The Role of ICS/LABA Fixed-Dose Combinations in the Treatment of Asthma and COPD: Bioequivalence of a Generic Fluticasone Propionate-Salmeterol Device.

Both asthma and chronic obstructive pulmonary disease (COPD) are inflammatory chronic respiratory conditions with high rates of morbidity and mortality worldwide. The objectives of this review are to briefly describe the pathophysiology and epidemiology of asthma and COPD, discuss guideline recommendations for uncontrolled disease, and review a new generic option for the treatment of asthma and COPD. Although mild forms of these diseases may be controlled with as-needed pharmacotherapy, uncontrolled or persistent asthma and moderate or severe COPD uncontrolled by bronchodilators with elevated eosinophilia or frequent exacerbations may require intervention with combination therapy with inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), according to international guidelines. Fixed-dose combinations of ICS/LABA are commonly prescribed for both conditions, with fluticasone propionate (FP) and salmeterol forming a cornerstone of many treatment plans. An oral inhalation powder containing the combination of FP and salmeterol has been available as Advair Diskus® in the United States for almost 20 years, and the first and only substitutable generic version of this product has recently been approved for use: Wixela™ Inhub™. Bioequivalence of Wixela Inhub and Advair Diskus has been established. Furthermore, the Inhub inhaler was shown to be robust and easy to use, suggesting that Wixela Inhub may provide an alternative option to Advair Diskus for patients with asthma or COPD requiring intervention with an ICS/LABA.

Albendazole solid dispersions prepared using PEG6000 and Poloxamer188: formulation, characterization and in vivo evaluation.

This study aimed to optimize the preparation process of albendazole (ABZ) solid dispersion (SD) and enhance its dissolution rate and oral bioavailability in dogs. The ABZ-SD formulations were prepared by a fusion method with ABZ and polyethylene glycol 6000 (PEG 6000), poloxamer 188 (P 188) polymers at various weight ratios or the combination of PEG 6000&P 188. The characterizations of the optimal formulations were performed by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), in vitro dissolution test and molecular docking. The in vivo pharmacokinetic study was conducted in beagle dogs. As a result, ABZ solid dispersion based on PEG 6000&P 188 (1:2) was successfully prepared. The ABZ-SD formulation could significantly improve the apparent solubility and dissolution rate of ABZ compared with commercial tablets. Furthermore, the water solubility of ABZ-SD was improved mainly based on hydrogen bond association. Besides, at an oral dosage of 15 mg/kg ABZ, the SDs had higher Cmax values and areas under the curve (AUCs) compared to those of commercial ABZ tablets. Preparation of ABZ-loaded SDs by PEG 6000&P 188 is a promising strategy to improve the oral bioavailability of ABZ.

Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Vactosertib is a novel inhibitor of transforming growth factor-ß signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

Comparative muscle irritation and pharmacokinetics of florfenicol-hydroxypropyl-ß-cyclodextrin inclusion complex freeze-dried powder injection and florfenicol commercial injection in beagle dogs.

Florfenicol (FF) is a novel animal-specific amidohydrin broad-spectrum antibiotic. However, its aqueous solubility is extremely poor, far below the effective dose required for veterinary clinic. Thus, FF is often used in large doses, which significantly limits its preparation and application. To overcome these shortcomings, the FF-hydroxypropyl-ß-cyclodextrin (FF-HP-ß-CD) inclusion complexes were developed using the solution-stirring method. The physical properties of FF-HP-ß-CD were characterized. A comparison was conducted between FF and FF-HP-ß-CD freeze-dried powder injection of their muscle irritation and the pharmacokinetics. The drug loading and saturated solubility of FF-HP-ß-CD at 37 °C were 11.78% ± 0.04% and 78.93 ± 0.42 mg/mL, respectively (35.4-fold compared with FF). Results of scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared showed that FF was entrapped in the inner cavity of HP-ß-CD, and the inclusion complex formed in an amorphous state. In comparison with FF commercial injection, FF-HP-ß-CD increased the elimination half-life (t1/2ß), transport rate constant (K10, K12, K21), and maximum concentration (Cmax) after intramuscular injection in beagle dogs. Conversely, it decreased the distribution half-life (t1/2α), absorption rate constant (Ka), apparent volume of distribution (V1/F), and peak time (Tmax). These results suggest that FF-HP-ß-CD freeze-dried powder injection is a promising formulation for clinical application.

Formulation and Characterization of Spray-Dried Powders Containing Vincristine-Liposomes for Pulmonary Delivery and Its Pharmacokinetic Evaluation From In Vitro and In Vivo.

Vincristine (VCR) has been used in the treatment of lung cancer. To improve its efficacy, the designs of elevating lung exposure to drug and decreasing the clearance with extended time were brought out. Pulmonary delivery is regarded as a good choice in pulmonary diseases treatment. Spray-drying is a technology for the preparation of drugs that can be delivered to lung via a dry powder inhaler. The results showed an appropriate particle size and shape for the pulmonary delivery. The aerosol behaved a sustained-release profile while VCR solution released rapidly within 10 h. The antitumor activity was characterized by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide assay, and half maximal inhibitory concentration values of VCR-liposomes spray-dried powder were 24.42 ± 1.88 nM and 55.28 ± 4.76 nM in MCF-7 and A549 cells, respectively. Compared with the free VCR, the aerosol performed better pharmacokinetic behavior: increased maximum concentration (630.8%) and systemic exposure (429.6%) and decreased elimination half-life (81.1%). The clearance was decreased by 83.2%. Comprehensively, the pulmonary delivery seemed to be a recommendable way to effectively treat the pulmonary disease.

Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model.

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused rat lung (IPL) model. Two particle size distributions (d50 = 1.2 µm and d50 = 2.8 µm) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter ( kex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter ( kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 µM), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 µm). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between kex vivo and kin vitro. The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design: Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting: One US site. Subjects: Healthy, adult, nondependent, recreational opioid users. Methods: Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on "at the moment" Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results: Mean maximum effect for "at the moment" Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled "at the moment" Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions: The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Efavirenz dissolution enhancement III: Colloid milling, pharmacokinetics and electronic tongue evaluation.

Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is part of first-line therapy for the treatment of human immunodeficiency virus type 1 infection (HIV-1/AIDS). This drug shows relatively low oral absorption and bioavailability, as well as high intra- and inter-subject variability. Several studies have shown that treatment failure and adverse effects are associated with low and high EFV plasma concentrations, respectively. Some studies suggest different EFV formulations to minimize inter-patient variability and improve its solubility and dissolution; however, all of these formulations are complex, using for instance, cyclodextrins, dendrimers and polymeric nanoparticles, rendering them inviable industrially. The aim of this work was to prepare simple and low-cost suspensions of EFV for improvement of solubility and dissolution rate by using colloid mill, spray or freeze-drying, and characterization of the powders obtained. The results demonstrated an increase in the dissolution rate of EFV, using 0.2% of sodium lauryl sulfate (SLS) and 0.2% of hydroxypropylcellulose (HPC) or hydroxypropylmetilcellulose (HPMC) in both freeze and spray dried powders. The pharmacokinetic studies demonstrated improved pharmacokinetic parameters for the formulation containing SLS and HPC. The powders obtained, which present enhanced dissolution properties, can be incorporated in a solid dosage form for treatment of AIDS in paediatric patients with promising results.

Cardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: Impact on lead selection.

