**2. Non-steroidal anti-inflammatory drugs (NSAIDs)**

#### **2.1 General view and classification of NSAIDs**

NSAIDs are used for chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis, posttraumatic conditions (e.g. distortion, contusion), for relieving mild to moderate pain of varied origin, reducing fever, as well as for preventing local inflammation such as gout (Hinz & Brune, 2008; Lionberger et al., 2011; Patrono & Rocca, 2009). NSAIDs are employed in systemic as well as local dosage forms particularly for musculoskeletal pain and patients with inflammatory joint disorders. NSAIDs possess antipyretic effect in addition to analgesic-anti-inflammatory actions. NSAIDs may be responsible for side effects such as acute renal failure, undesirable central nervous effects, e.g. dizziness, allergic reactions and fluid retention in the body. Beside some side effects of NSAIDs mentioned before, NSAIDs lead to unfavorable effects on the stomach as a result of inhibition of prostaglandins, which play a role in protection of the gastric mucosa, in systemic administration e.g. oral, parenteral. The severity of this unfavorable gastrointestinal side effect may range from a simple ailment like dyspepsia to gastric bleeding potentially resulting in admission to hospital, necessitating surgery or even resulting in death (Hooper et al., 2004). Furthermore, the acidic character of NSAIDs may lead to local irritation, and lesions on the gastrointestinal mucosa are known as NSAIDs gastropathy (Heynemann et al., 2000). Within the past 20 years many COX inhibitors were removed for undesired drug effects shortly after entering the market e.g. benoxaprofen and isoxicam (Brune et al., 2010). Therefore, some NSAIDs are administered percutaneously to achieve local or systemic effect as an alternative to oral and parenteral administration (Heyneman et al., 2000; Hooper et al., 2004). NSAIDs are classified by their chemical structures as shown in Table 1.

#### **2.2 Mechanism of anti-inflammatory effect of NSAIDs**

NSAIDs usually act through decreasing reactions of inflammation that is accompanied with pain. It is known that prostaglandin (PG) derivatives, that are formed from arachidonic acid through COX enzyme, play an important role in formation of inflammation, and that the PGE1 and PGE2 levels are increased in the synovial fluid in patients with rheumatoid arthritis. All NSAIDs inhibit the COX enzyme and act through decreasing the synthesis of PGE2, PGD2, PGF2 , PGI2 and thromboxane A2 (TxA2) and prostacycline (Lionberger et al., 2010; Massey et al., 2010). Two isoforms of COX (COX-1 and COX-2) were identified and


Table 1. Classification of NSAIDs according to chemical structure (Heynemann et al., 2000; Hadgraft et al., 2000; Marnett, 2009).

26 Rheumatoid Arthritis – Treatment

2006). The most frequently used approach is to include penetration enhancers in formulations. In addition to penetration enhancers, there are studies available in which physical methods such as iontophoresis is used in improving of skin delivery of drugs (Guy,

The chapter deals with the classification and mechanisms of action of NSAIDs used in treatment of various rheumatic diseases as well as for osteoarthritis, low back pain and some joint diseases. The advantages of skin delivery of NSAIDs to target affected tissues and/or to achieve systemic effect are also emphasized. In particular, recent studies in which novel drug delivery systems were developed for dermal and transdermal administration of

