**3.3.1 Chemical enhancers**

Chemical penetration enhancers reversibly change the structure of the skin to improve the flux of drugs through the skin. The mechanism of action of penetration enhancers is explained by Lipid-Protein-Partition (LPP) Theory (Williams & Barry, 1991). According to this theory, penetration enhancers i) disrupt the lipid structure in intercellular domain of SC, or ii) denature or change the conformation of keratin in the intracellular domain and/or iii) improve drug partition to SC and thus establish a drug reservoir in SC to act (Williams&

Novel Formulation Approaches for Dermal and

pyrrolidone (NMP)

/OA/LA/LNA

Nimesulide OA/ Transcutol® Oleic acid (3%) in the presence of

skin.

Meloxicam N-methyl

Piroxicam Lauric acid

Tenoxicam OA/LA/oleyl

**3.3.2 Physical enhancement** 

Sieg & Wascotte, 2009).

Tiaprofenic acid

Tiaprofenic acid

alcohol

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 35

Meloxicam gel containing NMP as a solubilizer exhibited significant higher antiBachhav & Patravale, 2010

Gungor & Bergisadi, 2004

Santoyo & Ygartua, 2000

Gwak & Chun,

Okyar et al., 2008

Okyar et al., 2010

2002

inflammatory in rats compared to commercial gel formulation.

Transcutol® (30%) has led to a significant increase in permeation of drug across the

All enhancers showed similar extent of permeation, which was 3-fold higher than

The highest tenoxicam flux was obtained by

that of without enhancer

the addition of fatty acids at 3%

absorption of tiaprofenic acid (6-fold) significantly in excised pig skin, as compared

absorption of tiaprofenic acid (6-fold) significantly in excised rat skin. Gel with d-limonene increased tiaprofenic acid skin

vivo in rats, as compared to control

administration.

terpenes Gel containing d-limonene increased

to control gel.

gel.

terpenes Gel containing d-limonene increased

absorption of 10-fold in

Table 3. Effect of chemical penetration enhancers to increase skin permeation of NSAIDs.

enhancers to improve passage of NSAIDs through the skin and the results obtained.

Barry, 2004; Thong HY et al., 2007). Co-solvents such as alcohols, oil alcohols, propylene glycol, diethyleneglycol monoethylether (Transcutol), and compounds like fatty acids terpenes, Azone, dimethylsulfoxide (DMSO), pyrrolidones, urea and surfactants are frequently included in dermal/transdermal formulations as penetration enhancers (Williams & Barry, 2004; Mohammed et al., 2007). Table 3 summarizes the penetration

Iontophoresis is one of the most frequently used physical methods in improving dermal penetration of drugs. Iontophoresis enhances dermal penetration of drug molecules by applying low levels of electrical currents (0,5 mA/cm2) (Marro et al., 2002). Unlike passive diffusion-based transdermal administration, particularly, iontophoresis ensures dermal penetration of polar and charged drug molecules in high amounts loaded (Kalia et al., 1998;

There are studies investigating whether the iontophoresis technique enhanced dermal penetration of NSAIDs. Curdy et al. (2001) dermally administered a commercial gel formulation containing piroxicam, and studied dermal penetration of piroxicam by using

concentration to PG.

**NSAIDs Enhancers Results Refs** 


Addition of the mixture of oleic acid/dlimonene as enhancer into diclofenac sodium formulations has been found to be effective for the dermal and subdermal injuries.

Dermal administration of diclofenac containing DMSO vehicle has been found to be effective for knee osteoarthritis, and has showed better tolerability than oral

of etodolac (1,5-fold) significantly in excised rat skin, as compared to control gel.

The efficacy and safety of dermal nitro ester of flurbiprofen was shown with lipophilic ointment containing chemical enhancers.

and l-menthol (3%) has showed high in vivo

Fatty acids (PA, OA, LA, and LNA) extracted from Botryococcus braunii was found effective enhancers to improve the skin

ethanol (>10-fold flux enhacement) across silicone membrane and human skin.

