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Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis., Competing Interests: Declarations Ethics approval and consent to participate The animal experiments were approved by the Ethics Committee for Experimental Use of Animals of the Shanghai Jiao Tong University School of Medicine (approval code: #SYXK-2013-0050). Consent for publication All authors agree for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The aim of this study was to investigate the impact of using microneedle patches in addition to topical therapy for the treatment of psoriasis. Using continuous liquid interface production (CLIP) 3D printing we manufactured round microneedle array patches (MAPs) with a diameter of 14 mm. Needle geometries were varied from square pyramidal, conical, and obelisk, with varied needle lengths of 400 µm, 600 µm, 800 µm, or 1000 µm. MAPs were characterized for force to fracture, skin penetration, skin damage, as well as their ability to deliver a novel oleogel-based corticosteroid (betamethasone dipropionate (BDP) formulation into ex-vivo porcine skin. We found that the obelisk shaped MAPs are more durable compared to the conical and square pyramidal-shaped MAPs. When the obelisk shaped MAPs were used in combination with the oleogel-based BDP formulation, the amount of BDP penetrating the skin was significantly increased with greater needle lengths., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The aim of this work was the development of a film-forming formulation (FFF) for the topical treatment of psoriasis that shows an increased substantivity compared to conventional semi-solid dosage forms. The developed formulation is an oleogel. It is based on a combination of castor oil and medium chain triglycerides, and the oil-soluble film former MP-30 (Croda GmbH, Nettetal, Germany), a polyamide that upon mixing with a polar oil entraps the oil und thus substantially increases the viscosity of the formulation up to a semisolid state. Betamethasone dipropionate (BDP) and calcipotriole (CA) were used as active pharmaceutical ingredients (APIs). Oleogels of different compositions were evaluated regarding substantivity, rheological properties, ex-vivo penetration into the skin and ex-vivo permeation through the skin. Marketed products were used as controls. It was found that the amount of betamethasone dipropionate penetrating and permeating into and through the skin from the film-forming formulation is at an intermediate value compared to the marketed products. The substantivity of the developed formulation is described by an amount of 57.7 % formulation that remains on the skin surface and is thus significantly higher compared to the marketed products. In the film forming formulation, the proportion of API penetrating the skin remains the same when the skin repetitively brought in contact with a piece of textile during the penetration experiment. In contrast with the in-market formulations tested, this proportion was reduced by up to 97 %. As a result, the developed formulations can lead to an increased patient compliance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Membrane permeability plays an important role in oral drug absorption. Caco-2 and Madin-Darby Canine Kidney (MDCK) cell culture systems have been widely used for assessing intestinal permeability. Since most drugs are absorbed passively, Parallel Artificial Membrane Permeability Assay (PAMPA) has gained popularity as a low-cost and high-throughput method in early drug discovery when compared to high-cost, labor intensive cell-based assays. At the National Center for Advancing Translational Sciences (NCATS), PAMPA pH 5 is employed as one of the Tier I absorption, distribution, metabolism, and elimination (ADME) assays. In this study, we have developed a quantitative structure activity relationship (QSAR) model using our ∼6500 compound PAMPA pH 5 permeability dataset. Along with ensemble decision tree-based methods such as Random Forest and eXtreme Gradient Boosting, we employed deep neural network and a graph convolutional neural network to model PAMPA pH 5 permeability. The classification models trained on a balanced training set provided accuracies ranging from 71% to 78% on the external set. Of the four classifiers, the graph convolutional neural network that directly operates on molecular graphs offered the best classification performance. Additionally, an ∼85% correlation was obtained between PAMPA pH 5 permeability and in vivo oral bioavailability in mice and rats. These results suggest that data from this assay (experimental or predicted) can be used to rank-order compounds for preclinical in vivo testing with a high degree of confidence, reducing cost and attrition as well as accelerating the drug discovery process. Additionally, experimental data for 486 compounds (PubChem AID: 1645871) and the best models have been made publicly available (https://opendata.ncats.nih.gov/adme/)., (Published by Elsevier Ltd.)

We have previously developed a maternal-fetal physiologically-based pharmacokinetic (m-f PBPK) model to dynamically predict (and verify) fetal-maternal exposure to drugs that passively diffuse across the placenta. Here, we extended the application of this model to dynamically predict fetal exposure to drugs which are effluxed by placental P-glycoprotein, namely the antenatal corticosteroids (ACS; dexamethasone [DEX], and betamethasone [BET]). To do so, we estimated both the placental P-gp mediated efflux clearance (CL) and the passive diffusion CL of the ACS. The efficacy and toxicity of the currently used maternal ACS dosing regimens to prevent neonatal respiratory distress syndrome could be improved by altering their dosing regimens. Therefore, to illustrate the utility of our m-f PBPK model, we used it to design alternative dosing regimens of DEX and BET that could potentially improve their efficacy and reduce their toxicity. The redesigned dosing regimens are convenient to administer, maintain maternal-fetal exposure (area under the concentration-time curve [AUC]) or maximum plasma concentration (C max ) or both (DEX and BET) or minimize maternal exposure while maintaining fetal drug plasma concentrations above the minimum therapeutic threshold of 1 ng/ml for 48 h (BET only; based on efficacy data in sheep). To our knowledge, this is the first study to dynamically predict fetal plasma concentrations of placental P-gp effluxed drugs. Our approach and our m-f PBPK model could be used in the future to predict maternal-fetal exposure to any drug and to design alternative dosing regimens of the drug., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Posterior eye diseases are a common cause of vision problems in developing countries, which have encouraged the development of new treatment models for these degenerative diseases. Intraocular implants are one of the drug delivery systems to the posterior region of the eye. Using these implants, the blood-eye barrier can be bypassed; the complications caused by repeated in vitro administrations can be eliminated, and smaller amounts of the drug would be used during the treatment process. Meanwhile, biodegradable implants have received more attention due to their biodegradable structure and the lack of need for re-surgery to remove the rest of the system from the eye. The aim of this study is to employ biodegradable implants composed of polyethylene glycol (PEG) and 3-hydroxybutyrate-co-3-hydroxyvalerat (PHBV) to deliver betamethasone to the back of the eye in the treatment of retinopathy. PHBV polymer has been selected as the main polymer with a certain ratio of drug to polymer for fabrication of enamel and different amounts of PEG with three molecular weights used as pore generators to control drug release over a period of time. Based on the analysis of the results of differential scanning calorimetry (DSC) and FTIR spectroscopy, none of the polymers were degraded in the temperature range of the manufacturing process, and among betamethasone derivatives, the best option for implant preparation is the use of its basic form. Drug release studies over a period of three months showed that implants containing PHBV HV2% and PEG 6000 had a more appropriate release profile.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC 50 /SC 50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC 50 ), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/F IM of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.

