Agar Graft Modification with Acrylic and Methacrylic Acid for the Preparation of pH-Sensitive Nanogels for 5-Fluorouracil Delivery.

Agar, a naturally occurring polysaccharide, has been modified by grafting it with acrylic (AcA) and methacrylic (McA) acid monomers, resulting in acrylic or methacrylic acid grafted polymer (AA-g-AcA or AA-g-McA) with pH-sensitive swelling behavior. Different ratios between agar, monomers, and initiator were applied. The synthesized grades of both new polymer series were characterized using FTIR spectroscopy, NMR, TGA, DSC, and XRD to ascertain the intended grafting. The percentage of grafting (% G), grafting efficiency (% GE), and % conversion (% C) were calculated, and models with optimal characteristics were further characterized. The swelling behavior of the newly synthesized polymers was studied over time and in solutions with different pH. These polymers were subsequently crosslinked with varying amounts of glutaraldehyde to obtain 5-fluorouracil-loaded nanogels. The optimal ratios of polymer, drug, and crosslinker resulted in nearly 80% loading efficiency. The performed physicochemical characterization (TEM and DLS) showed spherical nanogels with nanometer sizes (105.7-250 nm), negative zeta potentials, and narrow size distributions. According to FTIR analysis, 5-fluorouracil was physically incorporated. The swelling and release behavior of the prepared nanogels was pH-sensitive, favoring the delivery of the chemotherapeutic to tumor cells. The biocompatibility of the proposed nanocarrier was proven using an in vitro hemolysis assay.

Formulation of Budesonide-Loaded Polymeric Nanoparticles into Hydrogels for Local Therapy of Atopic Dermatitis.

Budesonide is a mineral corticoid applied in the local therapy of pediatric atopic dermatitis. Unfortunately, its dermal administration is hindered by the concomitant adverse effects and its physicochemical properties. The characteristic pH change in the atopic lesions can be utilized for the preparation of a pH-sensitive nanocarrier. In this view, the formulation of Eudragit L 100 nanoparticles as a budesonide delivery platform could provide more efficient release to the desired site, improve its penetration, and subsequently lower the undesired effects. In this study, budesonide-loaded Eudragit L100 nanoparticles were prepared via the nanoprecipitation method (mean diameter 57 nm, -31.2 mV, and approx. 90% encapsulation efficiency). Their safety was proven by cytotoxicity assays on the HaCaT keratinocyte cell line. Further, the drug-loaded nanoparticles were incorporated into two types of hydrogels based on methylcellulose or Pluronic F127. The formulated hydrogels were characterized with respect to their pH, occlusion, rheology, penetration, spreadability, and drug release. In conclusion, the developed hydrogels containing budesonide-loaded nanoparticles showed promising potential for the pediatric treatment of atopic dermatitis.

Thermosensitive Hydrogel-Functionalized Mesoporous Silica Nanoparticles for Parenteral Application of Chemotherapeutics.

Hydrogels can offer many opportunities for drug delivery strategies. They can be used on their own, or their benefits can be further exploited in combination with other nanocarriers. Intelligent hydrogels that react to changes in the surrounding environment can be utilized as gatekeepers and provide sustained on-demand drug release. In this study, a hybrid nanosystem for temperature- and pH-sensitive delivery was prepared from MCM-41 nanoparticles grafted with a newly synthesized thermosensitive hydrogel (MCM-41/AA-g-PnVCL). The initial particles were chemically modified by the attachment of carboxyl groups. Later, they were grafted with agar (AA) and vinylcaprolactam (VCL) by free radical polymerization. Doxorubicin was applied as a model hydrophilic chemotherapeutic drug. The successful formulation was confirmed by FT-IR and TGA. Transmission electron microscopy and dynamic light scattering analysis showed small particles with negative zeta potential. Their release behaviour was investigated in vitro in media with different pH and at different temperatures. Under tumour simulating conditions (40 °C and pH 4.0), doxorubicin was almost completely released within 72 h. The biocompatibility of the proposed nanoparticles was demonstrated by in vitro haemolysis assay. These results suggest the possible parenteral application of the newly prepared hydrogel-functionalized mesoporous silica nanoparticles for temperature-sensitive and pH-triggered drug delivery at the tumour site.

