**4. Plasticizers in transdermal drug delivery systems**

Many of the polymers used in pharmaceutical formulations are brittle and require the addition of a plasticizer into the formulation. Plasticizers are added to pharmaceutical polymers intending to ease the thermal workability, modifying the drug release from polymeric systems and improving the mechanical properties and surface properties of the dosage form (Felton, 2007; Lin et al., 2000; Wang et al., 1997; Wu & McGinity, 1999; Zhu et al., 2002).

The plasticizers used in pharmaceutical formulations present a) in coating material of solid dosage forms, and b) in transdermal therapeutic systems. The list of frequently used plasticizers in pharmaceutical formulations is given below (Table 1) (Wypch, 2004).


Table 1. Plasticizers Used in the Pharmaceutical Formulations (Wypch, 2004).

It is observed that the plasticizers added to transdermal therapeutic systems are mostly used in the proportions between 5-20%. The chemical formulas of 6 plasticizers frequently used in transdermal drug delivery studies are given in Table 2.

plasticizer are DSC analyses and the decrease in glass transition temperature when

In pharmaceutical formulations, effectiveness of a plasticizer agent substantially depends on its amount added to the formulation and on the polymer-plasticizer interaction. When an aqueous dispersion is in question, the proportion and amount of partition was found to be dependent on the solubility of the plasticizer in water and its affinity to the polymer phase. When water-insoluble plasticizers will be dispersed in an aqueous medium, they should

Many of the polymers used in pharmaceutical formulations are brittle and require the addition of a plasticizer into the formulation. Plasticizers are added to pharmaceutical polymers intending to ease the thermal workability, modifying the drug release from polymeric systems and improving the mechanical properties and surface properties of the dosage form (Felton, 2007; Lin et al., 2000; Wang et al., 1997; Wu & McGinity, 1999; Zhu et

The plasticizers used in pharmaceutical formulations present a) in coating material of solid dosage forms, and b) in transdermal therapeutic systems. The list of frequently used

plasticizers in pharmaceutical formulations is given below (Table 1) (Wypch, 2004).

Glycerol and esters Hydrophilic Glycerine, Glycerine triacetate,

Glycol derivatives Hydrophilic Propylene glycol, Poliethylene

Sebacic acid esters Lipophilic Dibutyl sebacate, Diethyl sebacate

Citric acid esters Hydrophilic Triethyl citrate, Tributhyl citrate

It is observed that the plasticizers added to transdermal therapeutic systems are mostly used in the proportions between 5-20%. The chemical formulas of 6 plasticizers frequently used in

Phthalic acid esters Lipophilic Dibutyl phthalate, Diethyl

Glyceryltributyrate

glycol

phthalate

plasticizer is added to polymer (Felton, 2007; Zhu et al., 2002).

firstly be emulsified and then added to the polymer (Felton, 2007).

**Group Hydrophilic/Lipophilic Plasticizer** 

Oleic acid esters Hydrophilic Oleil oleate

Tartaric acid esters Lipophilic Diethyl tartarate

Table 1. Plasticizers Used in the Pharmaceutical Formulations (Wypch, 2004).

Sugar alcohols Hydrophilic Sorbitol

transdermal drug delivery studies are given in Table 2.

**4. Plasticizers in transdermal drug delivery systems** 

al., 2002).

Table 2. The chemical formulas of the frequently used plasticizers in transdermal formulations.

Among the plasticizers commonly used in the formulation of transdermal films, there are the phthalate and citrate esters and glycol derivatives (Gal & Nussinovitch, 2009). The plasticizers used in the studies conducted through last 20 years, their proportions and the polymers they are used with are given as a table (Table 3).

Following are the reasons which can be counted among those for adding plasticizers to the polymer films to be used in transdermal drug delivery systems:


Plasticizers in Transdermal Drug Delivery Systems 101

Eudragit RL PO, E100, S100

Triacetin 25-125 Eudragit NE40D Matrix Cilurzo et al., 2008

Propylene glycol 10 Pectin Matrix Güngör et al., 2008

Triacetin 10-45 Eudragit E 100 Matrix Elgindy & Samy, 2009

Polyvinylpyrrolidone Hydroxypropylcellulose Acrylate copolymer Acrylate/Octylacrylamide

and NE 40D

copolymer Silicon Gum Polyvinyl Alcohol Polyisobutylene

20, 40 Polyvinyl Alcohol

<sup>10</sup>Polyvinyl Alcohol :