Despite antenatal corticosteroids therapy, respiratory distress syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date, the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women > 27 weeks' gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood, and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood, and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70 kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median (95% confidence interval (CI)) transplacental transfer of betamethasone was estimated to 35% (95% CI 0.11-0.67). After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e., < 1 ng/mL): odds ratio of 1.10 (95% CI 1.01-1.19) per day increase (P < 0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease without effective treatment. The utilization of all trans-retinoic acid (TRA) and betamethasone (BT) for the treatment of psoriasis is still facing difficulties, due to their relatively poor stability, limited skin permeation, and systemic side effects. Flexible liposomes are excellent in deeper skin permeation and reducing the side effects of drugs, which is promising for effective treatment of skin disorders. This work aimed to establish dual-loaded flexible liposomal gel for enhanced therapeutic efficiency of psoriasis based on TRA and BT., Results: Flexible liposomes co-loaded with TRA and BT were successfully prepared in our study. The characterization examination revealed that flexible liposomes featured nano-sized particles (around 70 nm), high drug encapsulation efficiency (> 98%) and sustained drug release behaviors. Flexible liposomes remarkably increased the drug skin permeation and retention as compared with free drugs. Results on HaCaT cells suggested that flexible liposomes were nontoxic, and its cellular uptake has a time-dependent manner. In vivo studies suggested the topical application of TRA and BT dual-loaded liposomal gel had the best ability to reduce the thickness of epidermal and the level of cytokines (TNF-α and IL-6), largely alleviating the symptoms of psoriasis., Conclusions: Flexible liposomal gel dual-loaded with TRA and BT exerted a synergistic effect, which is a promising topical therapeutic for the treatment of psoriasis.

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE 2 ) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE 2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log 10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model., Methods: We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS., Results: Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability., Conclusion: Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses., Competing Interests: The authors have declared that no competing interests exist.

In our study, a method for the determination for tazarotene and betamethasone dipropionate in human tissue-engineered skin was established. Tazarotene gel, betamethasone dipropionate cream or a combination cream was administered to the skin. Then the skin was taken off at 0.25, 0.75, 1.75, 3, 5, 8, 12, 24, 36, 48 h time points after the residual drug was removed. The concentrations of tazarotene, betamethasone dipropionate and their major metabolites in skin were determined by LC-MS. Tazarotene and tazarotenic acid were detected in the concentration range of 2-200 μg/mL with an LLOQ of 2 μg/mL. Betamethasone dipropionate was detected in the concentration range 0.5-300 μg/mL with an LLOQ of 0.5 μg/mL, and betamethasone was detected at 2-200 μg/mL with an LLOQ of 2 μg/mL. The intra- and inter-day precisions of the four analytes in the skin homogenate were all <15% (RSD, %). The results showed that tazarotene could be metabolized to tazarotenic acid and betamethasone dipropionate could be metabolized to betamethasone in tissue-engineered skin. The results also revealed that this method was suitable for the simultaneous determination of tazarotene, betamethasone dipropionate and their metabolites in tissue-engineered skin., (© 2019 John Wiley & Sons, Ltd.)

Betamethasone and dexamethasone are the most widely studied antenatal corticosteroids (ACS) administered to pregnant women, just prior to the birth of a preterm neonate, to accelerate fetal lung maturation. Although betamethasone, predominantly used in developed countries, has been shown to be an effective and safe intervention for reducing neonatal mortality, the choice of ACS and optimal dosing in low and middle income countries (LMICs) remains unclear. This is primarily because the exposure-response relationships have not been established for ACS despite the long history of use. As the first step toward the optimal use of ACS in LMICs, we developed physiologically-based pharmacokinetic (PBPK) models to describe the kinetics of ACS following i.v., p.o., or i.m. dosing. In vitro data describing the cytochrome P450 3A4 enzyme contribution were incorporated and this was refined using clinical data. The models can be applied prospectively to predict kinetics of ACS in pregnant women receiving various dosing regimens., (© 2019 Certara USA, Inc.Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Conventional dosage form like eye drops showed poor therapeutic response and also require frequent dosing. Therefore, developing the dosage form to deliver the drug to the target site without much loss of drug or without causing any systemic side effects is the challenging job for the researchers in pharmaceutical industries., Objective: The main aim of the present work was to formulate and evaluate hydrogel-based drug delivery containing combination of neomycin sulphate and betamethasone sodium phosphate in order to provide prolonged release and also better bioavailability of drugs for the treatment of eye infections., Methods: In this study, poloxamer 407 and chitosan at different concentrations were used as the gelling agents. The prepared formulations were evaluated for clarity, pH, drug content, gelling capacity, gelling temperature and in vitro drug release study., Results: From the preliminary studies, F5 formulation was selected as an optimized formulation. The optimized formulation was further evaluated for ex vivo permeation study, sterility test, HET-CAM and ocular irritation testing using rabbits. Ocular irritation by HET-CAM assay showed that the formulated gel does not cause any irritation to the blood vessels. Draize irritation test was performed using rabbits and results showed that formulation was non-irritant to the eye., Conclusion: The formulated hydrogel formulation can be used as an alternative to conventional ophthalmic eye drop formulation of drugs neomycin and betamethasone for the purpose of providing prolonged therapy for the treatment of conjunctivitis.