Doxorubicin and Quercetin Double Loading in Modified MCM-41 Lowered Cardiotoxicity in H9c2 Cardioblast Cells In Vitro.

BACKGROUND: One of the therapeutic limitations of the use of doxorubicin (DOX) as an anticancer drug is its cardiotoxicity. Its hydrophilicity also causes difficulties in achieving sustained release. The simultaneous delivery with the well-known natural antioxidant quercetin could ameliorate its cardiotoxicity. Thus, the main aim of this work is to study the potential of carboxylated and non-carboxylated mesoporous silica MCM-41 nanoparticles for double loading of the hydrophilic doxorubicin hydrochloride and hydrophobic quercetin (Q) in one nanocarrier with a modified release pattern to reduce the cardiotoxic side effects of doxorubicin in vitro. METHODS: The methods included the modification of MCM-41, single and double loading of modified and non-modified MCM-41, physicochemical characterization, in vitro release tests and kinetic study, and in vitro cell viability studies. RESULTS: Doxorubicin and quercetin were successfully double-loaded with encapsulation efficiency (EE) of 43 ± 4.1% and 37 ± 4.5%, respectively, in native MCM-41. The post-synthetic carboxylation led to 49 ± 4.3% EE (DOX) and 36 ± 4.0% (Q) and double lowering of the cardiotoxicity on H9c2 (IC50 = 5.96 µm). Sustained release profiles over 72 h were achieved. CONCLUSIONS: A successful procedure was proposed for the efficient double loading of a hydrophilic drug and a hydrophobic drug. The carboxy-modified double-loaded nanosystems demonstrate a decreased in vitro cardiotoxicity of doxorubicin and can be considered as a potential chemotherapeutic formulation.

Gel Formulations for Topical Treatment of Skin Cancer: A Review.

Skin cancer, with all its variations, is the most common type of cancer worldwide. Chemotherapy by topical application is an attractive strategy because of the ease of application and non-invasiveness. At the same time, the delivery of antineoplastic agents through the skin is difficult because of their challenging physicochemical properties (solubility, ionization, molecular weight, melting point) and the barrier function of the stratum corneum. Various approaches have been applied in order to improve drug penetration, retention, and efficacy. This systematic review aims at identifying the most commonly used techniques for topical drug delivery by means of gel-based topical formulations in skin cancer treatment. The excipients used, the preparation approaches, and the methods characterizing gels are discussed in brief. The safety aspects are also highlighted. The combinatorial formulation of nanocarrier-loaded gels is also reviewed from the perspective of improving drug delivery characteristics. Some limitations and drawbacks in the identified strategies are also outlined and considered within the future scope of topical chemotherapy.

Advantageous Combinations of Nanoencapsulated Oregano Oil with Selected Antibiotics for Skin Treatment.

The aim of the present study was to evaluate the antimicrobial activity of combinations between encapsulated oregano oil and the most commonly applied antibiotics (ciprofloxacin or gentamicin) against skin infections. In particular, chitosan-alginate nanoparticles loaded with oregano oil and the selected antibiotics were included in methylcellulose hydrogels. Consistency, spreadability, pH of the hydrogel and in vitro release rate of the oil were considered appropriate for topical application. The combination of encapsulated oil and gentamicin in the hydrogel resulted in a synergistic effect against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus strains. It was expressed in a fourfold reduction in the effective concentration of gentamicin and 98% inhibition of the bacterial metabolic activity. When ciprofloxacin was included in the combination instead of gentamicin, an additive effect with a two-fold decrease in the effective drug concentration and a 96% reduction in the bacterial metabolic activity were observed. Both combinations significantly inhibited the formation of MRSA biofilm by more than 90% when applied. In vivo application of the hydrogel containing the synergistic combination between the encapsulated oil and gentamicin did not induce irritation of the rabbit skin.

Superior proapoptotic activity of curcumin-loaded mixed block copolymer micelles with mitochondrial targeting properties.