PG and (PG: water) systems has increased the fluxes of ibuprofen due the increase in

containing Brij 92 exhibited less gastric side effect and higher anti-inflammatory effect

lumiracoxib through skin and its retention in

Eucalyptus oil has showed the highest permeation enhancer effect for the transdermal

delivery of ketorolac across rat skin.

formulation flurbiprofen containing turpentine oil has been shown to increase 5.56 times with respect to its oral

Escribano et al.,

Simon et al., 2009

Taş et al., 2007

Minghetti et al.,

Charoo et al., 2008

Morimoto et al.,

Fang et al., 2004

Watkinson et al.,

Watkinson et al.,

Amrish & Kumar,

El-Setouhy & El-Ashmony, 2009

Moreira et al., 2010

2003

2000

2009

2008

2009

2003

**NSAIDs Enhancers Results Refs** 

diclefenac.

Etodolac terpenes Gel containing anethol increased absorption

Flurbiprofen Turpentine oil The bioavailability of transdermal patch

Flurbiprofen l-menthol/ethanol Flurbiprofen gel containing ethanol (25%)

Ibuprofen Ethanol The flux of ibuprofen was increased by the

Lumiracoxib OA Oleic acid (10%) has increased the flux of

administration.

absorption rate in rabbits.

delivery flurbiprofen.

skin partition of ibuprofen.

IPM/ Brij 92 Dermal formulations of ketorolac trometamol

viable epidermis.

than that of containing IPM.

Diclofenac Oleic acid(OA)/

Diclofenac Dimethyl sulfoxide (DMSO)

Flurbiprofen (nitro ester)

d-limonene

Transcutol®/(OA) lauroglycol isopropyl myristate

(IPM)

Flurbiprofen Linoleic acid (LA)/

Ibuprofen Propylene glycol (PG)

Ketorolac DMSO/d-limonene

Ketorolac trometamol eucalyptus oil/ Transcutol®

/linolenic acid (LNA)/(OA) Palmitic acid (PA)


Table 3. Effect of chemical penetration enhancers to increase skin permeation of NSAIDs.

Barry, 2004; Thong HY et al., 2007). Co-solvents such as alcohols, oil alcohols, propylene glycol, diethyleneglycol monoethylether (Transcutol), and compounds like fatty acids terpenes, Azone, dimethylsulfoxide (DMSO), pyrrolidones, urea and surfactants are frequently included in dermal/transdermal formulations as penetration enhancers (Williams & Barry, 2004; Mohammed et al., 2007). Table 3 summarizes the penetration enhancers to improve passage of NSAIDs through the skin and the results obtained.

### **3.3.2 Physical enhancement**

Iontophoresis is one of the most frequently used physical methods in improving dermal penetration of drugs. Iontophoresis enhances dermal penetration of drug molecules by applying low levels of electrical currents (0,5 mA/cm2) (Marro et al., 2002). Unlike passive diffusion-based transdermal administration, particularly, iontophoresis ensures dermal penetration of polar and charged drug molecules in high amounts loaded (Kalia et al., 1998; Sieg & Wascotte, 2009).

There are studies investigating whether the iontophoresis technique enhanced dermal penetration of NSAIDs. Curdy et al. (2001) dermally administered a commercial gel formulation containing piroxicam, and studied dermal penetration of piroxicam by using

Novel Formulation Approaches for Dermal and

MediaPharma 2011).

al., 2003; Pandey et al., 2009).

**4.1.2 Ointments, creams and lotions** 

**4.1.1 Gels** 

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 37

**NSAIDs Formulation type** Benzydamine Gel, cream Felbinac Gel

Diclofenac epolamine Patch Diclofenac sodium Gel, spray gel Diclofenac potassium Gel Diclofenac diethylammonium Gel, emulgel

> Etofenamate Gel, cream Ibuprofen Gel, cream Ketoprofen Gel Naproxen Gel Nimesulide Gel Piroxicam Gel

Salicylic acid Cream, ointment, lotion Table 4. Commerical dermal formulations of NSAIDs (Micromedex, electronic version, Rx

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

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,

Bufexamac Cream, ointment, lotion, emulgel

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 low plasma exposure.
