Title:  Treatment of auto-immune diseases by photochemotherapy

United States Patent:  6,350,772

Assignee:  Meiji Seika Kaisha, Ltd. (Tokyo, JP)

Filed:  June 16, 1999

PCT NO:  PCT/JP97/03769

102(e) Date:  June 16, 1999

PCT PUB. Date:  May 14, 1998

Foreign Application Priority Data:  Nov 06, 1996[JP] (8-293061); Jul 30, 1997[JP] (9-204711)

As a novel photochemotherapeutical method for the treatment or prevention of an auto-immune disease, there is provided a method for treating an auto-immune disease, which comprises administering to the patient mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or a pharmacologically acceptable salt thereof, followed by subjecting the blood vessel blood of the patient containing the administered compound to exposure with an ultraviolet ray or a laser light, thereby to excite said compound photochemically. This method is effective to decrease the level of auto-antibody in the blood of the patient and is also of high safety.

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) ##STR1##

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 been bonded by an amido linkage in place of L-aspartic acid.

Mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 used as the photosensitive substance according to this invention may be in the form of a pharmacologically acceptable salt thereof and may generally be in the form of a salt which is formed by reacting with a pharmacologically acceptable base. As examples of such salts, there may be given those salts with sodium, potassium, calcium, magnesium, ammonium, triethylammonium, trimethylammonium, morpholine and piperidine.

Further, according to a second aspect of this invention, there is provided a method for photochemotherapeutically treating an auto-immune disease, which comprises administering orally or parenterally to a patient having an auto-immune disease to be treated a therapeutically effective amount of mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or a pharmacologically acceptable salt thereof, irradiating the blood stream present in the blood vessel and containing the administered compound with an ultraviolet ray or a laser light, thereby to subject the mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or salt thereof contained in said blood stream to exposure with the irradiating ultraviolet ray or laser light and to excite said compound photochemically, and effecting the administration of the mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or salt thereof only once or two times or more and also repeating once more, twice or more times more the irradiation of the ultraviolet ray or laser light for the photochemical excitation of said compound contained in the blood stream, until the antibody value of the auto-antibody which is present in the blood of the patient and is specific to the auto-immune disease to be treated has been decreased significantly.

In the therapeutic method according to the second aspect of this invention, mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or a salt thereof, when administered parenterally, may be administered by intravenous or intramuscular injections. The administration of the compound may also be made orally or per rectum. The dose for administration of the compound may be an effective amount thereof sufficient to decrease the antibody value of the auto-antibody existing in the blood stream, when being subjected later to the irradiation of the ultraviolet ray or laser light so as to excite said mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or the salt thereof photochemically in the blood stream. The effective amount of the compound may be administered all at once or in two parts, i.e. twice, or more.

Ultraviolet ray or laser light to be irradiated may be irradiated as its beam onto the whole body or various parts of the patient, for example, the abdominal region, the leg region or the hand region over the skin thereof. Thus, the irradiation of the light may be effected in a manner that the light can transmit through the skin layer and the blood vessel wall layer so that the ultraviolet ray or laser light can reach the blood stream in the blood vessel under the skin. The irradiation may also be effected to such blood stream which is circulated extracorporeally.

The number of the times of the irradiation of ultraviolet ray or laser light may be one or more, independently upon the number of the times of the administration of the compound used. In other words, the combination of the number of times of administration of the compound with the number of times of irradiation of the ultraviolet ray or laser light may be of option so far as it is sufficient to decrease significantly the antibody value of the auto-antibody in the blood stream.

In practicing the method according to the second aspect of this invention, the total number of the times of administration of mono-L-aspartyl chlorin e6 or mono-L-glutamyl chlorin e6 or a salt thereof may, for example, be 1 time to 100 times, while the total number of the times of the irradiation of the ultraviolet ray or laser light may, for example, be 5 to 100 times. The number of the times required of both the administration of the compound and the irradiation of the light may easily be determined by preliminary testings made by those skilled in the art, according to the purposes of the therapy.

The ultraviolet ray or laser light to be irradiated is preferably such one having a wave length in a range of 620.about.760 nm and may be irradiated at a radiation intensity in a range of 10.about.100 mW/cm².

The pharmaceutical composition according to the first aspect of this invention and the photochemo-therapeutical method according to the second aspect of this invention are effective for the therapeutic treatment or prevention of a systemic auto-immune disease such as systemic lupus erythematosus, systemic pachyderma, multiple myositis, dermatomyositis or polyarteritis nodosa. This invention is expectable also for the therapy of such auto-immune diseases as auto-immune hemolytic anemia and Hashimoto's thyroiditis.

