Jonghwi Lee

Cryoprotectants for freeze drying of drug nano-suspensions: Effect of freezing rate

Drug nanoparticles are often prepared in a liquid medium, and a drying method such as freeze drying is used to convert them to an oral solid dosage form. When the dried form is reconstituted in an aqueous system, it may be redispersed to achieve its original particle size. The redispersibility of dried nanoparticles depends on the parameters of the freeze drying process. In this study, an apparatus with a freezing rate gradient was used to systematically investigate the effect of cryoprotectants on the redispersibility of nanoparticles as a function of freezing rate. Sucrose, lactose, mannitol, and polyethylene glycol were used as cryoprotectants for a naproxen nano-suspension. A fast freezing rate and a high cryoprotectant concentration were generally favored. However, under certain conditions, a slower freezing rate resulted in better redispersibility. This is probably because slow freezing can produce a more cryo-concentrated liquid phase, and the concentrated cryoprotectant in the liquid phase can more effectively protect the nanoparticles. An irreversible aggregation map was constructed as a function of the freezing rate and the cryoprotectant concentration, and shows both the favorable and unfavorable effects of cryoprotectants.

Effective polymeric dispersants for vacuum, convection and freeze drying of drug nanosuspensions

Drying nanosuspensions into redispersable powders is a critical issue in developing solid dosage forms of drug nanoparticles. The particle fusion and chain entanglement of polymeric steric stabilizers adsorbed onto the nanoparticle surface should be prevented to retain redispersibility after drying. Herein, we report that only a small amount of polymeric dispersants such as carrageenan, gelatin, and alginic acid between 0.5 and 3 wt.% in various drug nanosuspensions can provide sufficient redispersibility in vacuum, convection, and freeze drying. In vacuum and freeze drying of naproxen nanosuspensions, the addition of only 0.5 wt.% carrageenan resulted in the formation of redispersable nanoparticulate powders. The amounts of polymeric dispersants required for redispersibility was lowest for carrageenan and highest for gelatin. The specific interactions between the dispersants and steric stabilizers (or drugs), in addition to viscosity increase during drying, appeared to effectively prevent irreversible particle aggregation.

Mechanism of freeze-drying drug nanosuspensions

Drug nanoparticles prepared in a liquid medium are commonly freeze-dried for the preparation of an oral dosage in solid dosage form. The freezing rate is known to be a critical parameter for redispersible nanoformulations. However, there has been controversy as to whether a fast or slow freezing rate prevents irreversible aggregation. A systematic investigation is presented herein regarding the effect of both the molecular weight of the cryoprotectant and the freezing rate in order to elucidate the mechanism underlying irreversible aggregation. It was found that irreversible aggregation occurred during drying rather than freezing, although a proper freezing rate is critical. A more homogeneous distribution of the cryoprotectant and drug nanoparticles led to more redispersible powders. Thus, keeping the local concentration distribution of the nanoparticles and cryoprotectant fixed during the freezing step plays a critical role in how the freezing rate affects the redispersibility. The kinetic approach of excluding the tendency of ice crystal growth permitted an explanation of the controversial results. This study will facilitate an in-depth understanding of the aggregation process of nanoparticles or proteins during freeze-drying.

Effect of Polymer Molecular Weight on Nanocomminution of Poorly Soluble Drug

The reduction of particle size to nanometers has been an important tool used for efficient drug delivery. Solid drug nanoparticles can be conveniently prepared by nanocomminution. This process relies on mechanical energy and the selection of a proper polymeric stabilizer. The long chains of polymers provide steric stabilization for drug nanoparticles. In this research, itraconazole and hydroxypropyl cellulose were used to study the effect of the molecular weight of a polymer on particle size reduction. In principle, an increase in molecular weight produces two counteracting effects: a decrease in the diffusion rate of chains and an increase in the physical adsorption of a polymer. The effects of particle size reduction are more pronounced in systems involving smaller molecular weights, and the effects of changing molecular weights disappear with time. Systems of higher molecular weight show larger aggregates in their redispersion after drying. Based on the results of our research, it appears that polymers of smaller molecular weight are more suitable than larger polymers for efficient nanocomminution. This indicates that the kinetic aspects of molecular weight are important.