The aim of this study was to identify an adequate formulation for a poorly soluble lead molecule (BI-A) that would achieve sufficiently high plasma concentrations after oral administration in dogs to enable a robust cardiovascular safety pharmacology assessment in telemetry-instrumented conscious dogs during lead optimization in drug discovery. A spray-dried dispersion of BI-A (BI-A-SDD) containing a 1:2 ratio of BI-A and hydroxypropyl methylcellulose acetate succinate-LF was prepared using a Büchi spray dryer B-90 (B-90). Physical form characterization, an in vitro dissolution test and a preliminary pharmacokinetic (PK) study following oral administration of BI-A-SDD were performed. Thereafter, effects on cardiovascular parameters in conscious, chronically-instrumented dogs were investigated for 24h after a single oral dose (5, 10, and 50mg/kg) using a modified Latin square cross-over study design. The BI-A-SDD powder was confirmed to be amorphous and was stable as an aqueous suspension for at least 4h. The BI-A-SDD suspension provided a greater rate and extent of dissolution than the crystalline BI-A suspension and the supersaturation was maintained for at least 4h. In PK studies the Cmax of the BI-A-SDD formulation (25.4µM; 77-fold the projected efficacious Cmax of 0.33µM) was 7.5-fold higher than the Cmax observed using oral administration of a 10% hydroxypropyl-ß-cyclodextrin formulation at 100mg/kg in dogs (3.4µM). In conscious, chronically-instrumented dogs, the doses tested and plasma concentrations achieved were sufficient to enable a robust safety pharmacology evaluation. Multiple off-target hemodynamic effects were detected including acute elevations in aortic blood pressure (up to 22% elevation in systolic and diastolic blood pressure) and tachycardia (68% elevation in heart rate), results that were confirmed in other in vivo models. These results led to a deprioritization of BI-A. The study demonstrated that a spray-dried dispersion, prepared using the B-90 in drug discovery, enhanced the oral exposure of a poorly water-soluble molecule, BI-A, and thereby enabled its evaluation in safety pharmacology studies that ultimately resulted in deprioritization of BI-A from a pool of lead compounds.

Dermal quercetin smartCrystals®: Formulation development, antioxidant activity and cellular safety.

Flavonoids are natural plant pigments, which possess high antioxidative and antiradical activities. However, their poor water solubility led to a limited bioavailability. To overcome this major hurdle, quercetin nanocrystals were produced implementing smartCrystals® technology. This process combines bead milling and subsequent high-pressure homogenization at relatively low pressure (300bar). To test the possibility to develop a dermal formulation from quercetin smartCrystals®, quercetin nanosuspensions were admixed to Lutrol® F127 and hydroxythylcellulose nonionic gels. The physicochemical properties (morphology, size and charge), saturation solubility, dissolution velocity and the antioxidant properties (DPPH assay) as well as the cellular interaction of the produced quercetin smartCrystals® were studied and compared to crude quercetin powder. Quercetin smartCrystals® showed a strong increase in the saturation solubility and the dissolution velocity (7.6 fold). SmartCrystals® loaded or not into gels proved to be physically stable over a period of three months at 25°C. Interestingly, in vitro DPPH assay confirmed the preservation of quercetin antioxidative properties after nanonization. In parallel, the nanocrystalline form did not display cellular toxicity, even at high concentration (50µg/ml), as assayed on an epithelial cell line (VERO cells). In addition, the nanocrystalline form confirmed a protective activity for VERO cells against hydrogen peroxide induced toxicity in vitro. This new formulation presents a promising approach to deliver quercetin efficiently to skin in well-tolerated formulations.

Drug Permeation Characterization of Inhaled Dry Powder Formulations in Air-Liquid Interfaced Cell Layer Using an Improved, Simple Apparatus for Dispersion.

PURPOSE: An improved, simple apparatus was developed to easily and uniformly disperse dry powders onto an air-liquid interfaced cultured cell layer. We investigated drug permeation in cell cultures with access to the air-liquid interface (ALI) following deposition of a dry powder using the apparatus. METHOD: The improved apparatus for dispersing the powders was assembled. Dry powders containing model drugs were prepared and dispersed onto the cell layer with ALI. After the dispersion, the permeation of each model drug was measured and compared with other samples (solutions with the same compositions). RESULTS: The improved apparatus could with ease uniformly disperse 40% of the loading dose onto the cell layer with ALI. Dry powders showed higher drug permeability compared to the samples. without cytotoxicity or an effect on tight junctions. The high drug permeability of dry powders was independent of the molecular weight of model drugs. The contribution of active transport was small, while an increase in passive drug transport via trans- and paracellular routes was observed. CONCLUSIONS: Inhaled dry powder formulations achieved higher drug permeability than their solution formulations in ALI. A high local concentration of drugs on the cell layer, caused by direct attachment of the inhaled dry powder, contributed to increased drug permeability via both trans- and paracellular routes.