Targeting tumor cell mitochondria is a prospective strategy for highly effective anticancer therapy. Consequently, the development of potent systems for the targeted delivery of mitochondria-acting therapeutics to mitochondria has the potential to boost this sector of nanomedicine. In this study, a functional mixed micellar system based on two co-assembled triblock copolymers, poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) bearing triphenylphosphonium ligands (PDMAEMA(TPP+)20-b-PCL70-b-PDMAEMA(TPP+)20) and poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO113-b-PCL70-b-PEO113), was assessed for the mitochondria targeted delivery of curcumin. The high proapoptotic activity of the system and the sub-cellular mechanisms of cytotoxicity were demonstrated using a chemosensitive HL-60 cell line and its resistant alternative HL-60/DOX. Next, the successful localization of nanocarriers in mitochondria was proved by fluorescence microscopy with the aid of DAPI (4',6-diamidino-2-phenylindole) as a cellular localization tracker. The in vitro experiments revealed the great potential of the functional system developed for the targeted delivery of curcumin to mitochondria, causing programmed tumor cell death.

A novel approach for fabricating nanocomposite materials by embedding stabilized core-shell micelles into polysaccharide cryogel matrix.

We report a novel approach for fabricating nanocomposite polysaccharide-based carriers for sustained delivery of poorly-water-soluble drugs by embedding stabilized core-shell micelles (SPM) possessing hydrophobic cores into super-macroporous hydroxypropyl cellulose (HPC) cryogels. Firstly, nano-sized SPM were synthesized by loading and photochemical crosslinking of pentaerythritoltetraacrylate (PETA) in poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO19PPO29PEO19) core-shell micelles. Next, HPC cryogels containing different amount of SPM were fabricated by combination of cryogenic treatment and photo-crosslinking. A crosslinking agent, N,N'-methylenebisacrylamide, was used to enhance the density of polymer network. The effect of SPM concentration on gel fraction yield, swelling degree, cryogel morphology and mechanical properties were studied. Nanocomposite cryogels were loaded with curcumin and their encapsulation efficiency and drug release profile as a function of SPM content were investigated. The cytotoxic effect of blank and curcumin loaded nanocomposite cryogels was assessed as well.

10 years EU regulation of pediatric medicines - impact on cardiovascular drug formulations.

INTRODUCTION: Child-appropriate drug formulations are mandatory for an efficient and safe drug therapy in children. Since the implementation of supportive legislations development of novel drug formulations has significantly been enforced despite the fact that children are a heterogeneous group of patients with varying needs according to age, maturation and disease. AREAS COVERED: In this review, recent advances and current strategies are evaluated how to overcome the specific hurdles in pediatric drug development. For cardiovascular diseases as an example, EMA's decisions on pediatric investigation plans (PIPs) have been evaluated. New developments with innovative platform technologies such as mini-tablets and orodispersible preparations have been identified indicating a clear shift from liquid preparations to small-sized solid (multiparticulate) or orodispersible dosage forms. Reasons for this shift of paradigm are discussed. EXPERT OPINION: Innovative platform technologies for solid drug dosage forms such as mini-tablets, orodispersible tablets or film preparations will continue to conquer the pharmaceutical market. Still, there are some major issues to be resolved, e.g. how to ensure quality of the new dosage forms and dose accuracy in flexible dosing, but the governmental incentives will continue to accelerate development of pediatric medicines and will bridge the still existing gaps in the near future.

Orodispersible drug formulations for children and elderly.

Various orodispersible drug formulations have been recently introduced into the market. Oral lyophilisates and orodispersible granules, tablets or films have enriched the therapeutic options. In particular, the paediatric and geriatric population may profit from the advantages like convenient administration, lack of swallowing, ease of use. Until now, only a few novel products made it to the market as the development and production usually is more expensive than for conventional oral drug dosage forms like tablets or capsules. The review reports the recent advances, existing and upcoming products, and the significance of formulating patient-friendly oral dosage forms. The preparation of the medicines can be performed both in pharmaceutical industry and in community pharmacies. Recent advances, e.g. drug printing technologies, may facilitate this process for community or hospital pharmacies. Still, regulatory guidelines and pharmacopoeial monographs lack appropriate methods, specifications and global harmonization to foster the development of innovative orodispersible drug dosage forms.