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.

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.

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.

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.

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.

[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.

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.

Benzathine penicillin G: a model for long-term pharmacokinetic comparison of parenteral long-acting formulations.

WHAT IS KNOWN AND OBJECTIVE:   Long-acting intramuscular penicillin G injection is an important product for the management of some severe infections. However, testing the bioequivalence of such long-acting formulations is difficult. Our aim was to undertake such a test using a generic formulation containing 1 200 000 IU of benzathine penicillin G powder and an innovator's product (Retarpen(®) 1·2 million units; Sandoz, Switzerland). METHODS:   In an open, double-blind, randomized, two-periods, two-group crossover study, 12 healthy male volunteers received both formulations of benzathine penicillin G on two different days with a 5-month washout period between the doses and a sampling period of over 500 h. A simple, sensitive and rapid high-performance liquid chromatography (HPLC)-UV method was developed and validated for determination of penicillin G plasma concentrations and other pharmacokinetic (PK) parameters. RESULTS AND DISCUSSION:   The analytical method used produced linear responses within a wide analyte concentration range with average within-run and between-run variations of below 15% with acceptable recovery, accuracy and sensitivity. The primary PK parameters we used were maximum plasma concentration (Cmax ), time to reach the maximal concentration (Tmax ) and the area under the plasma concentration vs. time curve from time zero to the last sampling time (AUC0→t ) using a standard non-compartmental approach. Based on these parameters, the two formulations were bioequivalent. WHAT IS NEW AND CONCLUSION:   We illustrate the bioequivalence testing of a very long-acting product. The data indicate that the generic test formulation and the branded reference formulation were bioequivalent in fasting healthy Iranian male volunteers.

Self nano-emulsifying simvastatin based tablets: design and in vitro/in vivo evaluation.

The aim of this work is to improve the oral bioavailability of poorly water soluble drug, simvastatin (SV) through combining the advantages of self-nanoemulsifying systems (SNEs) and tablets. Ternary phase diagram was constructed using Labrafil, Tween 80 and Transcutol, in order to evaluate self-nanoemulsification domain. The particle size distribution and zeta potential of the prepared systems were evaluated using Malvern Zetasizer. Liquisolid powders were prepared using Aeroperl(®) as a coating material and Avicel(®) or Starch 1500 as carrier materials, the powder flow properties were then evaluated. Compressed SV SNE based tablets were evaluated regarding their physical characteristics, in-vitro release properties as well as in-vivo pharmacokinetic evaluation in six healthy human volunteers using a validated LC/MS/MS method. The in-vitro release results revealed that the developed SNE based tablets improved the release of SV significantly, compared to commercially available SV tablets (Zocor(®)). The optimal SV SNE tablet formulation was S3St10 (10% Labrafil, 60% Tween 80, and 30% Transcutol). The in-vivo evaluation of S3St10 revealed that rapid and enhanced absorption of SV could be obtained from the SNE based tablet, with a 1.5 fold increase in bioavailability than that obtained after administration of Zocor(®). Hence such an approach could be promising in improving the bioavailability of SV.

[Studies on absorption kinetics characteristics of diterpenoid alkaloids in rats after oral administration of Sini Tang powder].

The purpose of this study was to investigate the absorption kinetics of aconitine, mesaconitine and hypaconitine in rats after oral administration of Sini Tang powder. With cannulate portal and jugular veins cannulated (double-cannulate), conscious moving rats were orally administered Sini Tang. Then samples of portal and systemic blood were collected at the designated periods of time and analyzed for aconitine, mesaconitine and hypaconitine by HPLC. Apparent absorption coefficient of aconitine, mesaconitine and hypaconitine was caculated respectively. The results indicated that the apparent absorption coefficient of aconitine, mesaconitine and hypaconitine come from Sini Tang were 0. 336, 0. 090, 0. 176, respectively, which had some differences among them. It was also suggested that double-cannulated rat was useful for estimating the absorption kinetics of aconitine, mesaconitine and hypaconitine after orally administered Sini Tang by determining the AUC values for drugs in portal and systemic blood samples. The three alkaloids could all be detected in blood, but the absorption differences were existed among the three alkaloids.

[Study on compound compatibility of Jinglingzi powder based on absorption-metabolism model].

