Development of a film-forming oleogel with increased substantivity for the treatment of psoriasis.

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.

Design and In Vitro Evaluation of a Slow-Release Intraocular Implant of Betamethasone.

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.

Therapeutic Fluorescent Hybrid Nanoparticles for Traceable Delivery of Glucocorticoids to Inflammatory Sites.

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.

Antenatal corticosteroid treatment: factors other than lung maturation.

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.

Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate.

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.

Functionalized silica nanoparticles as a carrier for Betamethasone Sodium Phosphate: Drug release study and statistical optimization of drug loading by response surface method.

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.

Enhanced topical delivery and ex vivo anti-inflammatory activity from a betamethasone dipropionate formulation containing fish oil.

OBJECTIVE AND DESIGN: To probe ex vivo the influence of fish oil (FO) on the topical delivery and anti-inflammatory properties of betamethasone dipropionate (BD). MATERIALS OR SUBJECTS: Freshly excised porcine ear skin. TREATMENT: Ointment formulations containing BD + salicylic acid (SA), BD + SA + FO, or base as control, applied to the skin mounted in Franz cells. METHODS: Comparative depth profiling; skin probed by immunohistochemistry for cyclooxygenase-2 (COX-2) and by ELISA for prostaglandin E2 (PGE2). RESULTS: More BD was obtained in the first 30 layers and the remaining epidermis with BD + SA. However, more penetrants were recovered from the remaining skin treated with BD + SA + FO. Although BD + SA reduced COX-2 expression within the epidermis, greater reduction was observed with BD + SA + FO as indicated by reduced COX-2 expression. FO alone had a comparable effect on the expression of COX-2. Modulation of PGE2 production also supported the anti-inflammatory properties of fish oil, reducing PGE2 levels by an amount comparable to the reduction by BD. Combining FO and BD, however, did not provide the anticipated potentiation effect. CONCLUSIONS: Fish oil enhanced the delivery of BD and SA across skin. Addition of fish oil also enhanced the anti-inflammatory activity of BD, attributed to increased amounts of BD present in the skin and/or the intrinsic anti-inflammatory activity of fish oil.

Polymeric nanoparticles encapsulating betamethasone phosphate with different release profiles and stealthiness.

The purpose of this study was to engineer nanoparticles with various sustained profiles of drug release and prolonged circulation by blending poly(D,L-lactic acid)/poly(D,L-lactic/glycolic acid) (PLA/PLGA) homopolymers and poly(ethylene glycol) (PEG)-block-PLA/PLGA copolymers encapsulating betamethasone disodium 21-phosphate (BP). Nanoparticles of different sizes, drug encapsulation/release profiles, and cellular uptake levels were obtained by mixing homopolymers and block copolymers with different compositions/molecular weights at various blend ratios by an oil-in-water solvent diffusion method. The in vitro release of BP increased with nanoparticles of smaller size or of PLGA homopolymers instead of PLA homopolymers. Furthermore, the uptake of nanoparticles by macrophage-like cells decreased with nanoparticles of higher PEG content, and nanoparticles of PEG-PLGA block copolymers were taken up earlier than those of PEG-PLA block copolymers after incubation with serum. In addition, prolonged blood circulation was observed with nanoparticles of smaller size with higher PEG content, and nanoparticles of PEG-PLA block copolymers remained longer in circulation than those of PEG-PLGA block copolymers. Analysis of BP concentration in organs revealed reduced liver distribution of blended nanoparticles compared with PLA nanoparticles. This is the first study to systematically design and characterize biodegradable PLA/PLGA and PEG-PLA/PLGA-blended nanoparticles encapsulating BP with different release profiles and stealthiness.

The effects of chorioamnionitis and betamethasone on 11beta hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor in preterm human placenta.

OBJECTIVE: Preterm birth is one of the major problems faced in perinatal medicine and is often associated with underlying clinical infection. Treatment with maternal betamethasone has helped to improve neonatal morbidity and mortality. We hypothesized that betamethasone treatment and chorioamnionitis would alter the bioavailability of placental glucocorticoids through the regulation of the 11beta hydroxysteroid dehydrogenase (11beta HSD) isozymes and the glucocorticoid receptor (GR). METHODS: Placental samples were obtained from three groups of women who delivered prematurely: (1) those who delivered in the absence of infection, (2) those who received betamethasone treatment before delivering without infection, and (3) those who had pregnancies complicated with chorioamnionitis. Western blotting was used to determine 11beta HSD-1, 11beta HSD-2, GRT, and GRalpha expression, and 11beta HSD-2 activity was determined in each group. JEG-3 cells were used to study the regulation of the 11beta HSD isozymes. RESULTS: In cases of chorioamnionitis where mothers had not been treated with betamethasone, placental 32-kd 11beta HSD-1 protein expression was increased. In cases of chorioamnionitis regardless of betamethasone treatment, placental 11beta HSD-2 expression and activity was decreased compared to controls. In these placental samples, the expression of GRT and GRalpha did not change significantly. In JEG-3 cells, 11beta HSD-1 32-kd expression was increased with interleukin (IL)-1beta and tumor necrosis factor alpha (TNF-alpha), while 11beta HSD-2 expression was unaffected. CONCLUSION: These data suggest that there could be an increased fetal exposure to maternal glucocorticoids in cases of chorioamnionitis as a result of changes in the expression and activity of the placental 11beta HSD isozymes.

