Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-01-14
2002-11-05
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S579000, C564S463000, C564S503000
Reexamination Certificate
active
06476004
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition and composition for kit containing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. More particularly, the present invention relates to a pharmaceutical composition containing 2-amino-2-[2-(4-octylphenyl)ethyl]-propane- 1,3-diol or a pharmaceutically acceptable acid addition salt thereof and a cyclodextrin as a stabilizer, which is suitable for the suppression of rejection in organ (e.g., kidney, liver, heart, small intestine and the like) or bone marrow transplantation, for immunosuppressive sustention therapy or for the treatment of autoimmune diseases, and which can be formulated into a liquid preparation.
BACKGROUND OF THE INVENTION
2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and a pharmaceutically acceptable acid addition salt thereof are known to be useful as a suppressant of rejection in organ or bone marrow transplantation or as a therapeutic agent of various autoimmune diseases such as psoriasis, Behcet's disease and the like and rheumatic diseases, as described in, for example, WO94/08943.
This compound has been developed as a preparation for oral administration. When it is used as a suppressant of the rejection in organ or bone marrow transplantation, its administration immediately after the transplantation is desirable to produce effects as quickly as possible. In consideration of the condition of the patient, however, the administration route should be an injection rather than an oral one. When said compound is used for an eye disease such as Behcet's disease, it needs to be applied in the form of an eye drop.
The above-mentioned WO94/08943 discloses a preparation of said compound as an injection, and the solubilizer therefor disclosed is polyethylene glycol or ethanol. Nevertheless, polyethylene glycol shows undesirable effects such as local irritation and hemolysis, and the use thereof will be limited. In addition, ethanol is unapplicable to injections due to the local irritation it causes.
Moreover, WO97/24112 discloses, as an external preparation of the above-mentioned compound, an eye drop of said compound employed polyoxyethylene hardened castor oil, which is surface active, for a solubilizer.
When the above-mentioned compound, particularly 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter sometimes referred to as the present compound through the specification) is dissolved in distilled water, the aqueous solution thereof shows hemolysis and foams by surface active action of the present compound itself. While the present compound is water-soluble, it is problem that the crystalline deposits of the present compound is found in the aqueous solution at a particular concentration by the influence of peculiar dissoluble mechanism of the present compound. As an additive ordinary employed in a liquid preparation such as an injection or an eye drop, an aqueous solution of the present compound added with isotonicity such as sodium chloride and/or solubilizer such as polyoxyethylene hardened castor oil or viscosity-increasing agent such as polyvinylpyrrolidone, possessed the aforementioned problems such as hemolysis, foaming or crystalline deposits, and was not satisfactory.
Japanese Patent Unexamined Publication No. 316065/1995 discloses FR901469 substance preparation containing a cyclodextrin, which is associated with less hemolysis and local irritation. Japanese Patent Unexamined Publication No. 228532/1995 discloses an aqueous liquid preparation containing a cyclodextrin, which is improved water-solubility and water-stability of a water-insoluble pharmaceutical agent, and Japanese patent Unexamined Publication No. 133960/1976 discloses a foam-disappearing method produced by surface active agent characterizing adding a cyclodextrin in an aqueous, industrial surface active agent solution which is foaming.
SUMMARY OF THE INVENTION
In view of the above situation, the present inventors have made intensive studies in an attempt to obtain a pharmaceutical composition containing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, which is associated with less side effects such as hemolysis or local irritation, superior to foam-disappearing effect and whose active ingredient compound does not deposit as crystals, and which can be prepared into a liquid preparation such as an injection or an eye drop, and found that the addition of a cyclodextrin achieves the objects, which resulted in the completion of the present invention.
Accordingly, the present invention relates to a pharmaceutical composition containing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof and a cyclodextrin, which can be easily prepared into a pharmaceutical preparation, which is associated with less side effects such as hemolysis, which causes less local irritation, which is superior to foaming-disappearing effect and whose active ingredient compound does not deposit as crystals, and therefore is suitable for a liquid preparation. In the present invention, it is characteristic that, by adding a cyclodextrin as a stabilizer to 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutical acceptable acid addition salt thereof, all aforementioned problems are settled at the same time. Particularly, it is characteristic of obtaining a liquid preparation which is superior to foam-disappearing effect and whose the active ingredient compound dose not deposit as crystals. The present invention has also noted that the addition of a sugar selected from monosaccharides, disaccharides and sugar alcohols to said composition results in a liquid composition further improved in local irritation.
The pharmaceutical composition of the present invention contains 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, a cyclodextrin, if desired, a sugar, and a conventional, pharmaceutically acceptable carrier or diluent, preferably a carrier or diluent suitable for liquid preparations.
The active ingredient, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and a pharmaceutically acceptable acid addition salt thereof of the pharmaceutical composition of the present invention can be produced by the method disclosed in WO94/08943. Preferred compound is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride. Examples of other acid addition salt include hydrobromide, sulfate, acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate.
2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is added in a proportion of 0.01-20% by weight, particularly 0.1-10% by weight, of the total weight of the composition.
The cyclodextrin to be used in the present invention is a natural cyclodextrin, a branched cyclodextrin, an alkyl-cyclodextrin or a hydroxyalkyl-cyclodextrin. Specific examples thereof include &agr;-cyclodextrin [e.g., Cerdex A- 100, trademark, manufactured by Nippon Shokuhin Kako Co. Ltd.], &bgr;-cyclodextrin [e.g., Cerdex B-100, trademark, manufactured by Nippon Shokuhin Kako Co. Ltd.], &ggr;-cyclodextrin [e.g., Cerdex G-100, trademark, manufactured by Nippon Shokuhin Kako Co. Ltd.], dodecakis-2,6-O-methyl- &agr;-cyclodextrin, tetradecakis-2,6-O-methyl- &bgr;-cyclodextrin, hexadecakis-2,6-O-methyl- &ggr;-cyclodextrin, tetradecakis-2,6-O-ethyl- &bgr;-cyclodextrin, &agr;-cyclodextrin partially etherized with 2-hydroxypropyl, &bgr;-cyclodextrin partially etherized with 2-hydroxypropyl (HP-&bgr;-CyD, e. g., Cerdex HP-&bgr;-CD, trademark, manufactured by Nippon Shokuhin Kako Co. Ltd.) and branched &agr;-cyclodextrin and branched &bgr;-cyclodextrin wherein glucose or malt
Chiba Kenji
Fujii Tsuneo
Masuda Rumiko
Mishina Tadashi
Sakai Atsushi
Crowell & Moring LLP
Mitsubishi Pharma Corporation
Owens, Jr. Howard V.
Richter Johann
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