Definition and validation of the Design Space for co-milled nasal powder containing nanosized lamotrigine.

OBJECTIVE: Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS. MATERIALS AND METHODS: Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the in vitro dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses. RESULTS: Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5 h, 400 rpm, 0.8 PVA:LAM ratio) showed around 100 nm drug particles and 97% drug release in five minutes. CONCLUSION: From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.

Severe Postoperative Complications may be Related to Mesenteric Traction Syndrome during Open Esophagectomy.

BACKGROUND: During abdominal surgery, traction of the mesenterium provokes mesenteric traction syndrome, including hypotension, tachycardia, and flushing, along with an increase in plasma prostacyclin (PGI2). We evaluated whether postoperative complications are related to mesenteric traction syndrome during esophagectomy. METHODS: Flushing, hemodynamic variables, and plasma 6-keto-PGF1α were recorded during the abdominal part of open ( n = 25) and robotically assisted ( n = 25) esophagectomy. Postoperative complications were also registered, according to the Clavien-Dindo classification. RESULTS: Flushing appeared in 17 (open) and 5 (robotically assisted) surgical cases ( p = 0.001). Mean arterial pressure was stable during both types of surgeries, but infusion of vasopressors during the first hour of open surgery was related to development of widespread (Grade II) flushing ( p = 0.036). For patients who developed flushing, heart rate and plasma 6-keto-PGF1α also increased ( p = 0.001 and p < 0.001, respectively). Furthermore, severe postoperative complications were related to Grade II flushing ( p = 0.037). CONCLUSION: Mesenteric traction syndrome manifests more frequently during open than robotically assisted esophagectomy, and postoperative complications appear to be associated with severe mesenteric traction syndrome.

[Formulation of new generation drug delivery system for dry powder inhalation.] / Not available.

Based on the formulation method the dry powder inhalers (DPIs) can be divided in too types: carrier-based and carrier-free drug delivery systems. The newest researches report about several high potency carrier-free formulations, where the active ingredient and the excipients are together formulated to the DPI form. However, in Hungary the commercially available DPIs are carrier-based (e.g. lactose), which means that only the mic-onized active ingredient reaches the deeper lungs, the big carrier deposits in the upper airways. The present work is about formulating a high efficacy mannitol-based Pulmonary Drug Delivery System (PDDS), which is able to delivery different types of active ingredients to the deeper lungs with higher deposition rate. The present study involves the physico-chemical and aerodynamical characterisation of mannitol-based PDDS. The results demonstrated the use of the appropriate excipients (leucine, poly-vinyl-alcohol, cyclodextrine) and solvent combination (ethanol-water) during the co-spray drying, increases the inhalation properties of the mannitol. Such carrier systems with optimized properties can increase the aerolization efficacy of the active ingredient.

Post-endoscopic retrograde cholangiopancreaticography complications in liver transplanted patients, a single-center experience.

BACKGROUND: Complications in the biliary tract occur in 5%-30% after liver transplantation and the main part of the complications is successfully managed with endoscopic retrograde cholangiopancreaticography (ERCP). The incidence and risk factors for post-ERCP complications in liver transplantation patients are not well described. Our objective was to define the frequency of post-ERCP complications in liver transplantation patients at the Abdominal Center, Rigshospitalet, the only Liver Transplantation Center in Denmark. METHODS: Retrospective study of all ERCPs performed in liver transplantation patients during a 9-year period. RESULTS: A total of 292 ERCPs were included. Overall post-ERCP complications occurred in 24 procedures (8.2%): pancreatitis in 8 (2.7%), bleeding in 5 (1.7%), and cholangitis in 13 (4.5%) procedures. Simultaneous pancreatitis and cholangitis, and simultaneous bleeding and cholangitis occurred after two procedures, respectively. Multivariate analysis concerning overall complications identified biliary sphincterotomy (p = 0.006) and time since liver transplantation within 90 days postoperatively (p = 0.044) as risk factors for post-ERCP complications. Specifically concerning post-ERCP pancreatitis (PEP), it was found that pre-ERCP cholangitis was another independent risk factor for PEP (p = 0.026). Stent in the biliary tract prior to ERCP seemed to be protective (p = 0.041). CONCLUSIONS: Complications were of surprisingly mild degree. The rates of post-ERCP complications in our study were in line with previous studies with liver transplantation patients. Cholangitis prior to ERCP may be another risk factor for post-ERCP pancreatitis.

Polymorph screening of an active material.

Polymorph screening is currently one of the most important tasks for innovators and for generic companies from both pharmaceutical and intellectual property rights aspects. The different polymorphs have different physicochemical properties, such as the crystal polymorph-dependent solubility which influences the bioavailability. A former drug candidate obtained from Sanofi Pharmaceutical Company (Hungary) was investigated to explore its polymorphism, to distinguish the morphologies generated by analytical examinations and to investigate their relative stabilities. An Avantium Crystal 16 automatic laboratory reactor system was used for the polymorph studies and the studies of their dissolution. Eight polymorphs were obtained by crystallization and transformation methods then characterized by XRPD, DSC, and Raman spectroscopy, scanning electron microscopy, and light microscopy. All the morphologies could be stored in solid without any form transformation for a long time (2 years investigated). According to the first relative stability results, Form I, III, IVa, V, VI, VII are unambiguously metastable forms. Form II and IVb have similar thermodynamic stabilities, that were higher than those of the other polymorphs. A special dissolution medium was developed in which the eight polymorphs showed clear differences in the rate of dissolution.

Formulation of poorly water-soluble Gemfibrozil applying power ultrasound.

The dissolution properties of a drug and its release from the dosage form have a basic impact on its bioavailability. Solubility problems are a major challenge for the pharmaceutical industry as concerns the development of new pharmaceutical products. Formulation problems may possibly be overcome by modification of particle size and morphology. The application of power ultrasound is a novel possibility in drug formulation. This article reports on solvent diffusion and melt emulsification, as new methods supplemented with drying in the field of sonocrystallization of poorly water-soluble Gemfibrozil. During thermoanalytical characterization, a modified structure was detected. The specific surface area of the drug was increased following particle size reduction and the poor wettability properties could also be improved. The dissolution rate was therefore significantly increased.

Cytotoxicity testing of carrier-based microcomposites for DPI application.

Inhalation is an attractive delivery route for systemic and local therapy. High local drug concentrations may permit non-invasive delivery, lower therapeutic doses, reduced systemic side-effects, and reduced metabolic degradation of the drug in the liver. In our earlier study, carrier-based microcomposites were prepared and investigated. The present study introduces studies of the cytotoxicity of meloxicam-containing microcomposites on monolayers of Calu-3 cells, in order to acquire information on its availability in pulmonary formulations. By relating cytotoxicity and drug dissolution, the appropriate amount of meloxicam for dry powder inhalation could be determined.

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam.

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion-diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200-900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.

Water-soluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation.

The majority of active pharmaceutical ingredients are poorly soluble in water. The rate-determining step of absorption is the dissolution of these drugs. Inclusion complexation with cyclodextrin derivatives can lead to improved aqueous solubility and bioavailability of pharmacons due to the formation of co-crystals through hydrogen-bonding between the components. Inclusion complexes of loratadine were prepared by a convenient new method involving microwave irradiation and the products were compared with those of a conventional preparation method. Dissolution studies demonstrated that the solubility and rate of dissolution of loratadine increased in both of the methods used. The interactions between the components were investigated by thermal analysis and Fourier Transform Infrared studies. The microwave treatment did not cause any chemical changes in the loratadine molecule.