**8. Bioadesive plasticized polymers**

Plasticized polymers play an unsubstitutable role in the formulation of the bioadhesive drug delivery systems (BDDS). Bioadhesive polymers have been formulated into tablets, patches, or microparticles, typically as a matrix into which the drug is dispersed, or as a barrier through which the drug diffuses (Ahuja et al., 1997).

In most instances bioadhesive formulations are preferred over the conventional dosage forms, because bioadhesion allows the retention of the active substance in the place of application, or even absorption, and thus increases transmucosal fluxes. As mostly the hepatic first-pass metabolism is avoided, drug bioavailability may be enhanced. Target sites for bioadhesive drug delivery include the eye, GIT, oral cavity, nasal cavity, vagina, and cervix. The development of the adhesive dosage forms for controlled drug delivery to or via mucous membranes is of interest with regard to local drug therapy, as well the systemic administration of peptides and other drugs poorly absorbable from the gastrointestinal

Pharmaceutical Applications of Plasticized Polymers 81

In order to improve the flexibility and adhesiveness of the drug-loaded Eudragit E film plasticized with triacetin, secondary plasticizer can be supplemented. Polyethylene glycol 200, propylene glycol, diethyl phthalate, and oleic acid can serve as the secondary

The adhesive properties were revealed in plasticized star-like branched terpolymers of dipentaeythritol, D,L-lactic acid and glycolic acids, where dipentaerythritol in concentration 3 %, 5 % , or 8 % as the branching agent was used in the synthesis by polycondenzation. The common plasticizer, triethyl citrate, as well the non-traditional plasticizers methyl salicylate, ethyl salicylate, hexyl salicylate, and ethyl pyruvate were used (Fig. 1). These multifunctional plasticizers can serve not only as plasticizers, but potentially pharmacodynamic

Presently, there is still no universal test method for bioadhesion measurement. Tensile testing systems are the most widely used in-vitro method for assessing the strength of the bioadhesive interactions. The instrumental variables such as contact force, contact time and speed of withdrawal of probe from the substrate can affect the results of the adhesion

The adhesiveness of the plasticized branched oligoesters was measured as the maximal force needed for the detachment of the adhesive material from the substrate, using the material testing machine Zwick/Roel T1-FR050TH.A1K (Snejdrova & Dittrich, 2009). The porcine stomach mucin gel served as a model substrate. All the plasticizers used provide high effectiveness in viscosity lowering, and thus a perfect spreading of the adhesive material on the contact surface as the prerequisite for good adhesion. Sufficient bioadhesion force was revealed in the wide range of dynamic viscosity (Fig. 2) (Snejdrova

Fig. 1. Adhesiveness of branched oligoester carriers of the drug influenced by plasticizer type and concentration: triethyl citrate (TEC), methyl salicylate (MS), ethyl salicylate (ES).

plasticizer to improve adhesion (Lin, et al., 1991, 1995).

efficient ingredients.

measurements.

& Dittrich, 2008).

tract. There is an important difference between the technical adhesion and bioadhesion; it is the presence of water, which is necessary for bioadhesion but impedes most technical applications.

Similar to the plasticization mechanism also the mechanism of bioadhesion is usually analysed based on the polymer chains attractive and repulsive forces. Generally, bioadhesion is regarded as a two-step process. The first step is considered to be an interfacial phenomenon influenced by the surface energy effects and spreading process; a second step involves chain entanglement across a large distance, i.e. polymer chains show interdiffusion. Plasticizers can significantly influence both of these mentioned steps.

According to the wetting theory of bioadhesion (Smart, 2005), there is a significant effect of the viscosity of the plasticized polymer on adhesivity. A plasticized polymer due to a lower viscosity has a higher ability to spread onto a surface as a prerequisite for the development of adhesion.

The plasticizer reduces the aggregation process caused by the intermolecular attraction of the polymer, and it results in an increase in bioadhesiveness. The strength of bioadhesion should be sufficient, but not so sharp as to damage the biological tissue in the application site. The molecular weight, solubility parameter and concentration of the plasticizers used play an significant role. Further, a lower molecular weight or a higher concentration of plasticizers might lead to a greater plasticizing action (Qussi, & Suess, 2006).

Since the strength of adhesion is dependent on the number and type of interfacial interactions, different polymers and the way of their plasticization will exhibit different adhesive properties depending on both the chemical structure and physico-chemical properties of the polymer, as well the plasticizer used. Many approved pharmaceutical excipients, which are well known and widely used, possess bioadhesive properties and are the first choice candidates for the formulation of bioadhesive preparations particularly due to easier registration.

Bioadhesive materials are generally hydrophilic macromolecular compounds that contain numerous hydrogen bond forming groups, notably carboxyl, hydroxyl, amide and amine groups, and will hydrate and swell when placed in contact with an aqueous solution. Most often these materials need to hydrate to become adhesive but overhydration usually results in the formation of a slippery mucilage and loss of the adhesive properties (Peppas & Sahlin,1996). The invention provides mucoadhesive bioerodible, water soluble carriers for ocular delivery of pharmaceuticals for either systemic or local therapy (Warren et al., 2008).

Plasticizer efficiency in bio/mucoadhesion is negatively influenced by inducing of the drugpolymer interactions. In this case, the drug in BDDS is not only the active ingredient but represents an antiplasticizing additive responsible for the lowering of the adhesion strength.

The triacetin-plasticized Eudragit E can serve as a film-forming material for the selfadhesive drug-loaded film for transdermal application of piroxicam. Piroxicam did not represent only a simple model drug, it acts as an additive by molecularly dispersing it in the Eudragit E film. Drug-polymer interaction occurring between piroxicam and the Eudragit E film might be responsible for a decrease in adhesion strength.

tract. There is an important difference between the technical adhesion and bioadhesion; it is the presence of water, which is necessary for bioadhesion but impedes most technical

Similar to the plasticization mechanism also the mechanism of bioadhesion is usually analysed based on the polymer chains attractive and repulsive forces. Generally, bioadhesion is regarded as a two-step process. The first step is considered to be an interfacial phenomenon influenced by the surface energy effects and spreading process; a second step involves chain entanglement across a large distance, i.e. polymer chains show

According to the wetting theory of bioadhesion (Smart, 2005), there is a significant effect of the viscosity of the plasticized polymer on adhesivity. A plasticized polymer due to a lower viscosity has a higher ability to spread onto a surface as a prerequisite for the development

The plasticizer reduces the aggregation process caused by the intermolecular attraction of the polymer, and it results in an increase in bioadhesiveness. The strength of bioadhesion should be sufficient, but not so sharp as to damage the biological tissue in the application site. The molecular weight, solubility parameter and concentration of the plasticizers used play an significant role. Further, a lower molecular weight or a higher concentration of

Since the strength of adhesion is dependent on the number and type of interfacial interactions, different polymers and the way of their plasticization will exhibit different adhesive properties depending on both the chemical structure and physico-chemical properties of the polymer, as well the plasticizer used. Many approved pharmaceutical excipients, which are well known and widely used, possess bioadhesive properties and are the first choice candidates for the formulation of bioadhesive preparations particularly due

Bioadhesive materials are generally hydrophilic macromolecular compounds that contain numerous hydrogen bond forming groups, notably carboxyl, hydroxyl, amide and amine groups, and will hydrate and swell when placed in contact with an aqueous solution. Most often these materials need to hydrate to become adhesive but overhydration usually results in the formation of a slippery mucilage and loss of the adhesive properties (Peppas & Sahlin,1996). The invention provides mucoadhesive bioerodible, water soluble carriers for ocular delivery of pharmaceuticals for either systemic or local therapy (Warren et al., 2008). Plasticizer efficiency in bio/mucoadhesion is negatively influenced by inducing of the drugpolymer interactions. In this case, the drug in BDDS is not only the active ingredient but represents an antiplasticizing additive responsible for the lowering of the adhesion strength. The triacetin-plasticized Eudragit E can serve as a film-forming material for the selfadhesive drug-loaded film for transdermal application of piroxicam. Piroxicam did not represent only a simple model drug, it acts as an additive by molecularly dispersing it in the Eudragit E film. Drug-polymer interaction occurring between piroxicam and the Eudragit E

interdiffusion. Plasticizers can significantly influence both of these mentioned steps.

plasticizers might lead to a greater plasticizing action (Qussi, & Suess, 2006).

film might be responsible for a decrease in adhesion strength.

applications.

of adhesion.

to easier registration.

In order to improve the flexibility and adhesiveness of the drug-loaded Eudragit E film plasticized with triacetin, secondary plasticizer can be supplemented. Polyethylene glycol 200, propylene glycol, diethyl phthalate, and oleic acid can serve as the secondary plasticizer to improve adhesion (Lin, et al., 1991, 1995).

The adhesive properties were revealed in plasticized star-like branched terpolymers of dipentaeythritol, D,L-lactic acid and glycolic acids, where dipentaerythritol in concentration 3 %, 5 % , or 8 % as the branching agent was used in the synthesis by polycondenzation. The common plasticizer, triethyl citrate, as well the non-traditional plasticizers methyl salicylate, ethyl salicylate, hexyl salicylate, and ethyl pyruvate were used (Fig. 1). These multifunctional plasticizers can serve not only as plasticizers, but potentially pharmacodynamic efficient ingredients.

Presently, there is still no universal test method for bioadhesion measurement. Tensile testing systems are the most widely used in-vitro method for assessing the strength of the bioadhesive interactions. The instrumental variables such as contact force, contact time and speed of withdrawal of probe from the substrate can affect the results of the adhesion measurements.

The adhesiveness of the plasticized branched oligoesters was measured as the maximal force needed for the detachment of the adhesive material from the substrate, using the material testing machine Zwick/Roel T1-FR050TH.A1K (Snejdrova & Dittrich, 2009). The porcine stomach mucin gel served as a model substrate. All the plasticizers used provide high effectiveness in viscosity lowering, and thus a perfect spreading of the adhesive material on the contact surface as the prerequisite for good adhesion. Sufficient bioadhesion force was revealed in the wide range of dynamic viscosity (Fig. 2) (Snejdrova & Dittrich, 2008).

Fig. 1. Adhesiveness of branched oligoester carriers of the drug influenced by plasticizer type and concentration: triethyl citrate (TEC), methyl salicylate (MS), ethyl salicylate (ES).

Pharmaceutical Applications of Plasticized Polymers 83

di(2-ethylhexyl) phthalate, diisononyl phthalate, diisodecyl phthalate, epoxidized triglyceride,

linseed oil, castor oil,

Ethyl cellulose dibutyl sebacate coatings

propylene glycol, poly(caprolactone triol)

diethyl phthalate

triethyl citrate, triacetin, acetyltriethyl citrate

Eudragit® L dibutyl sebacate enteric film coatings

glycerol, ethylenglycol,

and chitosan sorbitol, glycerol, PEG 400 free membrane

polyhydric alcohols (glycerol, xylitol, sorbitol), secondary plasticizers (stearic acid, sucrose, urea)

PEGs

glycerol, sorbitol, mannitol, sucrose, citric acid, tartaric acid, maleic acid,

vegetable oils from soybean oil,

sunflower oil, fatty acid esters

dibutyl phthalate, PEG 600,

triacetin, acetylated monoglyceride,

diethyl phthalate microparticles

propylenglycol, PEGs free membrane

historically the first plasticized polymer used as a medicinal

preparation (wounds covering)

medical devices (bags, catheters, gloves, intravenous fluid containers, blood bags, medical tubings)

free membranes

system

delivery

polymeric membranes for transdermal

enteric or colonic drug

press-coated tablets for colon targeting

polymeric matrices

free membranes

**polymer Plasticizer Applied as** 

**Pharmaceutically used** 

("collodion") castor oil

Cellulose nitrate

Cellulose acetate

Hydroxypropyl

Hydroxypropyl

Chitosan salts

Shellac

succinate

Amylose Cassava starch

Gelatin

Blends of hydroxypropyl methylcellulose and ethylcellulose

Cellulose acetate phthalate Cellulose acetate trimellitate

methylcellulose phthalate Polyvinyl acetate phthalate

methylcellulose acetate

Blends of ethyl cellulose and

(chloride, lactate, gluconate)

Blend of native rice starch

Thermoplastic starch

PVC

Fig. 2. Relation between viscosity and adhesivity of the branched oligoester carriers plasticized by various type and concentration of the plasticizers (triethyl citrate (TEC), methyl salicylate (MS), ethyl salicylate (ES).
