Historical

The effects of pharmaceutical photoinstability have been with us for many centuries. The ancient Egyptians may not have known why certain effects took place but they were wise enough to be able to see their positive effects and exploit them for the treatment of known maladies. Examples supporting this statement are the use of crude psoralens by ancient Egyptians to treat vitiligo, a fact well documented by Abdel M. Mofty14 of the University of Cairo in the 1940's and during more modern times the 1903 Nobel Prize in Medicine, given to, Niels R. Finsen for his finding that skin lesions of tuberculosis often resolved after exposure to ultraviolet light.14

Table 2 is a list of the companies who supported the work of Amy and his associates15'16' 17'18 in this field in 1926. Some of these companies no longer exist, many have been merged together but a few still exist, under the same name. The point I wish to make is that this is not a new field and the industry has been aware of it for many decades.

There are two very basic questions which I think the list presented in Table 1 brings to mind and are of greatest interest to those seeking to do photostability studies. First, can one source provide all of the information required, regardless of the application. Secondly, which source will produce the results desired in the shortest time and is the safest source to use. I would define "safest", from a development standpoint as that selection which will yield the maximum amount of data and be less likely to lead to post-marketing surprises. Postmarketing surprises are an embarrassment to both companies and regulatory authorities.

To use this approach is to adopt the "worst-case scenario". The value of this approach is in that it assures that all possible pharmaceutically relevant photochemical problems have been considered. There is no guarantee that in vitro photochemical data, as presently practised, will always correlate with in vivo performance but there is some indication that some of the studies might.19 The ability to correlate in vitro with in vivo performance will depend greatly on whether very similar sources are used for both tests, as they were in this instance.

Table 2. Sponsors of the research of Amy and associates.u

• Dow Chemical Co.

Sharpe and Dohme

• Drug Products

Dr. William J. Schieffelin.

• Hynson, Wescott & Dunn

Squibb & Sons

• Lehn & Fink

Frederick Sterns & Sons

• Eli Lilly & Co.

The Upjohn Company

• William S. Merrill

Warner Co.

• Merck & Co.

Perdue Frederick

• Chas. Pfizer & Co

Coming Glass

The work of Cole and associates with psoralens and UV-A lamps,19 reproduced in Figure 1, is a good illustration of a positive correlation between in vitro and in vivo photoreactivity. These workers were able to demonstrate that a measured decrease in vivo phototherapeutic performance was caused by a change in the SPD of the lamp used. The in vitro problem had been previously reported by Forbes and associates.20

The measured change by Cole and associates19 was roughly of the same magnitude in vitro as in vivo. To obtain these data they plotted the effectiveness of both lamps by weighing their output by the published action spectra for 8-methoxypsoralen and plotting these values against wavelength, Figure 1. "Integrating the energy beneath the curves yielded a 2.2 to 1 ratio of estimated effectiveness of the BL-0 compared to the BL-N lamp". Similar data regarding the effectiveness of certain wavelengths of electromagnetic radiation have also been published for the treatment of hyperbilirubinemia by Tan and his associates.21

These studies point out several important points to the pharmaceutical photostability chemist. The first point is the necessity of using a source which has a SPD matching or at least irradiating the entire "activation spectra" of the test substance. With an sample in a variety of matrices, i.e., solid, solution and cream, for example, only a broad-band continuous source with no spectral gaps can assure you of complete irradiation of the sample.

An "activation spectrum" (sometimes referred to as action spectrum) is defined as "the reciprocal of the number of incident photons required to produce a given effect compared with the wavelength of the radiation employed".22*24 The importance of activation spectra lies in the fact that they represent the most active photochemical wavelengths of a test substance/system. While the absorption spectrum may often correlate directly with the activation spectra, this is not always assured. Searle22'24 has written extensively on this particular topic.

Bathochromic or hypsochromic shifts in absorption spectra are possibly due to any one of a number of factors including, most often, changes in matrices. Likewise the test substance

Perylene Diol

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