Pharmacokinetic Comparison of Omeprazole Granule and Suspension Forms in Children: A Randomized, Parallel Pilot Trial.

Although, omeprazole is widely used for treatment of gastric acid-mediated disorders. However, its pharmacokinetic and chemical instability does not allow simple aqueous dosage form formulation synthesis for therapy of, especially child, these patients. The aim of this study was at first preparation of suspension dosage form omeprazole and second to compare the blood levels of 2 oral formulations/dosage forms of suspension & granule by high performance liquid chromatography (HPLC). The omeprazole suspension was prepared; in this regard omeprazole powder was added to 8.4% sodium bicarbonate to make final concentration 2 mg/ml omeprazole. After that a randomized, parallel pilot trial study was performed in 34 pediatric patients with acid peptic disorder who considered usage omeprazole. Selected patients were received suspension and granule, respectively. After oral administration, blood samples were collected and analyzed for omeprazole levels using validated HPLC method. The mean omeprazole blood concentration before usage the next dose, (trough level) were 0.12±0.08 µg/ml and 0.18±0.15 µg/ml for granule and suspension groups, respectively and mean blood level after dosing (C2 peak level) were 0.68±0.61 µg/ml and 0.86±0.76 µg/ml for granule and suspension groups, respectively. No significant changes were observed in comparison 2 dosage forms 2 h before (P=0.52) and after (P=0.56) the last dose. These results demonstrate that omeprazole suspension is a suitable substitute for granule in pediatrics.

Inhaled sildenafil nanocomposites: lung accumulation and pulmonary pharmacokinetics.

CONTEXT: Administration of sildenafil citrate (SC) is considered as a strategy in the treatment of pulmonary hypertension. OBJECTIVE: This study reports production of the inhalable microparticles containing SC-loaded poly(lactide-co-glycolic acid)-nanoparticles. METHODS: SC-nanoparticles were prepared by the double emulsion solvent evaporation method. Next, free SC and SC-loaded nanoparticles were spray dried in the presence of appropriate excipients (lactose, maltose and trehalose). Physicochemical properties and aerodynamic behavior of prepared powders were evaluated. In addition, drug accumulation from selected formulations in the rat lung tissue was compared with oral and IV administration. RESULTS: Size and fine particle fraction of selected nanocomposites and free SC microparticles were 7 and 4.5 µm, and 60.2% and 68.2%, respectively. Following oral and IV administration, the drug was not detectable in the lung after 4 and 6 h, respectively, but in SC-loaded nanoparticles, the drug was detectable in the lung even after 12 h of inhalation. Respirable particles containing free SC provided high concentration at first that was detectable up to 6 after insufflation. CONCLUSION: In vivo study demonstrated that pulmonary administration of sildenafil and sildenafil nanoparticles produced longer half-life and higher concentration of the drug in the lung tissue as compared to oral and IV administration. So, these formulations could be more effective than oral and IV administration of this drug.

A novel nasal powder formulation of glucagon: toxicology studies in animal models.

BACKGROUND: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. METHODS: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits. RESULTS: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading. DISCUSSION: The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes. CONCLUSION: This novel drug product is well tolerated in animal models.

[Pharmacokinetic and pharmacodynamic characteristics of berberine and jateorhizine in Coptidis Rhizoma powder and their monomeric compounds in type 2 diabetic rats].

