Nanogels Based on N,N-Dimethylacrylamide and ß-Cyclodextrin Triacrylate for Enhanced Solubility and Therapeutic Efficacy of Aripiprazole.

Aripiprazole (ARZ) is a medication used for the treatment of various diseases such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Despite its therapeutic benefits, ARZ is characterized by a poor water solubility which provoked the development of various delivery systems in order to enhance its solubility. In the present work, a nanoscale drug delivery system based on N,N-dimethylacrylamide (DMAA) and ß-cyclodextrin triacrylate (ß-CD-Ac3) as potential aripiprazole delivery vehicles was developed. The nanogels were synthesized by free radical polymerization of DMAA in the presence of ß-CD-Ac3 as a crosslinking agent and then loaded with ARZ via host-guest inclusion complexation. The blank- and drug-loaded nanogels were evaluated using different methods. Fourier transform infrared (FTIR) spectroscopy was employed to confirm the incorporation of ß-CD moieties into the polymer network. Dynamic light scattering (DLS) was used to study the size of the developed systems. The samples exhibited a monomodal particle size distribution and a relatively narrow dispersity index. The hydrodynamic diameter (Dh) of the gels varied between 107 and 129 nm, with a tendency for slightly larger particles as the ß-CD-Ac3 fraction increased. Loading the drug into the nanocarrier resulted in slightly larger particles than the blank gels, but their size was still in the nanoscopic range (166 to 169 nm). The release profiles in PBS were studied and a sustained release pattern with no significant burst effect was observed. A cytotoxicity assessment was also conducted to demonstrate the non-toxicity and biocompatibility of the studied polymers.

Interpenetrating Polymer Networks of Poly(2-hydroxyethyl methacrylate) and Poly(N, N-dimethylacrylamide) as Potential Systems for Dermal Delivery of Dexamethasone Phosphate.

In this study, a series of novel poly(2-hydroxyethyl methacrylate) (PHEMA)/poly(N,N'-dimethylacrylamide) (PDMAM) interpenetrating polymer networks (IPNs) were synthesized and studied as potential drug delivery systems of dexamethasone sodium phosphate (DXP) for dermal application. The IPN composition allows for control over its swelling ability as the incorporation of the highly hydrophilic PDMAM increases more than twice the IPN swelling ratio as compared to the PHEMA single networks, namely from ~0.5 to ~1.1. The increased swelling ratio of the IPNs results in an increased entrapment efficiency up to ~30% as well as an increased drug loading capacity of DXP up to 4.5%. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) show the formation of a solid dispersion between the drug DXP and the polymer (IPNs) matrix. Energy-dispersive X-ray (EDX) spectroscopy shows an even distribution of DXP within the IPN structure. The DXP release follows Fickian diffusion with ~70% of DXP released in 24 h. This study demonstrates the potential of the newly developed IPNs for the dermal delivery of DXP.

Conceptualization and Investigation of Multicomponent Polymer Networks as Prospective Corticosteroid Carriers.

Dexamethasone (DXM) is a highly potent and long-acting synthetic glucocorticoid with anti-inflammatory, anti-allergic, and immunosuppressive effects. However, the systemic application of DXM can cause undesirable side effects: sleep disorders, nervousness, heart rhythm disorders, heart attack, and others. In the present study, multicomponent polymer networks were developed as potential new platforms for the dermal application of dexamethasone sodium phosphate (DSP). First, a copolymer network (CPN) comprising hydrophilic segments of different chemical structures was synthesized by applying redox polymerization of dimethyl acrylamide onto poly(ethylene glycol) in the presence of poly(ethylene glycol) diacrylate (PEGDA) as a crosslinker. On this basis, an interpenetrating polymer network structure (IPN) was obtained by introducing a second network of PEGDA-crosslinked poly(N-isopropylacrylamide). Multicomponent networks obtained were characterized by FTIR, TGA, and swelling kinetics in different solvents. Both CPN and IPN showed a high swelling degree in aqueous media (up to 1800 and 1200%, respectively), reaching the equilibrium swelling within 24 h. Additionally, IPN showed temperature-responsive swelling in an aqueous solution as the equilibrium swelling degree decreased considerably with an increase in the temperature. In order to evaluate the networks' potential as drug carriers, swelling in DSP aqueous solutions of varied concentration was investigated. It was established that the amount of encapsulated DSP could be easily controlled by the concentration of drug aqueous solution. In vitro DSP release was studied in buffer solution (BS) with pH 7.4 at 37 °C. The results obtained during DSP loading and release experiments proved the feasibility of the developed multicomponent hydrophilic polymer networks as effective platforms for potential dermal application.

Chitosan-Based Nanoparticles for Targeted Nasal Galantamine Delivery as a Promising Tool in Alzheimer's Disease Therapy.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer's dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan-alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C.

Interpenetrating Polymer Networks of Polyacrylamide with Polyacrylic and Polymethacrylic Acids and Their Application for Modified Drug Delivery - a Flash Review.

