Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-16
2002-02-26
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S429000, C514S023000
Reexamination Certificate
active
06350772
ABSTRACT:
This application is a 371 of PCT/JP97/03769 filed Oct. 17, 1997 which claims proof from Japanese Patent Application no. 9-204711 filed Jul. 30, 1997 and Japanese Patent Application no. 8-293061 filed Nov. 6, 1996.
TECHNICAL FIELD
This invention relates to a novel pharmaceutical composition for the therapeutic treatment of an auto-immune disease, which is to be used in a photochemotherapeutical method or a photodynamo-therapeutical method. This invention further relates to a novel photochemotherapeutical method for treating an auto-immune disease.
BACKGROUND ART
A photochemotherapeutical method or photodynamo-therapeutical method means a method of treating a disease by administration of such a photosensitive substance which is capable of displaying a therapeutic action for the first time i only when said substance is excited by being irradiated with an ultraviolet ray or a laser light. This method is a chemotherapy in which the therapy of a disease is effected by applying an irradiation of a light to a part or parts of the tissues of a living body of the patient where said photosensitive substance already administered is presented and accumulated, or by applying the light irradiation to a flow of intracorporeal blood containing said photosensitive substance or to a flow of blood as formed by extracorporeal circulation of the blood containing said photosensitive substance, so that said photosensitive substance is photochemically excited to display its therapeutic action.
A typical example of photosensitive substances, which were first proposed in the beginnings of the development of the photochemotherapy, is Photofrin. Photofrin has been used mainly for the purpose of the therapy of cancers because Photofrin has destructive actions against a variety of tumors. The function of Photofrin is explained to be such that Photofrin having n o activity by itself, but having an affinity for tumors is administered to a living body and thereby is allowed to accumulate itself around the newly formed vasculature of tumors, followed by irradiating the so accumulated Photofrin with a laser light of a certain wave-length range so that the energy of light is absorbed in said substance and the energy so elevated of said substance will excite the oxygen existing in the tumor cells to produce activated oxygen, and so that the activated oxygen gives obstructions to the tumor cells so as to cause necrosis of the tumor tissue.
Japanese Patent Publications Hei-6-88902 and Hei-6-89000 as well as United States Patent specification No. 4, 675,338 disclose such fluorescent tetrapyrrole derivatives in which at least one carboxyl group of a certain tetrapyrrole compound having a plural number of side chains in the form of carboxyl groups or carboxylic acid types has been condensed via one or more amido-linkages with the amino group of an amino-dicarboxylic acid of 4 to 10 carbon atoms, for example, aspartic acid or glutamic acid, and which is, for example, mono-L-aspartyl chlorin e6 and mono-L-glutamyl chlorin e6, or salts thereof, along with processes for the preparation of said derivatives. Also disclosed therein are uses of these tetrapyrrole derivatives as a photochemotherapeutic agent for the purposes of diagnosis and therapy of tumors. The Japanese patent publications and U.S. patent specification referred to in the above further disclose that the above-mentioned fluorescent tetrapyrrole derivatives accumulated within the tumor tissue after their administration can be excited photochemically by subjecting to the irradiation with a strong light, for example, a laser beam and thereby can display an activity to kill the tumor cells.
With respect to the photochemotherapy, the prior art further reports, in addition to the above-mentioned therapy for cancers, that the use of mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6, or their sodium salts is also applicable to the method for obstruction of newly formed blood vessels such as choroideae of eyes (refer to U.S. Pat. No. 5,633,275).
Further, U.S. Pat. No. 5,028,594 discloses the application of photochemotherapy to a method of the selective removal of hemopoietic cells participating in rheumatoid arthritis. On the other hand, Kenneth et al., propose a method for therapeutic treatment of proliferative arthropathia by application of photochemotherapy thereto, which method is characterized by the occurrence of destruction of synovial cells (see PCT Application International published specification WO94/17797).
As described above, there have been reported various applications of photochemotherapy for the destruction of tumor cells, removal of hemopoietic cells, destruction of proliferative synovial cells causative for articular rheumatism, and so on. Until now, however, there is no announcement as to such fact that the therapy of an autoimmune disease, for example, systemic lupus erythematosus, etc. was effected by applying photochemotherapy thereto.
An object of this invention is to provide a novel, pharmaceutical composition for the therapeutic treatment of a variety of auto-immune diseases, including systemic lupus erythematosus, systemic pachyderma, multiple myositis, dermatomyositis or polyarteritis nodosa and autoimmune hemolytic anemia and Hashimoto's thyroiditis, for example. Another object of this invention is to provide a novel photochemotherapeutical method for treatment of an auto-immune disease.
DISCLOSURE OF INVENTION
We, the inventors of this invention, have investigated on therapeutic agents for an auto-immune disease such as systemic lupus erythematosus, etc. to achieve the above-mentioned objects. And, we have now found that, when a photosensitive substance, mono-L-aspartyl chlorin e6 tetra-sodium salt (abbreviation: NPe6) which was described in Japanese Patent Publications Hei-6-88902 and Hei-6-89000 and U.S. Pat. No. 4,675,338 shown above and which has been examined in clinical testing for a photochemotherapy of malignant tumors is intravenously administered to mice employed as a model of a spontaneous systemic auto-immune disease, followed by irradiation of the mice with a laser light at 664 nm, either at such tissue of the whole parts or a part of the mice body, or at the circulating blood stream in the mice, which is or are containing said compound accumulated, the mono-L-aspartyl chlorin e6 tetra-sodium salt (i.e. NPe6) possesses an action capable of decreasing remarkably the antibody value of the auto-antibody in the blood of the mice. It is further expectable that as similar as NPe6, the free acid itself of mono-L-aspartyl chlorin e6 and mono-L-glutamyl chlorin e6 or tetra-sodium salt thereof, if excited photochemically, have the action capable of decreasing the antibody value of the auto-antibody in the blood, too. On the basis of these findings, we have completed this invention.
According to a first aspect of this invention, therefore, there is provided a pharmaceutical composition for photochemotherapeutically treating an auto-immune disease, characterized in that said composition contains as an active ingredient mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or a pharmacologically acceptable salt thereof.
Mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 which is used as the active ingredient in the pharmaceutical composition for treatment of an auto-immune disease according to this invention, has been confirmed, by precise analyses of various NMR spectra, etc., to be such a tetrapyrrole derivative represented by the following formula (A)
wherein n is 1 for mono-L-aspartyl chlorin e6, and n is 2 for mono-L-glutamyl chlorin e6.
Mono-L-aspartyl chlorin e6 mentioned above is such a compound of the formula(A) wherein the amino group of L-aspartic acid has been bonded, by an amido linkage, to one of the carboxyl groups as the side chains of the tetrapyrrole ring shown in the formula (A) above. Mono-L-aspartyl chlorin e6 may preferably be used in the form of tetra-sodium salt thereof at the four carboxyl groups.
Mono-L-glutamyl chlorin e6 is such a compound of the formula (A) wherein L-glutamic acid has bee
Aizawa Katsuo
Araake Minako
Kuroiwa Yukari
Suwa Hiroshi
Abelman ,Frayne & Schwab
Meiji Seika Kaisha Ltd.
Travers Russell
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