Background/purpose: Stimuli from the oral cavity may penetrate through exposed dentinal tubules and evoke inflammatory pulp response. Anti-bacterial and anti-inflammatory drugs applied to exposed dentin may infiltrate through the dentinal tubules and cause pulp recovery. This study investigated the dentin permeability of anti-bacterial and anti-inflammation drugs via an in-vitro transwell dentin disc tube model., Methods: Twenty-seven dentin discs prepared from extracted human molars were collected. Nine kinds of drugs were investigated with three dentin discs in each group. These nine drugs included two anti-bacterial drugs (ampicillin sodium and clindamycin phosphate), two corticosteroids (betamethasone sodium phosphate and hydrocortisone sodium succinate), three non-steroidal anti-inflammatory drugs (NSAIDs, piroxicam, lysine acetylsalicylate, and diclofenac sodium), and two natural extracts with anti-inflammatory effect (Ginsenoside Rg1 and Hinokitol). The drugs were introduced to the transwell dentin disc tube model and the 4-hour cumulative release of the drug was detected and recorded by UV-visible spectroscopy., Results: We found that ampicilin sodium had better dentin permeability than clindamycin phosphate. Betamethasone sodium phosphate revealed better dentin permeability than hydrocortisone sodium succinate. Lysine acetylsalicylate showed the best dentin permeability among the three NSAIDs. Ginsenoside Rg1 had the best dentin permeability among the nine drugs tested. However, Hinokitiol could not penetrate the dentin disc after 4 h., Conclusion: Regarding the dentin permeability, Ginsenoside Rg1 is the best among the seven anti-inflammatory drugs tested and ampicilin sodium is the better one between the two anti-bacterial drugs tested. Therefore, these two drugs may have high potential for treating exposed dentinal tubule diseases., (Copyright © 2018. Published by Elsevier B.V.)

Treatment of inflammatory disorders with glucocorticoids (GCs) is often accompanied by severe adverse effects. Application of GCs via nanoparticles (NPs), especially those using simple formulations, could possibly improve their delivery to sites of inflammation and therefore their efficacy, minimising the required dose and thus reducing side effects. Here, we present the evaluation of NPs composed of GC betamethasone phosphate (BMP) and the fluorescent dye DY-647 (BMP-IOH-NPs) for improved treatment of inflammation with simultaneous in vivo monitoring of NP delivery. Methods: BMP-IOH-NP uptake by MH-S macrophages was analysed by fluorescence and electron microscopy. Lipopolysaccharide (LPS)-stimulated cells were treated for 48 h with BMP-IOH-NPs (1×10 -5 -1×10 -9 M), BMP or dexamethasone (Dexa). Drug efficacy was assessed by measurement of interleukin 6. Mice with Zymosan-A-induced paw inflammation were intraperitoneally treated with BMP-IOH-NPs (10 mg/kg) and mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI) were treated intranasally with BMP-IOH-NPs, BMP or Dexa (each 2.5 mg/kg). Efficacy was assessed in vivo by paw volume measurements with µCT and ex vivo by measurement of paw weight for Zymosan-A-treated mice, or in the AAI model by in vivo x-ray-based lung function assessment and by cell counts in the bronchoalveolar lavage (BAL) fluid and histology. Delivery of BMP-IOH-NPs to the lungs of AAI mice was monitored by in vivo optical imaging and by fluorescence microscopy. Results: Uptake of BMP-IOH-NPs by MH-S cells was observed during the first 10 min of incubation, with the NP load increasing over time. The anti-inflammatory effect of BMP-IOH-NPs in vitro was dose dependent and higher than that of Dexa or free BMP, confirming efficient release of the drug. In vivo , Zymosan-A-induced paw inflammation was significantly reduced in mice treated with BMP-IOH-NPs. AAI mice that received BMP-IOH-NPs or Dexa but not BMP revealed significantly decreased eosinophil numbers in BALs and reduced immune cell infiltration in lungs. Correspondingly, lung function parameters, which were strongly affected in non-treated AAI mice, were unaffected in AAI mice treated with BMP-IOH-NPs and resembled those of healthy animals. Accumulation of BMP-IOH-NPs within the lungs of AAI mice was detectable by optical imaging for at least 4 h in vivo , where they were preferentially taken up by peribronchial and alveolar M2 macrophages. Conclusion: Our results show that BMP-IOH-NPs can effectively be applied in therapy of inflammatory diseases with at least equal efficacy as the gold standard Dexa, while their delivery can be simultaneously tracked in vivo by fluorescence imaging. BMP-IOH-NPs thus have the potential to reach clinical applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The fixed-combination of Cal/BD aerosol foam is now entering the Italian market. This drug was developed with a technology that allows an enhanced penetration of the active ingredients into the skin. This enhanced penetration improves local bioavailability and, consequently, Cal/BD aerosol foam therapy is associated with improved clinical outcomes if compared with other products with the same components. The efficacy and safety of Cal/BD aerosol foam were confirmed both in clinical trials and in "field-practice" studies. This short review discusses current evidence on the Cal/BD aerosol foam combination; some preliminary data collected in the Italian clinical practice will be also presented.

Corticoids are actives widely used in the treatment of skin diseases. This work aims to study the penetration of 3 corticoids (betamethasone, clobetasol, and flurandrenolide), their relationship with their Log D values and the effects of the vehicles. The 3 compounds were applied on a Franz-type diffusion cell in propylene glycol solution and their respective commercial creams and ointments. The active amounts found in the stratum corneum, epidermal, and dermal layers of the skin were investigated. Their diffusions were greatly affected by the formulation; moreover higher amounts of substance in the epidermis and dermis were detected in ointments than in creams. The enhancement effect of propylene glycol was also observed. The differences between the 3 substances could be related to their lipophilicity, molecular structure, and molecular weight. The more hydrophobic compounds (clobetasol and betamethasone) are present in higher amounts in the epidermis and dermis, while the hydrophilic compound (flurandrenolide) is mostly present in the receptor fluid., (Copyright © 2018 John Wiley & Sons, Ltd.)

Psoriasis is a chronic-relapsing skin disorder which requires long-term treatments. Therapeutic options for psoriasis include topical treatments, phototherapy and systemic therapy. However, those treatments, and particularly the topical drug therapies, may present some limitations, including poor efficacy/tolerability ratio and lack of adherence. Recently, the supersaturated aerosol foam formulation of the fixed combination calcipotriene plus betamethasone dipropionate (Cal/BD) has gained major attention because it overcomes some of the limitations associated with other topical treatments. This fixed-combination has increased efficacy compared with its individual components. Moreover, the alcohol-free aerosol foam formulation allows a higher penetration of the active ingredients into the skin, resulting in enhanced bioavailability and, consequently, in better clinical outcomes than other products with the same components. Given the short duration of therapy course and the fast onset of action, a reduced amount of Cal/BD foam formulation would be required for the treatment of psoriasis patients, resulting also in cost saving. Therefore this novel formulation could represent an alternative to other topical agents and a first-line therapy in the treatment of mild and mild-to-moderate psoriasis.

