RICERCA ITALIANA     

Polymer Processing for Biomedical Applications By Innovative and Sustenaible Technologies

Università degli Studi di Trieste

Abstract

The production processes of polymers and the synthesis of new polymers with different properties is a prerequisite for the utilization of these materials as biomaterials.
GMP practices are required for the production processes in the case of biomaterials. Special attention is paid to the elimination of any contaminant. The peculiar characteristics of supercritical fluids and, particularly, of supercritical carbon dioxide allows the replacement of organic solvents in the industrial applications producing new materials not obtainable using the traditional techniques and without solvent residual in the final product. The materials thet will be used in the present research project are monomers for the production of polymers that successively will be modified with the introduction of drugs or other compounds with angiogenic activity. For the same scope commercially available polymers (but approved for biomedical use) will be used. The following techniques will be used: the dispersion polymerization with supercritical carbon dioxide, the precipitation with supercritical antisolvent, the atomization assisted by the supercritical fluid, the impregnation of polymer matrices and the production of foams or polymeric membranes.
The research units will be involved both on process engineering and new products development. The design and construction of bench-scale plants will be carried out, and the effect of process parameters on the properties of the materials will be analysed. The obtained materials will be characterized using advanced analytical laboratory techniques, according with international standards. Among the studied materials and processes, the more promising ones will be developed on pilot scale plants, and a technological and economical feasibility evaluation will be presented. <<<

Principal Investigator

Ireneo KIKIC Università degli Studi di TRIESTE

Research Objectives

The chemical engineering research activity is moving, in the last years towards sectors that are common to others scientific areas: materials science, pharmaceutical science and technology, biology, medicine. It is a need to study phenomena different from those typical of the chemical industry but that can be solved with the same methodologies. For example, the study of diffusional processes inside a catalyst pellet or of the diffusion of a liquid in a liquid-liquid extraction unit are not different from the study of the release process of a drug inside the human body. The new problem is perhaps more difficult due to the boundary conditions.
Starting from this need the goal of the present research project is the application of new advanced technologies that are developed in the chemical engineering environment, to the solution of problems in the biomedical area. The scope is the production of drug release systems, of polymers for biomedical use through a new chemical synthesis process, of micro and macro polymeric systems for the tissue engineering. The production processes will be characterized by a very low environmental impact.
The technology proposed is based on the use of supercritical fluids.
The research units involved in the project present a good expertise for the different processes based on the use of supercritical fluids. This is demonstrated by the scientific production of the different components and from the fact that the Coordinator of the project is actually president of the International Society for the Advancement of Supercritical Fluids (I.S.A.S:F.).
The use of different techniques is justified by the need of producing materials with different morphologies, sizes, and functions starting from organic solutions, from aqueous solutions, from supercritical solutions. The programme has been based on the complementarity of the techniques and on the rationalization of the resources. The complementarity allows studying the same problem with different techniques. The results can be compared and a common solution can be proposed.
The choice of the technique most suitable of an industrial application will be done through a comparison of the results obtained by the different Research Units.
Similarly, the production of composites drug/polymer can be carried out by means of different techniques that have advantages and drawbacks that have to be evaluated on a scientific base. For what concerns the rationalization of the resources, research units will share their ability and knowledge. In this manner experimental apparatus and analytical instruments will be used at the best of their potentiality. At the beginning of the programme the coordinator will prepare a scheme of the resources available that can be shared by the units.
Different Units from Pharmaceutical and medicine departments will collaborate to the present project even if there are not officially participating to the project as research units. This is very important since in the next future it will be possible to integrate the activities and to present a common research project. <<<

