A comparative study of the in vitro dermal absorption of radiolabeled benzophenone through human skin.

Octocrylene is a common sun filter ingredient used to protect the skin from damaging UV rays. Benzophenone is an impurity found in formulations containing octocrylene. [14C]-Benzophenone was spiked (0.1 g/L) into 2 commercial sunscreen formulations; Neutrogena® Beach Defense Sunscreen Spray Broad Spectrum SPF 70 Aerosol, Neutrogena® Ultra Sheer Body Mist Sunscreen Broad Spectrum SPF 30 Aerosol, and an acetone vehicle. The formulations were applied (ca 2 µL/cm2) to dermatomed human skin mounted in static diffusion cells in vitro. Receptor fluid was collected up to 24 h post dose. All samples were analyzed by liquid scintillation counting. The dermal delivery of [14C]-Benzophenone was 10.02, 9.04 and 5.19% for the 3 formulations. However, the [14C]-Benzophenone mass balances were low; 81.5, 85.3 and 8.02%, respectively. A volatility test was performed replacing skin with aluminum foil for the sunscreen formulations only. The [14C]-Benzophenone mass balance at dosing was 99% but fell to 56.9 and 60.6% at 24 h post dose, confirming the losses were due to [14C]-Benzophenone volatility. A conservative dermal absorption value of 12.42% was proposed to cover [14C]-Benzophenone containing formulations.

3D printing and enteric coating of a hollow capsular device with controlled drug release characteristics prepared using extruded Eudragit® filaments.

This work focuses on the extrusion of a brittle, tacky, cationic copolymer i.e. Eudragit® E-100 to prepare filament and subsequent 3D printing of hollow capsular device using the extruded filament. An optimum amount of talc and triethyl citrate was used for the possible extrusion of the polymer. There was no thermal and chemical degradation of the polymer observed after extrusion confirmed by DSC and FTIR analysis. Microscopic analysis of the printed capsule showed the layer-by-layer manner of 3D printing. Capsule parts were printed according to the set dimensions (00 size) with minimal deviation. Printed capsule showed the soluble behaviour in gastric fluid pH 1.2 where within 15 min the encapsulated drug encounters with the dissolution medium and almost 70% drug was dissolved within 4 hr. In case of phosphate buffer pH 6.8, the printed capsule showed a longed swelling behaviour up to 12 hr and then gradually bursting of capsule occurred wherein more than 90% encapsulated drug was dissolved within 36 hr. Enteric coating of the printed capsule showed similar behaviour in alkaline medium that observed with non-enteric capsule. This indicates the potential application of this printed capsules for both gastric and intestinal specific delayed drug delivery by a single step enteric coating process.

Curing of UV prints - Assessment of possible toxicological hazard for consumers.

In an experimental setting a laboratory analysis of substances migrating from UV prints under mechanical stress into sweat and saliva simulant was performed. The influence of paper type and curing degree on UV prints was investigated. Five substances were identified at concentrations above the limit of detection in the simulants PPG-3 glyceryl triacrylate, ethoxylated trimethylolpropane triacrylate, trimethylolpropane triacrylate, 2/4-isopropylthioxanthone (ITX), and 2,4-diethylthioxanthone (DETX). Migration of the acrylates and photoinitiators into saliva and sweat simulants were increased when the UV inks were printed on uncoated paper in comparison to coated paper. With an exposure scenario considering a person to leaf through 80 pages of UV-printed paper per day while touching each page with a licked fingertip, Risk Characterisation Ratios (RCR) for oral exposure well below 1 were obtained for all five substances indicating no risk for the general population. The three acrylates are classified for skin sensitisation. The migrated amounts per skin surface area of these three were compared with the EC3 value for a hypothetical substance that could be categorised as strong sensitiser (EC3 = 0.1%). The results show that the risk of skin sensitisation even under worst case conditions can be considered as negligible.

Transdermal Drug Delivery for Hair Regrowth.

Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To this end, many efforts have been made to enhance drug penetration efficiency. This review focuses on the advancement of the transdermal drug delivery strategies for hair loss therapy reported in the last five years, especially those via nanoformulations for topical administration and microneedles for transdermal delivery. In addition, physical or chemical penetration enhancers are also introduced, which are often applied with the drug delivery systems to achieve a synergy effect.

Evaluation of pyraoxystrobin bioconcentration in zebrafish (Danio rerio) using modified QuEChERS extraction.

Pyraoxystrobin is a novel strobilurin fungicide that is widely used on many crops. The high log Kow of pyraoxystrobin implies that it tends to accumulate in aquatic organisms. This study optimized the sorbents of QuEChERS (quick, easy, cheap, effective, rugged, and safe) using 13C-labelled pyraoxystrobin as the internal standard (IS). It has been established a QuEChERS-LC-MS/MS IS method to study the bioconcentration and elimination of pyraoxystrobin in zebrafish (Danio rerio). The results indicated that the method had satisfactory linearity between 0.234 and 15 µg L-1 (R2 = 0.9996). The limits of detection (LOD) and quantification (LOQ) for pyraoxystrobin were 0.01 and 0.03 µg L-1, respectively. The LOQs of the method for water and zebrafish were 0.05 µg L-1 and 0.01 mg/kg, respectively. The mean recovery of pyraoxystrobin in zebrafish and water at fortification levels of 0.01-0.3 mg kg-1 and 0.05-1.5 µg L-1 ranged from 98.31 to 105.61% and 101.87 to 108.48%, respectively, with a % RSD (relative standard deviation) of 0.94-3.57%. The bioconcentration has been evaluated. The bioconcentration factors for pyraoxystrobin in zebrafish were 1,792 and 3,505 after exposure to 0.5 µg L-1 for 168 h and 0.05 µg L-1 for 216 h, respectively. The half-life of pyraoxystrobin in zebrafish was 9.0-9.5 d.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Cellular Uptake of Gold Nanoparticles and Their Movement in 3D Multicellular Tumor Spheroids: Effect of Molecular Weight and Grafting Density of Poly(2-hydroxyl ethyl acrylate).

It is known that the size of gold nanoparticles (GNPs) is not the only determining factor in the uptake by cells such as cancer cells. The surface functionalization plays a crucial role, in particular the nature of the ligand as well as the molecular weight and the grafting density. Here, poly(2-hydroxy ethyl) acrylate (pHEA) with molecular weights ranging from 10, 20 to 39 g mol-1 via reversible addition-fragmentation chain transfer polymerization is synthesized. These polymers are used directly to coat GNPs with sizes of 20, 40, and 70 nm as the trithiocarbonate functionality can strongly bind to the gold surface. The library of nine GNP is found to be nontoxic against lung carcinoma cells A549 and has negligible albumin protein absorption as determined by quartz crystal microbalance. Laser scanning confocal microscopy and flow cytometry reveal that GNP coated with medium length pHEA displays the highest cellular uptake while the effect of the size is not statistically significant. In contrast, multicellular tumor spheroids, which is a 3D model that simulates the tissue, enable the penetration of GNP coated with the longest pHEA chain while it also appears that smaller GNPs have now a clear advantage.

Investigations on the uptake and transformation of sunscreen ingredients in duckweed (Lemna gibba) and Cyperus alternifolius using high-performance liquid chromatography drift-tube ion-mobility quadrupole time-of-flight mass spectrometry.

The uptake, translocation and transformation of three UV-blockers commonly employed in sunscreens, namely avobenzone, octocrylene and octisalate from water by Lemna gibba and Cyperus alternifolius was investigated. Reversed phase high performance liquid chromatography coupled to drift-tube ion-mobility quadrupole time-of-flight mass spectrometry was used for analyzing the extracts from the selected plants after incubation with the UV-blockers for one week. For avobenzone several transformation products resulting from hydroxylation, demethylation and oxidation of the parent molecule could be identified by measuring accurate mass, performing MS/MS experiments and by determining their drift-tube collision cross sections employing nitrogen as drift gas. In addition, the plants were subjected to two commercially available sunscreens, providing similar results to those obtained for the standard solutions of the UV-blockers. Finally, a kinetic study on the uptake and transformation of avobenzone, octocrylene and octisalate was conducted over a period of 216 h, revealing that the UV-filters were mostly present in their parent form and only to a smaller part converted into transformation products.

