ORIGINAL ARTICLE

A randomized, double-blind, vehicle-controlled study of a novelliposomal dithranol formulation in psoriasis

ABIR SARASWAT1, RAVINDRA AGARWAL2, OM P. KATARE2, INDERJEET KAUR3 &

BHUSHAN KUMAR3

1Skin Clinic, Lucknow, India, 2University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India, and3Department of Dermatology, Venereology & Leprology, Postgraduate Institute of Medical Education & Research,

Chandigarh, India

AbstractDithranol is infrequently used in psoriasis in spite of excellent efficacy due to its local adverse effects. We have synthesized anovel formulation of dithranol in which the drug is entrapped in phospholipid liposomes. This formulation has shownmarkedly low irritation and minimal staining of skin and clothes in preliminary studies. Twenty patients with bilaterallysymmetrical stable plaque psoriasis applied 0.5% dithranol lipogel to lesions over one side of the body. On the other side, 10patients were randomized to apply pure liposomal base and 10 applied a conventional cream containing 1.15% dithranol,1.15% salicylic acid and 5.3% coal tar in a 30-minute, short contact regimen for 6 weeks. Patients were assessed for diseaseseverity, perilesional erythema and skin staining, pruritus and any other adverse effects at baseline, 2, 4 and 6 weeks. Bothlipogel and the cream significantly reduced the total severity score compared to the liposomal base at 4 (p50.004) and 6(p50.01) weeks. There was no significant difference in the clinical response of dithranol cream and lipogel. Markedly lowincidence and severity of perilesional erythema (pv0.001) and skin staining (pv0.05) was seen with the lipogel incomparison with the cream.

Key words: Adverse effects, dithranol, liposome, psoriasis, topical therapy

Introduction

Since its introduction more than 80 years ago,

dithranol has been one of the most effective topical

treatments for psoriasis, but its side effects of

irritancy and staining of skin and clothes have

restricted its use. Several attempts have been made

to eliminate these troublesome side effects while

maintaining efficacy. Shorter application times have

been recommended (1), followed by washing the

skin with special cleansing agents (2), and aqueous

cream (3) and wax-ester-based preparations (4) have

been introduced. However, dithranol use remains

limited in spite of various modifications in thera-

peutic regimens and topical formulations.

In 1992, Gehring et al. (5) demonstrated

increased skin penetration and clinical effect of

dithranol when compounded in a vehicle containing

liposomes. However, that formulation did not

contain liposome-entrapped dithranol. We have

prepared a new, stable, liposome-entrapped formu-

lation of dithranol in an aqueous gel base. This

dithranol lipogel has shown good skin penetration

and pharmacokinetics on animal skin (6). Our

preliminary open-label studies on psoriasis patients

have revealed a marked lack of skin staining and

irritation coupled with good efficacy (7), and fabric-

staining studies have shown much lighter and easily

washable staining compared to conventional pre-

parations (8).

The aim of the present study was to test the

clinical efficacy and acceptability of dithranol lipogel

against the only commercially available dithranol

preparation in India, a conventional cream-based

product containing dithranol, salicylic acid and coal

tar.

Materials and methods

This trial was a randomized, double-blind, vehicle-

controlled, within-patient comparison. It was con-

ducted at the Dermatology outpatient department of

the Postgraduate Institute of Medical Education and

Research, Chandigarh, which is a tertiary-level

referral centre in northern India. This study was

Correspondence: Abir Saraswat, B 7, Indira Nagar, Lucknow (UP), PIN 226 016, India. E-mail: abirsaraswat@yahoo.com

(Received 10 May 2006; accepted 1 July 2006)

Journal of Dermatological Treatment. 2007; 18: 40–45

ISSN 0954-6634 print/ISSN 1471-1753 online # 2007 Taylor & Francis

DOI: 10.1080/09546630601028729

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performed in accordance with standard operating

procedures with the permission of the Drug

Controller General of India.

Inclusion criteria

Male or female patients aged 12 years or older, with

bilaterally symmetrical stable plaque psoriasis invol-

ving less than 10% of the body surface area, who

were registered at the Psoriasis Clinic of the

Dermatology outpatient department, were eligible

for enrolment in the study. The nature of the study

was explained to the patients. Twenty-three patients

satisfying these criteria were recruited. After a 2-

week wash-off period, during which only topical

bland emollients were allowed, 20 patients were

randomized to receive treatment.

Exclusion criteria

Patients who had ever used dithranol in the past, or

had taken any systemic anti-psoriatic treatment in

the 8-week period to randomization were excluded

from the study. Known intolerance to the ingredi-

ents of the topical agents used was also an exclusion

criterion. During the study period, patients were

allowed only topical bland emollients apart from the

medications given. Systemic antihistamines were

allowed in patients with moderate to severe pruritus.

