Annalisa Dalmoro

Intensifying the microencapsulation process: ultrasonic atomization as an innovative approach.

In this review, new approaches to the microencapsulation processes, widely used in the manufacturing of pharmaceutical products, are discussed focusing the attention on the emerging ultrasonic atomization technique. Fundamentals and novel aspects are presented, and advantages of ultrasonic atomization in terms of intensification and low energy requests are emphasized.

Liposomes as siRNA Delivery Vectors

Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new agents with limited side effects, potentially useable against a wide range of diseases, including cancer. Among them, the short interfering RNAs (siRNAs), represent very effective molecules. Despite their in vitro efficacy, the major drawback that limits siRNAs usage consists in a difficult delivery due to their very low stability in physiological fluids, and to their limited membrane-permeability through physiological barriers. On the other hand, the liposomes (lipid bilayers closed in vesicles of various sizes) represent interesting drug delivery systems (DDSs) which can be tailored in order to get the best performance in terms of load, vesicle size and transfection yield. In this work, the current state of study in these two fields, and the connections between them, are briefly summarized.

PHEA-PLA biocompatible nanoparticles by technique of solvent evaporation from multiple emulsions.

Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly water soluble drugs. In this work the technique of solvent evaporation from multiple emulsions was applied to produce nanovectors based on new amphiphilic copolymer, the α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-polylactic acid (PHEA-PLA), purposely synthesized to be used in the controlled release of active molecules poorly soluble in water. To this aim an amphiphilic derivative of PHEA, a hydrophilic polymer, was synthesized by derivatization of the polymeric backbone with hydrophobic grafts of polylactic acid (PLA). The achieved copolymer was thus used to produce nanoparticles loaded with α tocopherol (vitamin E) adopted as lipophilic model molecule. Applying a protocol based on solvent evaporation from multiple emulsions assisted by ultrasonic energy and optimizing the emulsification process (solvent selection/separation stages), PHEA-PLA nanostructured particles with total α tocopherol entrapment efficiency (100%), were obtained. The drug release is expected to take place in lower times with respect to PLA due to the presence of the hydrophilic PHEA, therefore the produced nanoparticles can be used for semi-long term release drug delivery systems.

Analysis of Size Correlations for Microdroplets Produced by Ultrasonic Atomization

Microencapsulation techniques are widely applied in the field of pharmaceutical production to control drugs release in time and in physiological environments. Ultrasonic-assisted atomization is a new technique to produce microencapsulated systems by a mechanical approach. Interest in this technique is due to the advantages evidenceable (low level of mechanical stress in materials, reduced energy request, reduced apparatuses size) when comparing it to more conventional techniques. In this paper, the groundwork of atomization is introduced, the role of relevant parameters in ultrasonic atomization mechanism is discussed, and correlations to predict droplets size starting from process parameters and material properties are presented and tested.

In vitro dissolution of pH sensitive microparticles for colon-specific drug delivery

Objective: The objective of this work is to prepare oral dosage systems based on enteric materials in order to verify their possible use as Colon-Specific Drug Delivery Systems (CSDDSs). Methodology: In particular, three different copolymers of methyl-methacrylate (MMA) - acrylic acid (AA) are synthesized with increasing percentage of MMA (from 70% to 73%) and they are used to produce microparticles by the double-emulsion solvent evaporation method. The microparticles, loaded using theophylline as model drug, are then tested for drug release under varying pH to reproduce what happens in the human GI tract. Results: All the investigated systems have shown an effective pH sensitiveness: they show a good gastro-resistance, releasing the model drug only at higher pH, small intestine or colon, depending on the kind of used copolymer. Conclusion: The results confirm the usefulness of both the materials and the methods proposed in this study for colon-specific delivery applications.

Hydrophilic drug encapsulation in shell-core microcarriers by two stage polyelectrolyte complexation method.

In this study a protocol exploiting the combination of the ultrasonic atomization and the complexation between polyelectrolytes was developed to efficiently encapsulate a hydrophilic chemotherapeutic agent essentially used in the treatment of colon cancer, 5-fluorouracil, in enteric shell-core alginate-based microcarriers. The atomization assisted by ultrasound allowed to obtain small droplets by supplying low energy and avoiding drug degradation. In particular microcarriers were produced in a home-made apparatus where both the core (composed of alginate, drug, and Pluronic F127) and shell (composed of only alginate) feed were separately sent to the coaxial ultrasonic atomizer where they were nebulized and placed in contact with the complexation bulk. With the aim to obtain microstructured particles of alginate encapsulating 5-fluorouracil, different formulations of the first complexation bulk were tested; at last an emulsion made of a calcium chloride aqueous solution and dichloromethane allowed to reach an encapsulation efficiency of about 50%. This result can be considered very interesting considering that in literature similar techniques gave 5-fluorouracil encapsulation efficiencies of about 10%. Since a single complexation stage was not able to assure microcarriers gastroresistance, the formulation of a second complexation bulk was evaluated. The solution of cationic and pH-insoluble Eudragit® RS 100 in dichloromethane was chosen as bulk of second-stage complexation obtaining good enteric properties of shell-core microcarriers, i.e. a 5-FU cumulative release at pH 1 (simulating gastric pH) lower than 35%. The formation of interpolyelectrolyte complex (IPEC) between countercharged polymers and the chemical stability of 5-FU in microcarriers were confirmed by FTIR analysis, the presence of an amorphous dispersion of 5-FU in prepared microparticles was also confirmed by DSC. Finally, shell-core enteric coated microcarriers encapsulating 5-fluorouracil were used to prepare tablets, which can be potentially used as oral administration dosage systems for their 5-fluorouracil slower release.

