Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-05-30
2002-01-01
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06335465
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the field of medicine, particularly pharmacotherapeutics and pharmacodetection, using photosensitizing agents and precursors thereof, especially 5-aminolevulinic acid, also known by the acronym “ALA.” More specifically, this invention relates to colored ALA, especially sterilized ALA, which is stable under commercial conditions.
2. Description of Related Art
Photodynamic therapy involves the administration of a photosensitizing agent to a subject, including administration of a precursor of a photosensitizing agent such as ALA, and subsequent irradiation with light of the target cells or tissue of the subject. The photosensitizing agent preferentially accumulates in the target cells, namely cells or tissues that are more rapidly proliferating or growing than other cells or tissues in the target environment. The target cells may be more rapidly proliferating because they are malignant or non-malignant, of infective agent origin, e.g. viral, bacteria, parasite or fungal origin or not of infective agent origin; are normally hyperproliferative, such as the endometrium of pre-menopausal women, or are abnormally hyperproliferative, such as cells infected with an infective agent.
Although not intending to be bound by any particularly theory, it has been proposed that following administration of ALA, as a result of their more rapid proliferation, the target cells or tissue contain relatively greater concentrations of light sensitive porphyrins and thus are more sensitive to light.
The target cells or tissue containing sufficiently high concentrations of the photosensitizing agent, including the metabolites of ALA, selectively absorb greater amounts of light and can be selectively localized and distinguished from the adjacent cells or tissues via fluorescence, or damaged or destroyed. The effect of the light, as is well known in the art, depends on the photosensitizer selected; the wavelength, intensity and duration of administration of the light; and the timing of irradiation vis-a-vis the administration of the photosensitizing agent, and results in fluorescence or impairment or destruction of the target cells or tissue.
A variety of photosensitizing agents have been used for photodynamic therapy. The only commercially available photosensitizing agent is PhotofrinrP, a hemato porphyrin or HPD, sold by QLT Phototherapeutics, Inc. Vancouver, British Columbia. Synthetic porphyrins often have the disadvantage of having longer half-lives and lowered sensitivity to the rapidly growing cells as contrasted with normal cells than do naturally occurring porphyrins. The half-life of the photosensitizing agent is significant, since the buildup of excess porphyrins in the skin can result in reddening or burning of the skin.
An alternative to synthetic porphyrins are natural porphyrins. Natural porphyrins appear to have shorter half-lives than their synthetic counterparts, but are difficult to synthesize and more importantly, are unstable ex vivo under environmental conditions to which drugs are subjected in normal commercial distribution and storage channels.
A revolutionary discovery made in the late 1980's was that the naturally occurring amino acid ALA, a precursor in the metabolic pathway to heme, could be used in photodynamic therapy instead of synthetic porphyrins. ALA appears to act in the body as a precursor to naturally occurring, light sensitive porphyrins, which avoids the ex vivo problems associated with natural porphyrins noted above. This discovery has brought photodynamic therapy to a world wide interest level never before achieved with synthetic porphyrins.
ALA has a very short half-life, depending on the route of administration, is highly tissue specific and, as a naturally occurring amino acid, minimizes complications and side effects which arise when foreign substances are administered to the body. Unlike synthetic porphyrins, ALA also makes it possible to distinguish small or flat tumors, e.g. in the bladder, from normal tissues, visually by means of fluorescence excitation.
It is believed that ALA is converted by the cells and tissues in vivo or ex vivo into protoporphyrin IX and related endogenous biochemicals, which fluoresce or are degraded by light of the appropriate wavelength. The preferential accumulation of such naturally occurring porphyrins in rapidly growing cells permits the targeting of such cells.
One of the roadblocks to the commercial use of ALA has been its extreme liability to destruction under ambient conditions. Aqueous solutions of ALA maintained under ambient conditions are progressively, degraded quite rapidly, resulting in degradation products, primarily 2,5-pyrazine dipropionic acid and intermediate degradation products which have not been able to be identified due to their transient nature. However, the intermediate degradation products are believed to include 2,5 (beta-carboxymethyl)-dihydropyrazine.
FIG. 1
depicts the degradation of ALA to 2,5 (beta-carboxymethyl)-dihydropyrazine and then to 2,5-pyrazine dipropionic acid. Formulating ALA in nonaqueous creams and gels did not prevent this degradation. Even ALA pressure-sensitive adhesive mixtures did not totally stop oxidative reactions. Likewise, the preparation of pharmacological equivalents of ALA such as functional derivatives of the carboxylic acid group, substitution of the amino group, blocking of the oxo group or the use of simple or more complex acid addition, acid, base or neutral salts has not completely overcome this problem because the more stable the product, the greater effect there may be on the metabolism of the product in the body.
SUMMARY OF THE INVENTION
One object of the invention is to provide ALA which does not suffer from the problems of the known art, particularly the extreme degradation of ALA. Another object of the invention is to provide sterile stable ALA which is pharmacologically active and can be used in photodynamic therapy and detection. Still another object of the invention is to provide a method for making sterile, stable ALA which does not suffer from the problems of the known art. Yet another object of the invention is to provide a combination of ALA and an endoscope for internal use in a mammal. Still another object of the invention is to provide a method for using ALA in the detection and/or treatment of a condition in a mammal.
The foregoing objects and other objects are achieved according to one aspect of the present invention by colored 5-aminolevulinic acid, preferably 5-aminolevulinic acid HCl. In a preferred embodiment, the color is imparted by irradiation of crystals, preferably gamma radiation. According to another aspect of the invention, there has been provided colored 5-aminolevulinic acid crystals having an F-center point defect in the crystal lattice, where said F-center point defect imparts said color to the crystals.
According to still another aspect of the invention, there has been provided a sterile aqueous ALA solution comprising the colored ALA crystals according to the invention, contained in water. According to yet another aspect of the invention, there has been provided a sterile package comprising colored ALA crystals according to the invention in a sealed sterile container. According to yet another aspect of the invention, there has been provided a method for preparing colored ALA crystals according to the invention, which includes exposing non-irradiated ALA crystals to a radiation source at a dose sufficient to impart a color which is different than any color present in the non-irradiated crystals. According to still another aspect of the invention, there has been provided a kit for internal and/or external treatment and/or detection of a condition in a mammal, which includes the sterile colored ALA crystals according to the invention and a sterile diluent, preferably water. In one mode of internal treatment and/or detection, the kit optionally includes a catheter and optionally an endoscope.
According to still another aspect of the inventi
Davis Brian J.
Dusa Pharmaceuticals, Inc.
Padmanabhan Sreeni
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