Directed Blood Vessel Growth Using an Angiogenic Microfiber/Microparticle Composite Patch

IO N Therapeutic angiogenesis has emerged as a promising strategy to treat various acute and chronic vascular diseases and to enhance tissue repair and regeneration. Revascularization therapies are commonly conducted by administering angiogenic growth factors, such as vascular endothelial growth factor (VEGF). [ 1 , 2 ] Successful angiogenic therapies rely greatly on the ability to engineer mature and functional neovessels, uniformly distributed within target tissues. Immature blood vessels with non-uniform distributions often stimulate an infl ammatory response and a limited therapeutic effi cacy. [ 3 , 4 ] This study presents an angiogenic microfi ber patch that releases angiogenic growth factors along aligned fi bers and subsequently directs the spacing and orientation of mature and functional neovessels. The angiogenic microfi ber patch was prepared by electrostatically binding electrosprayed VEGF-encapsulating poly(lactide-co-glycolide) (PLGA) microparticles with electrospun poly(lactide) (PLA) microfi bers. The PLGA microparticles released VEGF in a sustained manner, while the straightly aligned PLA fi bers guided cells to adhere along their orientation. Finally, microfi ber patches implanted in vivo resulted in the formation of neovessels, with controlled spacings and directionalities, together with a signifi cant increase in the blood vessel density. The angiogenic microfi ber patch developed in this study will be broadly useful for studying neovessel growth and will also signifi cantly improve the quality of clinical treatments requiring neovascularization. Several vascular biological studies have demonstrated that the spatiotemporal organization of multiple angiogenic growth factors and cytokines in tissues control the directional growth and spacing of neovessels during development and self-healing. [ 5 ]

A bio-inspired, microchanneled hydrogel with controlled spacing of cell adhesion ligands regulates 3D spatial organization of cells and tissue

Bioactive hydrogels have been extensively studied as a platform for 3D cell culture and tissue regeneration. One of the key desired design parameters is the ability to control spatial organization of biomolecules and cells and subsequent tissue in a 3D matrix. To this end, this study presents a simple but advanced method to spatially organize microchanneled, cell adherent gel blocks and non-adherent ones in a single construct. This hydrogel system was prepared by first fabricating a bimodal hydrogel in which the microscale, alginate gel blocks modified with cell adhesion peptides containing Arg-Gly-Asp sequence (RGD peptides), and those free of RGD peptides, were alternatingly presented. Then, anisotropically aligned microchannels were introduced by uniaxial freeze-drying of the bimodal hydrogel. The resulting gel system could drive bone marrow stromal cells to adhere to and differentiate into neuron and glial cells exclusively in microchannels of the alginate gel blocks modified with RGD peptides. Separately, the bimodal gel loaded with microparticles releasing vascular endothelial growth factor stimulated vascular growth solely into microchannels of the RGD-alginate gel blocks in vivo. These results were not attained by the bimodal hydrogel fabricated to present randomly oriented micropores. Overall, the bimodal gel system could regulate spatial organization of nerve-like tissue or blood vessels at sub-micrometer length scale. We believe that the hydrogel assembly demonstrated in this study will be highly useful in developing a better understanding of diverse cellular behaviors in 3D tissue and further improve quality of a wide array of engineered tissues.