OBJECTIVE To determine the pharmacokinetics of florfenicol, terbinafine, and betamethasone acetate after topical application to canine auricular skin and the influence of synthetic canine cerumen on pharmacokinetics. SAMPLE Auricular skin from 6 euthanized shelter dogs (3 females and 3 neutered males with no visible signs of otitis externa). PROCEDURES Skin adjacent to the external opening of the ear canal was collected and prepared for use in a 2-compartment flow-through diffusion cell system to evaluate penetration of an otic gel containing florfenicol, terbinafine, and betamethasone acetate over a 24-hour period. Radiolabeled 14 C-terbinafine hydrochloride and 3 H-betamethasone acetate were added to the gel to determine dermal penetration and distribution. Florfenicol absorption was determined by use of high-performance liquid chromatography-UV detection. Additionally, the effect of synthetic canine cerumen on the pharmacokinetics of all compounds was evaluated. RESULTS During the 24-hour experiment, mean ± SD percentage absorption without the presence of synthetic canine cerumen was 0.28 ± 0.09% for 3H-betamethasone acetate, 0.06 ± 0.06% for florfenicol, and 0.06 ± 0.02% for 14C-terbinafine hydrochloride. Absorption profiles revealed no impact of synthetic canine cerumen on skin absorption for all 3 active compounds in the gel or on skin distribution of 3 H-betamethasone acetate and 14 C-terbinafine hydrochloride. CONCLUSIONS AND CLINICAL RELEVANCE 3 H-betamethasone acetate, 14 C-terbinafine hydrochloride, and florfenicol were all absorbed in vitro through healthy auricular skin specimens within the first 24 hours after topical application. Synthetic canine cerumen had no impact on dermal absorption in vitro, but it may serve as a temporary reservoir that prolongs the release of topical drugs.

Quantitative evaluation and assessment of pharmacokinetic parameters of Diprospan ® (suspension for injection 7mg/mL (2mg+5mg/mL) of betamethasone) were performed in urine samples taken from patients with rheumatoid arthritis or ankylosing spondylitis for 28days after systemic intramuscular administration in routine clinical practice in an open-comparative prospective cohort study. The maximum betamethasone concentration was reached at day 4 of the follow-up; in some cases, β-phase of elimination of the drug was appeared at day 14 or at day 21 of the follow-up. The deferred β-phase elimination was likely a consequence of the physiological characteristics of the patients or of the influence of non-steroidal agents. The half-life of betamethasone was 8.5days. The elimination rate constant was 2.49h-1; the mean clearance was 4.72L/d. The recommended frequency of the drug administration to its complete elimination was estimated up to 48days. Mann-Whitney test showed no significant differences in pharmacokinetic characteristics between male and female subjects. The prolonged elimination phase was observed in patients with deviations in their body mass index, continual treatment by diclofenac and nimesulide or, possibly, after consuming an alcohol. The study was recorded in Clinical Trials open source with identifier NCT03119454., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure., Objective: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep., Study Design: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours., Results: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg., Conclusion: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The use of corticosteroids, such as betamethasone, in performance horses is tightly regulated. The objective of the current study was to describe the plasma pharmacokinetics of betamethasone as well as time-related urine and synovial fluid concentrations following intra-articular administration to horses. Twelve racing-fit adult Thoroughbred horses received a single intra-articular administration (9 mg) of a betamethasone sodium phosphate and betamethasone acetate injectable suspension into the right antebrachiocarpal joint. Blood, urine, and synovial fluid samples were collected prior to and at various times up to 21 days post drug administration. All samples were analyzed using tandem liquid chromatography-mass spectrometry. Plasma data were analyzed using compartmental pharmacokinetic modeling. Maximum measured plasma betamethasone concentrations were 3.97 ± 0.23 ng/mL at 1.45 ± 0.20 h. The plasma elimination half-life was 7.48 ± 0.39 h. Betamethasone concentrations were below the limit of detection in all horses by 96 h and 7 days in plasma and urine, respectively. Betamethasone fell below the limit of detection in the right antebrachiocarpal joint between 14 and 21 days. Results of this study provide information that can be used to regulate the use of intra-articular betamethasone in the horse. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Meibomian glands are modified sebaceous glands embedded within specific types of dense connective tissues. This study investigated drug penetration into meibomian glands following a single topical administration in rabbits. We measured time course concentrations of the selective glucocorticoid receptor agonist (SEGRA) SA22465 and betamethasone in lid margins, palpebral conjunctival epithelium, and meibomian glands following a single instillation using a newly established collection method. We also visualized the distribution of 14 C-SA22465 in eyelid tissue sections using microautoradiography. Concentrations of SA22465 and its major metabolite SA22313 were highest in lid margins, followed by palpebral conjunctival epithelium and meibomian glands in a 100-fold descending order. Betamethasone exhibited similar distribution profiles with smaller concentration differences. The distribution of silver grains as a quantitative index of radioactivity in eyes and eyelids was determined in a subjective manner using microautoradiographs, which revealed that the highest distribution of silver grains was associated with the cornea, followed by posterior segment tissues, such as the sclera, choroid, and retina. Low levels were associated with more internal ocular tissues and a greater number of compartments. Moderate levels of radioactivity were associated with meibomian glands and connective tissues, including the nictitating membrane. In contrast, meibomian ducts contained only background levels of radioactivity. Our findings indicate that the transconjunctiva is the most likely route of drug entry into meibomian glands following ocular administration rather than the central meibomian duct; however, this distribution is limited. A physiologic barrier may restrict drug penetration across the tarsal plate., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Antenatal corticosteroid (CS) therapy improves both fetal lung mechanism and gas exchange due to accelerated morphologic development of type one and two pneumocytes. This therapy also enhances the production of surfactant binding proteins and fetal lung antioxidant enzymes. In women with threatening preterm delivery, a single course is advocated between 24 and 34 weeks' gestation with either betamethasone (two doses of 12 mg 24 h apart) or dexamethasone (four doses of 6 mg at 12-h intervals). Such treatment reduces the rate of respiratory distress syndrome, comorbidity, and mortality in neonates in the first 48 h of life. The optimal time interval between CS administration and delivery is reported to be 1-7 days. Weekly repeat courses reduce the occurrences and severity of respiratory diseases but are associated with reduce fetal growth. Multiple courses should be avoided. However, a repeat course should be considered in women at risk of preterm birth 7 or more days after an initial course in women who remain at risk of preterm birth <34 weeks' gestation. CS may be harmful in growth restricted fetuses associated with an absent or reversed end-diastolic UA flow since they are at increased risk of acidosis and perinatal death. The purpose of this publication is to update and highlight antenatal CS therapy.