Polyvinyl Alcohol: Polyvinylpyrrolidone Ethyl cellulose: Polyvinylpyrrolidone

Eudragit L100 Eudragit L100-55 Eudragit S100

Ethyl cellulose: Polyvinylpyrrolidone Ethyl cellulose:

cellulose Ethyl cellulose

cellulose

Hydroxypropyl methyl

Carboxy methyl cellulose

Hydroxypropyl methyl

**Type of Transdermal Formulation**

Film forming polymeric solution

NE40D Matrix Inal et al., 2008

cellulose:Ethyl cellulose Matrix Limpongsa &

Polyvinylpyrrolidone Matrix Barhate et al., 2009

Polyvinylpyrrolidone Matrix Gal & Nussinovitch, 2009

**Reference** 

Schroeder et al., 2007, b

Umprayn, 2008

Matrix Jadhav et al., 2009

Matrix Marzouk et al., 2009

Matrix Pandit et al., 2009

Kumar Dey, 2010

Matrix Bagchi &

**Plasticizer % w/w Polymer** 

1-6 2.1 4

Triacetin 20 Eudragit E 100: Eudragit

Triethyl citrate 30 Hydroxypropyl methyl

Triethyl citrate Triacetin

Tributyl citrate

Dibutyl phthalate

Glycerin Polyethylene glycol 400 Propylene Glycol

Glycerin Polyethylene glycol 200 Polyethylene glycol 400

Propylene Glycol Dibutyl phthalate

Propylene Glycol Polyethylene glycol 400

Propylene Glycol 20,

Dibutyl phthalate 30

30 30

5, 10

30,40

Dibutyl phthalate


5.48 Eudragit E 100 Drug free

40 Cellulose acetate Drug free

Hydroxypropylcellulose Hydroxypropylcellulose:

Hydroxypropylcellulose:

Hydroxypropylcellulose:

glycol 600 10-50 Cellulose Acetate Membrane Wang et al., 2002

Glycerine 4 Polyvinyl Alcohol 72000 Matrix Padula et al., 2003

glycol 400 40 Carboxymethyl Guar Matrix Murthy et al., 2004

(70%) 2 Polyvinyl Alcohol Matrix Nicoli et al., 2005

(70%) 4 Polyvinyl Alcohol Matrix Nicoli et al., 2006

Hydroxypropylcellulose

Eudragit RL PO Silicon Gum Acrylate copolymer

(70%) 4 Polyvinyl Alcohol 83400 Matrix Femenia-Font et al., 2006

Dibutyl phthalate 10 Eudragit E 100 Matrix Gondaliya &

Eudragit E 100

Carbopol 971P

Polycarbophil

Ethyl cellulose: Polyvinylpyrrolidone

Polyvinylpyrrolidone

Eudragit:

**Type of Transdermal Formulation**

Drug free film

Polyvinylpyrrolidone Matrix Amnuaikit et al., 2005

Polyvinylpyrrolidone Matrix Dey et al., 2007

Xanthan Gum Matrix Kumar et al., 2007

Film forming polymeric solution

**Reference** 

Arvanitoyannis et al.,

film Lin et al., 1991

1997

film Rao & Diwan, 1997

Matrix Repka & McGinity, 2001

Matrix Mukherjee et al., 2005

Pundarikakshudu, 2003

Schroeder et al., 2007,a

**Plasticizer % w/w Polymer** 

Sucrose 20 Polyvinyl Alcohol:

Dibutyl phthalate 30 Ethyl cellulose

Dibutyl phthalate 30 Ethylcellulose:

Propylene Glycol 20 Polyvinyl Alcohol

Chitosan

Triacetin 1.43-

Dibutyl phthalate Propylene glycol Polyethylene glycol 600

Polyethylene glycol 3350 <sup>5</sup>

Polyethylene

Triethyl citrate

Polyethylene

Dibutyl phthalate 20

Sorbitol Solution

Sorbitol Solution

Sorbitol Solution

Dibutyl phthalate

Triethyl citrate 6

Sorbitol


Plasticizers in Transdermal Drug Delivery Systems 103

The selection of plasticizers depends on the characteristics of polymer used to prepare transdermal formulation. When the composition of transdermal film/patch formulations in the patents was looked over, it was seen that polyvalent alcohols *e.g.* glycerin and 1,2 propandiol (propylene glycol) are generally used as plasticizers to softening the polymers in the formulation (Deurer et.al. 1999; Herrmann & Hille, 1999; Selzer 2001; Selzer, 2004). Higher alcohols such dodecanol, or mineral oil, silicone oil, isopropyl myristate; isopropyl palmitate; polyethylene glycol 400; diethyl sebacate and/or dibutyl sebacate; hydrocarbons, alcohols, carboxylic acids and derivatives thereof were also added into transdermal

formulations as plasticizer (Petereit et.al. 2005; Salman & Teutsch 2011; Selzer, 2001).