Study design

Patients who met the study criteria were randomized

to either of the two treatment arms at a 1:1 ratio.

The investigator and patients were blinded as to the

composition of the topical medication dispensed.

The study duration was 6 weeks.

Treatment

Dithranol lipogel was produced by optimal entrap-

ment of dithranol in multilamellar liposomes com-

posed of phosphatidyl choline and cholesterol, with

minimal free drug. The mean diameter of liposomes

was 5¡1.25 mm. Further details of the preparation

and in vitro evaluation of dithranol lipogel have been

published earlier (6). Each patient was given two

identical 25 g tubes, one of which contained 0.5%

dithranol lipogel. The other tube contained either

pure liposomal base without dithranol, or Derobin

ointment (1.15% dithranol, 1.15% salicylic acid,

5.3% decolourized coal tar in a cream base)

depending on the treatment arm. To ensure

adequate blinding, a yellow food-grade dye was

added to the liposomal base, which resembled the

yellow colour of the dithranol-loaded product.

Each patient was randomly assigned to apply one

of the tubes to all lesions on the right side of the

body, and the other to the left side. Patients were

instructed to apply the medication with a plastic/

wooden applicator, carefully avoiding perilesional

skin, and to wash off both the sides with ordinary

bathing soap after 30 minutes of application.

Following this, topical emollients were applied to

the lesions immediately and ad libitum thereafter.

Treatment was continued for 6 weeks or until a total

sign score of 0 was reached, whichever was earlier.

Clinical evaluation

Patients were examined at screening, baseline and at

weeks 2, 4 and 6. The signs evaluated were

erythema, induration and scaling. The severity of

each sign was scored on a 0–3 scale (05absent,

15mild, 25moderate and 35severe) and the sum of

the scores constituted the total severity score (TSS).

If different lesions on the same side showed differing

sign scores, the mean of all lesional sign scores was

used. Perilesional erythema was also scored on a

similar 0–3 score, and lesional and perilesional

brown staining of skin was scored on the 0–3 score

given by Mustakallio (9). Lesional itching was

scored on a 0–10 visual analog scale (VAS) by the

patients. For each of the above parameters, separate

scoring for left and right sides was done at each visit.

Patients were also asked about any burning sensation

on application, overall cosmetic acceptability and

cloth staining on both sides.

Statistical methods

The efficacy analysis was conducted on the intent-

to-treat (ITT) population on patients with at least

one post-baseline assessment. The primary efficacy

variable was the fall in TSS, which was analysed at

each visit by the Kruskal–Wallis one-way analysis of

variance on ranks, which does not require a normal

distribution of observations. This was followed by all

pairwise multiple comparison procedure (Student–

Newman–Keuls method). Multiple comparisons

taking the dithranol lipogel group as the control by

Dunn’s method were also performed. The power of

all performed tests was more than 80% with

alpha50.05%. Non-parametric data were compared

by the chi-squared test. All statistical tests were

performed using Sigma StatH software.

Results

A total of 23 patients entered the 2-week pre-study

washout period and three patients dropped out at

the end of this period due to unrelated reasons.

Twenty patients were randomized to two treatment

arms (dithranol lipogel versus liposomal base, n510;

dithranol lipogel versus cream, n510). Two patients

in the lipogel versus cream group discontinued the

treatment: one had severe irritation on only the site

treated with cream at 2 weeks and the other had

Liposomal dithranol in psoriasis 41

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moderate to severe irritation on both sides at 4

weeks. Both patients were advised to stop treatment

on both sides and periodic assessments were

continued until the end of the study (6 weeks).

None of the patients stopped treatment in the lipogel

versus liposomal base group.

Key demographic data and disease characteristics

at baseline are presented in Table I. All demo-

graphic and disease parameters were similar between

both treatment groups.

Efficacy

Complete clearance of disease (TSS50) was seen in

5/20 (25%) dithranol lipogel-treated sides (at 3

weeks in one patient, 4 weeks in three patients, and 6

weeks in one patient), 3/10 (33.3%) cream-treated

sites (at 3 weeks in all) and none of the liposomal

base-treated sites (pw0.05) (Figure 1A and B). Only

mild erythema (score51) without any induration or

scaling remained at 6 weeks in a further five patients

on the lipogel-treated side. The fall in erythema,

induration and scaling scores over the treatment

period with the three preparations is presented in

Figures 2A, B and C. All three treatments reduced

scaling the most, followed by induration and

erythema. In all three parameters, there was no

significant difference between the dithranol lipogel

versus liposomal base and dithranol lipogel versus

cream groups or individually between the three

treatments at baseline and 2 weeks. However, both

dithranol lipogel- and cream-treated sites showed

significantly less erythema, induration and scaling

than liposomal base-treated sites at 4 and 6 weeks

(pv0.05). There was no significant difference in the

mean scores of the cream- and lipogel-treated sites at

any point in the study. The changes in the TSS in

the three groups are presented in Table II.

