Treating psoriasis using novel drug delivery systems

Psoriasis is a chronic skin disorder marked by periodic flare-ups of sharply defined red patches covered by a silvery and flaky surface as illustrated in Figure 1.

The disease can affect almost every part of the human body, including trunk, scalp, genitals etc (Figure 2). Hyper-proliferation of epidermal keratinocytes due to reduced time-scale of cell maturation of skin leads to unbearable symptoms including inflammation, irritation, itching, burning, pain, scaling and dryness of the skin.

Psoriasis, in its various forms, tends to affect nearly 125 million people round the globe, i.e., around 2 – 3 per cent  of the total world population. Psoriasis today is one of the thrust areas of research globally, with the most prevalent form being the stable plaque psoriasis. The enormity and severity of the disease has led to the formation of as many as 60 psoriasis societies and associations world-wide for the cause. Each year, the 29th October is declared as World Psoriasis Day (WPD). Table 1 enlists the various types of psoriasis affecting human population and their major symptoms.

Topical therapy is the mainstay of treatment for mild to moderate psoriasis and serves as a useful adjunct support to systemic therapy in severe disease. However, efficacy and compliance to topical therapy in psoriasis have been a major concern. Approximately, 70 per cent of the psoriasis patients in three large surveys were found to be unsatisfied or moderately satisfied with their current treatment. Lack of effective delivery of drugs and undesirable skin interactions of the topical treatments are the main reasons for patient non-compliance. Nevertheless, newer developments in the formulation approaches have raised hopes in making topical therapy more useful and acceptable. The present paper endeavours to review the overall developments in the field of Novel Drug Delivery Systems (NDDS) pertaining to the topical treatment of psoriasis.

Challenges in topical delivery of drugs in psoriatic skin
Delivery of solutes through the skin is associated with a number of difficulties as shown in Table 2. ‘Rigidization’ of psoriatic skin has been attributed to a rise in the levels of cholesterol and fall in the levels of ceramides. Apart from this, normal moisturizing factors (NMFs) like water are almost absent in the psoriatic skin. As a result of various factors, targeting the psoriatic tissues using topical route poses a big challenge. The intricacies of the topical delivery into the psoriatic skin have lately been proposed to be addressed by the lipoidal carrier systems, such as liposomes. The latter resolve the problem of lipid imbalance by imparting the unsaturated fatty acids like linoleic acid to restore the normal skin conditions. Hence, these liposomal and allied carriers can result in an effective delivery of drugs across the psoriatic skin.

Several topical therapeutic agents are available for the treatment of psoriasis. Nevertheless, none of them can be regarded as an ideal drug molecule. This may either be due to their inherent side effects or their improper incorporation in the conventional vehicles. It is a well-known fact that due to variation in the physicochemical characteristics of the carrier and of the active compounds used, the degree of drug absorption through skin may vary, and so may be the drug efficacy. Hence, the carriers based on scientific approach can modify the physicochemical properties of the drugs and can help to decrease the intensity and frequency of side effects associated with these active moieties. Formulations like gels, creams, ointments and lotions are frequently used for the topical delivery of the anti-psoriatic agents. However, these formulations are often not able to mask the drug-related issues causing obvious problems with patient acceptance and compliance (Table 3). The topical delivery vehicle must be suitably designed and developed to attain the desirable attributes for use in extremely dehydrated and thickened psoriatic skin having lipid imbalance and sensitive to irritants.

Novel drug delivery systems in topical therapy for psoriasis
The NDDS with their unique advantageous features provide favourable skin interactions as desired in the diseased conditions like psoriasis (Figure 3). Considering the benefits, there have been several recent attempts to use the NDDS approach to improve the existing topical drug formulations in psoriasis. Table 4 provides a glimpse of the various carrier systems employed for the drugs effective in psoriatic treatment. A brief recount of the efforts presents here the current scenario.

Dithranol and Coal-tar
Dithranol, with a long history of use spanning over more than 100 years, is one of the most effective topical therapy in psoriasis. But in the existing form of products, it has not been fully accepted, mostly because of its irritation and staining properties. This made a long standing demand on the researchers world-wide to search for the modified molecule or formulation.

It included enormous efforts as reflected in more than 1500 publications, patents and exclusive meetings on the dithranol per se. Various efforts like chemical modifications of the molecule, formulation changes, new treatment modifications or strategies and other miscellaneous approaches like short-contact therapy did not provide any definite solution. Subsequent work on liposomal systems with dithranol led to the improvement in its skin penetration. Agarwal et al. (2001) developed dithranol entrapped in liposomal and niosomal vesicles (0.5 per cent) and found both of them superior to conventional formulation, while liposomes showed better results than niosomes employing mice skin. They found both of them superior to conventional formulation, while liposomes showed better results than niosomes. Gidwani et al. (2003) in their patent application revealed the usefulness of mixed vesicular systems of dithranol with and without salicylic acid. The formulations, when tested on more than 12 patients for 4 weeks, proved to be effective and devoid of irritation and staining.

The study on liposomal dithranol continued by Katare et al. (2007) resulted in the development of a product. This product when tested clinically in an open label as well as randomized double blind trials showed that dithranol in greatly reduced doses (0.5 per cent) in liposomes could clear the psoriasis plaques to match that of 1.15 per cent commercially available dithranol ointment. The advantages of liposomal dithranol in terms of efficacy and compliance (non-irritancy and non-staining) have been attributed to the ability of strategic liposomal formulation design.  In the later form, the reactivity of drug is moderated to the desired level, while favourable drug-skin interactions as a result of membranous layers of liposomes do not allow for irritancy and deep staining of clothes.

