RESEARCH & DEVELOPMENT

Thpkal delivery enhanced by hyaluronic acid

-Rodgu HolI-

Hyaluronic acid bas shown potential as a vehicle for the topical delivery of diclofeoac. It appears that a greater amount of dkloCenac is rttalDeclln the epidermis wben this delivery method is used, compared with topical delivery via a buffer control. The clinical dfeds of this diclofenacJhyaJuronic acid combination in patients with actinic keratoses wert demonstrated in an open study, the resu1ts of whkh wert: presented at Dennatology Update '95 [Montnal, CantuUz; OcIOHr 1995]. In view of these ftndings, many raearc:bers DOW agree that the traditional idea of byaluronic acid as a simple molecule with a protedive, sbock-absorbing and structu.re-stabilisiDg role in connective tissue is simplistic and inaccurate.

Hyaluronic acid is a natura1ly occurring, high mol­ecular weight polysaccharide. It is a major constituent of the extracellular matrix and it has a critical role in a wide variety of biological processes. In some instances its role is mechanical, as seen in the syno­vial fluid and vitreous humour. In other situations, hyaluronic acid is involved in processes such as inflammation. wound healing. tissue hydration, cell division . migration and differentiation, and in facilitating the movement of ions and metabolites between cells.

It appears that many of the biological roles of hyal­uronic acid are mediated by. or are the result of. its interaction with a number of binding entities known as hyaJadherins, said Dr Stephen Gustafson from the University of UppsaJa, Sweden. HyaJadherins include specific cell surface receptors and cell adhesion molecules. such as interce llular adhesion molecule nCAM)-1.

<Hyaluronic tlCid is alhceptively simple molecule. Its impOrlD.nce is shown by [the ftICllluJJ itluu been] highly conserved • •.

and it clearly regulDus a variety of interesting phenomena.'

Prof~ssor Ella 11Irlty, Univtnily of Manitoba, ClJfIIJ{}Q

The idea that hyaluronic acid may be used to target certain cells and to deliver drugs to the skin came as a result of investigations which showed that: • receptors with a high affinity for hyaluronic acid

are present in the majority of cells • hyaluronic acid is well tolerated and non­

immunogenic. Based on such information, the pharmaceutical

company Hyal developed CT- llOle, a therapeutic agent that is composed of diclofenac 3% in a 2.5% hyaluronic acid gel. HyaJ tested this agent in an open­label study involving patients with actinic keratoses. The preliminary results of the study were discussed in lnpha~ last year.· This year, at Dermatology Update. the final results of this study were presented, aJong with research that provided insight into the ef­fect of hyaluronic acid on the retention of diclofenac in the epidermis.

cr-nol® Is etrective In adInk: keratooes In the open-label study, CT-1l0l e lg was

administered on a twice-daily basis to 29 patients with actinic keratoses for a period of 60-180 days. The mean age of the patients was 61 years.

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Flnalreaubfram .. ~ IIIUdy at CT·1101" CInIcIII__ .

At the follow-up assessment (on day 210), a c0m­plete response was seen in 81% of patients, and marked Improvement in 15%, while 1 patient failed to show any improvement. The average number of days to 'cure' was 94 (range 56-194). --CT·11 01· was generally well tolerated, and no signi-ficant changes from baseline were documented for any laboratory tests. 28% of patients developed an irritant type of contact dermatitis, which was confined to the treatment site. Treatment was discontinued in 10 patients, but 30 days after discontinuation, 8 of these patients were described .s complete responders, while the re­maining 2 patients showed marked improvement.

Assessments were made at baseline and at 60,120, 180 and 210 days after therapy initiation [see boxed text]. Clinical measures recorded at each visit included: • lesion count • treatment response, which was measured on a

6-point scale ranging from 'much worse' to 'cured' • tolerability, which was measured on a 4-point sca1e

ranging from 'poor' to 'excellent' . Haematological and biochemical parameters were

evaluated before and after treatment , and adverse events were recorded in a standardised form.

Cf-il 0 i- was highly efficacious in the treatment of actinic keratoses. Adverse effects were generally well tolerated and patient tolerance was considerably better than that associated with masoprocol or fluorouracil, said Dr lason Rivers from the University of British Columbia, Canada.

'freatlng adInk: keratooes TopicaJ fluorouracil and topical masoprocol are

among the several forms of therapy that are used to treat actinic keratoses. Others include cryotherapy, curettage and diathermy. The problem with these treatments is that they can cause considerable discom­fort and pain.

Thus, new treatments that are better tolerated are of great importance, particularly as prompt treatment

9

10 RESEARCH & DEVELOPMENT

Hyaluronic acid - con/inued

is recommended in order to reduce the risk of develop­ing invasive squamous cell carcinoma.

Dr Rivers believes that the results with Cf-llOl­in actinic keratoses are very promising. and provide confirmation of recent anecdotal reports that the com­bination product leads to clinical regression without significant irritation. He added that phase m. random­ised, double-blind trials are now underway in Australia. the US and Canada.

In _ sIudy darifIes elreds oCbyaIurmic add Other researchers have focused their efforts on

determining how hyaluronic acid improves the effi­cacy of dielofenac. In one study, an in vitro human skin diffusion model was used to look at the trans­dermal diffusion and deposition of dielefenac, with or without hyaluronic acid. Studies were carried out using fresh. surgically excised samples of human skin in Franz diffusion cells. Radiolabelled diclofenac was applied to the cells in either a buffer control or in 2.5% hyaluronic acid.

Compared with the control, diffusion of diclofenac was reduced and its retention in the epidermis was increased, when applied in combination with hyal­uronic acid, said Dr Mark Brown from King's College, London, UK.

In the hyaluronic acid-containing samples, diclofenac had penetrated all layers of the skin within 168 hours, but the majority of activity was retained in the epidermis. Autoradiographs showed that the activity seemed to be concentrated at the epidennalJ dermal junction. Dr Brown concluded that in the hya1uronic acid formulation, a depot or reservoir of diclofenac was formed in the area of the basement membrane. -,-,.. Editorial comttUnI: In September 1994, the US Health Protection Boord ,ranted Emergency Drug Release starus to Hyal's CI-JlOl for the treatnunt of actinic keratoses.

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