**2. Transdermal drug delivery systems**

Transdermal drug delivery systems, also known as "patches", are dosage forms designed to deliver a therapeutically effective amount of drug across a patient's skin in a predetermined time at controlled rate and to maintain constant drug plasma concentration over a long period (Aulton 2007; Vasil'ev et.al., 2001). Transdermal patches have superiorities such as improved patient compliance and flexibility of dosage in which formulation can be removed immediately (Brown et.al. 2006; Guy 1996; Tanner & Marks 2008; Williams 2003). The transdermal systems of drugs including scopolamine, nitroglycerin, isosorbide dinitrate, clonidine, estradiol, fentanyl, nicotine, testosterone, norelgestromin+ethinyl estradiol, oxybutynin, selegeline, methylphenidate, buprenorphine, rivastigmine, rotigotine and granisetron have been approved (Guy 2010).

The major technical considerations by developing a transdermal formulation include (Meathrel, 2011; Quan, 2011):


### **2.1 Types of transdermal drug delivery systems**

Although transdermal systems are classified in different types, transdermal patches can be divided into three main categories depending on the incorporation style of the drug in the system (Figure 1): (Delgado-Charro & Guy 2001; Padula et.al. 2007; Vasil'ev et.al., 2001; Williams, 2003).


polymer, preventing film cracking, increasing film flexibility and obtaining desirable mechanical properties (Wypych, 2004). One of the many advantages of plasticizers used in transdermal formulations is the controlling of the release rate of therapeutic compound which can be done by the selection of the plasticizer type and the optimization of its concentration in the formulation. The commonly used plasticizers in transdermal patches include phthalate esters, phosphate esters, fatty acid esters and glycol derivatives

The objectives of this chapter are to summarize the compositions and types of the transdermal drug delivery systems; to emphasize the role and effectiveness of plasticizers in transdermal drug delivery systems and to cover the research studies and current

Transdermal drug delivery systems, also known as "patches", are dosage forms designed to deliver a therapeutically effective amount of drug across a patient's skin in a predetermined time at controlled rate and to maintain constant drug plasma concentration over a long period (Aulton 2007; Vasil'ev et.al., 2001). Transdermal patches have superiorities such as improved patient compliance and flexibility of dosage in which formulation can be removed immediately (Brown et.al. 2006; Guy 1996; Tanner & Marks 2008; Williams 2003). The transdermal systems of drugs including scopolamine, nitroglycerin, isosorbide dinitrate, clonidine, estradiol, fentanyl, nicotine, testosterone, norelgestromin+ethinyl estradiol, oxybutynin, selegeline, methylphenidate, buprenorphine, rivastigmine, rotigotine and

The major technical considerations by developing a transdermal formulation include

Drug compatibility with polymers, adhesives, plasticizers and other excipients used in

Balance between adhesion and easy patch removal depending on the duration of patch

Although transdermal systems are classified in different types, transdermal patches can be divided into three main categories depending on the incorporation style of the drug in the system (Figure 1): (Delgado-Charro & Guy 2001; Padula et.al. 2007; Vasil'ev et.al., 2001;

developments related to the development of transdermal formulations.

(Bharkatiya et al, 2010; Wypych, 2004).

**2. Transdermal drug delivery systems** 

granisetron have been approved (Guy 2010).

Size of the drug molecule and the required daily dose

Physical and chemical stability of the final formulation

**2.1 Types of transdermal drug delivery systems** 

(Meathrel, 2011; Quan, 2011):

the formulation

Size of the patch

application.

Williams, 2003).

 Reservoir Systems Matrix Systems Adhesive Systems

Fig. 1. Schematic representation of transdermal patch types: A. Reservoir, B. Matrix, C. Drug-in-Adhesive transdermal systems.

a. **Reservoir Systems:** In these systems, the drug is in a reservoir as liquid. Drug molecules are contained in the storage part, as a suspension in a viscous liquid or dissolved in a solvent. In the second type, there is a membrane made of a polymer with different structure, which separates the reservoir from the adhesive layer. In these systems, the membrane controls the release rate of the drug. The membrane can be porous or nonporous. The adhesive polymer on the exterior surface of the membrane enables the transdermal to adhere to skin. In these systems, drug release rate can be controlled by membrane thickness and adhesive layer (Delgado-Charro & Guy 2001; Padula et.al. 2007; Williams, 2003).

Transderm-Nitro (Nitroglycerin), Transderm-Scop (Scopolamine), Catapress-TTS (Clonidine), Estraderm (Estradiol) can be given as examples to the commercially available membrane diffusion controlled systems.