Random l-lactide/ε-caprolactone copolymers as drug delivery materials

In this work, the degradation phenomena and the release kinetics of an active molecule from matrices systems made of random copolymers of ε-caprolactone (CL) and l-lactide (LA) were investigated by exposing the matrices, shaped as thin films, to simulated physiological environments. α-tocopherol was incorporated into the films as hydrophobic model molecule with the aim to investigate both its release pattern and its effect on erosion phenomena. In particular, the films have been kept at controlled conditions (temperature, stirring, pH) and they were characterized in terms of weight loss, water uptake, thermal properties, and change of number average molecular weight, in order to explain the molecule release kinetics and the degradation pathways of the copolymers. The main findings of this study are that the erosion phenomena take place significantly only when a critical value of the molecular mass was obtained in the sample; that the presence of the drug stabilizes the matrix and it decreases the rate of molecular mass decrease; and that crystallinity, reducing the chain mobility, causes lower erosion rates.

New Preparative Approaches for Micro and Nano Drug Delivery Carriers.

The full success of pharmacological therapies is strongly depending on the use of suitable, efficient and smart drug delivery systems (DDSs). Thus DDSs development is one of the main challenges in pharmaceutical industry both to achieve tailored carrier systems based on drug features and to promote manufacturing innovations to reduce energetic resources, emissions, wastes and risks. Main functions of an ideal DDS are: to protect loaded active molecules from degradation in physiological environments; to deliver them in a controlled manner and towards specific organs or tissues, to allow the maintenance of drug concentration within therapeutic window. Smart features, such as those able to induce active molecule release upon the occurrence of specific physiological stimuli, are also desirable. Under the manufacturing point of view, the current industrial scenery is obliged to respond to the increasing market requirements and to the mandatory rules in sustainable productions such as raw material and energy savings. In this work a general framework on drug delivery systems preparation techniques is presented. In particular two sections on innovation in preparative approaches carried out are detailed. These latter involve the use of microwave and ultrasonic energy applied in the production of polymeric and lipidic delivery systems on micro- and nanometric scale. The novelties of these preparative approaches are emphasized and examples of developed drug delivery carriers, loaded with vitamins and drug mimicking siRNA, are shown.

In situ coronary stent paving by Pluronic F127–alginate gel blends: Formulation and erosion tests

In this work the development of an experimental protocol to perform the in situ gel-paving of coronary stent is presented. Biocompatible aqueous blends of Pluronic F127 and sodium alginates are used as potential drug dosage system for pharmacological in situ treatment of coronary in-stent restenosis. Pluronic F127/alginate aqueous blend has the unique characteristic to be liquid at room condition and to form gel at physiological temperature. The proposed protocol is based on the blend injection on stent wall previously implanted in a flexible silicon pipe mimicking the coronary artery. Injected blend is warmed up until human body temperature achieving a soft gel, then it is reticulated by copper bivalent ions to obtain an hard gel. To test the gel paving resistance to erosion phenomena when it is exposed to fluid flux (i.e. blood flux) a dedicated device, (the Simulated Artery Device, SAD), was built to simulate the human circulatory apparatus. The SAD is an hydraulic circuit in which a buffer solution (at pH 7.4) was fluxed by a peristaltic pump through the pipe hosting the covered stent. Erosion tests were performed monitoring, by gravimetric and spectrophotometric methods, the residual mass anchored to stent mesh after given times. The obtained results showed that the in situ gel-paving developed protocol was efficacious and reliable. The gel-paving was completely eroded in a time of the same order of magnitude of the physiological period required to restore the coronary lesion (subsequent to the atheroma removal) and of a pharmacological therapy to inhibit the in-stent-restenosis pathology.

In Vitro Simulation of Human Digestion: Chemical and Mechanical Behavior

The drug release pattern from an orally administrated pharmaceutical dosage form can be significantly affected by simultaneous food intake and drug administration due to the changes in the gastrointestinal physiology, in particular because of the pH profile evolution and of the mixing conditions. In this work, the release from a commercial diclofenac tablet subjected to the pH conditions experienced by the gastrointestinal tract in fed conditions was analyzed and then compared with the release pattern obtained using a conventional dissolution method. The tablets behaved differently because of the partial dissolution of the coating due to high pH values in the first stage of the dissolution method, which takes into account the fed-state conditions. Tablets composed of a homemade enteric polymer loaded with diclofenac overcame this drawback. Moreover, an in vitro device mimicking peristaltic contractions in the stomach was proposed, and the release pattern from commercial tablets was compared with that obtained under conventional dissolution conditions. The release pattern was strongly influenced by the hydrodynamics. The two experimental setups (pH and peristalsis simulations) demonstrate that a gastrointestinal reproduction closer to the real physiology is necessary to achieve an accurate and reliable prediction of the behavior of pharmaceuticals.