Objective: To analyze the effect of maternal betamethasone given for fetal lung maturation on fetal short-term variation (STV) and average acceleration and deceleration capacity (AAC/ADC). Both of these factors are calculated by phase-rectified signal averaging (PRSA) and represent new parameters to assess the fetal autonomic nervous system., Study Design: A longitudinal prospective study including 26 pregnant women at risk for preterm delivery was performed. Two injections of 12mg betamethasone were administered intramuscularly at a 24h interval for lung maturation. Cardiotocography recordings were performed at defined time intervals: day 0 (before the first injection) and days 1, 2, 4 after the first corticosteroid administration. AAC/ADC and STV were calculated., Results: An increase of all parameters (STV, AAC and ADC) was documented between day 0 and day 1. Between day 1 and day 2, all three indices were significantly reduced (p<0.05). STV declined by 19.8%, AAC by 10.1% and ADC by 14.8%. A normalization of these values was seen after 96h., Conclusion: Similar to STV, AAC/ADC shows significant changes after maternal betamethasone administration. The corticosteroid-induced transient decrease of the levels needs to be taken into account in the assessment of the fetal status to avoid misinterpretation of these parameters., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Antenatal steroids are standard of care for cases of anticipated preterm labor to improve neonatal outcomes. However, steroids are potent drugs, and their use in pregnancy remains largely unoptimized., Objective: The objective of the study was to measure the maternofetal pharmacokinetics of constant, low-dose intravenous betamethasone phosphate infusions and correlate these data with the transcriptional effect exerted by subclinical betamethasone exposures on the ovine fetal lung., Study Design: Thirty-two ewes carrying a single fetus had surgery to catheterize fetal and maternal jugular veins at 116 days of gestation (term, 150 days). Animals were recovered for 2 days and then were randomized to receive 2 sequential maternal intravenous infusions of either (n = 4/group) of the following: 1) saline, 0.125, 0.04, or 0.0125 mg/kg betamethasone phosphate over 3 hours; or 2) saline, 0.25, 0.08, or 0.025 mg/kg betamethasone phosphate over 12 hours. Each infusion was separated by 2 days. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction and an ovine-specific microarray. Plasma betamethasone levels from time-course catheter samples were determined by mass spectrometry. Data were assessed for distribution, variance, and tested by an analysis of variance., Results: Betamethasone was detectable (>1 ng/mL) in fetal plasma only in animals randomized to 0.125 mg/kg 3 hour or 0.250 mg/kg 12 hour infusions. Fetal betamethasone half-lives were 1.7-2.8 times greater than maternal values. At maximum concentration, fetal plasma betamethasone levels were approximately 10% of maternal levels. Compared with saline control, all animals, other than those receiving 0.0125 mg/kg 3 hour betamethasone phosphate infusions, had evidence of dose-dependent glucocorticoid transcriptional responses in the fetal lung., Conclusion: Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The association between maternal serum concentration of betamethasone given for fetal lung maturity and perinatal outcome has not been investigated. This may be due to an absence of a reliable method for measuring serum betamethasone concentrations. We aimed in the current study to assess the feasibility of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements after a course of betamethasone for fetal lung maturity., Methods: Pregnant women at risk for preterm birth who received betamethasone between 24 and 34 weeks of gestation were prospectively included. Serum concentrations were determined before administering betamethasone (baseline), and 36 hours, 48 hours, 72 hours, and 5 to 7 days after the 1(st) dose. Betamethasone concentration in samples was determined using Corticosteroid ELISA kit. The Friedman test was used to test whether there were significant differences between the measurements., Results: Five singleton pregnancies were included. Using the ELISA kit, betamethasone concentration in maternal serum samples was obtained for all women. Among the five measurements performed, the concentration was highest at 36 hours after the 1(st) dose and close to baseline at the 5(th) measurement performed after 5 to 7 days (p < 0.05). Serum concentration varied at each time point between the five women but similar trend was observed., Conclusion: Betamethasone concentration is measurable in the serum of pregnant women with this ELISA kit.

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra-articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration-time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non-compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater Tmax (Tmax 0.8 h) vs. urine (Tmax 7.1 h). Urine BTM concentration (ng/mL) and amount (AUClast ; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (Tlast ; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC-MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine., (© 2015 John Wiley & Sons Ltd.)

Mesoporous silica nanoparticles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane (APTES), and their performance as a carrier for drug delivery system was studied. Chemical structure and morphology of the synthesized and modified SBA-15 were characterized by SEM, BET, TEM, FT-IR and CHN technique. Betamethasone Sodium Phosphate (BSP) as a water soluble drug was loaded on the mesoporous silica particle for the first time. The response surface method was employed to obtain the optimum conditions for the drug/silica nanoparticle preparation, by using Design-Expert software. The effect of time, pH of preparative media, and drug/silica ratio on the drug loading efficiency was investigated by the software. The maximum loading (33.69%) was achieved under optimized condition (pH: 1.8, time: 3.54 (h) and drug/silica ratio: 1.7). The in vitro release behavior of drug loaded particles under various pH values was evaluated. Finally, the release kinetic of the drug was investigated using the Higuchi and Korsmeyer-Peppas models. Cell culture and cytotoxicity assays revealed the synthesized product doesn't have any cytotoxicity against human bladder cell line 5637. Accordingly, the produced drug-loaded nanostructures can be applied via different routes, such as implantation and topical or oral administration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Topical glucocorticosteroids were incorporated into nanocarrier-based formulations, to overcome side effects of conventional formulations and to achieve maximum skin deposition. Nanoparticulate carriers have the potential to prolong the anti-inflammatory effect and provide higher local concentration of drugs, offering a better solution for treating dermatological conditions and improving patient compliance. Nanoparticles were formulated with poly-ϵ-caprolactone as the polymeric core along with stearic acid as the fatty acid, for incorporation of betamethasone-21-acetate. Oleic acid was applied as the coating fatty acid. Improvement of the drug efficacy, and reduction in drug degradation with time in the encapsulated form was examined, while administering it locally through controlled release. Nanoparticles were spherical with mean size of 300 nm and negatively charged surface. Encapsulation efficiency was 90%. Physicochemical stability in aqueous media of the empty and loaded nanoparticles was evaluated for six months. Drug degradation was reduced compared to free drug, after encapsulation into nanoparticles, avoiding the potency decline and promoting a controlled drug release over one month. Fourier transform infrared spectroscopy and thermal analysis confirmed drug entrapment, while cytotoxicity studies performed in vitro on human keratinocytes, Saccharomyces cerevisiae models and Artemia salina, showed a dose-response relationship for nanoparticles and free drug. In all models, drug loaded nanoparticles had a greater inhibitory effect. Nanoparticles increased drug permeation into lipid membranes in vitro. Preliminary safety and permeation studies conducted on rats, showed betamethasone-21-acetate in serum after 48 h application of a gel containing nanoparticles. No skin reactions were observed. In conclusion, the developed nanoparticles may be applied as topical treatment, after encapsulation of betamethasone-21-acetate, as nanoparticles promote prolonged drug release, increase drug stability in aqueous media, reducing drug degradation, and increase drug permeability through lipid membranes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A specific, fast and sensitive LC-MS/MS assay was developed for the determination of finasteride in human plasma using betamethsone dipropionate as the internal standard (IS). The limit of quantification was 1.0 ng/ml and the method was linear in the range of 1.0-25.0 ng/ml. The retention times were 0.75 min for finasteride and 0.85 min for IS. Method intra-batch precision and accuracy ranged from 3.6 to 7.1%, and 96.6 to 103.9%, respectively. Inter-batch precision ranged from 2.5 to 3.4%, while Inter-batch accuracy ranged from 100.3 to 103.5%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of 2 different pharmaceutical formulations containing 1.0 mg of finasteride. This study evaluated 38 volunteers in a randomized, 2-period crossover study with 7 days washout period between doses. The geometric mean and respective 90% CI of finasteride test/reference percent ratios were 95.68% (91.2 - 104.6%) for Cmax, 97.5% (92.1-103.3%) for AUC0-t and 98.1 (92.67-103.8) for AUC0-inf. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of finasteride., (© Georg Thieme Verlag KG Stuttgart · New York.)

What Is Known and Objective: To treat preterm labour, antenatal corticosteroids and tocolytics are often co-administered. OBE001 is an orally active oxytocin receptor antagonist under development for preterm labour treatment., Methods: Co-administration of OBE001 and betamethasone to determine pharmacokinetic interactions was studied during an open-label, randomized, three-period crossover study. Twelve healthy post-menopausal volunteers received either two consecutive OBE001 administrations of 600 mg/day, two intramuscular injections of 12 mg/day betamethasone or the two drugs administered in combination. The area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) and the time to Cmax (tmax) for OBE001 and betamethasone were measured., Results and Discussion: There was no effect on geometric mean Cmax after the second administration and AUCs of OBE001 [geometric mean ratio point estimate (90% CI): Cmax (Day2) 1·05 (0·98-1·12) and AUC(0-24 h )1·11 (0·99-1·23)/AUC(24 h-∞) 0·99 (0·93-1·06), respectively]; Cmax after the first administration together with betamethasone was increased by 12% [geometric mean ratio point estimates (90% CI): Cmax (Day1) 1·12 (0·96-1·32)]. Tmax after concomitant administration with betamethasone occurred with a median delay of 1 h. Geometric mean Cmax and AUCs of betamethasone were not affected by concomitant OBE001 administration [geometric mean ratio point estimate (90% CI): Cmax (Day1) 1·02 (0·98-1·07)/Cmax (Day2) 1·03 (0·98-1·08) and AUC(0-24 h) 1·07 (1·04-1·11)/AUC(24 h-∞ )1·04 (1·01-1·08), respectively], with no effect on median tmax . No subject was discontinued from the study due to adverse events., What Is New and Conclusion: AUC and Cmax of the betamethasone and OBE001 combination did not differ significantly between treatments. Co-administration of OBE001 and betamethasone was well tolerated and resulted in a tmax median delay of 1 h for OBE001 but not for betamethasone. Co-administration of OBE001 and betamethasone in clinics is feasible and does not require any specific precaution or administration adaptation., (© 2015 John Wiley & Sons Ltd.)

1. The present study was designed to investigate drug-drug interaction in a new combination cream which contains both tazarotene (TZRT) and betamethasone dipropionate (BTMSDP) by comparing the pharmacokinetic (PK) behaviors of TZRT, BTMSDP, and their major metabolites, tazarotenic acid (TZRTAC) and betamethasone (BTMS) with those in the commonly prescribed TZRT gel and BTMSDP cream. 2. The trial was performed on six Bama mini-pigs. The different regions on the back side of each pig were randomly assigned to one of three treatment groups: TZRT 0.05% gel, BTMSDP 0.05% cream, and combination cream. The stratum corneum and epidermis-dermis samples were collected at various times after drug administration and analyzed for TZRT, TZRTAC, BTMSDP, and BTMS by LC-MS/MS. Compared with TZRT gel alone, TZRT + BTMSDP did not significantly change the PK profiles of TZRT; neither did BTMSDP + TZRT significantly change the PK profiles of BTMSDP, compared with the BTMSDP cream alone. In addition, the concentrations of TZRTAC and BTMS in most samples were below the lower limit of quantitation (LLOQ). 3. The results suggest that there was no significant drug-drug interaction trend between TZRT and BTMSDP in the process of transdermal permeation of combination cream into the stratum corneum and epidermis-dermis of mini-pigs.

Aim: The primary aim of present work was to develop effective combination drug therapy for topical treatment of psoriasis., Methods: Betamethasone dipropionate and calcipotriol loaded solid lipid nanoparticles (CT-BD-SLNs) were prepared by hot melt high shear homogenization technique, which were then incorporated in Carbopol gel matrix. The anti-psoriatic potential was tested by sequential in vitro (skin permeation and dermal distribution, anti-proliferative effect in HaCaT cells) and in vivo (Draize patch irritation, transepidermal water loss (TEWL) and anti-psoriatic mouse tail studies) experiments., Results: A negligible amount in receptor compartment, yet confined distribution of drugs to epidermal and dermal region of skin was observed in case of SLNs, which is essential for safe and effective anti-psoriatic therapy. Draize patch test and TEWL demonstrated negligible skin irritation and better skin tolerability of SLNs. The in vitro HaCaT cell line study demonstrated that SLNs delayed the abrupt growth of keratinocytes, while in vivo mouse tail model showed that SLNs gel significantly decreased the epidermal thickness and increased melanocyte count in comparison to commercial Daivobet® ointment., Conclusions: The developed SLNs gel is expected to be potential strategies for treatment of psoriasis and other topical diseases.

Background: Inhaled steroids are widely used for the treatment of asthma. Concerns over adrenal suppression when used at high doses or in combination with drugs such as ritonavir exist, requiring the measurement of serum cortisol. Herein, we investigate the cross-reactivity of the inhaled steroids betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay, in addition to five other steroids., Methods: Five replicates were produced from a serum pool for each of the eight steroids at a final concentration of 0.1 and 1 µg/mL. Each steroid was dissolved in 50% methanol, with 50% methanol of the same volume added to the control sample. The cross-reactivity of each steroid in the cortisol assay was calculated., Results: There was no statistically or clinically significant cross-reactivity in the measurement of cortisol when fluticasone, beclomethasone or betamethasone were spiked at 0.1 and 1.0 µg/mL, except for beclomethasone at a concentration of 1 µg/mL (1490 nmol/L) with a cross-reactivity of 1.6%, which is unlikely to be clinically significant. At both steroid concentrations investigated, prednisolone, 17-hydroxyprogesterone and 11-deoxycortisol exhibited statistically significant cross-reactivities that were greater than the least significant change of the assay (13.1%), whereas dexamethasone and metyrapone did not. Mean inter-assay precision was 1.5% (405-1586 nmol/L)., Conclusion: The cross-reactivity of the inhaled steroids; betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay are unlikely to be clinically significant at the concentrations found in patients on therapeutic doses. This will enable confident assessment of adrenal status in patients at risk of adrenal suppression., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: The aim of this study was to determine the bioequivalence of generic (test) and branded (reference) formulations of betamethasone injectable suspension in healthy Iranian subjects for the purpose of meeting regulatory requirements for bioequivalence of the generic formulation in Iran., Methods: 24 healthy Iranian male volunteers were participated for this single-dose, randomized, open label, 2 period crossover study separated by a 2-week washout period. For the assessment of betamethasone, blood samples were obtained before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after drug administration. Plasma concentration of betamethasone was analyzed with a simple, rapid and validated high performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters, representing the rate (Cmax, Tmax), and the extent (AUC0-t and AUC0-∞) of betamethasone absorption were calculated and analyzed for 2 formulations. The 2 formulations were to be considered bioequivalent if the 90% confidence intervals (CI)s for the logarithm-transformed values of Cmax, AUC0-t and AUC0-∞ fell within the predetermined range of 80-125%., Results: The 90% CIs of Cmax, AUC0-t and AUC0-∞ were 85.4-104.4%, 96.2-112.1% and 98.3-115.8%, respectively., Conclusion: Based on the 90% CIs of Cmax, AUC0-t and AUC0-∞ in these healthy Iranian male subjects, the test and reference formulations of betamethasone injectable suspension met the regulatory requirements for bioequivalence., (© Georg Thieme Verlag KG Stuttgart · New York.)

Even though intra-articular injections play an important role in the treatment of joint-related lameness in horses, little is known about pharmacokinetic properties of substances used. Therefore, an ex vivo model for pharmacokinetic studies was developed using distal forelimbs of slaughtered horses. The extremity was perfused with gassed Tyrode solution for up to 8 h. Tissue viability was confirmed by measurements of glucose consumption, lactate production, and lactate dehydrogenase activity in the perfusate. Standard criteria for tissue viability had been determined in preliminary experiments (n = 11), which also included histological examinations of the joint capsule. As the model's first implementation, the articular efflux rate of betamethasone (BM), administered as BM disodium phosphate intra-articularly to the fetlock joint (4 mg BM/joint), was investigated. The concentration of BM in the venous perfusate of the radial vein was measured by means of high-performance liquid chromatography. The average BM efflux rate per minute was calculated to be 5.1 μg/min with values ranging from 9 μg/min to 2.9 μg/min. 7.5 h after i.a. application, 2.3 mg BM had left the joint via the radial vein. Using this inexpensive setup, the presented model allows studying a variety of pharmacological topics without the ethical limitations of animal studies., (© 2012 Blackwell Publishing Ltd.)

Background: Betamethasone is used for its antiinflammatory and immunosuppressive effects in disorders of many organ systems. However, the pharmacokinetic properties of betamethasone in plasma after intramuscular injection of betamethasone sodium phosphate and betamethasone acetate dual-acting suspension need further investigation., Objectives: The main aim of this study was to determine the pharmacokinetic parameters of betamethasone, betamethasone acetate, and betamethasone phosphate after the administration of a single intramuscular dose of the dual-acting suspension to healthy human volunteers., Methods: Two different studies were conducted in healthy males. Volunteers were judged healthy based on their medical history, physical examination, and laboratory test results. Before confinement, all volunteers were tested for freedom from alcohol and drugs of abuse. Following a 10-hour overnight fasting, a single dose of 1 mL of the dual-acting suspension containing 3 mg of betamethasone phosphate and 3 mg of betamethasone acetate was administered by intramuscular injection. Blood sampling covered 48 hours. The plasma samples obtained in the second study were stabilized to enable pharmacokinetic profiling of betamethasone esters., Results: Twenty-four healthy males with mean (SD) age of 27 (6.62) years participated in each study. No incidences of serious adverse events were recorded during the studies. Six mild adverse events were reported in 2 subjects in the second study. One subject suffered from pain at the injection site and insomnia, and another subject complained of heartburn and drowsiness. Betamethasone phosphate appeared to be readily absorbed with a mean AUC(0-t) of 96.01 ng/h/mL and an AUC(0-∞) of 97.96 (23.38) ng/h/mL. Betamethasone peak plasma concentration reached a mean t(½) of 12.92 hours. Betamethasone acetate was not detected in the volunteers' plasma in either study (total of 2208 plasma samples)., Conclusion: The observed pharmacokinetic parameters suggested that the acetate ester, and not the phosphate ester, of betamethasone acts as a prodrug or reservoir for betamethasone, conferring on it sustained- and extended-release characteristics., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Vesicular systems have shown their ability to increase dermal and transdermal drug delivery. Their mechanism of drug transport into and through the skin has been investigated but remains a much debated question. Several researchers have outlined that drug penetration can be influenced by modifying the surface charge of liposomes. In the present work we study the influence of particle surface charge on skin penetration. The final purpose is the development of a carrier system which is able to enhance the skin delivery of two model drugs, betamethasone and betamethasone dipropionate. Liposomes were characterised by their size, morphology, zeta potential, encapsulation efficiency and stability. Ex vivo diffusion studies using Franz diffusion cells were performed. Confocal microscopy was performed to visualise the penetration of fluorescently labelled liposomes into the skin. This study showed the potential of negatively charged liposomes to enhance the skin penetration of betamethasone and betamethasone dipropionate., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: The therapeutic effects of betamethasone phosphate (BP) encapsulated in biocompatible and biodegradable blended nanoparticles of poly(lactic acid) (PLA) homopolymers and PEG-block-PLA copolymers (stealth nanosteroids) were examined in an experimental autoimmune uveoretinitis (EAU) model in Lewis rats., Methods: EAU was induced by S-antigen peptide in Lewis rats. Accumulation of systemically administered Cy7-labeled stealth nanoparticles in inflamed eyes of rats with EAU was assessed using in vivo fluorescence imaging, and the therapeutic effect of stealth nanosteroids, nonstealth nanosteroids, or saline on EAU was examined. The eyes were obtained 7 days after the treatment, and the histologic score was determined using pathologic findings. The expression of inflammatory cytokines including IL-6, IL-17, and VEGF was determined immunohistochemically., Results: Cy7-stealth nanoparticles accumulated in inflamed eyes of rats with EAU and remained in situ for a 3-day period. Systemically administered stealth nanosteroids (100 μg of BP) reduced the clinical scores of rats with EAU within 1 day and maintained the effect for 2 weeks. This treatment also decreased the histologic scores and the expression of inflammatory cytokines in the retina of EAU., Conclusions: The strong therapeutic benefit on EAU obtained with the stealth nanosteroids may have been due to prolonged blood circulation and targeting to the inflamed uvea and retina, in addition to sustained release in situ.