Review of the safety of octocrylene used as an ultraviolet filter in cosmetics.

Octocrylene or octocrilene is an organic ultraviolet (UV) filter which absorbs mainly UVB radiation and short UVA wavelengths. It is used in various cosmetic products to either provide an appropriate sun protection factor in sunscreen products or to protect cosmetic formulations from UV radiation. There is no discussion that UV filters are beneficial ingredients in cosmetics since they protect from skin cancer, but octocrylene has been recently incriminated to potentially induce adverse effects on the endocrine system in addition to having allergic and/or photoallergic potential. However, the substance has the advantage to work synergistically with other filters allowing a beneficial broad photoprotection, e.g. it stabilizes the UVA filter avobenzone (i.e. butylmethoxydibenzoylmethane). Like all chemicals used in cosmetics, the safety profile of octocrylene is constantly under assessment by the European Chemical Agency (ECHA) since it has been registered according to the European regulation Registration, Evaluation, Authorisation and Restriction of Chemicals. Summaries of safety data of octocrylene are publicly available on the ECHA website. This review aims to present the main safety data from the ECHA website, as well as those reported in scientific articles from peer-reviewed journals. The available data show that octocrylene does not have any endocrine disruption potential. It is a rare sensitizer, photocontact allergy is more frequent and it is considered consecutive to photosensitization to ketoprofen. Based on these results, octocrylene can be considered as safe when used as a UV filter in cosmetic products at a concentration up to 10%.

Systemic availability of lipophilic organic UV filters through dermal sunscreen exposure.

BACKGROUND: Chemical UV filters are common components in sunscreens and cosmetic products and used to protect the skin against harmful effects of sunlight like sunburn. However, the effectiveness of sunscreens in the prevention of skin cancer is in some parts still controversial. Meanwhile, questions about negative effects of the chemical UV filters on human health arise and request an effective risk assessment. Real-life exposure data in humans after application of these products are still rare. Thus, we explored whether and to what extent UV filters are absorbed through the skin into the human body. MATERIAL AND METHODS: Plasma and urine samples from 20 healthy volunteers were collected before, during and after a real-life exposure scenario (1st application: 2 mg/cm2; 2nd and 3rd (after 2 and 4 h): 1 mg/cm2 each) using a commercial sunscreen formulation for one day. These samples were analyzed for their content of the currently prominent UV filters octocrylene and avobenzone as well as 2-cyano-3,3-diphenylacrylic acid (CDAA) as the main octocrylene metabolite by using different liquid chromatography electrospray-ionization tandem mass spectrometric procedures. RESULTS: Following dermal sunscreen exposure, avobenzone, octocrylene and CDAA reached concentrations up to 11 µg/L, 25 µg/L and 1352 µg/L in plasma. In urine detection rates of avobenzone and octocrylene were low while CDAA showed a high detection rate and reached up to 5207 µg/g creatinine. Kinetic models could be fitted for octocrylene and CDAA in plasma and CDAA in urine. Concentration peaks were reached between 10 and 16 h after first application and half-life periods were in the range of 1.5 to 2 days. The lipophilic UV filter octocrylene and its metabolite CDAA showed a much slower elimination than other more hydrophilic UV filters. Concordantly, the metabolite CDAA in particular showed a markedly increased renal excretion over the whole sampling period and indicated high internal exposure to OC. DISCUSSION: Real-life sunscreen usage leads to considerable bioavailability of organic UV filters and their metabolites which is rarely seen for other environmental exposures. A combined monitoring of the parent compound and its metabolites is important to fully address internal exposure to the UV filter in humans. Considering the kinetic profiles a prolonged systemic release due to depot formation in skin and a potential accumulation through multi-day exposure is presumed. High in-vivo loads call for a critical toxicological assessment of the UV filters and their metabolites.

Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment.

Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6 months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4 °C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Urinary metabolites of the UV filter octocrylene in humans as biomarkers of exposure.

Octocrylene (OC) is a UV filter used in sun screens and other personal care products, but also in polymers and food contact materials for stabilization. In this study, we investigate human OC metabolism and urinary excretion after oral dosage of approx. 5 mg OC [≙ 61.8-89.5 µg/(kg body weight)] in three male volunteers. In a screening approach, we tentatively identified six urinary OC metabolites. For three, renal elimination kinetics was quantitatively investigated using authentic standards: the sidechain oxidation product 2-ethyl-5-hydroxyhexyl 2-cyano-3,3-diphenyl acrylate (5OH-OC), the beta-oxidation product 2-(carboxymethyl)butyl 2-cyano-3,3-diphenyl acrylate (dinor OC carboxylic acid; DOCCA), and the ester hydrolysis product 2-cyano-3,3-diphenylacrylic acid (CPAA). CPAA was the major urinary metabolite, representing 45% (range 40-50%) of the OC dose. 5OH-OC and DOCCA were only minor metabolites with low, but highly consistent renal conversion factors of 0.008% (0.005-0.011%) and 0.13% (0.11-0.16%), respectively. Peak urinary metabolite concentrations were observed between 3.2 h and 4.2 h postdose. All three metabolites were excreted with biphasic elimination kinetics, with considerably longer elimination half-lives for DOCCA (1st phase: 3.0 h; 2nd phase: 16 h) and CPAA (5.7 h and 16 h) compared to 5OH-OC (1.3 h and 6.4 h). 99% of all 5OH-OC was excreted within 24 h compared to 82% of DOCCA and 77% of CPAA. After dermal exposure, we detected the same metabolites with similar ratios in urine, however, at much lower concentrations and with considerably delayed elimination.

Radiation preparation of L-arginine/acrylic acid hydrogel matrix patch for transdermal delivery of propranolol HCl in hypertensive rats.

In the present study, L-arginine/acrylic acid (Arg/AAc) batch hydrogel was successfully prepared by gamma irradiation for transdermal delivery of propranolol HCl in hypertensive rats. The resulted system has been characterized by FTIR to confirm the hydrogel formation. The swelling behavior of the prepared hydrogels was investigated as a function of time and pH. The kinetics of swelling has been investigated. In vivo pharmacokinetics evaluation, skin irritation test, and histopathological studies were investigated. Furthermore, the antihypertensive efficacy of transdermal propranolol-loaded Arg/AAc hydrogel on methyl prednisolone acetate-induced hypertensive rats was evaluated. It was found that the prepared patches exhibited a sustained release of the drug into systemic circulation over oral route which is subjected to hepatic first-pass metabolism, coupled with a short plasma half-life. Transdermal administration displayed a prolonged antihypertensive effect in spontaneously hypertensive rats. Moreover, the skin irritation test and histopathological examination indicated that the prepared patches are not irritant and can be safely applied on the skin. These results indicated that the hydrogel system composed of Arg and AAc has potential as a transdermal delivery system.

Microwave assisted synthesis of binary grafted psyllium and its utility in anticancer formulation.

A binary grafted copolymer of Psyllium mucilage (Psy) with acrylic acid (AA) and acrylonitrile (An) has been successfully synthesized under microwave conditions for in vitro drug release study. The grafting was confirmed by FTIR spectroscopy, XRD, SEM, EDX, TGA analytical techniques and the intrinsic viscosity study. The swelling behavior of grafted material has been studied in solution of different pH and time. We also prepare Psy-g-Poly (AA-co-An) based beads with anti-cancer drug [(2-Chloro-3-(4-hydroxyphenylamino) naphthalene-1, 4-dione)]. The drug release behavior of Psy-g-Poly (AA-co-An) based beads has been determined in aqueous medium at different pH. It has been observed that highest drug release at pH 1.6. The drug release kinetics was analysed using the different models. This study demonstrates that the release of drug depends on the composition of beads and pH of release medium. Kinetics of drug release from beads is best fitted by zero order and first order model.

