**5. Matrix polymeric systems**

74 Recent Advances in Plasticizers

emulsification of plasticizers with soya lecithin. The tensile stress of the material was decreased with increasing concentrations of the plasticizer, permeability of water vapours

Biodegradable films were prepared from a protein isolated from sunflower oil with additions of various polyalcohols, such as glycerol, ethylene glycol, propylene glycol, polyethylene glycols. The mixture was subjected to thermo-moulding at 150 °C using 150 MPa. Tensile strength of films was 6.3 to 9.6 MPa and elongation at break was 23 to 140 %. Permeability of water vapours was low; films were resistant against aqueous environment only in a limited degree, as migration of the plasticizer took place (Orliac et al.,

Transdermal systems are based on the adhesion of the system containing the active ingredient onto the intact skin and the transfer of the dissolved active ingredient through the skin. The limiting factor for the velocity of transdermal absorption is most frequently the thin membrane or a polymeric matrix structure. To fulfil the necessary precondition of the barrier principle as the controlling system of transdermal absorption, the velocity of permeation through the membrane or matrix must be lower than the velocity of penetration into the skin structures. Plasticizers are of extraordinary importance as they ensure not only suitable mechanical properties, in particular flexibility of the system, but also in connection

In the development of a suitable membrane for transdermal use, cellulose acetate casted from a chloroform solution was used. The polymer was plasticized with dibutyl phthalate, polyethylene glycol 600 and propylene glycol in a concentration of 40 %. The prepared membranes were characterized from the standpoint of mechanical properties, transfer of water vapours and permeability of diltiazem hydrochloride and indomethacin. Permeability of the active ingredient was the highest with the use of polyethylene glycol as the plasticizer, the lowest in the case of dibutyl phthalate (Rao & Diwan, 1997). The plasticizer of membranes from cellulose acetate was poly(caprolactone triol), and the pore forming agent was water (Meier et al., 2004). On the basis of testing the permeability of paracetamol, water was demonstrated to be a suitable porosigen with a possible regulation of porosity by its concentration, the plasticizer suitably acting as the modulator of permeation of the active ingredient. A combination of these two excipients yielded the membranes whose values of

The matrix system from polyvinyl acetate containing polyethylene-2 oleyl ether as the enhancer of permeation and triethyl citrate as the plasticizer resulted in a significant increase in the bioavailability of the antihistamine drug triprolidine. The effect was demonstrated after the administration of the system to the abdominal rabbit skin (Shin & Choi, 2005). Roughness, mechanical and adhesive properties of skin patch were studied. An adhesive plaster was prepared from a blend of polyvinyl alcohol and polyvinylpyrrolidon with glycerol or polyethylene glycols 200 or 400 as the plasticizers. The adhesivity of the system was ascertained only in contact with wet surfaces. Glycerol in a concentration of 10 % did not influence the very smooth texture of the surface of the plaster. The effect of the plasticizer was increased with decreasing molecular mass (Gal & Nussinovitch, 2009).

2003). The plasticizers used were evaluated as suitable for protein films.

**4. Polymeric membranes for transdermal system** 

with a decreased value of Tg increase the diffusivity of polymers.

the coefficients of permeation of paracetamol ranged from 10-7 to 10-5 cm s-1.

was moderately increased.

Matrix polymeric systems are heterogeneous systems composed of a polymer, plasticizers, other additives and the active ingredient, and they can be porous. They include primarily oral preparations with prolonged or retarded release of the active ingredient, or implants produced by extrusion or hot moulding or compression.

Extrusion is a process of conversion of raw materials to form a product of a uniform shape and density by forcing it through a nozzle under controlled conditions (Breitenbach, 2002). Plasticizers facilitate the manufacture and improve the parameters of preparations such as porosity, tortuosity, mechanical resistance, diffusivity, or compatibility of the components. Hot-melt extrusion, in which it is possible to process materials with higher Tg values, is advantageous.

Due to their little volatility, the plasticizers which are in the solid state in room temperature are advantageous. For plasticization of polyacrylate polymers, e.g. matrices from Eudragit RS PO, citric acid, in particular its monohydrate, turned out to be useful. Tensile strength and the elastic modulus were decreased, whereas elongation was increased. The plasticizing effect of citric acid achieved the plateau stage at its 25% concentration in polyacrylate, i.e. when achieving the solubility value of (Schilling et al., 2007). The continous process of extrusion and subsequent division of the extruded body into tablets was used in the formulation of enterosolvent preparations from the polyacrylate material Eudragit L100-55. Mixtures of two plasticizers, triethyl citrate and citric acid, were employed. Triethyl citrate markedly decreased the Tg value and thus decreased the temperatures in the individual zones of the extruder and the pressure during extrusion. The optimal concentration of citric acid was 17 %. 5-aminosalicylic acid was employed as the model active ingredient (Andrews et al., 2008).