skin is important (Gal & Nussinovitch, 2009).

Without a plasticizer, a very hard but brittle film is obtained. This means that, external forces such as bending, stretching and stripping from surface will cause tearing of the film without too much effort. However, when transdermal patches are in question, rather than reduction in the hardness of the patch, its endurance when positioned or repositioned on the

In studying the mechanical properties of transdermal patches or films, tensile testing is the primarily interested subject. Tensile tests enable to study the mechanical properties of the formulation such as stress strain curves and stress at failure. These properties provide information about the resistance to damage during storage and usage. The effect of the type and proportion of the plasticizer in a formulation on the mechanical properties can also be

The tensile strength of the transdermal films varies with the type of the polymer and plasticizer used. Generally a soft and weak polymer is identified with low tensile strength and low elongation values, a hard and brittle polymer is identified with moderate tensile strength and low elongation values and a soft and tough polymer is identified with high

Barhate et al. have prepared matrix type transdermal patches using polyvinyl alcohol and polyvinyl pyrolidone as polymer and using glycerin, polyethylene glycol 400 and propylene glycol in proportions 20% and 40% as plasticizer and studied carvedilol permeation from these patches. Plasticizers used have ethylene oxide groups and display their effects thanks to the hydrogen bonds they form with polymer molecules. This interaction gives flexibility to the polymer. Tensile strength measures the ability to patch to withstand rupture. In the formulations prepared, highest tensile strength has obtained when glycerine was used as plasticizer. On the other hand, it was determined that in vitro permeation of carvedilol

Drug free polymeric patches have been prepared using various polymers (Eudragit, hydroxypropylmethyl cellulose, cellulose acetate, polyvinyl pyrolidone and polyethylene glycol 4000) and effect of various plasticizers on mechanical and physicochemical properties of the patches have been investigated. Polyethylene glycol 400, dibutyl phthalate and propylene glycol were used as plasticizer in proportion of 40% (w/w) of the weight of the dry polymer. Tensile strength and folding endurance properties of the patches prepared with dibutyl phthalate have been found higher compared to those prepared with propylene

understood by this way (Gal & Nussinovitch, 2009; Rajabalaya et al., 2010).

tensile strength and high elongation values (Bharkatiya et al., 2010).

increased when polyethylene glycol 400 was used (Barhate et al., 2009).

glycol and polyethylene glycol 400 (Bharkatiya et al., 2010).


Table 3. The plasticizers used in the transdermal studies conducted through last 20 years, their proportions and the polymers they are used with.

Cellulose acetate Hydroxypropyl methyl

Polyvinylpyrrolidone Polyethylene glycol 4000 Eudragit RL 100-RS 100

Hydroxypropyl methyl cellulose E15: Eudragit RS 100 Hydroxypropyl methyl cellulose E15: Eudragit RL

Hydroxypropyl methyl

Glycerin 4 Polyvinyl Alcohol 29, 83,115 Matrix Padula et al., 2010

Hydroxypropyl methyl cellulose, Eudragit RL 100,

Hydroxypropyl methyl

Polyvinylpyrrolidone Eudragit RS100

Hydroxypropyl methyl

Table 3. The plasticizers used in the transdermal studies conducted through last 20 years,

