Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-09
2004-06-15
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06750212
ABSTRACT:
The present invention relates to pharmaceutical compositions for use in the treatment of disorders or abnormalities of the skin and other body surfaces by photochemotherapy.
Abnormalities or disorders, such as neoplasms or psoriatic plaques, of the skin or other epithelial, e.g. mucosal, organs are conventionally treated by surgery, radiotherapy, cryotherapy or chemotherapy. These treatments however, often have significant and serious drawbacks such as toxicity, carcinogenicity, or other unpleasant side effects or general discomfort resulting from the treatment.
Photochemotherapy or photodynamic therapy (PDT) as it is also known, is a recently up-coming technique for the treatment of various abnormalities or disorders of the skin or other epithelial organs, especially cancers or pre-cancerous lesions, as well as certain non-malignant lesions for example skin complaints such as psoriasis. Photochemotherapy involves the application of photosensitizing (photochemotherapeutic) agents to the affected area of the body or systemic application, followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form, whereby the affected cells are killed or their proliferative potential diminished.
A range of photosensitizing agents are known, including notably the psoralens, the porphyrins, the chlorins and the phthalocyanins. Such drugs become toxic when exposed to light.
Photosensitizing drugs may exert their effects by a variety of mechanisms, directly or indirectly. Thus for example, certain photosensitizers become directly toxic when activated by light, whereas others act to generate toxic species, e.g. oxidising agents such as singlet oxygen or other oxygen-derived free radicals, which are extremely destructive to cellular material and biomolecules such as lipids, proteins and nucleic acids. Psoralens are an example of directly acting photosensitizers; upon exposure to light they form adducts and cross-links between the two strands of DNA molecules, thereby inhibiting DNA synthesis. The unfortunate risk with this therapy is that unwanted mutagenic and carcinogenic side effects may occur.
This disadvantage may be avoided by selecting photosensitizers with an alternative, indirect mode of action. For example porphyrins, which act indirectly by generation of toxic oxygen species, have no mutagenic side effects and represent more favourable candidates for photochemotherapy. Porphyrins are naturally occurring precursors in the synthesis of heme. In particular, heme is produced when iron (Fe
3+
) is incorporated in protoporphyrin IX (Pp) by the action of the enzyme ferrochelatase. Pp is an extremely potent photosensitizer, whereas heme has no photosensitizing effect.
One such porphyrin-based drug, PHOTOFRIN® vascular stroma-localizing photosensitizer (Gomer and Dougherty, Cancer Research, 39, p146-151, 1979; originally named Photofrin II) has recently been approved as a photosensitizer in the therapy of certain cancers. PHOTOFRIN® vascular stroma-localizing photosensitizer consists of large oligomers of porphyrin and it does not readily penetrate the skin when applied topically and must therefore be administered systemically. Thus, its main disadvantage is that since it must be administered parenterally, generally intravenously, it causes photosensitization of the skin which may last for several weeks following i.v. injection. Similar problems exist with other porphyrin-based photosensitizers such as the so-called “hematoporphyrin derivative” (Hpd) (Lipson et al., J. Natl. Cancer Ins., 60, p1-10, 1961) which has also been reported for use in cancer photochemotherapy (see for example S. Dougherty., J. Natl. Cancer Ins., 52, p1333, 1974; Kelly and Snell, J. Urol., 115, p150, 1976). Hpd is a complex mixture obtained by treating haematoporphyrin with acetic and sulphuric acids, after which the acetylated product is dissolved with alkali. Clearly, there are disadvantages in using an undefined mixture as a drug. Moreover since Hpd must also be administered by injection, it suffers from the same type of undesirable photosensitization drawback as does PHOTOFRIN®vascular stroma-localizing photosensitizer.
To overcome these problems, precursors of Pp have been investigated for photochemotherapeutic potential. In particular the Pp precursor 5-aminolevulinic acid (ALA) has been investigated as a photochemotherapeutic agent for certain skin cancers. ALA, which is formed from succinyl CoA and glycine in the first step of heme synthesis, is to a limited extent able to penetrate the skin and lead to a localised build-up of Pp; since the action of ferrochelatase (the metallating enzyme) is the rate limiting step in heme synthesis, an excess of ALA leads to accumulation of Pp, the photosensitizing agent. Thus, by applying ALA topically to skin tumours, and then after several hours exposing the tumours to light, a beneficial photochemotherapeutic effect may be obtained (see for example WO91/01727). Since the skin covering basaliomas and squamous cell carcinomas is more readily penetrated by ALA than healthy skin, and since the concentration of ferrochelatase is low in skin tumours, it has been found that topical application of ALA leads to a selectively enhanced production of Pp in tumours.
However, whilst the use of ALA represents a significant advance in the art, photochemotherapy with ALA is not always entirely satisfactory. ALA is not able to penetrate all tumours and other tissues with sufficient efficacy to enable treatment of a wide range of tumours or other conditions and ALA also tends to be unstable in pharmaceutical formulations. Some of these problems may be overcome by using ALA derivatives, for example ester derivatives such as ALA-methylester, ALA-ethylester, ALA-propylester, ALA-hexylester, ALA-heptylester and ALA-octylester and salts thereof as described in our co-pending application WO96/28412.
Like ALA, the ester derivatives exert their effects by enhancing production of Pp; upon delivery to the desired site of action hydrolytic enzymes such as esterases present in the target cells break down the esters into the parent ALA, which then enters the haem synthesis pathway and leads to a build-up of Pp. However, the ester derivatives have a number of advantages over ALA itself. Firstly, they are more lipophilic and better able to penetrate skin and other tissues as compared with ALA; the penetration is both deeper and faster. This is an important advantage, especially for topical administration. Secondly, the esters are better enhancers of Pp production than ALA; Pp production levels following administration of the ALA esters are higher than with ALA alone. Thirdly, the ALA esters demonstrate improved selectivity for the target tissue to be treated, namely the Pp production-enhancing effect is localised to the desired target lesion and does not spread to the surrounding tissues. This is especially evident with tumours. Finally, the esters appear to localise better to the target tissue upon administration. This may be especially important for systemic application, since it means that undesirable photosensitization effects, as reported in the literature for other porphyrin-based photosensitizers, may be reduced or avoided.
Whilst such ALA esters represent a considerable advance in the field of photochemotherapy, not all abnormalities or disorders respond to PDT using known methods to prevent tumour growth and thus there is still a need for better and alternative photochemotherapeutic agents to retard or prevent tumour growth. The present invention thus aims to provide photochemotherapeutic compositions which have an enhanced photochemotherapeutic effect over those described in the prior art.
Studies conducted by the authors have shown that efficient eradication of tumours by PDT requires destruction of both cellular components and also vascular stroma of tumours (Peng & Moan, Br. J. Cancer, 72, p565-574, 1995; Peng et al., Cancer Res., 55, p2620-2626, 1995 and Peng et al., Ultrastructural Pathology, 20, p109-129, 1996). ALA ha
Giercksky Karl E.
Moan Johan
Nesland Jahn M.
Peng Qian
Warloe Trond
Flood Michele C.
PhotoCure AS
Schwegman Lundberg Woessner & Kluth P.A.
Tate Christopher R.
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