Subcutaneous implants of a diameter of 1.5 mm and length of 18 mm weighing 40 mg containing thermolabile recombinant proteins and peptides were prepared from plasticized poly(lactide-co-glycolide) as the carrier and ethanol as the plasticizer (Mauriac & Marion, 2006). First, a 10% solution of the polymer in ethanol was prepared, followed by drying to achieve an ethanol concentration of 20 %. The polymer plasticized in such a way was mixed with the unplasticized one and the mixture was extruded at 75 °C. The following step was grinding of the extrudate at -5 to -10 °C with an ethanol content of 8 %. The active ingredient and other additives were added to the powder and the mixture was extruded at a temperature up to 70 °C. Another example of extremely volatile plasticizer is supercritical carbon dioxide (Lakshman, 2008). This compoud is added to facilitate processing of materials by extrusion method.

Starch is the biomaterial which has excellent parameters from the standpoint of availability, price and biocompatibility. In the presence of water and suitable polar hydrophilic compatible plasticizers during extrusions at temperatures over 100 °C amylopectin flows and at the same time native starch granules partially melt. The material can have two markedly different values of Tg. Interactions between starch and plasticizers with strong hydrogen bonds (Pushpadass et al., 2008) were demonstrated in it. The use of glycerol in a concentration of 25 % and secondary plasticizers such as stearic acid, sucrose or urea in markedly lower concentrations are advantageous. It thus yields a flexible material suitable as a biodegradable drug carrier.

Pharmaceutical Applications of Plasticized Polymers 77

spite of it, in praxis there are antimicrobial and hormonal preparations based on this principle. The system based on the principle of rapid precipitation of the solutions of the biotechnological copolymer PHB/PHC in different solvents was employed to formulate ISFI of the film type acting preventively against adhesions of the tissues as undesirable

Other types of ISFI are three-block copolymers of ABA or BAB types based on the gelation of their solutions after administration due to increased temperatures. Oligomers composed of polyethylene glycol blocks and the blocks of polyesters of aliphatic hydroxy acids are advantageous (Quiao et al, 2007; Tang & Singh, 2009). An advantage of the system ReGel® is the absence of toxic organic solvents and a solubilizing potential of the block copolymer. In pharmacotherapeutic praxis the system ReGel® with paclitaxel called OncoGel® is employed (Matthes et al., 2007; ). For some active ingredients, some polymers and some modes of administration a too intensive burst effect, changes in the velocity of release of the active ingredient, or irritability of the polymer, which in the systems is used in higher

Instead of polymer solutions in hydrophilic solvents, hydrophobic solvents of lower concentrations than the polymer concentration can be employed. They are thus the plasticized polymers. The behaviour of the system after its administration into the tissue is different, the system is not distributed into the environment. The polymer and possibly the plasticizer are subject to biodegradation, the mechanism of the release of the active ingredient is due to the enzymatic or hydrolytic destruction of the implant. A sufficiently low viscosity can be achieved, besides the use of the plasticizer, by increasing the temperature of the applied system. The maximal painless temperature in humans is stated as 53 °C, the maximal tolerable temperature without necrotic changes is 60 °C (Liu &

The flowable composition relates to a sustained released delivery system with risperidone was patented. It may be injected into the tissue whereupon it coagulates to become the solid

An in-situ-hardening paste, containing a biodagradable polymer and water soluble polymeric plasticizer was developed as delivery system for an active agent in the field of tissue regeneration. The hardened paste can be used as bone and cartilage replacement

The following Table 1 presents a survey of hydrophobic plasticizers suitable for ISFI.

Substance Melting point Boiling point Solubility

Benzyl alcohol -15 °C 205 °C 4.0 Benzyl benzoate 70 °C 324 °C 1.5 x 10-5 Ethyl heptanoate -66 °C 189 °C 3.0 x 10-4 Propylene carbonate -55 °C 242 °C 17.5 Triacetin 3 °C 258 °C 7.0 Triethyl citrate -55 °C 235 °C /20 kPa 6.5 Table 1. Characteristics of selected plasticizers with limited miscibility with water.

in water [%]

phenomena in post-surgical applications (Dai et al., 2009).

concentrations, can occur (Packhaeuser et al., 2004).

or gel, monolitic implant (Dadey, 2010).

matrix (Hellebrand et. al., 2009).

Wilson, 1998).

The matrix system containing a plasticized polymer can be also prepared by coating the pellets with a plasticized polymer and their subsequent compression to form tablets (Abdul et al., 2010). The use of a plasticizer does not require a curing step, which is heating after preparation. Pellets without a plasticizer are very brittle and break on compression. After an addition of 10 % triethyl citrate to the polymer Kollicoat SR30D (aqueous colloidal dispersion of polyvinyl acetate) the flexibility of the material was dramatically improved (Savicki & Lunio, 2005).