Polyvinyl Alcohol Polyvinylpyrrolidone Trimethoxysilane

cellulose

100

cellulose Eudragit RL 100

cellulose

Eudragit RL 100 Hydroxypropyl methyl **Type of Transdermal Formulation**

Bilayered

30,40 Gum Copal Matrix Mundada & Avari, 2010

Polyvinylpyrrolidone Matrix Rajabalaya et al., 2010

Eudragit RS 100 Matrix Amgoakar et al., 2011

L30D55 Matrix Nesseem et al., 2011

100, Polyvinylpyrrolidone Matrix Rajan et al., 2010

**Reference** 

Matrix Bharkatiya et al., 2010

Matrix Karunakar et al., 2010

Matrix Madishetti et al., 2010

Matrix Mamatha et al., 2010

Matrix Shinde et al., 2010

Matrix Guo et al., 2011

Matrix Irfani et al., 2011

Matrix Parthasaraty et al., 2011

**Plasticizer % w/w Polymer** 

40

15,

Dibutilsebacate 5, 10 Eudragit E100

glycol 400 5, 10 Eudragit RL 100

30

Dibutyl phthalate 5-25 Eudragit RS 100, Eudragit RL

Chitosan

cellulose

Ethyl cellulose

cellulose

Glycerin 5 Polyvinyl Alcohol:Eudragit

their proportions and the polymers they are used with.

Dibutyl phthalate Propylene Glycol Polyethylene glycol 400

Propylene Glycol 15

Propylene Glycol 20

Propylene Glycol 20

Polyethylene glycol 400 Dibutyl phthalate

Dibutyl phthalate

Triethyl citrate 5

Glycerin 10

Dibutyl phthalate 10

Glycerin 10, 20,

Polyethylene

Glycerin

Sorbitol

The selection of plasticizers depends on the characteristics of polymer used to prepare transdermal formulation. When the composition of transdermal film/patch formulations in the patents was looked over, it was seen that polyvalent alcohols *e.g.* glycerin and 1,2 propandiol (propylene glycol) are generally used as plasticizers to softening the polymers in the formulation (Deurer et.al. 1999; Herrmann & Hille, 1999; Selzer 2001; Selzer, 2004). Higher alcohols such dodecanol, or mineral oil, silicone oil, isopropyl myristate; isopropyl palmitate; polyethylene glycol 400; diethyl sebacate and/or dibutyl sebacate; hydrocarbons, alcohols, carboxylic acids and derivatives thereof were also added into transdermal formulations as plasticizer (Petereit et.al. 2005; Salman & Teutsch 2011; Selzer, 2001).

Without a plasticizer, a very hard but brittle film is obtained. This means that, external forces such as bending, stretching and stripping from surface will cause tearing of the film without too much effort. However, when transdermal patches are in question, rather than reduction in the hardness of the patch, its endurance when positioned or repositioned on the skin is important (Gal & Nussinovitch, 2009).

In studying the mechanical properties of transdermal patches or films, tensile testing is the primarily interested subject. Tensile tests enable to study the mechanical properties of the formulation such as stress strain curves and stress at failure. These properties provide information about the resistance to damage during storage and usage. The effect of the type and proportion of the plasticizer in a formulation on the mechanical properties can also be understood by this way (Gal & Nussinovitch, 2009; Rajabalaya et al., 2010).

The tensile strength of the transdermal films varies with the type of the polymer and plasticizer used. Generally a soft and weak polymer is identified with low tensile strength and low elongation values, a hard and brittle polymer is identified with moderate tensile strength and low elongation values and a soft and tough polymer is identified with high tensile strength and high elongation values (Bharkatiya et al., 2010).

Barhate et al. have prepared matrix type transdermal patches using polyvinyl alcohol and polyvinyl pyrolidone as polymer and using glycerin, polyethylene glycol 400 and propylene glycol in proportions 20% and 40% as plasticizer and studied carvedilol permeation from these patches. Plasticizers used have ethylene oxide groups and display their effects thanks to the hydrogen bonds they form with polymer molecules. This interaction gives flexibility to the polymer. Tensile strength measures the ability to patch to withstand rupture. In the formulations prepared, highest tensile strength has obtained when glycerine was used as plasticizer. On the other hand, it was determined that in vitro permeation of carvedilol increased when polyethylene glycol 400 was used (Barhate et al., 2009).

Drug free polymeric patches have been prepared using various polymers (Eudragit, hydroxypropylmethyl cellulose, cellulose acetate, polyvinyl pyrolidone and polyethylene glycol 4000) and effect of various plasticizers on mechanical and physicochemical properties of the patches have been investigated. Polyethylene glycol 400, dibutyl phthalate and propylene glycol were used as plasticizer in proportion of 40% (w/w) of the weight of the dry polymer. Tensile strength and folding endurance properties of the patches prepared with dibutyl phthalate have been found higher compared to those prepared with propylene glycol and polyethylene glycol 400 (Bharkatiya et al., 2010).

