Photostability Problems Of Topical Dosage Forms Of Antimycottcs

The determination of the photoinstability of the drug substance is the first step of the photo-stability testing procedure of drugs. The next one is the investigation of the light sensitivity of the drug substance in its preparation. Antimycotics are often used externally. In many cases it is necessary to determine the photostability of such substances in their topical dosage form. As examples results with natamycin and nystatin will be presented.

In methanolic solution the photolysis of natamycin is very fast. Already after 10 sec more than 10% of the drug was destroyed, after 10 min no drug substance is detectable any more. Therefore, natamycin belongs to the drugs with extremely high light sensitivity. Its tetraene structure, which could be detected in 5 degradation products, is more and more transformed to a triene structure found in other photodegradation products. Natamycin is part of two topical dosage forms, shown in Figure 18. In both it is suspended. The diameter of the particles reached 30 ¡im in the cream, in the eye ointment the particle diameter was mainly below 10 |im.

Of course both preparations are protected from light in tubes during storage. However, sunlight exposure of the ointments after application results in a fast photodegradation of the drug. The preparations were applied in a layer thickness of 1 mm. After 30 min about 50% of the drug substance was decomposed in both preparations.

Photodecomposition of drugs after application on the skin has been demonstrated for other drug substances, too, e.g. for corticosteroid gels.13

The second drug which will be to presented is nystatin. Nystatin consists of a mixture of various polyenes. Its photolysis in solution is very fast. After 1 min irradiation more than 50% of the initial drug content was destroyed. Already after 30 sec 3 photodegradation products with tetraene structure are detectable. The fourth degradation product has got a different structure. Longer lasting irradiation resulted in the formation of further degradation products.

In the topical preparations, two creams and three paraffin/polyethylene-ointments, nystatin is suspended as thin crystal needles of about 10 nm.

Figure 18 Photodegradation of natamycin in topical preparations (Suntest CPS, UVfilter): cream (20 mg/g) eye-ointment (10 mg/g) ^

Figure 18 Photodegradation of natamycin in topical preparations (Suntest CPS, UVfilter): cream (20 mg/g) eye-ointment (10 mg/g) ^

Figure 19 Photodegradation of nystatin in topical preparations after irradiation (Suntest CPS, UV filter): creams ointments M-W- Tk time (min)

Figure 19 Photodegradation of nystatin in topical preparations after irradiation (Suntest CPS, UV filter): creams ointments M-W- Tk

The topical preparations were applied as layers of 1 mm thickness and irradiated. After 60 min a degree of 13% of the initial drug content was found in two of three ointments. The third ointment showed only a loss of 3% nystatin because of the presence of zinc oxide. Zinc oxide is a pigment with good light reflective properties and therefore can be regarded as a light protective agent in this preparation. Both of the creams were significantly more stable than the ointments (Figure 19).

Because of these results changes for the monographs in the European Pharmacopoeia should be taken into consideration for both drug substances, natamycin and nystatin. They have shown photodegradation kinetics similar to nifedipine, of which the light sensitivity is very well known. Therefore light protection during the analytical handling should be demanded in the monographs. For topical application on uncovered parts of the body, light protection by pigments or light absorbing excipients should be taken into consideration.

How is it possible to photostabilise light sensitive drugs? As a model drug the very light sensitive substance terconazole has been chosen.

A methanolic solution of terconazole was stabilised by adding excipients as antioxidative substances and substances which absorb light in a similar wavelength range like the drug itself (vanillin, /»-aminobenzoic acid) (Figure 20).

Figure 20 Influence of excipients on the photostability of terconazole in methanolic solution (10mg/100ml, Suntest CPS, UVfilter)

time (min)

Figure 20 Influence of excipients on the photostability of terconazole in methanolic solution (10mg/100ml, Suntest CPS, UVfilter)

Without the addition of a protective excipient 70% of terconazole were degraded within 20 min of light exposure. The redox stabilisers sodium bisulfite and ascorbic acid had only little effect on the photostability of terconazole solutions. Whereas excipients showing spectral overlay of the absorption spectrum of terconazole had good light protective properties: The addition of p-aminobenzoic acid and the addition of vanillin (lOOmg/100ml) to the ter-

conazole solutions resulted in a good photostabilisation of the drug. Only 5% to 6% were degraded after 20 min of irradiation. The photodegradation kinetics were reduced by the factor of 20. The photostabilisation principle of spectral overlay is often successfully ap-plied.14'15'16'17

References

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12. N. J. Goldberg and M. B. Sulzberger, Arch. Dermatol, 1960, 81, 859.

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14. K. Thoma and R. Klimek, Inter. J. Pharm., 1991, 67, 169.

15. K. Thoma and R. Kerker, Pharm. Ind., 1992, 54, 359.

16. K. Thoma, in 'Photostability of Drugs and Drugs Formulation', H. H. Tonnesen (Ed.), Taylor and Francis, London, 1996, p. 111.

17. K. Thoma and R. Kerker, Pharm. Ind., 1992, 54, 630.

Photoreactivity versus Activity of a Selected Class of Phenothiazines: A Comparative Study

Beverley D. Glass, Michael E. Brown and Patricia M. Drummond School of Pharmaceutical Sciences Rhodes University Grahamstown, 6140 South Africa

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