Plasticizers in Transdermal Drug Delivery Systems 95

d. **Semipermeable (release) membrane:** It takes place in reservoir type transdermal systems and multi-layer adhesive systems. Ethylene-vinyl acetate copolymer, silicones, highdensity polyethylene, polyester elastomers, cellulose nitrate and cellulose acetate are used

f. **Backing layer:** It protects the system from external effects during administration and ensures integrity of the system in the storage period. For this purpose, the materials impermeable for drug molecule are used as backing layer. The backing layer must be inert and not compatible with the drug and other substances used in the formulation. Generally, ethylene vinyl acetate, polyethylene, polypropylene, polyvinylidene chloride

g. **Release liner:** This is the part which protects the formulation from external environment and which is removed before the system is adhered to skin. Ethylene vinyl acetate, aluminum foil or paper can be used. Ideally, it should be easily peeled from the adhesive layer and should not damage the structure of adhesive layer. Also, silicone,

h. **Solvents, penetration enhancers:** Various solvents are used to solve or disperse the polymer and adhesive or drug used in preparation of the transdermal systems. Among those, chloroform, methanol, acetone, isopropanol and dichloromethane are used frequently. Also, various penetration enhancer substances are added to the formulations to increase permeation from skin of the drug. Terpenes, fatty acids, water, ethanol, glycols, surface-effective substances, azone, dimethyl sulfoxide are widely used

i. **Plasticizers:** In transdermal systems, plasticizers are used to improve the brittleness of

Plasticizers are generally non-volatile organic liquids or solids with low melting temperature and when added to polymers, they cause changes in definite physical and mechanical characteristics of the material (Bharkatiya et al, 2010; Felton, 2007; Gooch,

The main reasons of adding plasticizers to polymers, improving flexibility and processability are counted (Harper, 2006; Höfer & Hinrichs, 2010; Rahman & Brazel, 2004; Whelan, 1994). Upon addition of plasticizer, flexibilities of polymer macromolecules or

and polyurethane are used as backing layer (Williams 2003).

fluorosilicone, perfluorocarbon polymers can be used (Williams 2003).

in the transdermal formulations as permeation enhancer (Williams 2003).

the polymer and to provide flexibility (Williams 2003).

**3.1 The role of plasticizers in pharmaceutical formulations** 

as membrane. These membranes control the release rate of drugs (Williams 2003). e. **Adhesive:** Adhesive should enable the transdermal system to easily adhere to the skin and should not be irritant/allergen for skin. Generally, pressure-sensitive adhesives are used in transdermal systems. Commonly used pressure-sensitive adhesives are collected under 3 classes as a) acylates, b) polyisobutilene adhesives and c) polysiloxan

(Delgado-Charro & Guy 2001; Williams 2003).

adhesives (Williams 2003).

**3. Plasticizers** 

2010; Meier et al., 2004).

sodium alginate, chitosan), synthetic (Eudragit, polyvinyl pyrolidon, PVA) and semisynthetic polymers (e.g. cellulose derivatives) are used as polymer (Amnuaikit et al., 2005; Güngör et al., 2008; Lin et al., 1991; Nicoli et al., 2006; Schroeder et al., 2007,a). c. **Reservoir:** In this type of transdermal patches, a semi-permeable membrane controlling the drug release rate is used. The drug presents in a reservoir as liquid or solid

b. **Matrix Systems:** In this type of systems, the drug is dispersed homogeneously within a polymer matrix which has hydrophilic or lipophilic character. Outer side of the formulation is covered with a backing layer. In these systems, patch is held on the skin with a adhesive polymer as a strip. Matrix type formulations can also be prepared by dispersing the drug in an adhesive polymer that is sensitive to direct pressure and then covering this system with an impermeable backing layer. Since in matrix type formulations, release from semi-solid matrix of the drug is not controlled by any membrane, drug release from these systems is related to the surface area to which the patch is applied (Delgado-Charro & Guy 2001; Padula et.al. 2007; Williams, 2003).

Minitran (Nitroglycerin), Emsam (Selegeline), Exelon (Rivastigmine), Sancuso (Granisetron) and Oxytrol (Oxybutyne) can be given as examples to commercially available matrix diffusion controlled systems.

c. **Adhesive Systems:** In these systems, drug reservoir is prepared by dispersing the drug in an adhesive polymer. At the outmost, an impermeable backing layer takes place. Under the drug reservoir layer, there exists an adhesive membrane controlling the drug release rate. In this type of transdermal systems, drug release rate is controlled both by the matrix in which the drug is dispersed and also by a membrane. Although this type of systems can be designed with a single drug layer, they can be also designed as multilayered (Delgado-Charro & Guy 2001; Padula et.al. 2007; Williams, 2003).

Nitrodur (Nitroglycerin), Daytarana (Methyl phenidate) and Duragesic (fentanyl) can be given as examples to commercially available adhesive systems.