Plasticizers in Transdermal Drug Delivery Systems 105

found that, the effect of the plasticizer on drug transport is related to the physicochemical properties of the permeant, in particular to its solubility in the plasticizer (Padula et al.,

In transition studies conducted with diltiazem hydrochloride and indomethacine, diffusion of the drug has been found as the films plasticized with polyethylene glycol 600 > dibutyl phthalate > propylene glycol, in order. It has been concluded that, permeation of the drugs and mechanical properties of the film were affected by the choice of suitable plasticizer and

In their study, Amgokar and coworkers have prepared transdermal films of budesonide. In the films, Eudragit RL 100: Eudragit RS and ethylcellulose-polyvinylpyrolidone (in proportions of 7:3 and 7:2, respectively) have been used as polymers and polyethylene glycol 400 has taken place as plasticizer. While drug release has found proportional to the polymer concentration, increase in the plasticizer amount has caused an increase in the weight of the film. It has also been observed that, increase in the plasticizer amount has also increased the humidity absorption of the transdermal films. It has been reported that, permeation of budesonide was the highest when polyethylene glycol 400 has been used in

Irfani and coworkers have used different combinations of hydoxypropyl methylcellulose, Eudragit RS 100 and polyvinylpyrolidone, when preparing transdermal films of the active substance, valsartan. In the formulations, different proportions (10%, 20% and 30%) of glycerin have been tried as plasticizer. It has been found that, increasing plasticizer concentration was increasing the diffusion rate of the active substance. Besides, when also the polymer combination of Eudragit RS and hydroxypropyl methylcellulose has been used with 30% glycerine, an increase in the diffusion rate of valsartan has been determined (Irfani

In a study, effects of two plasticizers, dibutyl phthalate and dibutyl sebacate, on the mechanical properties of the transdermal films prepared with Eudragit 100 polyvinylpyrolidone polymer mixture have been researched. It was shown that tensile strength was gradually decreased as the plasticizer concentration in the patch increased. It can be concluded from this result that plasticizer molecules disrupt the inter-chain cohesive forces of the polymer. Dibutyl phthalate and dibutyl sebacate have affected the mechanical properties of the transdermal system similarly. The finding that dibutyl sebacate is a suitable plasticizer for a more rapid release has been found in conformance with the finding of Siepmann and colleagues stating that dibutyl sebacate ensures faster release, whereas plasticizers containing phthalate group should be preferred when extended effect is

In the study where Gum copal has been used as polymer, hydrophobic dibutyl phthalate and hydrophilic glycerin and polyethylene glycol 400 have been preferred as plasticizer. It has been observed that, the films prepared by using dibutyl phthalate were more homogeneous and clear and also, their tensile strength and % elongation values have been found higher. In the study where verapamil hydrochloride has taken place as active substance, the release has realized longer and more controlled than the films containing 30%

2010).

et al., 2011).

its concentration (Rao and Diwan, 1997).

proportion of 10% (Amgaokar et al., 2011).

required (Rajabalaya et al., 2010; Siepmann et al., 1999).

dibutyl phthalate (Mundada and Avari, 2010).

In a study conducted with cellulose acetate transdermal films, it has been determined that when dibutyl phthalate and polyethylene glycol 600 have been used as plasticizer, the transparency of the films were not differing from the films not containing plasticizer, on the other hand, when propylene glycol has been used, it created a light opaqueness. Besides, the flexibility of the films plasticized with 40% plasticizer has been determined to be much better than unplasticized films and they could be removed without rupture from the surface they were adhered to (Rao & Diwan, 1997).

In a study where polyvinyl alcohol and polyvinyl alcohol-Xanthan gum mixture has been used as polymer, propylene glycol and dibutyl phthalate have been chosen as plasticizer. It has been observed that, addition of xanthan gum and dibutyl phthalate to the films prepared with only polyvinyl alcohol decreases the tensile strength and increases the percentage elongation. On the other hand, in polyvinyl alcohol films prepared with propylene glycol, tensile strength has been found higher. Besides, in vitro release of the terbutaline sulphate, which is an active substance, has been found higher in the propylene glycol containing films (Kumar et al., 2007).