Nose-to-brain delivery of insulin enhanced by a nanogel carrier.

Recent evidences suggest that insulin delivery to the brain can be an important pharmacological therapy for some neurodegenerative pathologies, including Alzheimer disease (AD). Due to the presence of the Blood Brain Barrier, a suitable carrier and an appropriate route of administration are required to increase the efficacy and safety of the treatment. Here, poly(N-vinyl pyrrolidone)-based nanogels (NG), synthetized by e-beam irradiation, alone and with covalently attached insulin (NG-In) were characterized for biocompatibility and brain delivery features in a mouse model. Preliminarily, the biodistribution of the "empty" nanocarrier after intraperitoneal (i.p.) injection was investigated by using a fluorescent-labeled NG. By fluorescence spectroscopy, SEM and dynamic light scattering analyses we established that urine clearance occurs in 24h. Histological liver and kidneys inspections indicated that no morphological alterations of tissues occurred and no immunological response was activated after NG injection. Furthermore, after administration of the insulin-conjugated nanogels (NG-In) through the intranasal route (i.n.) no alteration or immunogenic response of the nasal mucosa was observed, suggesting that the formulation is well tolerated in mouse. Moreover, an enhancement of NG-In delivery to the different brain areas and of its biological activity, measured as Akt activation levels, with reference to free insulin administration was demonstrated. Taken together, these results indicate that the synthesized NG-In enhances brain insulin delivery upon i.n. administration and strongly encourage its further evaluation as therapeutic agent against some neurodegenerative diseases.

Formulation and characterization of Phospholipon 90 G and tween 80 based transfersomes for transdermal delivery of eprosartan mesylate.

The objective of the current study was to formulate the eprosartan mesylate loaded transfersomes using different proportions of Phospholipon® 90 G and Tween® 80 (95-75:5-25% w/w). The prepared transfersomes were characterized for their vesicles size, shape, polydispersity index, zeta potential, entrapment efficiency, in vitro skin permeation, confocal laser scanning microscopy, and in vivo skin irritation. Results revealed that the formulated transfersomes were negatively charged, spherical unilamellar structure of 71.18-85.66 nm with entrapment efficiency of 83.00-88.19%, and presented transdermal flux of 1.78-5.02 µg/cm2/h across rat skin. Confocal laser scanning microscopy confirmed that the formulated rhodamine 6 G loaded transfersomes could penetrate deeply and uniformly into rat skin. Additionally, in vivo skin irritation studies revealed that the prepared transfersomes were devoid of any skin irritation potential (erythema and edema). Results of this study revealed that the transfersomes prepared with Tween® 80 could be used to enhance the transdermal delivery of eprosartan mesylate. In conclusion, transdermal transfersomes formulation may prove to be an encouraging drug carrier for eprosartan mesylate and other actives, particularly owing to their simple formulation and unsophisticated scale-up methods.

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease.

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1ß release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Design and evaluation of acrylate polymeric carriers for fabrication of pH-sensitive microparticles.

Colon-targeted microparticles loaded with a model anti-inflammatory drug were fabricated using especially designed acrylic acid-butyl methacrylate copolymers. Microparticles were prepared by oil-in-oil solvent evaporation method using Span 80 as emulsifier. Microparticles were found to be spherical in shape, hemocompatible and anionic with zeta potential of -27.4 and -29.0 mV. Entrapment of drug in the microparticles was confirmed by Fourier transform infrared (FTIR) spectroscopy. However, X-ray diffraction (XRD) and differential scanning calorimetry (DSC) revealed amorphous nature of microparticles due to the dilution effect of amorphous polymer. The microparticles released less than 5% drug at pH 1.2, while more than 90% of the drug load was released at pH 7.4. This suggested the colon targeting nature of the formulations. In experimentally developed colitis in Wistar rats, the microparticle formulation showed significant reduction (p < .05) in the disease activity score (disease symptoms), the colon-to-body weight ratio (tissue edema) and the myeloperoxidase, tumor necrosis factor (TNF)-α and interleukin (IL)-1ß activities.