Safety and tolerability

Perilesional erythema was observed at any visit on 1/

20 lipogel-treated sides, 7/10 cream-treated sides

and none of the liposomal base-treated sides (x2 test,

pv0.01). Erythema was mild in the dithranol

lipogel-treated side, whereas it was mild in three

patients, moderate in three patients and severe in

one patient on the cream-treated side.

Lesional/perilesional staining of skin was seen in 8/

20 dithranol lipogel-treated sites and it was scored 1

(brownish hue) in all of them. Skin staining was seen

Table I. Patient demographics and disease characteristics at

baseline.

Dithranol lipogel

versus liposomal

base n510

Dithranol lipogel

versus DerobinH

n510a

Mean age, years (¡SD) 40.1¡16.2 44.7¡14.9

Sex (male:female) 7:3 8:2

Median duration of

disease, years (range)

6 (0.6–32) 8 (1–47)

Mean % body surface

area involved (¡SD)

5.3¡2.1 6.1¡1.9

aTwo patients withdrew from the study after 2 weeks.

(A) (B)

Figure 1. (A) Pretreatment appearance of a patient in the dithranol lipogel (right) versus dithranol cream (left) group; (B) almost total

clearance with dithranol cream and more than 90% improvement with dithranol lipogel at 4 weeks.

42 A. Saraswat et al.

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in 9/10 cream-treated patients (x2 test, pv0.05). It

was scored 1 in one patient, 2 (reddish brown) in

seven patients and 3 (dark brown) in one patient

(Figure 3). The only patient with no staining had

discontinued treatment at 2 weeks due to severe

irritation.

The VAS for itching showed a bilaterally symme-

trical flat or downward trend in all patients except

two in the dithranol cream versus dithranol lipogel

group, in whom the cream-treated side experienced

increased itching at 2 weeks, followed by subsidence

of pruritus. There was no significant difference in

pruritus at 6 weeks between any of the three

treatments.

Two patients reported a transient burning sensa-

tion after application: one on only the cream-treated

side and the other on both cream- and dithranol

lipogel-treated sides. Fifteen patients preferred the

lipogel preparation for overall acceptability and

efficacy and five reported no particular preference.

Overall, five patients reported accidental staining of

clothes: two in the liposomal base versus dithranol

lipogel group and three in the cream versus dithranol

lipogel group. All of them reported that stains on the

side of dithranol lipogel application were easily and

almost completely washable with soap and water,

whereas the latter three commented on the deep,

permanent staining due to cream.

Discussion

This study showed that 0.5% liposome-entrapped

dithranol in an aqueous gel base has comparable

efficacy to a 1.15% commercially available dithranol

ointment, and this difference is exclusive of the

beneficial effect of the liposomal base itself.

Moreover, we have seen a remarkable difference

between the two products with regard to skin

irritation and staining. Similar to our observations

in a preliminary study (7), the dithranol lipogel had

significantly lighter skin staining compared to con-

ventional dithranol cream, even when both were

applied for identical 30-minute contact periods. A

marked reduction was also observed in the incidence

and severity of perilesional erythema with the

lipogel. These effects may be explained based on

the novel drug delivery mechanisms used in this

preparation.

Efficacy

Dithranol is highly unstable and is degraded quickly

in a pH-dependent manner in the presence of water

and oxygen to inactive metabolites like danthron and

dithranol dimer (10). Previous attempts to enhance

stability have involved the addition of a-hydroxy

acids such as salicylic acid (e.g. in the conventional

cream product used in this study) and antioxidants

such as ascorbyl palmitate (11,12). Dithranol has

been embedded in crystalline monoglycerides in a

relatively recent formulation (MicanolH) to enhance

stability and reduce perilesional spread (4). In the

liposomal gel used in this study, we have ensured

stability by two means: efficient liposomal drug

loading with minimum free drug, and the addition

of butylated hydroxytoluene, which is a potent

antioxidant. Stability is further enhanced by lipo-

some encapsulation, which protects dithranol mole-

cules from oxygen and water. Liposomes also

provide targeted delivery with slow and sustained

drug release, acting as ‘drug localizers’, and not

only as ‘drug transporters’. This is because simi-

larly to biological membranes, they can store both

Figure 2. (A) Fall in mean erythema score with the three

treatments; (B) fall in mean induration score with the three

treatments; (C) fall in mean scaling score with the three

treatments.