Acid- and salt-triggered multifunctional poly(propylene imine) dendrimer as a prospective drug delivery system.

A novel dendrimeric compound is designed with the objective of simultaneously addressing issues commonly encountered in drug delivery, i.e., stability in biological milieu as well as targeting. For this purpose, a multifunctional dendrimeric system derived from diaminobutane poly(propylene imine) dendrimers (DAB) is prepared bearing at its external surface poly(ethylene glycol) chains and guanidinium moieties. For these moieties, it has been established that they exhibit protective and targeting properties, respectively. The release of encapsulated compounds is triggered by titration with acids followed by the addition of sodium chloride solution. Specifically for pyrene, the solubilization site of which can be clearly traced, protonation leads to a distribution between the core and the poly(ethylene glycol) chains in the periphery of the dendrimer while it is released to the aqueous bulk solution by the addition of sodium chloride. The release of betamethasone valerate is also triggered by the addition of sodium chloride solution.

Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration.

OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of betamethasone in maternal and fetal circulations after maternal or fetal intramuscular administration. STUDY DESIGN: Ewes that bore single fetuses underwent surgery at approximately 96 days of pregnancy for the implantation of fetal and maternal vascular catheters. At approximately 103 days, five ewes were injected intramuscularly with betamethasone (0.5 mg/kg body weight) or five fetuses received ultrasound-guided intramuscular injections of betamethasone (0.5 mg/kg estimated fetal weight). Maternal and fetal blood samples were collected serially for the measurement of plasma betamethasone concentrations. RESULTS: Fetal injection caused higher peak fetal betamethasone concentrations (341.2+/-23.7 nmol/L) than maternal injection (37.6+/-3.7 nmol/L; P<.001) and greater cumulative betamethasone exposure. The half-life of betamethasone in the fetal circulation was shorter after fetal injection (1.1+/-0.3 hours) than after maternal injection (8.5+/-2.0 hours; P=.006). CONCLUSION: The duration of fetal and maternal exposure to betamethasone can be minimized by direct fetal intramuscular administration that, in sheep, affords lung maturation without adverse effects on fetal growth.

Efecto de la quinacrina con agentes antiinflamatorios sobre el desarrollo del tumor TA3 en ratón AJ / Quinacrine effects with antiinflamatory agents over TA3 tumor development in AJ mice

Objetivo: analizar la eventual potenciación mutua del efecto antineoplásico que presentan la quimacrina, los glucocorticoides y los antiinflamatorios no esteroidales (AINEs). Material y método: se utilizaron trasplantes de tumor TA3 en ratones machos AJ. Se establecieron 29 grupos con diferentes combinaciones terapéuticas, y se hizo un análisis estadístico de la sobrevida y del diámetro tumoral promedio en cada grupo. Resultados: la quimacrina combinada con betametasona y un agente AINE, permite obtener una alta tasa de regresión completa y definitiva de los tumores TA3. Discusión: la betametasona y los AINEs, forma separada no modifican la curva de crecimiento de los tumores TA3. La administración simultánea de quimacrina con betametasona o con un AINE, y su administración triple demuestra poseer una potente acción antitumoral, con regresiones totales que llegan a 50 o 70 por ciento de los tumores, variando en forma inversamente proporcional al lapso de días previos al inicio del tratamiento. El mecanismo de acción puede relacionrse con la apoptosis de células endoteliales de los capilares intratumorales que se observa en los animales tratados

Penetration of topically applied betamethasone sodium phosphate into human aqueous humour.

Gas Chromatography combined with Negative Chemical Ionisation Mass Spectrometry (GCMS) was used to determine the absorption of topically applied beta-methasone sodium phosphate into the aqueous humour of human subjects undergoing routine intraocular surgery. The Betamethasone concentration was greatest in the interval 91-120 minutes following topical administration (mean peak concentration = 7.7 ng/ml). At twelve hours post instillation the mean concentration of Betamethasone was 2.5 ng/ml and detectable levels were recorded in the aqueous humour 24 hours after application (mean concentration 0.4 ng/ml).