of dilution-stable nanostructures, while insertion into the hydrophobic silk motifs inhibited self-assembly. The SELP assemblies retained their lower critical solution temperature (LCST) thermal response, allowing up to eightfold volumetric changes due to temperature-induced size change. A model hydrophobic drug was incorporated into SELP nanoassemblies utilising a combination of precipitation, incubation and tangential flow filtration. While the nanoconstructs degraded in response to MMP activity, drug release kinetics was independent of MMP concentration. Drug release modelling suggests that release is driven by rates of water penetration into the SELP nanostructures and drug dissolution. In vitro testing revealed that SELP nanoassemblies reduced the immunotoxic and haemolytic side effects of doxorubicin in human blood while maintaining its cytotoxic activity.

Skin permeability and transdermal delivery route of 30-nm cyclosporin A-loaded nanoparticles using PLGA-PEG-PLGA triblock copolymer

The aim of this study was to investigate the skin permeability of a hydrophobic drug when using poly(dl-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(dl-lactide-co-glycolide) triblock copolymers (PLGA-PEG-PLGA) as a drug carrier. Two types of PLGA-PEG-PLGA nanoparticles with an average particle size of 30 nm and poly(dl-lactide-co-glycolide) (PLGA) nanoparticles for comparison were prepared using a combination of an antisolvent diffusion method with preferential solvation. Cyclosporin A was used as a hydrophobic model drug. From the results of the in vitro release test, it was confirmed that the release of the drug from the nanoparticles was relatively fast in the PLGA-PEG-PLGA nanoparticles. This result suggested that, compared to PLGA nanoparticles, the thermodynamic activity of PLGA-PEG-PLGA nanoparticles increased and the diffusion of the drug into the stratum corneum was promoted. The results of studies on skin permeability using rat skin and a transdermal delivery route showed that PLGA-PEG-PLGA nanoparticles were useful for efficient drug skin permeation and can deliver the drugs deep into the epidermal and dermal layers. Additionally, in the membrane permeability tests using Strat-M®, which imitates human skin, the membrane permeation amount of the drug was significantly increased when PLGA-PEG-PLGA nanoparticles were used compared with when PLGA nanoparticles were used.

Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing.

A continuous processing platform was developed to produce polymeric micelles. A block copolymer of mPEG (5kD)-PCL (2kD) was used as the model drug carrier. The polymeric micelles were produced using an innovative co-axial turbulent jet with co-flow continuous technology to precisely control the physicochemical properties of the micelles. A 3×3×4 full factorial design of experiment (DoE) study was conducted to optimize the polymeric micelle processing to achieve the desired critical quality attributes such as particle size and polydispersity index (PDI). Curcumin was used as a hydrophobic model drug as polymeric micelles are traditionally used to improve solubility and chemical stability of hydrophobic drug molecules. A second DoE study was conducted to achieve maximal drug loading. The average size of the optimized curcumin-loaded polymeric micelles was 29.1±0.51 d.nm with a PDI value in the range of 0.05±0.02 and a maximum drug loading of 11.1±0.81% (w/w). When compared to polymeric micelles prepared using a manual ethanol injection method the particle size, PDI and drug loading for curcumin-loaded polymeric micelles was 74.8±8.68 d.nm, and 0.46±0.12 and 8.12±1.23%, respectively. These data show that the continuous processing method provided significant improvement in controlling the key quality attributes. The curcumin-loaded polymeric micelles exhibited a sustained release profile during dissolution of about 50% drug released in 12h compared to the free drug, which was completely released within 10h. The curcumin-loaded polymeric micelles were characterized for other key quality attributes such as critical micelle concentration (CMC), and morphology by transmission electron microscopy, X-ray powder crystallography, polarized light microscopy, and differential scanning calorimetry. A novel method for determining the CMC of the polymer was developed using dynamic light scattering (DLS). Curcumin-loaded polymeric micelles were further processed by lyophilization to prevent hydrolytic cleavage of the polymers and maintain long term stability. The current study highlighted the potential advantages of transitioning from manual batch processing to continuous processing and serves as an example of improving processing efficiency as well as product quality through utilization of advanced processing technologies.