This article focused on a comparative analysis on the pharmacokinetic and pharmacodynamic characteristics of berberine (BER) and jateorhizine(JAT) in Coptidis Rhizoma powder (HL-P) and their monomeric compounds (BER + JAT, BJ) in type 2 diabetic (T2D) rats to explore the beneficial. effect of HL-P in the treatment of T2D. The T2D rats were treated with HL-P, BER, JAT and BJ, respectively for 63 d. The pharmacokinetic parameters, dynamic changes in blood glucose level and blood lipid values were measured. The results showed that, compared with other corresponding group, t(max), T(½ka) of BER and JAT in HL-P group were reduced, while C(max), AUC(inf), AUC(last), V(L)/F were significantly increased; compared with model group, blood glucose levels were decreased significantly in HL-P group since the 18th day, while those in BER or BJ group were reduced since the 36th day, however, blood glucose levels showed no obvious changes in JAT group; compared with model group, FFA values in all treatment group were decreased significantly. Moreover, TG, HDL and LDL value in HL-P group, LDL value in BER group and HDL value in BJ group were improved significantly. The above results showed that Coptidis Rhizoma powder showed excellent pharmacokinetic characteristics and excellent activity of lowering blood glucose and lipid. It provided a scientific basis for oral application of Coptidis Rhizoma powder in the treatment of T2D.

Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of acemetacin.

Free-flowing proniosomal powders of acemetacin (AC) were prepared using the slurry method and maltodextrin as carrier. Positively charged proniosomes composed of 70:20:10 of Span 60/cholesterol (Chol)/stearylamine (SA), respectively, were successively compressed into tablets using direct compression method. The tablets were characterized for weight variability, friability, hardness, drug content uniformity, and dissolution properties. The in vivo evaluation of the prepared proniosomes (powder or tablet forms) after oral administration was investigated by the determination of AC and its active metabolite indomethacin (IND) in the blood of albino rabbits. Results indicated that the increase of Chol from 10% to 20% markedly reduced the efflux of the drug. Further Chol addition from 30% to 50% led to increased AC release rates. The proniosome tablets of AC showed greater hardness and disintegration time and less friability than AC plain tablets. The dissolution of proniosomal tablets indicated a lower drug release percentage compared to powdered proniosomes and AC plain tablets. The mean pharmacokinetic parameters of AC and IND from different formulations indicated increased t 1/2 and area under the curve (AUC) of both AC and IND for proniosomal tablets compared with both proniosomal powders and AC plain tablets. This study suggested the formulation of AC proniosomal powder into tablets to control and extend its pharmacologic effects.

Development and evaluation of a dry powder formulation of liposome-encapsulated oseltamivir phosphate for inhalation.

This study aims to develop oseltamivir phosphate (OP) liposomes as inhalation powders by spray-drying based on the single factor investigation, which was mainly composed of lactose, L-leucine and mannitol. It was found that the ratio of OP and liposomes (1:10), inlet temperature (110 °C) and airflow rate (2.3 mL/min) showed optimized physical properties of OP liposomes. Deposition was evaluated after the aerosolization of powders at 600 L/h via the Aerolizer® into a twin-stage impinger. The concentrations of OP and oseltamivir carboxylate (OSCA) in rats plasma using LC-MS have been determined and performed via pharmacokinetic software DAS 2.0 package. The liposomal OP dry powders displayed an average particle size around 3.5 µm with fine particle fraction (FPF = 35.40%). In vitro evaluation demonstrated a sustained release pattern accounting for 20% drug release compared to that of OP solution up to 90% drug release in 2 h. And the cumulative release percentage was up to 50% in 20 h. Atrioventricular fitting results indicated that all preparations were best fitted with a two-compartment model. There was a significant difference in MRT, Cmax and Tmax (p < 0.01) between the two groups of liposomal OP dry powders and OP solution with t-test, which indicated that the drug released slowly from liposomal OP dry powders in the lung. To sum up, dry powders formulation of liposome-encapsulated OP for inhalation was suitable for pulmonary administration, which offering the opportunity to reduce dosing frequency.