NSAIDs are used for chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis, posttraumatic conditions (e.g. distortion, contusion), for relieving mild to moderate pain of varied origin, reducing fever, as well as for preventing local inflammation such as gout (Hinz & Brune, 2008; Lionberger et al., 2011; Patrono & Rocca, 2009). NSAIDs are employed in systemic as well as local dosage forms particularly for musculoskeletal pain and patients with inflammatory joint disorders. NSAIDs possess antipyretic effect in addition to analgesic-anti-inflammatory actions. NSAIDs may be responsible for side effects such as acute renal failure, undesirable central nervous effects, e.g. dizziness, allergic reactions and fluid retention in the body. Beside some side effects of NSAIDs mentioned before, NSAIDs lead to unfavorable effects on the stomach as a result of inhibition of prostaglandins, which play a role in protection of the gastric mucosa, in systemic administration e.g. oral, parenteral. The severity of this unfavorable gastrointestinal side effect may range from a simple ailment like dyspepsia to gastric bleeding potentially resulting in admission to hospital, necessitating surgery or even resulting in death (Hooper et al., 2004). Furthermore, the acidic character of NSAIDs may lead to local irritation, and lesions on the gastrointestinal mucosa are known as NSAIDs gastropathy (Heynemann et al., 2000). Within the past 20 years many COX inhibitors were removed for undesired drug effects shortly after entering the market e.g. benoxaprofen and isoxicam (Brune et al., 2010). Therefore, some NSAIDs are administered percutaneously to achieve local or systemic effect as an alternative to oral and parenteral administration (Heyneman et al., 2000; Hooper et al., 2004). NSAIDs are classified by their chemical

NSAIDs usually act through decreasing reactions of inflammation that is accompanied with pain. It is known that prostaglandin (PG) derivatives, that are formed from arachidonic acid through COX enzyme, play an important role in formation of inflammation, and that the PGE1 and PGE2 levels are increased in the synovial fluid in patients with rheumatoid arthritis. All NSAIDs inhibit the COX enzyme and act through decreasing the synthesis of

2010; Massey et al., 2010). Two isoforms of COX (COX-1 and COX-2) were identified and

2) and prostacycline (Lionberger et al.,

2 and thromboxane A2 (TxA

1996; Benson, 2005; Williams, 2003).

**2. Non-steroidal anti-inflammatory drugs (NSAIDs)** 

**2.1 General view and classification of NSAIDs** 

NSAIDs are summarized.

structures as shown in Table 1.

2, PGF 2 , PGI

PGE

2, PGD

**2.2 Mechanism of anti-inflammatory effect of NSAIDs** 

Novel Formulation Approaches for Dermal and

glands) (Williams, 2003).

characteristics.

**3.3 Overcoming the barrier properties of the skin** 

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 29

hypodermis. In particular, *stratum corneum* (SC), the outermost layer of epidermis is formed by dead and keratinized cells, and thus it is a unique barrier to passage of drugs through the skin (Williams, 2003).The drug substances from dermal or transdermal formulations have to pass through the SC layer to reach lower layers of the skin and/or to enter systemic circulation. The physicochemical characteristics of drug molecules and the types of the formulations are an effective factor in both dermal and transdermal delivery (Hadgraft, 1999). The drugs pass through the skin via three different routes, which are transcellular, intercellular and/or transappendageal (shunt) routes (sweat glands, hair follicles, sebaceous

There are two pharmacological approaches in dermal administration of drugs, which are dermal and transdermal. In dermal administration, the applied formulation ensures localization of drugs in dermal layers. In transdermal administration, the drugs reach the dermis of skin via carrier systems and then go into systemic circulation (Williams, 2003). In dermal administration, the access of drugs to systemic circulation is prevented or minimized. Therefore, the systemic adverse effects of drugs are avoided. The advantages of transdermal administration include high patient compatibility with treatment, ability to discontinue treatment any time necessary, delivery of drug to organism at a controlled rate, ensuring fixed plasma drug level and eliminating the hepatic first-pass effect (Guy, 1996). NSAIDs administered dermally and transdermally penetrate slowly and in small quantities into the systemic circulation. These approaches also prevent high local drug levels in the alimentary tract and direct toxicity of NSAIDs e.g. vomiting, dyspepsia. Systemic administration of NSAIDs may cause drug-drug interactions. NSAIDs cause fluid retention in the body and may decrease efficacy of antihypertensive agents. Furthermore, dermal and transdermal formulations have better patient compliance (noninvasiveness) and they can be self-administered (Guy, 1996; Taner & Marks, 2008; Heynemann et al., 2000). It was reported that the use of dermal NSAIDs may have led to a reduction in the total daily dosage of systemic NSAIDs. This would cause an increment in side effects of NSAIDs in long term treatment (Sift Carter et al., 1997). Finally, dermally applied NSAIDs have a superior safety profile to oral formulations. Adverse effects secondary to dermal NSAID application occur in approximately 10 to 15% of patients and are primarily cutaneous in nature (rash and pruritus at the site of application (Heynemann et al., 2000)). NSAI drug concentration should reach therapeutic level in the synovial tissue, synovial fluid and intra-articular tissues during dermal application of NSAIDs. There are a number of factors that influence skin absorption of drugs. The greatest challenge for dermal penetration is SC, the uppermost layer of the skin, which as mentioned previously is the rate limiting step for epidermal drug transport. Therefore several formulation approaches are developed to improve its impermeability