Purpose: Difluprednate (6α,9-difluoro-11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate 17-butyrate, DFBA) has long been used as an anti-inflammatory dermatological agent. The main objectives of the current study were to evaluate the pharmacokinetic and pharmacodynamic features of DFBA when used as an ophthalmic agent, and to compare these features with those of other common ophthalmic agents, to determine which has the highest activity., Methods: A glucocorticoid (GC) receptor-binding test was performed to evaluate GC receptor-binding activity (GCRBA, the index of pharmacological effect). Using this information, we calculated dose-response curves, IC(50) values, and K(d) values to evaluate each drug's K(i) value. Finally, we performed studies in live rabbits to compare the activity of 4 formulations [0.002%, 0.01%, or 0.05% DFBA, or an ophthalmic solution of 0.1% betamethasone sodium phosphate (BMP)] at 4 time points (0.5, 1, 2, 4  h). At each time point, blood and eye samples were taken so that C(max) (the maximum equivalent concentration of the active DFBA metabolite, DFB), T(max) (the time at which C(max) was measured), and the area under the concentration-time curve could be compared across the 4 formulations., Results: BMP had the highest K(i) value (8.4 × 10(-8) nmol/L), whereas DFB had the lowest (6.1 × 10(-11) nmol/L). The GCRBA of DFBA was intermediate to these 2 values (7.8 × 10(-10) nmol/L). Instillation of the DFBA ophthalmic emulsion in the eyes of rabbits led to dose-dependent increases in GCRBA, which was mostly attributable to the activity of DFB. The 0.05% DFBA ophthalmic emulsion elicited the greatest response in both aqueous humor and iris/ciliary body tissues, though there were no significant dose-dependent differences in GCRBA in plasma samples., Conclusions: The 0.05% DFBA ophthalmic emulsion appears to be an effective and safe anti-inflammatory treatment in ocular tissues. It is comparable, and possibly even superior, to the 0.1% BMP solution, and may be particularly useful in cases of severe disease where treatment with BMP solution alone is insufficient.

The aim of this study was to evaluate the pharmacokinetic profiles of betamethasone (BOH, CAS 378-44-9) and betamethasone 17-monopropionate (B17P), the active metabolites of betamethasone phosphate (BSP) and betamethasone dipropionate (BDP), respectively, after administration of betamethasone i.m. (BSP 2 mg and BDP 5 mg). After ten healthy volunteers had received a single-dose intramuscular adminitration of betamethasone i.m., blood samples were collected pre-dose and for 336 h postdose. The plasma levels of B17P and BOH were measured by liquid chromatography-tandem mass spectrometry (LC-MS/ MS). When compared to BOH, B17P exhibited a longer time to maximum concentration (15.0 +/- 9.0 h vs. 2.8 +/- 1.7 h), a lower Cmax (0.6 +/- 0.2 ng/mL vs. 14.5 +/- 3.7 ng/mL), and a much longer half-life (80.8 +/- 22.7 h vs. 9.6 +/- 3.6 h). Betamethasone i.m. produced rapid onset and sustained action through an initial rapid-increased plasma concentration of BOH and a sustained plasma concentration of B17P, respectively.

Aims: This study aimed to investigate the efficacy of encapsulating steroids, which is a primary choice for the treatment of sensorineural hearing loss, in polyethylene glycol-coated polylactic acid nanoparticles for drug delivery to the cochlea., Materials & Methods: We prepared polyethylene glycol-coated polylactic acid nanoparticles encapsulating rhodamine or betamethasone phosphate (BP), and administered them systemically to CBA/N mice previously exposed to intense noise. We assessed nanoparticle distribution using rhodamine fluorescence, BP concentrations in tissues, nuclear translocation of glucocorticoid receptors and the function and histology of the mouse cochleae., Results & Conclusion: Polyethylene glycol-coated polylactic acid nanoparticles delivered BP to cochleae over a sustained period, resulting in significant reductions in histological and functional damage to cochleae and indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of BP in acute sensorineural hearing loss.

Objective: The goals of the study were to estimate the pharmacokinetic parameters of standard dose betamethasone in a large obstetrics population and evaluate the effect of maternal body size and multiple gestation on the pharmacokinetic parameters and their observed variability., Study Design: This was a prospective pharmacokinetic study. Liquid chromatography mass spectrometry was used to measure betamethasone plasma concentrations. Pharmacokinetic parameters and significant clinical covariates were estimated with mixed effect modeling. Bootstrap analysis confirmed validity of the model., Results: Two hundred seventy-four blood samples from 77 patients were obtained. The greatest effect on pharmacokinetic variability was observed with maternal lean body weight (LBW). The relationship between the pharmacokinetic parameters and LBW remained linear over a wide range of maternal body sizes. Multiple gestations did not affect the pharmacokinetic parameters., Conclusion: Individualization of betamethasone dosing by maternal LBW reduces variability in drug exposure. Mutiple gestations do not require betamethasone dosing adjustment, because pharmacokinetics are the same as singleton gestations., (Published by Mosby, Inc.)