Some studies have been conducted on very old but highly useful drug, coal tar, using novel phospholipid structured topical formulation. This approach has been reported to be beneficial in meeting the challenges of skin irritation and staining on cloth and skin. They also reported better anti-psoriatic activity of this novel formulation vis-à-vis the conventional formulation employing mouse tail model of psoriasis. The team of authors has successfully developed novel-formulations of coal-tar and dithranol and the products are available in the Indian market.  Figure 4 shows the products in the final packaging.

Methotrexate
Methotrexate (MTX) is the gold standard drug used systemically in psoriasis, though there are not many products available for its topical application.

The key reason for this is its inability to penetrate adequately in the skin and get access to the target cells. But of late, several formulations and delivery techniques have been employed in order to improve its delivery through skin. Strategies include the use of different penetration enhancers, adhesive laminate tapes as occlusive covering, physical techniques like iontophoresis, and development of novel drug delivery vehicles. In a study of liposomal formulation of MTX conducted in 6 patients, it resulted in clearance of psoriasis lesions, while one patient recovered completely.

Further modified version of liposomes, i.e., deformable liposome was found to be quite superior to that of aqueous solution and normal liposomes in vitro. In a double-blind placebo-controlled trial involving 40 psoriasis patients, niosomal systems in chitosan gel (0.25 per cent) resulted in better efficacy, tolerance and patient compliance, when compared to a marketed formulation. Another version of liposomal system containing ethanol, i.e., ethosomes, showed favourable skin permeation characteristics. Trotta et al. (1996) developed oil in water (o/w) microemulsions of MTX having six-fold higher permeation flux than that from the corresponding solutions in mice skin. Recently, MTX incorporated in a hydrogel formulation showed zero order kinetic release and antipsoriatic activity. This formulation was evaluated in 35 psoriasis patients and the application site was also irradiated with 80 joules diode laser of wavelength 650 nm, thrice a week. During eight  months' follow-up, up to 60 per cent of the patients treated with LMTX gel had no recurrence.  Solid lipid nanoparticles (SLN) of MTX have showed improved drug accumulation in human cadaver skin. This formulation was also investigated clinically on 24 psoriasis patients for six weeks period. The researchers reported that MTX SLN-gel significantly improved the therapeutic index in terms of Average Percent Improvement in Healing (APIH) of lesions and reduction in average score of degree of erythema and scaling.

Tamoxifen
Tamoxifen (TAM), an anti-estrogen compound given systemically, has recently been figured as a useful agent in the treatment of certain skin specific disorders like psoriasis. Enhanced epidermal transport of TAM employing different penetration enhancers has been reported. Katare et al. (2004) developed TAM liposomes of multilamellar nature, which exhibited appreciably enhanced skin permeation as well as retention of drug molecules in the skin.

Theophylline derivatives
Dyphylline, a derivative of theophylline, inactivates cyclic AMP (cAMP), and is, therefore, used in the management of psoriasis. Touitou et al.  (1992) reported significant increase in permeation of dyphylline across abdominal mice skin using liposomal systems, thus corroborating its promise in topical delivery.

Corticosteroids
Cortecosteroids, one of the most frequently used class of drugs in dermatology, have been in practice to treat psoriasis too, either alone or in combination with other drugs. Korting et al. (1990) developed liposomes containing 0.039 per cent betamethasone dipropionate (BDP) and compared it with a commercial propylene glycol gel containing 0.064 per cent BDP in a double-blind, randomized, paired trial lasting 14 days in 10 patients with psoriasis vulgaris and eczema. This report documented improvement in case of eczema, but not in psoriasis.

Psoralens
Psoralens, mainly employed in PUVA are 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5,8-trimethylpsoralen (TMP). Studies have shown that the application of an emulsion cream and a microemulsion of 8-MOP helps in localization of the drug. Baroli et al. (2000) developed microemulsions for topical delivery of 8-MOP at the target site and enhanced porcine skin accumulation of 8-MOP without systemic side effects Fang et al. (2008) developed nanoparticulate lipid-based drug carriers viz. SLNs and NLCs, with increased skin permeation and controlled release properties for psoralens.

Cyclosporin A
Cyclosporin A (CsA) is used in the treatment of psoriasis by oral as well as topical route. Its high molecular weight (more than 500 Da) and limited cutaneous permeation are the key challenges for topical delivery.[111] Many attempts have been made to achieve localized site-specific immunosuppression using conventional topical formulations of CsA, e.g. at Novartis Research Centre (Vienna, Austria), but of without any avail. Duncan et al. (1993) in a small double-blind, vehicle-controlled trial reported significant improvement in psoriasis lesions treated with topical CsA formulation with penetration enhancer(s). Guo et al. (2000) developed lecithin vesicular carriers for the transdermal delivery of CsA. They observed by in vitro permeation technique that the flexible vesicles are better carriers for dermal enhancement. Ugazio et al. (2002) incorporated CsA in SLNs and proposed for the exploitation through various routes. Boinpally et al. (2004) studied the effect of iontophoresis on topical delivery of CsA across human cadaver skin using lecithin-solubilized drug which resulted in appreciable drug transport across skin. Few reports demonstrated monoolein as penetration enhancer for the topical and transdermal delivery of CsA in various liquid crystalline systems. Verma et al. (2004) reported increased transport of CsA across skin employing alcoholic liposomes. Katare et al. (2005), demonstrated successful topical delivery of CsA through multicompartmental liposomes and microemulsified systems. Liu et al. (2006) reported  that 40 per cent ethanol and 10 per cent menthol shortened the lag time of the penetration of CsA into deeper skin layers.