Polyacrylic and polymethacrylic acids, in combination with polymers such as polyacrylamide, provide the ability for controlled and sustained drug delivery since they represent pHand temperature responsiveness. In addition, the synthesis techniques can be used to develop a higher level of supramolecular structures as the interpenetrating polymer networks - as bulk hydrogels or micro-/nanogels. They can provide the opportunity to organize and build up state-ofthe- art carriers for different types of drugs, thus providing the ability to control their loading capacity and drug release performance. This flash review aims to summarize the efforts for synthesizing such interpenetrating polymer networks and their properties and to demonstrate the authors' contributions to this field.

Polyacrylamide/poly(2-(dimethylamino) Ethyl Methacrylate) Interpenetrating Polymer Networks as Drug Delivery Systems for Diclofenac Sodium.

Nowadays, modern pharmaceutical investigations are directed toward the design and production of drug delivery systems for achieving prolonged and controlled drug delivery. In this respect, the use of interpenetrating polymer networks (IPNs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of novel poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) and polyacrylamide (PAAm)-based IPNs with different compositions and their application as diclofenac sodium delivery systems. The prepared IPNs were shown to possess phase-separated structures at the nano level, as revealed by SEM and TM-DSC. The IPNs' composition was shown to determine the swelling behavior of these novel materials, and the inclusion of the charged IPN component (PDMAEMA) has changed the water molecules type diffusion from Fickian to non-Fickian, as revealed by the swelling kinetics study. Loading efficiency of diclofenac sodium and diclofenac sodium content in the polymer network was evaluated, and in vitro drug release experiments were carried out in order to estimate the ability of the obtained IPNs to control the release of the water-soluble drug.

Design and Concept of Polyzwitterionic Copolymer Microgel Drug Delivery Systems In Situ Loaded with Non-steroidal Anti-inflammatory Ibuprofen.

Nowadays, the modern pharmaceutical investigations are directed toward obtaining of new polymer micro- and nano-sized drug delivery carriers. In this respect, the use of hydrogel carriers based on polyzwitterions (PZIs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of micro-structured p(VA-co-DMAPS) systems with different compositions in situ loaded with Ibuprofen by emulsifier-free emulsion copolymerization (EEC) in water. The mean size of the prepared microparticles was measured by SEM and particles have been visualized by AFM. The inclusion of Ibuprofen in the polyzwitterionic copolymer microgel systems was established by using DSC. In vitro drug release experiments were carried out in order to estimate the ability of the obtained microgels to modify the release of water-insoluble Ibuprofen.

pH-Sensitive cationic copolymers of different macromolecular architecture as potential dexamethasone sodium phosphate delivery systems.

This paper describes the synthesis and characterization of cationic copolymers with different macromolecular architecture and drug delivery properties of the corresponding dexamethasone sodium phosphate (DSP)-loaded systems. Copolyelectrolytes comprising poly[2-(acryloyloxy)ethyl] trimethylammonium chloride (PAETMAC) and poly(ethylene glycol) blocks as well as a tri-arm star-shaped PAETMAC were synthesized using cerium(IV) ion-mediated polymerization method. The obtained copolyelectrolytes and corresponding ionic associates with DSP have been characterized by (1)H NMR, Fourier Transform Infrared spectroscopy, and differential scanning calorimetry. The average diameter, size distribution, and ζ-potential of the copolymers and DSP-copolymer ionic associates were determined by dynamic light scattering, and particles were visualized by scanning electron microscopy and transmission electron microscopy. The biocompatibility and cytotoxicity of obtained copolymers were determined. In vitro drug release experiments were carried out to estimate the ability of the obtained nanoparticles for sustained release of DSP for a period of 24 h.

Evaluation of poly(2-ethyl-2-oxazoline) containing copolymer networks of varied composition as sustained metoprolol tartrate delivery systems.

Segmented copolymer networks (SCN) based on poly(2-ethyl-2-oxazoline) and containing 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and/or methyl methacrylate segments have been evaluated as potential sustained release systems of the water soluble cardioselective ß-blocker metoprolol tartrate. The structure and properties of the drug carriers were investigated by differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. Swelling kinetics of SCNs in various media was followed, and the conditions for effective MT loading were specified. MT-loaded SCNs with drug content up to 80 wt.% were produced. The release kinetics of metoprolol tartrate from the systems was studied and it was shown that the conetworks of different structure and composition are able to sustain the metoprolol tartrate release without additional excipients.

Stimuli sensitive super-macroporous cryogels based on photo-crosslinked 2-hydroxyethylcellulose and chitosan.

Original pH sensitive cryogels, based on two biodegradable natural polymers chitosan (CS) and 2-hydroxyethylcellulose (HEC), were obtained via cryogenic treatment of semi-dilute aqueous solutions and UV induced crosslinking in frozen state. H2O2 and N,N'-methylenebisacrylamide (BisAAm) were used as photoinitiator and crosslinking agent, respectively. BisAAm facilitated the formation of polymer co-network and increased both the gel fraction yield and mechanical strength of cryogels. The influence of chitosan content on the physico-mechanical properties of HEC-CS cryogels was investigated. In general, the increase of CS fraction in the polymer co-network increased the degree of swelling and enhanced significantly the storage modulus of materials. All HEC-CS cryogels obtained were opalescent sponge-like materials, which quickly release/uptake water due to their open porous structure. The incorporation of CS provided pH dependent swelling and good bioadhesive properties of cryogels. HEC-CS cryogels were further exploited as drug delivery systems of the highly water soluble drug metronidazole belonging to BCS Class l.

Development and evaluation of novel lozenges containing marshmallow root extract.

Lozenges (tablets intended to be dissolved slowly in the mouth) were evaluated as delivery system for polysaccharides extract from Althaea officinalis L. (marshmallow) root. The aim of investigation was to improve of the efficacy of convenient preparations for the treatment of irritated oropharyngeal mucosa and associated dry irritable cough. The formulations studied were prepared with water extract of roots of Althaea officinalis L. The polysaccharides extract was obtained by ultrasonification. Acute oral toxicity (LD 50 p.o.) of the obtained extract was estimated in mice. Four models of lozenges based on different excipients were formulated. The characteristics of the preparations: resistance to crushing, friability testing, disintegration time and drug release properties were evaluated.

Study of the potential of amphiphilic conetworks based on poly(2-ethyl-2-oxazoline) as new platforms for delivery of drugs with limited solubility.

Thermoresponsive amphiphilic conetworks comprising poly(2-ethyl-2-oxazoline) (PEtOx), 2-hydroxyethyl methacrylate, and 2-hydroxypropyl acrylate segments have been studied as new platforms for delivery of drug with limited solubility. Series of conetworks of varied composition were synthesized and swelling kinetics in aqueous media and ethanol were followed. The platforms were loaded with the hydrophobic drug ibuprofen by swelling in its ethanol solution. The structure and properties of the drug carriers were investigated by scanning electron microscopy and differential scanning calorimetry. The release kinetics profiles of ibuprofen from the studied platform were established. The investigation proved the feasibility of the PEtOx-based amphiphilic conetworks as highly effective platforms for sustained ibuprofen delivery.

Synthesis and characterization of Zwitterionic co-polymers as matrices for sustained metoprolol tartrate delivery.

Very stable co-polymer (vinyl acetate (VA)-co-3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate (DMAPS) (p(VA-co-DMAPS)) latexes with different compositions have been synthesized by emulsifier-free emulsion co-polymerization. The dry p(VA-co-DMAPS)s have been used in the preparation of drug tablets for sustained Metoprolol tartrate release. It has been shown that the tablet swelling depends on the mol fraction of DMAPS monomer units (m(DMAPS)), pH and ionic strength (I). An original explanation, based on the swelling behavior of p(VA-co-DMAPS), has been proposed for the "overshooting" phenomenon observed. It assumes the formation of hydrophilic domains with a higher m(DMAPS) in the co-polymer tablets. The formation of dipole-dipole clusters between the DMAPS units at different m(DMAPS) and I are the main cause for the established differences in both the swelling kinetics of the p(VA-co-DMAPS) matrices and Metoprolol tartrate release. The obtained results show that for p(VA-co-DMAPS) matrices-based tablets controlled sustained Metoprolol tartrate release can be realized just by varying two parameters, co-polymer composition and I.

Verapamil hydrochloride release characteristics from new copolymer zwitterionic matrix tablets.

The aim of this study was to synthesize stable copolymer (vinyl acetate-co-3-dimethyl[methacryloyloxyethyl] ammonium propane sulfinate) zwitterionic latex with different compositions for the first time by emulsifier-free emulsion copolymerization. Throughout the course of the study, a proposal was made for the explanation of the relationship between the "overshooting" phenomenon (a swelling kinetics with a maximum) and the specific self-association of the zwitterionic copolymers. The zwitterionic monomer unit mole fraction, pH, and ionic strength effects on this relationship, on the swelling kinetics of the zwitterionic copolymers, and on the sustained verapamil hydrochloride release from the model tablets were established by the study's authors.

New co-polymer zwitterionic matrices for sustained release of verapamil hydrochloride.

Stable co-polymer [vinyl acetate-co-3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate, p(VA-co-DMAPS)] latex of different compositions has been synthesized for the first time by emulsifier-free emulsion copolymerization. The unusual >>overshooting<< behavior of the co-polymer tablets has been explained by the formation of specific clusters from the opposite oriented dipoles-zwitterionic species. The change of their concentration with the DMAPS unit fraction (mDMAPS), pH and ionic strength has been considered responsible for the differences observed in the swelling kinetics. The results obtained prove that mDMAPS and ionic strength could be used to control the swelling degree of the p(VA-co-DMAPS) matrices and their sustained drug delivery. In this way, p(VA-co-DMAPS) matrices could be effectively used to control the sustained release of drugs with basic properties like verapamil hydrochloride from model tablets.