Matteo Cerea

Oral pulsatile drug delivery systems.

In the field of modified release, there has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable lag phase from the time of administration. In particular, the recent literature reports on a variety of pulsatile release systems intended for the oral route, which have been recognised as potentially beneficial to the chronotherapy of widespread diseases, such as bronchial asthma or angina pectoris, with mainly night or early morning symptoms. In addition, time-dependent colon delivery may also represent an appealing related application. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single- or multiple-unit systems provided with release-controlling coatings, capsular devices and osmotic pumps. Based on these premises, the aim of this review is to outline the rational and prominent design strategies behind oral pulsatile delivery.

Dry powder coating of pharmaceuticals: A review

Over the last half century, film coating technology has evolved significantly in terms of compositions and manufacturing processes, allowing for greater functionality, flexibility and efficiency. Driven by a combination of cost considerations and functionality, a range of dry powder coating technologies have been developed in both academic and industrial settings. These technologies can be generally classified into three major types based on the layer formation process: liquid assisted, thermal adhesion and electrostatic. In addition to specific manufacturing processes that must be implemented to achieve the desired product attributes, many of these techniques also require the use of novel excipients and specific formulations to provide acceptable manufacturability. This review summarizes the current dry powder coating technologies and highlights their industrial applicability with publicly disclosed case studies. Commentary on the future directions of dry powder coating is also provided.

Comparison of the In Vivo Pharmacokinetics and In Vitro Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing

ABSTRACT The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared in vivo the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions. In the in vivo study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.

Dry Coating of Soft Gelatin Capsules with HPMCAS

Dry coating is an innovative powder-layering technique that enables the formation of coatings on solid dosage forms with no need for using water or organic solvents. This technique envisages the distribution of polymer powder blends onto substrate cores and the concurrent or alternate nebulization of liquid plasticizers. In this work, a dry coating process based on hydroxypropyl methylcellulose acetate succinate (HPMCAS) was set up in a rotary fluid bed equipment to prepare enteric-coated soft gelatin capsules. Promising results were obtained in terms of process feasibility and product characteristics, thus suggesting the possibility of advantageous applications for the investigated technique when dealing with gelatin capsule substrates.

Polymeric coatings for a multiple-unit pulsatile delivery system: Preliminary study on free and applied films

In order to adapt a previously described swellable/erodible pulsatile delivery system to a multiple-unit configuration, insoluble films with adequate permeability and flexibility were proposed for application to its functional hydroxypropyl methylcellulose (HPMC) layer. By slowing down the penetration of water into the system, such films would be expected to improve the relevant effectiveness in delaying the onset of release without possibly impacting on the mechanism involved. Free films of Eudragit(®)NE containing differing amounts (10-20%) of a superdisintegrant, i.e. Explotab(®)V17, Ac-Di-Sol(®), Kollidon(®)CL or Kollidon(®)CL-M, were prepared by spraying technique and evaluated for hydration, permeability and tensile properties. The hydration and permeability characteristics were enhanced by the addition of the superdisintegrants, generally as a function of their concentration. Explotab(®)V17 was shown particularly useful to increase the film permeability. Moreover, it exerted a minor impact on the advantageous tensile properties of the acrylic polymer, especially in the wet state. Based on these results and on a preliminary release study performed with two-layer devices, the Eudragit(®)NE film with Explotab(®)V17 at the highest investigated percentage was identified as a potential formulation candidate for being applied to HPMC-coated cores thus allowing the onset of release to effectively be delayed by coatings of reduced thickness.

Oral delivery of insulin via polyethylene imine-based nanoparticles for colonic release allows glycemic control in diabetic rats.

In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption.

A study on the release mechanism of drugs from hydrophilic partially coated perforated matrices

Partially coated perforated systems (PCPS) based on low-viscosity hydroxypropyl methylcellulose (HPMC) as the polymeric material were formerly designed, prepared and evaluated in terms of in vitro behaviour. These systems proved to afford the pursued linear release with model drugs (metoprolol tartrate and benfluorex) of different solubility. To the aim of exploring the mechanisms concurring in the definition of zero-order kinetics, studies of drug release, polymer dissolution and medium penetration were performed on PCPS and constant release area systems (CRAS). According to the obtained results, PCPS release kinetics has to be mainly attributed to the progressive outward erosion of the core and to the related variation of the release area. The special geometry of the system, in fact, involves a gradual increase in the release surface, which allows the diffusional path lengthening to be offset. By properly selecting the shape and dimensions of the device as well as the physico-chemical characteristics of the hydrophilic polymer, the advantage of a zero-order release kinetics with programmable rate can be achieved.

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

This study aimed to develop a new formulation of Cryphonectria parasitica hypovirulent mycelium suitable for inoculations of tall trees from the ground. Cryphonectria 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.

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

Abstract 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 of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug.

Abstract The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates.