Eur J Clin Pharmacol (1990) 39:349-351

EuropeanJournalof ( ~ ~(~(~::~] © Springer-Verlag1990

Liposome encapsulation improves efficacy of betamethasone dipropionate in atopic eczema but not in psoriasis vulgaris H. C. K o r t i n g 1, H. Z i e n i c k e 1, M. Schfifer-Korting 2, and O. B r a u n - F a l c o ~ Dermatologische Klinik und Poliklinik der Ludwig-Maximilians-Universitfit Miinchen, and Pharmakologisches Institut far Naturwissenschaftler der Johann Wolfgang Goethe Universit~it Frankfurt/M., FRG Received: February 28,1990/Accepted: June 21,1990

Summary. The effect of a liposomal preparation of betamethasone dipropionate (0.039%, BDP) has been compared to that of a commercial propylene glycol-gel containing 0.064% B D P in a double-blind, randomized, paired trial lasting 14 d in 10 patients with atopic eczema and 10 patients with psoriasis vulgaris. In eczema, the liposome preparation tended to reduce erythema and scaling m o r e than the conventional gel, the difference in the latter p a r a m e t e r being significant on D a y 7. T h e r e was greater i m p r o v e m e n t of psoriasis on the side treated with the reference gel. Hence, liposome encapsulation of B D P may increase the antiinflammatory action but not the antiproliferative effect. Since inhibition of mitotic activity is linked to the atrophogenicity of topical corticosteroids, the results suggest that liposome encapsulation m a y improve the benefit-risk ratio in eczema.

Key words: b e t a m e t h a s o n e dipropionate, eczema; atopic eczema, psoriasis vulgaris, liposomes, gel, therapeutic efficacy

Liposomes are frequently considered as drug delivery systems for systemically applied chemotherapeutic agents and anticancer drugs (reviewed in 1, 2). Topical administration of liposome preparations to the skin has recently received attention, and studies have b e e n p e r f o r m e d with topical glucocorticoids [3-8], tetracaine [9] and econazole [10]. In 1988, the latter product has been registered in Switzerland (Pevaryl®-Lipogel, Cilag Corp.). Pharmacokinetic evaluation of triamcinolone acetonide [3, 4] and hydrocortisone [6-8] showed higher drug levels in the skin and lower systemic availability following application of liposomal corticosteroids as c o m p a r e d to conventional preparations. However, there did not appear to be any data on the influence of liposomal encapsulation on corticosteroid activity. The present study was a

comparison of the effects of a gel and a liposome preparation of betamethasone dipropionate (BDP).

Materials and methods The controlled double-blind studies were approved by the local Ethical Committee. Twelve out-patients with atopic eczema and 11 with psoriasis vulgaris took part in the study after giving voluntary written informed consent to it. Ten patients in each group finished the study; atopic eczema 10 females aged 33 (13) y, psoriasis vulgaris 8 f and 2 m aged 36 (16) y. Exclusion criteria were > 40% body surface area affected, pre-treatment with glucocorticoids within the last 5 days, pregnancy and lactation. Facial lesions were not treated with the study medication. The patients were randomized to receive the liposome preparation on one side of the body and the reference gel on the other. Medication was applied to the affected areas without occlusion once daily for 14 days. In addition to the study medication the patients were allowed to use a non-medicated preparation at an interval of 12 h. In eczema a cream (Vobaderm® Basiscreme, Hermal, Reinbek, E R. G.) and in psoriasis an ointment were offered (Psoralon ®Fettcreme, Hermal). Following the initial evaluation, patients returned for follow-up at 4, 7 and 14 days. At every visit the investigator clinically rates symptoms and signs; eczema-itching, erythema, oedema, vesicles, papules/nodules, exudation, scaling, lichenification, excoriation, and fissures; psoriasis-erythema, large and small infiltrates, scaling; scored as 0 (none), 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe). In addition, the gobal effect was rated 0 (healed), 1 (major improvement), 2 (moderate improvement), 3 (minor improvement), 4 (no change), 5 (worse). At the follow-up visits the patients were also asked about side-effects. The liposome preparation was a polyacrylate gel containing 0.039% betamethasone dipropionate (BDP) encapsulated in unilamellar liposomes with a mean diameter of 50 nm. Liposomes were produced from egg lecithin by detergent dialysis [11]. A conventional 0.064% betamethasone dipropionate gel containing propylene glycol (Diprosis ®Gel, Essex Pharma, Munich, F. R. G.) was used as the control. Data are expressed as arithmetic mean (SEM). Differences in treatment results were evaluated for significance using the Wilcoxon rank sum test for matched pairs. P < 0.05 was considered statistically significant.

H. C. Kortinget al.: Liposome- encapsulatedbetamethasone

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Fig.1. Rating (mean with SEM) of pruritus, erythema,scalingand excoriation in 10 patients with atopic eczema before the study (Day 0) and on three follow-upvisits,as wellas the globaltreatment response on the last treatment day.*: P < 0.05

Fig.2. Rating (mean with SEM) of erythema,large and smallinfiltrates and scalingin 10 patients withpsoriasisvulgarisbefore entering the study(Day 0) and on three follow-upvisits,as wellas the global treatmentresponse on the last treatment day.*: P 0.05). Papules/nodules (9 subjects), lichenification (n = 6) or fissures (n = 4) presented by the subjects responded by 67 to 83% on the sides treated with the liposome preparation, and by 77 to 83% on the other side. Oedema (one patient) and exudation (n = 2) were cured within 4 days following either treatment. With either preparation two patients were cured and in the others major or moderate improvement was seen within 14 days (Fig. 1). In contrast, the commercial BDP formulation was superior in the treatment of psoriasis (Fig.2). It cured one patient, major improvement was obtained in three and a minor to moderate one in six. Liposomal BDP induced minor (6 subjects) to moderate (4 patients) improvement of psoriasis. The reference gel was superior in six patients and the liposome preparation in one. Differences were observed in the signs of the disease. Erythema, large and small infiltrates and scaling improved by 9 to 33% following the liposome product and by 31 to 47% following the gel. A significant difference was seen in erythema and large infiltrates (Fig. 2). One patient with psoriasis was excluded from the study on Day 7 due to major pruritus on the side treated

Discussion

Liposomes have many potentially useful properties as drug delivery systems. Liposomes can adsorb to almost any cell type and once adsorbed they can be endocytosed, after which intralysosomal degradation will release entrapped drugs. Fusion of adsorbed liposomes with cells, too, may lead to a high intracellular drug level. In addition, liposomes can release incorporated drugs close to the adsorbing cell [12]. The use of liposomes in dermatology has recently been reviewed [12]. Liposomes may serve to improve topical therapy of skin disease. Due to the barrier function of the horny layer, current vehicles are only marginally effective in delivering active ingredients to the site of disease [13], and absorption rates amount only to a few percent [14]. In the case of topical glucocorticoids, systemic side-effects may be reduced by slow drug release, which might result in improved biotransformation to inactive metabolites. As the value of super-potent glucocorticosteroids

351

H. C. Korting et al.: Liposome - encapsulated betamethasone has been questioned, because of their systemic and local side effects [15], liposomal encapsulation might considerably improve their usefulness. An essential prerequisite for therapeutic success is appropriate drug release from the vehicle. Despite extensive pharmacokinetic investigation of liposome-encapsulated corticosteroids (3-8), this has not been demonstrated due to the limitations of the analytical methods. Moreover, until now pharmacodynamic experiments have not been performed with such preparations. Thus, it is not clear whether all the drug in the skin has been released or whether it is partly retained in the liposomes, where it would be pharmacologically inactive [12]. To evaluate the potential value of liposome preparations of a topical corticosteroid, betamethasone dipropionate has been investigated encapsulated in liposomes versus a conventional gel preparation in patients with atopic eczema and poriasis vulgaris. In eczema, BDP 0.039% in liposomes was at least equi-potent to a commercial propylene glycol containing gel of 0.064% B D P (Fig. 1). In psoriasis, however, the reference gel was superior (Fig.2). Previous studies showed a significant improvement in B D P activity on the addition of propylene glycol [16, 17]. Thus, in the present study liposomal BDP activity was comparable to the most potent gel available, suggesting that liposome encapsulation had improved BDP activity in eczema even more than the addition of glycol. The greater potency of the liposome preparation may result from a curative effect of the liposomal lipids. This is unlikely, however, since the amount of lipid in the liposome gel (3%) is low as compared to the quantity administered by the non-medicated cream (about 60%) applied to both sides. A specific effect of the liposomal lipids can also be excluded, since the liposomes were prepared from phospholipids, whereas in atopic eczema there is lack of ceramides [18]. In the treatment of eczema the antiinflammatory action of glucocorticoids is most relevant, whereas the antiproliferative effect appears to be most important in psoriasis [19]. Suppression of cell proliferation, however, is also considered to induce skin atrophy [20]. Since improved B D P activity was only seen in eczema, it may be speculated whether liposome encapsulation had selectively increased the antiinflammatory action. This might have resulted from modification of the pharmacokinetics of the glucocorticoid, leading to a high concentration in inflammatory cells and lower levels in, for example, keratinocytes and fibroblasts [21]. Thus, liposomes may represent a step forwards in the topical therapy of skin disease by improving the benefit-risk ratio of glucocorticoids and possibly other drugs.

Acknowledgements. The BDP liposome preparation, Diprosis Gel, and the vehicles were kindly made available by Hermal, Reinbek, ER.G.

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