Eudragit E 100, is a good polymer candidate in preparing transparent and self-adhesive transdermal films. However, its mechanical properties should be enhanced by adding a plasticizer. In a study evaluating drug free Eudragit E 100 films, it has been observed that elongation value of the films has increased depending on the increase of concentration of plasticizer. Triacetin used as plasticizer in combination with a cohesion promoter, succinic acid. It is thought that, the plasticizer ensures this effect with lubrication of the polymer chains. Differential Scanning Calorimetry (DSC) analyses have shown that, the crystallinity was decreased in plasticized Eudragit E 100 films when compared with those not plasticized. Increase in the mobility of the polymer chains and corresponding decrease in the crystallized area existing within the polymer are expected to enhance the active substance permeation. It has been concluded that, best cohesion promoter-plasticizer combination for Eudragit E 100 films was 7% succinic acid and 25% or 45% triacetine (Elgindy & Samy, 2009).

Although triacetin is considered as a good plasticizer for Eudragit E transdermal films, it has been determined that, addition of a secondary plasticizer such as polyethylene glycol 200, propylene glycol, diethyl phthalate or oleic acid to the system positively affects the transparency, flexibility and adhesive properties of the film (Lin et al., 1991).

Addition of plasticizer to the transdermal therapeutic systems may exhibit a facilitating effect in adhesion of the film to the other surfaces or membranes, by affecting the adhesiveness of the system (Gal & Nussinovitch, 2009; Rao & Diwan, 1997). Again in transdermal systems, humidity content and water absorption capacity of the system are measured and effect of the plasticizers on these values is researched (Rajabalaya et al., 2010). Water vapor transmission rate is closely related with the permeability characteristics of the transdermal films and can change according to the plasticizer and polymer type used (Bharkatiya et al, 2010).

It has been reported that, the plasticizers such as glycerine, sorbitol and polyethylene glycol can change release rate of the therapeutic components contained in the formula of transdermal drug delivery systems. Release rate of the drug can be adjusted by changing the type and concentration of the plasticizer (Lin et al., 2000; Wypch, 2004). Also it has been

In a study conducted with cellulose acetate transdermal films, it has been determined that when dibutyl phthalate and polyethylene glycol 600 have been used as plasticizer, the transparency of the films were not differing from the films not containing plasticizer, on the other hand, when propylene glycol has been used, it created a light opaqueness. Besides, the flexibility of the films plasticized with 40% plasticizer has been determined to be much better than unplasticized films and they could be removed without rupture from the surface

In a study where polyvinyl alcohol and polyvinyl alcohol-Xanthan gum mixture has been used as polymer, propylene glycol and dibutyl phthalate have been chosen as plasticizer. It has been observed that, addition of xanthan gum and dibutyl phthalate to the films prepared with only polyvinyl alcohol decreases the tensile strength and increases the percentage elongation. On the other hand, in polyvinyl alcohol films prepared with propylene glycol, tensile strength has been found higher. Besides, in vitro release of the terbutaline sulphate, which is an active substance, has been found higher in the propylene

Eudragit E 100, is a good polymer candidate in preparing transparent and self-adhesive transdermal films. However, its mechanical properties should be enhanced by adding a plasticizer. In a study evaluating drug free Eudragit E 100 films, it has been observed that elongation value of the films has increased depending on the increase of concentration of plasticizer. Triacetin used as plasticizer in combination with a cohesion promoter, succinic acid. It is thought that, the plasticizer ensures this effect with lubrication of the polymer chains. Differential Scanning Calorimetry (DSC) analyses have shown that, the crystallinity was decreased in plasticized Eudragit E 100 films when compared with those not plasticized. Increase in the mobility of the polymer chains and corresponding decrease in the crystallized area existing within the polymer are expected to enhance the active substance permeation. It has been concluded that, best cohesion promoter-plasticizer combination for Eudragit E 100 films was 7% succinic acid and 25% or 45% triacetine

Although triacetin is considered as a good plasticizer for Eudragit E transdermal films, it has been determined that, addition of a secondary plasticizer such as polyethylene glycol 200, propylene glycol, diethyl phthalate or oleic acid to the system positively affects the

Addition of plasticizer to the transdermal therapeutic systems may exhibit a facilitating effect in adhesion of the film to the other surfaces or membranes, by affecting the adhesiveness of the system (Gal & Nussinovitch, 2009; Rao & Diwan, 1997). Again in transdermal systems, humidity content and water absorption capacity of the system are measured and effect of the plasticizers on these values is researched (Rajabalaya et al., 2010). Water vapor transmission rate is closely related with the permeability characteristics of the transdermal films and can change according to the plasticizer and polymer type used

It has been reported that, the plasticizers such as glycerine, sorbitol and polyethylene glycol can change release rate of the therapeutic components contained in the formula of transdermal drug delivery systems. Release rate of the drug can be adjusted by changing the type and concentration of the plasticizer (Lin et al., 2000; Wypch, 2004). Also it has been

transparency, flexibility and adhesive properties of the film (Lin et al., 1991).

they were adhered to (Rao & Diwan, 1997).

glycol containing films (Kumar et al., 2007).

(Elgindy & Samy, 2009).

(Bharkatiya et al, 2010).

found that, the effect of the plasticizer on drug transport is related to the physicochemical properties of the permeant, in particular to its solubility in the plasticizer (Padula et al., 2010).

In transition studies conducted with diltiazem hydrochloride and indomethacine, diffusion of the drug has been found as the films plasticized with polyethylene glycol 600 > dibutyl phthalate > propylene glycol, in order. It has been concluded that, permeation of the drugs and mechanical properties of the film were affected by the choice of suitable plasticizer and its concentration (Rao and Diwan, 1997).

In their study, Amgokar and coworkers have prepared transdermal films of budesonide. In the films, Eudragit RL 100: Eudragit RS and ethylcellulose-polyvinylpyrolidone (in proportions of 7:3 and 7:2, respectively) have been used as polymers and polyethylene glycol 400 has taken place as plasticizer. While drug release has found proportional to the polymer concentration, increase in the plasticizer amount has caused an increase in the weight of the film. It has also been observed that, increase in the plasticizer amount has also increased the humidity absorption of the transdermal films. It has been reported that, permeation of budesonide was the highest when polyethylene glycol 400 has been used in proportion of 10% (Amgaokar et al., 2011).

Irfani and coworkers have used different combinations of hydoxypropyl methylcellulose, Eudragit RS 100 and polyvinylpyrolidone, when preparing transdermal films of the active substance, valsartan. In the formulations, different proportions (10%, 20% and 30%) of glycerin have been tried as plasticizer. It has been found that, increasing plasticizer concentration was increasing the diffusion rate of the active substance. Besides, when also the polymer combination of Eudragit RS and hydroxypropyl methylcellulose has been used with 30% glycerine, an increase in the diffusion rate of valsartan has been determined (Irfani et al., 2011).

In a study, effects of two plasticizers, dibutyl phthalate and dibutyl sebacate, on the mechanical properties of the transdermal films prepared with Eudragit 100 polyvinylpyrolidone polymer mixture have been researched. It was shown that tensile strength was gradually decreased as the plasticizer concentration in the patch increased. It can be concluded from this result that plasticizer molecules disrupt the inter-chain cohesive forces of the polymer. Dibutyl phthalate and dibutyl sebacate have affected the mechanical properties of the transdermal system similarly. The finding that dibutyl sebacate is a suitable plasticizer for a more rapid release has been found in conformance with the finding of Siepmann and colleagues stating that dibutyl sebacate ensures faster release, whereas plasticizers containing phthalate group should be preferred when extended effect is required (Rajabalaya et al., 2010; Siepmann et al., 1999).

In the study where Gum copal has been used as polymer, hydrophobic dibutyl phthalate and hydrophilic glycerin and polyethylene glycol 400 have been preferred as plasticizer. It has been observed that, the films prepared by using dibutyl phthalate were more homogeneous and clear and also, their tensile strength and % elongation values have been found higher. In the study where verapamil hydrochloride has taken place as active substance, the release has realized longer and more controlled than the films containing 30% dibutyl phthalate (Mundada and Avari, 2010).

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The characterization of the cellulose membranes where polyethylene glycol 600 has been used as plasticizer has been made and it has been determined that, besides the plasticizer concentration, preparation temperature was also effective on the membrane properties. It has been determined that, the membranes prepared at 40°C were more homogeneous and the diffusion of the active substance scopolamine, has realized through 3 days, controlled and constant, from the membranes containing 10% or 20% polyethylene glycol 600. It has been reported that, in order to improve the mechanical properties of the cellulose acetate membranes and to enable the linear release of the active substance, polyethylene glycol concentration should be optimized (Wang et al., 2002)
