**4.1.1 Gels**

36 Rheumatoid Arthritis – Treatment

both passive and iontophoresis method. They found that application of low electric current enhanced uptake of piroxicam to SC layer. Moreover, a high piroxicam concentration was obtained in the SC, live epidermis and dermis with the iontophoresis application. Mathy and coworkers studied the percutaneous penetration of flurbiprofen on hairless rats (Mathy et al., 2005). They investigated the flurbiprofen concentrations in the dermal and subcutaneous tissue following administration of iontophoresis. The data obtained demonstrated that application of iontophoresis ensured delivery of flurbiprofen at a high input rate to the dermis and underlying tissues at significant amounts, while maintaining

Conventional dosage forms of NSAIDs which are commercially available and and possible novel carrier systems of NSAIDs to improve their dermal and transdermal delivery are

Fig. 1. Schematic representation of the novel and conventional dermal drug delivery systems.

The classical dosage forms of NSAIDs for dermal use that are commercially available are usually gels, creams, ointments and lotions. Table 4 gives a list of NSAIDs which have

**4. Conventional formulations and novel approaches in dermal and** 

low plasma exposure.

summarized in Fig.

**transdermal delivery of NSAIDs** 

**4.1 Conventional formulations** 

commercial dermal preparations.

They are two-component semi-solid drug carriers that contain high levels of fluid and viscosity enhancing agents. Polar solvents such as water and alcohol are used in the liquid phase. They contain appropriate viscosity enhancers depending on the physicochemical properties of drug molecule and its compatibility with the vehicle. Simple gels are prepared with a natural polymer, such as carrageen, pectin or sodium alginate, or semi-synthetic stabilizers like cellulose derivatives or synthetic stabilizers like Carbomers (Williams, 2003). As can be seen on Table 3, gel formulations of most of NSAIDs are commercially available because gels are easy to administer, forming a thin film coating on the skin and ensuring rapid action without giving an oily feeling. They are preferred by patients due to these advantages. Besides they are cost-efficient since formulation inputs are less, and they are preferred by manufacturers. Although there are not commercially available dermal formulations of NSAIDs there are studies on development of gel-type formulation of tiaprofenic acid (Okyar et al., 2008 and 2010), meloxicam (Martinez et al., 2007; Jain & Pathak, 2010; Gupta et al., 2002), aceclofenac (Dua et al., 2010) and flurbiprofen (Minghetti et al., 2003; Pandey et al., 2009).

#### **4.1.2 Ointments, creams and lotions**

Ointments are semi-solid preparations administered on the skin. Their formulations contain high levels of oil. Typically they have an occlusive action on the skin, and are used for dry lesions. Creams have an emulsion structure although they are defined as semi-solid carrier systems. Emulsions are systems consisting of two phases containing water and oil, where one is disperse in the other. Creams are more acceptable for patients as they have lower viscosity than ointments and are less oily. Lotions are creams with less viscosity (Williams, 2003). There are cream and/or ointment-type preparations of benzydamine bufexamac,

Novel Formulation Approaches for Dermal and

Magraby et al., 2008; Williams, 2003).

4.2.2.2 Niosomes

characteristic of the SC layer.

4.2.2.3 Transfersomes

purposes (El Magraby et al., 2008; Williams, 2003).

available tenoxicam tablets (Ammar et al., 2011).

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 39

penetration of the drug. However, fusion of liposomes on the skin surface does not apply for macromolecular drugs. Another mechanism is penetration of liposomes to SC before fusion with SC lipids and releasing the drug there. With this mechanism, particularly the drug in liposomes that are dermally administered can be localized in different layers of the skin (El

Mezei & Gulasekharam (1980) used liposomes as "dermal drug carrier system" for the first time. However, liposomes are localized in the outermost layer of the skin (SC). Therefore, it is advantageous in cases where retaining drug in SC is desirable. It does not seem possible with these systems to penetrate the drug to deeper tissues of the skin or into systemic circulation. Therefore, it is rather preferred to increase dermal moisture for cosmetic

Niosomes are liposomes prepared with non-ionic surfactants. Dermal penetration of niosomes depend on i) potential penetration-enhancing activity of surfactants in its content, ii) penetration of the vesicle to SC, iii) accumulation of vesicle on the skin surface and/or increasing thermodynamic activity of the drug on the skin surface. These mechanisms depend on the physicochemical properties of the drug, the vesicle and the lipids used (Choi & Maibach, 2005; Williams, 2003). Niosomes are the vesicular systems that are most studies in dermal and transdermal formulations of NSAIDs. This is because niosomes prevent transepidermal water loss, and they act on the lipid structure in the intracellular domain with the effect of high amount of surfactant in their content and overcome the barrier

It has been observed that dermal retention and dermal penetration of the drug was enhanced with dermally administered noisome formulation of nimesulid. Besides, it has been determined that the noisome formulation has a faster anti-inflammatory activity than the commercial gel formulation (Shahiwala & Misra, 2002). Manosroi et al. (2008) obtained a higher flux of the drug in SC and deeper dermal tissues (live epidermis and dermis) with elastic noisome formulations loaded with diclophenac diethylammonium. Niosome-like vesicles consisting of hydrated mixtures of cholesterol and non-ionic surfactants are defined as "proniosomes" (Alsarra et al., 2005; Ammar et al., 2011). Alsarra et al. (2005) demonstrated that proniosomes of ketorolac improves permeation of the drug and shortens its lag time. In another study, formulations of proniosome were developed for transdermal delivery of tenoxicam. It has been stressed that proniosome formulation loaded with tenoxicam had higher anti-inflammatory and analgesic effect than the commercially

Transfersomes are defined as elastic vesicles that can be highly deformed. They are the first generation of elastic vesicles that contain phospholipids and an edge activator. Classical liposomes have a diameter varying from 200 to 400 nm, which is too large to pass through SC. However, transfersomes reach deeper dermal tissues and even the systemic circulation with their elasticity and highly deformable structure (Benson, 2009). It has been demonstrated that as classical liposomes cannot be deformed in the same way, transfersomes ensure higher skin permeation than liposomes in an in vitro comparison of skin permeation of transfersomes and liposomes loaded with meloxicam (Duangjit et al.,

etofenamate, ibuprofen and salicylic acid that are commercially available. Lotion-type preparations of bufexamac and salicylic acid are used in treatments (Table 4).