OBJECTIVE: To establish an absorption-metabolic model suitable for studying the complex traditional Chinese medicine (TCM) system, with the classic Jinlingzi Powder formula as the example, in order to explore the correlation among absorption behavior and absorption-metabolism behavior of different Jinlingzi Powder formulas and their compound compatibility. METHOD: An absorption-metabolic model suitable for TCM study was established according to in vivo characteristics of drugs, to combine the intestinal absorption model with the liver microsomal metabolism model. A quantitative analysis was conduced for absorbable components of Jinlingzi Powder and its absorption-metabolism components by HPLC. RESULT: The model could be used for studies on the absorption-metabolism process of TCM. Among the 15 main components which were derived from Jinlingzi Powder extracts, 10 could be absorbed by intestinal tract. A new component peak was shown after metabolism with the A-M model. The absorbable components of Jinlingzi Powder were related to its compatibility. Toosendan was found to be the major factor impacting the main component-absorption ratio (Ar) and absorption-metabolism ratio (Mr), followed by Rhizoma Corydalis. CONCLUSION: The absorption-metabolism model suitable for studying the complex traditional Chinese medicine system was established and used for the study on compound compatibility of Jinglingzi Powder. The compatibility of the formula has an impact on absorbable component ratio of Jinlingzi Powder, which helps interpret the theory of formula compatibility from the angle of in vitro compound pharmacokinetics (the difference between absorption and metabolism). Toosendan is the main factor impacting overall absorption and absorption-metabolism, while Rhizoma Corydalis is the minor factor.

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.

Production and characterization of HA and SiHA coatings.

Plasma sprayed hydroxyapatite (HA) coatings on metallic prostheses have been used clinically in dentistry and orthopedics since the mid 1980s. The coating properties are dependent on the spraying parameters. Since silicon-substituted hydroxyapatite (SiHA) has been shown to offer improved bioactivity over phase pure HA, SiHA coatings have the potential for enhanced performance in clinical application. In this study, phase pure HA and 0.8 wt% SiHA powders were synthesized with similar particle size distribution and morphology. The powders were plasma sprayed onto Ti-6Al-4V substrates at 37 kW and 40 kW plasma gun input power respectively. Four kinds of samples were prepared, HAC 37, HAC 40, SiHAC 37 and SiHAC 40. Materials characterization showed that the coatings were of relatively high phase purity. In vitro cell culture demonstrated that human osteoblast cells grew well on all samples, with the highest cell growth observed on SiHA coatings produced under the lower plasma gun input power.

Pharmacokinetics and pharmacodynamics of controlled release insulin loaded PLGA microcapsules using dry powder inhaler in diabetic rats.

The pulmonary route is an alternative route of administration for the systemic delivery of peptide and proteins with short-half lives. A long-acting formulation of insulin was prepared by encapsulation of protein into respirable, biodegradable microcapsules prepared by an oil in oil emulsification/solvent evaporation method. Insulin-loaded PLGA microcapsules prepared as a dry powder inhaler formulation were administered via the pulmonary route to diabetic rats and serum insulin and glucose concentrations were monitored. Control treatments consisted of respirable spray-dried insulin (RSDI) powder administered by intratracheal insufflation, insulin-loaded PLGA microcapsules and NPH (long-acting) insulin administered by subcutaneous (SC) administration. Pharmacokinetic analysis demonstrated that insulin administered in PLGA microcapsules illustrated a sustained release profile which resulted in a longer mean residence time, 4 and 5 fold longer than those after pulmonary administration of RSDI and SC injection of NPH insulin, respectively. Accordingly, the hypoglycemic profile followed a stable and sustained pattern which remained constant between 10 and 48 h. Results of the in vitro experiments were in good agreement with those of in vivo studies. Bronchoalveolar lavage fluid analysis indicated that microcapsules administration did not increase the activities of lactate dehydrogenase and total protein. However, histological examination of the lung tissue indicated a minor but detectable effect on the normal physiology of the rat lung. These findings suggest that the encapsulation of peptides and proteins into PLGA microcapsules technique could be a promising controlled delivery system for pulmonary administration.

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.

Lung deposition of aclidinium bromide from Genuair, a multidose dry powder inhaler.

BACKGROUND: Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). A next-generation multidose dry powder inhaler will be used for the delivery of aclidinium bromide. OBJECTIVES: To quantify whole lung deposition and regional lung deposition of aclidinium delivered by a multidose dry powder inhaler (Genuair) in healthy subjects. METHODS: A single dose (200 microg) of aclidinium bromide, radiolabelled with (99m)Tc, was administered from the multidose dry powder inhaler at a targeted peak inspiratory flow rate (PIFR) of 90 litres/min in 12 healthy males (18-63 years). Gamma scintigraphy was used to quantify drug deposition in the lungs and oropharynx, as well as amounts retained in the inhaler and exhaled. The quantities of drug deposited in 6 concentric regions within the lungs were also determined. RESULTS: The mean (+/- SD) PIFR was 79.0 +/- 9.4 litres/min. The mean (+/- SD) percentages of the metered dose deposited in the whole lung and oropharynx were 30.1 +/- 7.3 and 54.7 +/- 7.2%, respectively. Deposition of aclidinium occurred in all 6 lung zones, but was highest in the most central zone. CONCLUSIONS: These results demonstrated that the multidose dry powder inhaler delivered aclidinium efficiently to the lungs. The whole lung deposition seen in this study is an indication of the likely whole lung deposition in COPD patients who inhale with similar PIFRs; however, further studies in patients are required to confirm this.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device.

OBJECTIVES: The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. METHODS: The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. KEY FINDINGS: Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. CONCLUSIONS: Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

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.

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.