Karim Amighi

Formulation strategy and use of excipients in pulmonary drug delivery.

Pulmonary administration of drugs presents several advantages in the treatment of many diseases. Considering local and systemic delivery, drug inhalation enables a rapid and predictable onset of action and induces fewer side effects than other routes of administration. Three main inhalation systems have been developed for the aerosolization of drugs; namely, nebulizers, pressurized metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The latter are currently the most convenient alternative as they are breath-actuated and do not require the use of any propellants. The deposition site in the respiratory tract and the efficiency of inhaled aerosols are critically influenced by the aerodynamic diameter, size distribution, shape and density of particles. In the case of DPIs, since micronized particles are generally very cohesive and exhibit poor flow properties, drug particles are usually blended with coarse and fine carrier particles. This increases particle aerodynamic behavior and flow properties of the drugs and ensures accurate dosage of active ingredients. At present, particles with controlled properties are obtained by milling, spray drying or supercritical fluid techniques. Several excipients such as sugars, lipids, amino acids, surfactants, polymers and absorption enhancers have been tested for their efficacy in improving drug pulmonary administration. The purpose of this article is to describe various observations that have been made in the field of inhalation product development, especially for the dry powder inhalation formulation, and to review the use of various additives, their effectiveness and their potential toxicity for pulmonary administration.

Physical and thermal characterisation of Precirol and Compritol as lipophilic glycerides used for the preparation of controlled-release matrix pellets.

Physical and thermal properties of Compritol and Precirol as potential lipophilic binders in melt pelletisation process for the preparation of sustained-release matrix pellets were evaluated in this study. Experimental measurements were carried out using X-ray diffractometry, differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and rheological measurements. These studies have shown that the lipophilic binders may present a relatively complex behaviour depending on the sample treatment (untreated, freshly solidified, aged samples). DSC and HSM methods have shown the presence of polymorphism for Precirol. Moreover, both untreated and fresh solidified Precirol and Compritol samples present partially amorphous layered structure which slowly crystallise in time. The rate of crystallisation was found to be more rapid for Precirol, and highly dependent on the ageing conditions (storage temperature). Finally, the evaluation of the thermal and rheological properties of Precirol and Compritol mixtures have shown that the use of such mixtures, presenting well distinct melting properties, could be a very interesting tool for the preparation of high fatty binder content prolonged-release pellets in high shear mixers if the product temperature is carefully controlled (between 45 and 50 degrees C) during the pelletisation process.

Development and evaluation of prolonged release pellets obtained by the melt pelletization process

This study was performed in order to evaluate the possibility of obtaining prolonged release matrix pellets by a melt pelletization process in a laboratory high shear mixer (Mi-Pro, Pro-C-epT). Phenylephrine hydrochloride pellet formulations based on lactose 450 mesh and a mixture of Compritol 888 and Precirol ATO 5 as melting binders were evaluated. The fatty binder content of pellets was substantially increased (from 18 to 80% w/w). The effects of jacket temperature, massing time (MT) and impeller speed (IS) on the pellet characteristics were investigated. It was shown that pellets of narrow size distribution can be produced by using an IS of 800 rpm, a chopper speed of 4000 rpm and a MT of 8 min. On the other hand, the applicability of this technique for the production of sustained-release pellets using ciprofloxacin hydrochloride, ketoprofen and theophylline as less water soluble model drugs than phenylephrine hydrochloride was also studied. This study demonstrated that formulations based on an appropriate mixture of Precirol and Compritol can be used to produce in a short time prolonged release pellets for very hydrosoluble drugs like phenylephrine hydrochloride as well as for the other drugs tested.

3D printing in pharmaceutics: A new tool for designing customized drug delivery systems

Three-dimensional printing includes a wide variety of manufacturing techniques, which are all based on digitally-controlled depositing of materials (layer-by-layer) to create freeform geometries. Therefore, three-dimensional printing processes are commonly associated with freeform fabrication techniques. For years, these methods were extensively used in the field of biomanufacturing (especially for bone and tissue engineering) to produce sophisticated and tailor-made scaffolds from patient scans. This paper aims to review the processes that can be used in pharmaceutics, including the parameters to be controlled. In practice, it not straightforward for a formulator to be aware of the various technical advances made in this field, which is gaining more and more interest. Thus, a particular aim of this review is to give an overview on the pragmatic tools, which can be used for designing customized drug delivery systems using 3D printing.