Reversibly Stretchable, Optically Transparent Radio-Frequency Antennas Based on Wavy Ag Nanowire Networks

We report a facile approach for producing reversibly stretchable, optically transparent radio-frequency antennas based on wavy Ag nanowire (NW) networks. The wavy configuration of Ag NWs is obtained by floating the NW networks on the surface of water, followed by compression. Stretchable antennas are prepared by transferring the compressed NW networks onto elastomeric substrates. The resulting antennas show excellent performance under mechanical deformation due to the wavy configuration, which allows the release of stress applied to the NWs and an increase in the contact area between NWs. The antennas formed from the wavy NW networks exhibit a smaller return loss and a higher radiation efficiency when strained than the antennas formed from the straight NW networks, as well as an improved stability in cyclic deformation tests. Moreover, the wavy NW antennas require a relatively small quantity of NWs, which leads to low production costs and provides an optical transparency. These results demonstrate the potential of these wavy Ag NW antennas in applications of wireless communications for wearable systems.

Fabrication of 3D honeycomb-like porous polyurethane-functionalized reduced graphene oxide for detection of dopamine.

A three dimensional reduced graphene oxide/polyurethane (RGO-PU) porous material with connected pores was prepared by physical adsorption of RGO onto the surface of porous PU. The porous PU was prepared by directional melt crystallization of a solvent, which produced high pores with controlled orientation. The prepared RGO-PU was characterized by scanning electron microscopy, spectroscopy and electro-chemical methods. The RGO-PU porous material revealed better electrochemical performance, which might be attributed to the robust structure, superior conductivity, large surface area, and good flexibility. Differential pulse voltammetry (DPV) analysis of DA using the RGO-PU exhibited a linear response range over a wide DA concentration of 100-1150pM, with the detection limit of 1pM. This sensor exhibited outstanding anti-interference ability towards co-existing molecules with good stability, sensitivity, and reproducibility. Furthermore, the fabricated sensor was successfully applied for the quantitative analysis of DA in human serum and urine samples with acceptable recovery, which indicates its feasibility for practical application.

Folate-targeted drug-delivery systems prepared by nano-comminution.

Background: The size reduction ability of conventional wet comminution has been improved by proper polymeric stabilizer systems, and the resulting nano-comminution methods have led to the commercialization of many poorly water-soluble drugs after improving their bioavailability. During nano-comminution, polymer steric stabilizers physically adsorb onto the surface of drug particles. Method: In this study, the cross-linking and subsequent functionalization methods of the physically adsorbed polymers were used to widen the applicability of the nano-comminution. Chitosan was used as a steric stabilizer for two hydrophobic drugs, naproxen and paclitaxel. Results: Chitosan was successfully cross-linked (immobilized) by tripolyphosphate. The cross-linked stable polymer layer on drug nanoparticles was conjugated with folic acid, a model targeting moiety. The chemical reactions were performed without destroying the stabilities of drug nanosuspensions. The cross-linking and conjugation reactions significantly modified the release profiles of drug nanoparticles. Conclusion: This simple preparation method can be utilized to prepare novel drug encapsulations and folate-targeted delivery systems.

Superporous thermo-responsive hydrogels by combination of cellulose fibers and aligned micropores

In the area of artificial hydrogels, simultaneous engineering of the volume transition characteristics and mechanical properties of stimuli-responsive hydrogels is an important subject. By unrestricted architecting of hierarchical structures, natural hydrogels are able to provide a wide range of swelling and mechanical properties, beyond the limits of artificial hydrogels. Herein, a combination of nanostructures and microstructures was developed to construct superporous hydrogels. Fibers of microfibrillated cellulose (MFC), an eco-friendly reinforcing material, were used as nanostructures, aligned micropores were used as microstructures, and in situ photopolymerization was used to immobilize the two structures together within the gel networks of poly(N-isopropyl acrylamide) (PNIPAm). The introduction of MFC distinctly enhanced volume transition, mainly by decreasing the swelling ratios above the transition. The introduction of directional micropores increased the swelling ratio below the transition and decreased the swelling ratio above the transition, thereby also enhancing the volume transition. Additionally, the formation of aligned micropores achieved fast water infiltration, which is beneficial for superabsorbent applications. The introduction of aligned micropores reduced the elastic modulus, but this could partially be compensated for by reinforcement with MFC. This combination of crystalline nanofibers and aligned micropores has great potential for the development of stimuli-responsive superporous hydrogels outperforming current artificial hydrogels.