Liposomal dithranol in psoriasis 43

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water-soluble and lipophilic substances in their

different phases (13,14). These properties can

explain the comparable effect of the test formulation

with conventional dithranol cream in spite of having

a 56% lower dithranol concentration. Similar results

have been reported with liposomal formulations of

tretinoin, showing no loss of efficacy even with a

significantly reduced drug concentration (15).

A limitation of this study is the lack of a treatment

arm with a 0.5% conventional cream preparation of

dithranol. This means that the comparable efficacy

between 0.5% dithranol lipogel and 1.15% cream

cannot be attributed to the liposomal vehicle with

certainty.

Irritation

Histopathological studies done by us on normal rat

skin have shown that dithranol lipogel causes

minimal epidermal or dermal inflammatory changes

in comparison with other commercially available

dithranol formulations (submitted for publication).

Clinically, this was seen as almost no irritation in 19

of the 20 patients in this study. One patient who

reported irritation with the lipogel was found to be

sensitive to dithranol on a patch test and Repeated

Open Application Testing (ROAT). The explana-

tion of the reduced irritancy may lie in the

mechanism of dithranol irritation. It has been shown

that dithranol-derived free radicals are principally

responsible for perilesional erythema and inflamma-

tion, whilst paradoxically they mediate key antipsor-

iatic effects in lesional skin (16). Kersey et al. (17)

have suggested that dithranol-induced inflammation

could be due to an oxidation metabolite formed by

aryl hydrocarbon hydroxylase, an enzyme which is

induced in human skin by dithranol. Experimental

studies have shown that dithranol inhibits the

activity of endogenous free radical scavengers such

as superoxide dismutase and catalase in skin (18).

Thus, a combination of free radical-induced damage

and suppressed endogenous antioxidant activity

produces skin irritation. In this liposomal gel, slow

release of the drug from the multilamellar liposomes

and reduced dithranol-derived free radicals due to

enhanced stability may contribute to lowering the

irritancy. However, the exact reason for this effect is

a matter of conjecture.

Staining of skin

Brown discolouration of lesional and perilesional

skin is cosmetically the major adverse effect of

dithranol and is caused by the formation of insoluble

dithranol metabolites which cannot be easily washed

off. Danthron and dithranol dimer are orange and

pale yellow in colour and it is known that the violet-

brown skin staining is due to these and other

uncharacterized products derived from extensive

oxidation of dithranol (19). Therefore, it is expected

that enhancing the stability of dithranol will reduce

its oxidation and minimize skin staining. Moreover,

staining and irritation are concentration-dependent

and, therefore, 0.5% dithranol would be intrinsically

less staining and irritating than a 1.15% formulation.

Other adverse effects

The vehicle may be responsible for the local stinging,

itching, burning sensation and dryness of skin, as is

seen with conventional dithranol products (20). Co-

ingredients such as salicylic acid, which is present in

the conventional cream used in this study, are also

Table II. Fall in total severity score (¡SE) in the treatment groups.

Weeks

0 2 4 6

Dithranol lipogel 6.1¡1.3 3.8¡0.3 2.5¡0.3 1.6¡0.2

Conventional cream 6.3¡1.2 3.7¡0.3 2.3¡0.2 1.5¡0.2

Liposomal base 6.2¡1.2 5.3¡0.5 4.7¡0.5 4.1¡0.4

The inter-group differences were statistically significant at 4 and 6 weeks.

Figure 3. Perilesional pigmentation in a patient after 6 weeks of

treatment with dithranol cream (right) and dithranol lipogel (left).

44 A. Saraswat et al.

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known to produce local adverse effects. However,

the liposomal base has intrinsic emollient activity,

which was reflected in the slow, but steady improve-

ment in disease severity on the base-treated sites in

this study. These properties of liposomes and the

water-based gel formulation may account for the

excellent cosmetic acceptability and negligible local

adverse effects of the lipogel.

To conclude, this study has demonstrated that

0.5% liposomal dithranol gel is as effective as 1.15%

dithranol cream in the treatment of stable plaque

psoriasis and produces almost negligible local

adverse effects. Coupled with its low fabric and skin

staining and its easy washability, dithranol lipogel

has the potential to be much more acceptable to

patients and physicians than currently available

formulations. However, the extremely low irritation

and staining of the skin seen in this study needs to be

confirmed in larger studies.

Acknowledgement

We are grateful to Natterman Phospholipids GmbH,

Cologne, Germany, who supplied the liposomes and

GSK Pharmaceuticals (India), who provided pure

dithranol for this study free of charge.

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