Lactose characteristics and the generation of the aerosol

The delivery efficiency of dry-powder products for inhalation is dependent upon the drug formulation, the inhaler device, and the inhalation technique. Dry powder formulations are generally produced by mixing the micronised drug particles with larger carrier particles. These carrier particles are commonly lactose. The aerosol performance of a powder is highly dependent on the lactose characteristics, such as particle size distribution and shape and surface properties. Because lactose is the main component in these formulations, its selection is a crucial determinant of drug deposition into the lung, as interparticle forces may be affected by the carrier-particle properties. Therefore, the purpose of this article is to review the various grades of lactose, their production, and the methods of their characterisation. The origin of their adhesive and cohesive forces and their influence on aerosol generation are described, and the impact of the physicochemical properties of lactose on carrier-drug dispersion is discussed in detail.

Effect of some physiological and non-physiological compounds on the phase transition temperature of thermoresponsive polymers intended for oral controlled-drug delivery

Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candidate for controlled drug delivery systems. The polymer possesses a lower critical solution temperature (LCST) which was found to be around 32 degrees C in pure water, but which can be affected by the medium composition, i.e. presence of salts or surfactants. The knowledge of the effects of such substances on the LCST is very important while using PNIPAAm as a controlled drug delivery agent. The influence of a number of physiological and non-physiological salts and surfactants has been studied. The results obtained show that the addition of salts provokes an important decrease of the LCST of the polymer (salting out effect). A strong influence of the valence and of the size of the anions of the halide group was found. As to the surfactants, according to their type and concentration, a decrease or an increase of the LCST or even no effect at all were found. The effect of the GI secretions on the PNIPAAm phase separation temperature is also discussed.

Studies of pectin HM/Eudragit® RL/Eudragit® NE film-coating formulations intended for colonic drug delivery

Theophylline pellets were coated with Eudragit NE30D aqueous dispersions, containing various pectin HM/Eudragit RL30D ionic complexes, using an Uni-Glatt fluidized-bed apparatus. Dissolution studies were then carried out on the coated pellets at pH 6.0, in absence and in presence of commercial pectinolytic enzymes. The theophylline release from the coated pellets, after an initial latency phase, occurred linearly as a function of time. The theophylline release rate was dependent on the pectin HM content of the complexes incorporated in the coatings. The lowest theophylline release from the coated pellets was obtained when the pectin HM content of the complexes was 20.0% w/w (related to Eudragit RL), i.e. when the complexation between pectin HM and Eudragit RL is optimal. The theophylline release from the coated pellets was slower in presence of the pectinolytic enzymes when the pectin content of complexes is higher than 20% w/w. On the other hand, the effect of the enzymes induced an increase of the theophylline release when the pectin HM content of the coatings ranged between 10.0 and 15.0% w/w (related to Eudragit RL).

Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate

Theophylline pellets were coated with cellulosic (Aquacoat ECD 30, Surelease clear) or acrylic (Eudragit NE30D, RS30D) polymer aqueous dispersions, containing 10% (related to the insoluble polymer content) of pectin HM or calcium pectinate, using a Uni-Glatt fluidized-bed coating apparatus. When commercial pectinolytic enzymes were added to the dissolution media (0.05 M acetate - phosphate buffer, pH 6.0), the release of theophylline from the coated pellets was generally slower than that observed in the media without enzymes. The enzymatic slowing down of the drug release, depending on the type of the aqueous polymer dispersion used, is more important with mixed Eudragit NE/calcium pectinate coated pellets. The results obtained have been examined with regard to the validity of the approach based on the combination of pectins and the insoluble polymer aqueous dispersions intended for specific-delivery of drugs to the colon. The mechanism of the hydrophilic drug release from pellets coated with insoluble polymer aqueous dispersions containing an aqueous gel-forming polymer has been also discussed.

Evaluation of a new controlled-drug delivery concept based on the use of thermoresponsive polymers.

The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.

Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.