Several chemical and physical approaches are used to overcome the barrier property of the skin in dermal and transdermal administration of drugs. The most frequently used approach is to include chemical penetration enhancers in formulations. Recently, physical

**3.2 The superiorities and limitations of dermal and transdermal delivery** 

studies of their regulation and sites of expression led to the hypothesis that it is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. COX-1 is important for production of gastric mucus and maintenance of renal blood flow. On the other hand, COX-2 is induced by several cytokines, growing factors and endotoxins and plays a role in the inflammatory process observed at the site of inflammation. Nonselective NSAIDs inhibit both COX-1 and COX-2, and the current hypothesis is that COX-2 inhibition is responsible for the anti-inflammatory effects of NSAIDs, whereas COX-1 inhibition is responsible for some other undesired side effects, in particular for gastrointestinal toxicity. Therefore selective inhibition of COX-2 may prevent undesirable gastrointestinal effects of NSAIDs. The discovery and clinical development of selective COX-2 inhibitors (COXIBs) were achieved in the early 1990s. COXIBs have anti-inflammatory effects without side effects on the stomach as compared to traditional NSAIDs. However, these new NSAIDs also possess some side effects, since inhibition of COX-2 affects kidney function and blood pressure and possibly other physiological parameters (Brune & Hinz, 2004; Marnett, 2009; Patrono & Rocco, 2009; Mitchell et al., 1994). Rofecoxib and valdecoxib was withdrawn from the market due to serious cardiovascular side effects, and lumiracoxib was removed from several markets for serious liver toxicity unrelated to COX-2 inhibition. Celecoxib has been marketed in the United States, and celecoxib and etoricoxib was marketed in Europe (Hinz & Brune, 2008).

#### **2.3 Physicochemical properties of NSAIDs**

Table 2 demonstrates the open chemical formulas and physicochemical properties of NSAIDs, which have dermal and transdermal commercial preparations and of the molecules which are potential candidates in this group.

The physiochemical properties of drugs are important in dermal and transdermal administration (Potts and Francoeur, 1991; Kalia et al., 1998; Prausnitz & Langer, 2008). The ideal candidate drugs have the following properties: water-solubility (> 1 mg/ml), lipophilicity (log P= 1-3), low molecular weight (< 500 Dalton) and low melting temperature (< 200°C) (Guy, 2007). As can be seen in Table 2, all drugs are under 400 Dalton. The Log P values, which indicate lipophilic characteristics of pharmaceuticals, vary between 2.0 and 3.8 except for flurbiprofen, etofenamate and lumiracoxib. In other words, they have medium lipophilicity. Other NSAIDs except meloxicam and tenoxicam have a melting point under <200°C. Due to these physicochemical properties, NSAIDs are ideal molecules for dermal administration. As a matter of fact, dermal/transdermal commercial preparations of most of NSAIDs are available in pharmacies. Studies on development of skin delivery systems of other molecules are in progress.