First Results

The first attempt of the programme is the collection of physical and chemical properties of the materials to be processed. Bibliographic data and experimental analysis will be used.
Particularly, the main result of this first period is an in deep knowledge of the thermodynamic behavior of the mixture solvent/Supercritical fluid/solid at high pressure. Indeed, the knowledge of the phase behavior is fundamental for the phenomenological description of the processes.
In this step some experimental apparatus will be also, eventually modified. The Experimental tests on the selected compounds will be performed on lab-scale apparatus. Drugs, polymers and composite drug/polymer material will be generated. These materials will be characterized through the proper analytical techniques. The first result is the understanding of the phenomenology of the processes and the effect of the process parameters on the product properties. The main expected result is the production of one of more than one composite drug/polymer to be proposed and patented as drug delivery system. Finally, it will be proposed a scheme of applications of the process that allow to choice what material or class of material can be properly obtained with SCF-based processes.The scope of this last step is the development of the processes on the pilot scale, the study of the scaling, and the optimization of the processes (for example of the heat exchange, mixing..). <<<

Timescale

24 months

National and international background

No longer is the treatment of diabets, osteoporosis, asthma, cardiac problems, cancer and other diseases based only on conventional pharmaceutical formulations. Biology and the medicine are beginning to reduce the problems of disease to problems of molecular science, and are creating new opportunities for treating and curing disease. Such advances are coupled closely with advances in biomaterials and are leading to a variety of approaches for relieving suffering and prolonging life. Biomaterials are generally substances other than food or drug contained in therapeutic or diagnostic systems that are in contact with tissue or biological fluids.. They are used in many biomedical and pharmaceutical preparations; they play a central role in extracorporeal devices, from contact lenses to kidney dialysers, and are essential components of implants, from vascular grafts to cardiac pacemakers. There are many current biomaterial applications, found in about 8000 different kinds of medical devices, 2500 separate diagnostic products, and 40000 different pharmaceutical preparations [1].
Although biomaterials already contribute greatly to the improvement of health, the need exists for better polymer, ceramic, and metal systems. In particular improved methods of characterizing and producing polymers for: drug release systems, tissue applications and biomedical devices are needed.
Many biomaterials in clinical use were not originally designed as such and for this reason they allowed serial medical problems to be addressed.
A good alternative to the traditional production processes of polymeric biomaterials is the use of supercritical fluid based technologies [2, 3]. This use in many cases improves the traditional production processes due to the peculiar properties of supercritical fluids: mainly the possibility of tuning their physical properties (for example viscosity and diffusivity) between those characteristic of liquids and those of gases and the low environmental impact of supercritical fluids like carbon dioxide. The critical temperature (31.1°C) is suitable with the thermal stability of most materials and the critical pressure (74 bar) is easily reached in the industrial processes.
Different alternative processing based on the use of supercritical fluids can be envisaged: polymer synthesis, microparticles formation, impregnation and production of foams and membranes for the tissue engineering.
The main advantage of the use of supercritical carbon dioxide in the heterogeneous polymerization is the possibility of producing from the reactor, after depressurization, polymer powders with particle size ranging from about 50 nm to 1-2 micron or larger depending on the adopted operative conditions and the physico-chemical properties of the components of the reaction system [4]. A central role for the performance of a successful dispersion or emulsion polymerization is played by the surfactant. Since traditional surfactants, designed for use in aqueous or organic continuous phase, are completely insoluble in CO2, in order to stabilize the polymer colloid in CO2, special stabilizer compounds have been developed. All these molecules are characterized by a CO2-philic portion showing high solubility in the continuous medium and a CO2-phobic part which has high affinity to the polymer phase. The latter constitutes the anchoring portion of the surfactant which attaches to the surface of the polymer particle by either physical adsorption or chemical grafting depending on its nature. The CO2-philic portion extends in the continuous phase and prevents the onset of flocculation of the particles by imparting long-range repulsion among them which must be strong enough to compensate the long-range van der Waals attractions. A limited choice is possible for the nature of the CO2-philic portion of the interfacial active compound as the only polymers soluble in carbon dioxide under reasonable conditions (T < 100 °C, P < 40 MPa) are amorphous fluoropolymers, silicones and polyether-polycarbonate block copolymers. A more wide range of possibilities exist for the choice of the anchoring part which could be simply a block prepared with the same repeat unit incorporated in the polymer to be synthesized or a suitable reactive end-group which can react in situ with the growing polymer chains [5 - 7].