Attenuation of lead-induced oxidative stress in rat brain, liver, kidney and blood of male Wistar rats by Moringa oleifera seed powder.

Moringa oleifera is a tree belonging to Moringaceae family and its leaves and seeds are reported to have ameliorative effects against metal toxicity. In the present investigation, M. oleifera seed powder was tested against lead-induced oxidative stress and compared against meso-2, 3-dimercaptosuccinic acid (DMSA) treatment. Male Wistar rats (100-120 g) were divided into four groups: control (2000 ppm of sodium acetate for 2 weeks), exposed (2000 ppm of lead acetate for 2 weeks), Moringa treated (500 mg/kg for 7 days after lead exposure), and DMSA treated (90 mg/kg for 7 days after lead exposure). After exposure and treatment periods, rats were sacrificed and the brain was separated into cerebellum, hippocampus, frontal cortex, and brain stem; liver, kidney, and blood were also collected. The data indicated a significant (p<0.05) increase in reactive oxygen species (ROS), lipid perioxidation products (LPP), total protein carbonyl content (TPCC), and metal content of brain regions, liver, and kidney in the exposed group compared with their respective controls. In the blood, delta-amino levulinic acid dehydratase (ALAD) activity, RBC, WBC, hemoglobin, and hematocrit showed significant (p<0.05) decrease on lead exposure. However, administration of M. oleifera restored all the parameters back to control, tissue-specifically, and also showed improvement in restoration better than DMSA treatment, indicating reduction of the negative effects of lead-induced oxidative stress.

In vitro and in vivo performance of dry powder inhalation formulations: comparison of particles prepared by thin film freezing and micronization.

Recently, inhaled immunosuppressive agents have attracted increasing attention for maintenance therapy following lung transplantation. The rationale for this delivery approach includes a more targeted and localized delivery to the diseased site with reduced systemic exposure, potentially leading to decreased adverse side effects. In this study, the in vitro and in vivo performance of an amorphous formulation prepared by thin film freezing (TFF) and a crystalline micronized formulation produced by milling was compared for tacrolimus (TAC). Despite the relatively large geometric size, the TFF-processed formulation was capable of achieving deep lung delivery due to its low-density, highly porous, and brittle characteristics. When emitted from a Miat® monodose inhaler, TFF-processed TAC formulations exhibited a fine particle fraction (FPF) of 83.3% and a mass median aerodynamic diameter (MMAD) of 2.26 µm. Single-dose 24-h pharmacokinetic studies in rats demonstrated that the TAC formulation prepared by TFF exhibited higher pulmonary bioavailability with a prolonged retention time in the lung, possibly due to decreased clearance (e.g., macrophage phagocytosis), compared to the micronized TAC formulation. Additionally, TFF formulation generated a lower systemic TAC concentration with smaller variability than the micronized formulation following inhalation, potentially leading to reduced side effects related to the drug in systemic circulation.

Pharmacokinetics and safety of resveratrol derivatives in humans after oral administration of melinjo (Gnetum gnemon L.) seed extract powder.

Fruits and seeds of melinjo (Gnetum gnemon L.) are resveratrol derivative-rich materials. Pharmacokinetics of resveratrol derivatives in healthy volunteers after oral administration of 1000 mg of melinjo seed extract (MSE) powder were assessed and compared with those after oral dosing of trans-resveratrol (tRV) powder containing 4.8 mg of tRV only, equivalent to the content in 1000 mg MSE powder. Plasma tRV concentrations with enzymatic hydrolysis were maintained over 24 h, with a tmax of 12 h and a mean residence time (MRT) of 14 h, 5 and 2 times higher than those for tRV powder intake, respectively. Gnetin C, a resveratrol dimer, with hydrolysis was maintained in plasma for >96 h with a 36 h MRT. With repeated doses once daily for 28 days, plasma tRV and gnetin C concentrations with hydrolysis were in good agreement with the theoretical curves. MSE powder was well tolerated up to the oral dosing of 5000 mg with no serious adverse events.