Preparation and characterization of a powder manufactured by spray drying milk based formulations for the delivery of theophylline for pediatric use

The study considered different fat content cow milks to deliver theophylline orally. Powders were obtained by spray drying theophylline dispersed in fresh milk according to a full factorial design of experiments. The correlation of the independent (milk fat content, skimmed to whole milk, theophylline fraction, and drying temperature) with the dependent (yield of the process and residual moisture content of the powder, particle size and distribution, density, surface polarity and theophylline content) variables enabled the construction of a mathematical model and a desirability function to predict the optimized levels of the variables. Good predictability was achieved for density, fairly good for yield, moisture content, surface polarity and yield whereas theophylline content and particle size were poorly predicted. Powders with up to 60% theophylline presented spherical (3.7 \ub5m) and narrow sized distribution particles, with high density (1.6 g/cm 123) in high yields (>70%), stable for 6 month (25 \ub0C/65%RH) in a closed container and for no longer than 2 day, after reconstitution in water due to bacteria growth (no pathogens) without signs of crystallinity. Preparations obtained with low fat milk were less stable than high fat content milk. Therefore, fresh milk can be transformed into stable powder compositions to prepare oral solid/liquid dosage forms to deliver individualized doses of theophylline

Erodible drug delivery systems for time-controlled release into the gastrointestinal tract

In oral delivery, lag phases of programmable duration that precede drug release may be advantageous in a number of instances, e.g. to meet chronotherapeutic needs or pursue colonic delivery. Systems that give rise to characteristic lag phases in their release profiles, i.e. intended for time-controlled release, are generally composed of a drug-containing core and a functional polymeric barrier. According to the nature of the polymer, the latter may delay the onset of drug release by acting as a rupturable, permeable or erodible boundary layer. Erodible systems are mostly based on water swellable polymers, such as hydrophilic cellulose ethers, and the release of the incorporated drug is deferred through the progressive hydration and erosion of the polymeric barrier upon contact with aqueous fluids. The extent of delay depends on the employed polymer, particularly on its viscosity grade, and on the thickness of the layer applied. The manufacturing technique may also have an impact on the performance of such systems. Double-compression and spray-coating have mainly been used, resulting in differing technical issues and release outcomes. In this article, an update on delivery systems based on erodible polymer barriers (coatings, shells) for time-controlled release is presented

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems

In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit (R) L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A gamma-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the blood-stream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel

Dry coating of solid dosage forms : an overview of processes and applications

Dry coating techniques enable manufacturing of coated solid dosage forms with no, or very limited, use of solvents. As a result, major drawbacks associated with both organic solvents and aqueous coating systems can be overcome, such as toxicological, environmental, and safety-related issues on the one hand as well as costly drying phases and impaired product stability on the other. The considerable advantages related to solventless coating has been prompting a strong research interest in this field of pharmaceutics. In the article, processes and applications relevant to techniques intended for dry coating are analyzed and reviewed. Based on the physical state of the coat-forming agents, liquid- and solid-based techniques are distinguished. The former include hot-melt coating and coating by photocuring, while the latter encompass press coating and powder coating. Moreover, solventless techniques, such as injection molding and three-dimensional printing by fused deposition modeling, which are not purposely conceived for coating, are also discussed in that they would open new perspectives in the manufacturing of coated-like dosage forms

Preparation Process and in vitro release performances of HPMC-coated systems for pulsatile release of verapamil

The aim of this work was to evaluate the preparation process and in vitro release performances of HPMC coated systems for pulsatile release, containing verapamil as the active ingredient. Tableted cores of different size, formulated either for an immediate or prolonged drug liberation, were investigated in order to possibly meet diverse needs connected with the chronotherapy of ischemic heart disease, mainly occurring around awakening time.Tablets containing different amounts of verapamil hydrochloride were obtained by rotary press (AM8S, Ronchi, I) and coated with HPMC (Methocel\uaeE50 8% w/v aqueous solutions) in a tangential-spray rotary fluid bed (GPCG 1.1 Glatt\uae, D) equipped with a Teflon-coated disk. Release tests (n=3) were performed in a three-position USP28 disintegration apparatus (DT3, Sotax, CH; 800 ml distilled water, 37.0\ub10.5\ub0C). A single test unit was placed in each basket-rack assembly. Fluid samples were withdrawn automatically at fixed time points. Acetaminophen was quantified by spectrophotometer.The selected operating conditions allowed a feasible, high-yield process to be performed on the tablets in exam. Moreover, thanks to the relative flexibility of the coating technique, only minor modifications were introduced when coating different size cores. The in vitro release tests carried out on immediate release tablets with increasing coat thickness showed a typical lag phase preceding the prompt release of verapamil. Delayed release performances dependent on the coating level were also exhibited by systems prepared starting from prolonged release cores. From such systems, as pursued, the drug was released slowly over an extended time period. For all system typologies, a linear relationship was found between lag time and the applied amount of coating polymer.The results obtained in terms of low-viscosity HPMC-based aqueous spray-coating feasibility and programmable delayed release behavior seem to point out a potential suitability of the system for evening-dosing chronotherapy of ischemic heart diseas

New formulation and delivery method of Cryphonectria parasitica for biological control of chestnut blight

Aims: This study aimed to develop a new formulation of Cryphonectria parasitica hypovirulent mycelium suitable for inoculations of tall trees from the ground. C. parasitica hypovirulent strains are widely used for biological control of chestnut blight. However, it is often inconsistent and ineffective not only for biological reasons, but also because the current manual application of hypovirulent strains on adult plants is difficult, time-consuming and expensive. Here, we propose an improved formulation and more effective mode of application of hypovirulent strains, which could boost chestnut blight biocontrol. Methods and results: The Cp 4.2H hypovirulent strain was formulated as mycelium disks with polyethylene glycol (PEG) and hydroxypropyl methylcellulose (HPMC), loaded into lead-free pellets used as carriers to inoculate cankers on chestnut stems by shooting. The formulation of the mycelium did not hamper its viability which was stable, with an estimated shelf life of 72 days at 6\ub11 \ub0C. The inoculum effectiveness was confirmed ex planta and in planta in a small-scale pilot study in field, where formulated mycelium disks of hypovirulent strain Cp 4.2H were airgun shot into the chestnut bark. In planta, Cp 4.2H was recovered in 37% of bark samples taken around the inoculated points one year after the treatment. Conclusions: We demonstrated that the proposed airgun shooting inoculation method of C. parasitica hypovirulent strain formulated as mycelium disks is suitable for treatment of adult chestnut trees. Significance and impact of the study: The proposed method could be a valid alternative to the traditional manual technique of chestnut biocontrol. The main advantages are the cost-effectiveness and the ease to treat high-positioned, otherwise unreachable cankers both in orchards and forests. This article is protected by copyright. All rights reserved