Mono-L-aspartyl or mono-L-glutamyl chlorin e6 or salt thereof as the active ingredient in the pharmaceutical composition may be administered orally or parenterally by intravenous or intramuscular injections, and others. It is also possible to administer the compound percutaneously. For instance, mono-L-aspartyl or mono-L-glutamyl chlorin e6 or salt thereof may preferably be administered after having formulated in the form of a preparation, for example, a pharmaceutical composition which is containing said compound in the form of a tetra-sodium salt and which has been lyophilized and sterilized and containing no pyrogenic substance.

For using the pharmaceutical composition according to the first aspect of this invention for oral administration, the active ingredient, mono-L-aspartyl or mono-L-glutamyl chlorin e6 or salt thereof may be admixed with a conventional solid or liquid carrier or carriers which is or are pharmacologically acceptable, and the resultant admixture may be formulated, for example, in the form of tablets, intra-oral preparations, troches, capsules, suspension, syrup, and the like.

The content of the compound as the active ingredient in the pharmaceutical composition according to the first aspect of this invention may vary depending upon the form of the preparation intended and may conveniently be in the range of about 2.about.60% based on the weight of the dosage unit of the preparation.

When formulating the composition according to the first aspect of this invention in the form of an injectable preparation, a preferred form of the injectable preparations is a sterile aqueous solution or dispersion or a sterile lyophilized preparation. As a preferred liquid carrier to be used here, there may be mentioned, for example, water, ethanol, glycerol, propylene glycol, vegetable oils, and the like.

Where the composition according to the first aspect of this invention is to be formulated in the form of a liquid dispersion, the dispersion state of the compound as active ingredient may be maintained well by making the active ingredient compound to have a desired particle size and by incorporating therein a viscosity regulator such as lecithin. In most cases, the liquid dispersion may preferably contain further an isotonic agent, for example, sugar or sodium chloride.

Where the composition according to the first aspect of this invention is to be formulated in the form of an injection preparation, it is possible to incorporate additionally therein an agent for delaying the absorption of the active ingredient compound, for example, aluminium mono-stearate or gelatin.

The dosage of mono-L-aspartyl or mono-L-glutamyl chlorin e6 or salt thereof to be used in this invention may vary depending upon the nature of the diseases to be treated, the purpose of the therapeutic treatment and the level of symptom, and generally it may be 0.2.about.10 mg per day for adult patients, while the dosage may usually be administered all at once or in several times. Optimum dosage may be determined by a suitable preliminary testing made by those skilled in the art.

As an irradiation sources for the laser light to be used for the therapy after the administration of the photosensitive compound according to this invention, there may be utilized a powerful continuous laser beam source equipped with optical filters, excited pigments, and other laser beam-feeding systems. Among the available irradiation sources of laser light as above-mentioned, it is desirable to use such a laser source which can generate a laser beam at a full output power of at least 500 mW, at a radiation intensity of 10.about.100 mW/cm² and at a wave-length of 620.about.760 nm. At present, some of commercially available laser generators can satisfy the above-mentioned requisites for the laser generation.

The acute toxicity of NPe6 which is used as one example of the photosensitive compounds to be administered in this invention, is 164 mg/kg as LD₅₀ value when tested on CD-1 mice (male). Further, in a photo-toxicity test with NPe6, it is found that this compound shows no reactions such as erythema, edema, etc. and is therefore a highly safe compound.

Claim 1 of 4 Claims

What is claimed is:

1. A method for photochemotherapeutically treating systemic lupus erythematosus in a patient in need thereof, which comprises:

a) administering orally or parenterally to a patient being treated for systemic lupus erythematosus a compound selected from the group consisting of mono-L-aspartyl chlorin e6, mono-L-glutamyl chlorin e6, or pharmacologically acceptable salts thereof, at a dosage of about 0.2 to about 10 mg per day:

b) irradiating percutaneously the blood stream containing the administered compound within the blood vessels of the entire body, or a part or parts of the body of the patient, or irradiating an extracorporeally circulated blood stream containing the administered compound, with a laser light of a wavelength of about 620 to about 760 nm at a radiation intensity of about 10 to about 100 mW/cm², thereby subjecting said compound to exposure with the irradiating laser light whereby said compound is excited photochemically.

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