The more promising Supercritical fluid based processes are Supercritical Antisolvent precipitation (SAS) and Supercritical Assisted Atomization (SAA).
The supercritical antisolvent precipitation is a development of the conventional antisolvent crystallization, with the difference that the antisolvent is a SCF and not a liquid. It is applied feeding a precipitator through a coaxial injector the liquid solution containing the compound to be micronized and the CO2 at a given temperature and pressure. Due to the high diffusivity of carbon dioxide, the liquid solution became rapidly supersaturated. The elevated values of supersaturation allow the formation of spherical amorphous nuclei. Controlling the process parameters it is possible to modify the size and the morphology of the particles.
The Supercritical Assisted atomization process (SAA) mainly consists of three feed lines used to deliver supercritical CO2, the liquid solution and a inert gas and three main process vessels: saturator, precipitator, and condenser. The saturator is a high pressure vessel loaded with stainless steel perforated saddles. The high surface packing favours the contact between CO2 and the liquid solution obtaining the dissolution of the gaseous stream in the liquid. Then, a spray is produced that forms the droplets in the precipitator. A flow of heated N2 is also delivered that has the scope of favouring the evaporation of the liquid solvent. In this process the supercritical fluid improves the primary atomization of liquid droplets and promotes a decompressive atomization.
The first attempts of application of supercritical antisolvent precipitation (SAS) have been performed in 1989 [8] and are related to the formation of explosives microparticles. Then, this process has been applied to polymers [9], biopolymers and pharmaceutical products [10]. Tests have been performed in batch and continuous mode and mean particle diameters have been obtained from 1 micron to a hundred microns when different process arrangements and conditions have been used. In some cases, also 100 nanometer particles were obtained [11]. The results are very promising from an industrial point of view. In these last two-three years atomization processes assisted by supercritical fluids (SAA) have been also proposed [12] and they are very promising for the production of nanoparticles [13, 14].
The use of supercritical carbon dioxide as a drug solvent in the impregnation process involves several advantages. First of all, the plasticising effect on amorphous polymers [15] increases the mobility of polymer chains consenting then to reduce the heating need during impregnation; that is very important for the use of thermo-labile substances [16]. Moreover the entity of polymer swelling can be varied by simply modifying supercritical carbon dioxide density; the result is the possibility to modulate the solute amount that can be incorporated into the polymeric matrix [17, 18]. Finally polymer swelling improves diffusion processes of the solute; in fact the solute diffusion coefficients in the swollen polymer can be enhanced up to two orders of magnitude.
Two different impregnation mechanisms can be distinguished depending on solute affinity with the polymeric matrix. If solute/polymer affinity is low the drug tends to recrystallise during depressurisation. As a final result solute crystals are entrapped inside the polymeric matrix. On the contrary, when solute/polymer affinity is high, a specific interaction between the polymer and the solute can be established; that prevents recrystallisation and, after depressurisation, the solute can be found molecularly dispersed in the polymeric matrix . When the second mechanism occurs the solute partition factor between the polymer and the supercritical fluid is high and a good impregnation of the polymer is possible even though drug solubility in the supercritical fluid is low [19, 20].
Regeneration of naturals tissue from living cells to restore damaged tissues and organs is the objective of tissue engineering.
In vitro tissue reconstruction is based on three fundamental points: the cells, the supporting three-dimensional structures, called scaffolds, and the bioreactor. Scaffolds must be not only a physical support for cells but they must regulate also cell differentiation, proliferation and morphogenesis. Scaffolds are composed by a porous polymeric matrix that degrades in the biological environment leaving place to new regenerated tissue [21].
In scaffolds production there are four fundamental aspects: polymer choice, micro- and nano-architecture structure, surface funzionalization, and active principles delivery.
Among the different alternatives for the scaffolds production the gas antisovent precipitation seems very attractive [22]. With the gas antisolvent precipitation techniques it is possible to obtain nano-structured material, a complete elimination of residual solvents and loading of bioactive molecules during the production process [22, 23]. Moreover this last process minimizes the use of organic solvent because it requires mainly gases. <<<