#### **3. Dermal and transdermal administration of NSAIDs**

#### **3.1 Skin transport**

Human skin is the largest organ in our body with its size about 1.8-2.0 m2. It is a wellengineered organ that protects organism against environmental factors and regulates heat and water loss from the body. It is also easily accessible due to its large surface area. Therefore, it offers an ideal application site to deliver therapeutic agents for both local and systemic actions. The skin consists of three main layers; the epidermis, the dermis, and the

studies of their regulation and sites of expression led to the hypothesis that it is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. COX-1 is important for production of gastric mucus and maintenance of renal blood flow. On the other hand, COX-2 is induced by several cytokines, growing factors and endotoxins and plays a role in the inflammatory process observed at the site of inflammation. Nonselective NSAIDs inhibit both COX-1 and COX-2, and the current hypothesis is that COX-2 inhibition is responsible for the anti-inflammatory effects of NSAIDs, whereas COX-1 inhibition is responsible for some other undesired side effects, in particular for gastrointestinal toxicity. Therefore selective inhibition of COX-2 may prevent undesirable gastrointestinal effects of NSAIDs. The discovery and clinical development of selective COX-2 inhibitors (COXIBs) were achieved in the early 1990s. COXIBs have anti-inflammatory effects without side effects on the stomach as compared to traditional NSAIDs. However, these new NSAIDs also possess some side effects, since inhibition of COX-2 affects kidney function and blood pressure and possibly other physiological parameters (Brune & Hinz, 2004; Marnett, 2009; Patrono & Rocco, 2009; Mitchell et al., 1994). Rofecoxib and valdecoxib was withdrawn from the market due to serious cardiovascular side effects, and lumiracoxib was removed from several markets for serious liver toxicity unrelated to COX-2 inhibition. Celecoxib has been marketed in the United States, and celecoxib and etoricoxib was marketed in Europe (Hinz

Table 2 demonstrates the open chemical formulas and physicochemical properties of NSAIDs, which have dermal and transdermal commercial preparations and of the

The physiochemical properties of drugs are important in dermal and transdermal administration (Potts and Francoeur, 1991; Kalia et al., 1998; Prausnitz & Langer, 2008). The ideal candidate drugs have the following properties: water-solubility (> 1 mg/ml), lipophilicity (log P= 1-3), low molecular weight (< 500 Dalton) and low melting temperature (< 200°C) (Guy, 2007). As can be seen in Table 2, all drugs are under 400 Dalton. The Log P values, which indicate lipophilic characteristics of pharmaceuticals, vary between 2.0 and 3.8 except for flurbiprofen, etofenamate and lumiracoxib. In other words, they have medium lipophilicity. Other NSAIDs except meloxicam and tenoxicam have a melting point under <200°C. Due to these physicochemical properties, NSAIDs are ideal molecules for dermal administration. As a matter of fact, dermal/transdermal commercial preparations of most of NSAIDs are available in pharmacies. Studies on development of skin delivery systems of

Human skin is the largest organ in our body with its size about 1.8-2.0 m2. It is a wellengineered organ that protects organism against environmental factors and regulates heat and water loss from the body. It is also easily accessible due to its large surface area. Therefore, it offers an ideal application site to deliver therapeutic agents for both local and systemic actions. The skin consists of three main layers; the epidermis, the dermis, and the

& Brune, 2008).

**2.3 Physicochemical properties of NSAIDs** 

other molecules are in progress.

**3.1 Skin transport** 

molecules which are potential candidates in this group.

**3. Dermal and transdermal administration of NSAIDs** 

hypodermis. In particular, *stratum corneum* (SC), the outermost layer of epidermis is formed by dead and keratinized cells, and thus it is a unique barrier to passage of drugs through the skin (Williams, 2003).The drug substances from dermal or transdermal formulations have to pass through the SC layer to reach lower layers of the skin and/or to enter systemic circulation. The physicochemical characteristics of drug molecules and the types of the formulations are an effective factor in both dermal and transdermal delivery (Hadgraft, 1999). The drugs pass through the skin via three different routes, which are transcellular, intercellular and/or transappendageal (shunt) routes (sweat glands, hair follicles, sebaceous glands) (Williams, 2003).
