Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-01-06
2001-08-21
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S078000, C424S283100
Reexamination Certificate
active
06277888
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition and a composition for a kit, both 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 lecithin, 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 ART
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, Behçet's disease and the like and rheumatic diseases, as described in, for example, WO94/08943.
The above-mentioned WO94/08943 discloses a preparation of said compound as an injection, and the solubilizers therefor disclosed are polyethylene glycol and 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.
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 throughout the specification) is dissolved in distilled water to make a liquid preparation, the liquid preparation obtained problematically causes hemolysis and local irritation. Even a liquid preparation containing the present compound and an isotonizing agent, such as sodium chloride, as an additive ordinarily employed for a liquid preparation, such as an injection or an eye drop, could not reduce hemolysis and local irritation, and the preparation was not satisfactory.
Japanese Patent Examined Publication No. 48485/1975 discloses that a lecithin, particularly egg yolk lecithin, dose not show hemolysis. However, this publication does not teach that lecithin relieves hemolysis by the active ingredient compound. Further, Japanese Patent Unexamined Publication No. 340525/1994 discloses an eye drop characteristically containing vitamin A, hydrogenated lecithin and nonionic surfactant at a particular ratio in order to stabilize vitamin A and relieve irritation to the eye. This publication describes that, since a nonionic surfactant to be added to vitamin A, which is the active ingredient, causes irritation to the eye and, in order to relieve the irritation, hydrogenated lecithin is added at a ratio of 0.1 to 1 part per part of vitamin A, and 0.01 to 1 part per part of nonionic surfactant.
DISCLOSURE 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 and local irritation, and which can be prepared into a liquid preparation such as an injection and an eye drop, and found that the addition of lecithin 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 lecithin, which can be easily prepared into a pharmaceutical preparation, which is associated with less side effects such as hemolysis, and which causes less local irritation, and therefore is suitable for a liquid preparation. The present invention has also noted that the addition of a saccharide selected from monosaccharides, disaccharides and sugar alcohols to said composition results in a liquid composition further improved in irritation. The pharmaceutical composition of the present invention, for example in the form of an injection, can remarkably relieve irritation to the skin, blood vessel and the like. The pharmaceutical composition of the present invention contains lecithin in a proportion of not less than 5 parts by weight, generally 5-300 parts by weight, per part by weight of the active ingredient compound. By adding lecithin in a proportion of particularly 5-100 parts by weight, preferably 5-50 parts by weight, more preferably 5-20 parts by weight, per part by weight of the active ingredient compound, hemolysis and local irritation caused by the active ingredient compound can be remarkably relieved.
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, lecithin and, if desired, a saccharide.
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 lecithin to be used in the present invention is, for example, egg yolk lecithin, soybean lecithin and the like, or hydrogenated lecithin. For greater amounts of the active ingredient compound to be dissolved and higher transparency of the obtained liquid to be achieved, preferred lecithin is that having a high phosphatidylcholine content and a high iodine value, in which lysophosphatidylcholine and phosphatidylethanolamine are detected in small amounts. For example, preferred egg yolk lecithin is one containing phosphatidylcholine in a proportion of 65-95% and having an iodine value of about 60-80, in which lysophosphatidylcholine and phosphatidylethanolamine are contained in small amounts. Of these, purified egg yolk lecithin recited in the Japanese Pharmaceutical Codex is most suitable. By hydrogenated lecithin is meant lecithin having higher resistance to oxidation, which is attributable to the addition of hydrogen. It is specifically exemplified by hydrogenated egg yolk lecithin and hydrogenated soybean lecithin. These hydrogenated lecithins preferably have an iodine value of not less than 6. These lecithins to be used in the present invention are added in an amount of not less than 5 parts by weight, ordinarily 5-300 parts by weight, particularly 5-100 parts by weight, preferably 5-50 parts by weight, more preferably 5-20 parts by weight, per part by weight of the above-mentioned active ingredient.
The saccharide to be used in the present invention is selected from monosaccharides, disaccharides and sugar alcohols, such as glucose, fructose, D-maltose, lactose, sucrose, D-mannitol, D-xylitol and D-sorbitol, which may be used alone or in combination. These saccharides are added in an amount of 1-100 parts by weight, particularly 5-80 parts by weight, per part by weight of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof.
The preparation form of the pharmaceutical composition of the present invention is a liquid, which is specifically an injection, an eye drop, a nasal drop, an ear drop, a tr
Masuda Rumiko
Sakai Atsushi
Crowell & Moring , L.L.P.
Jarvis William R. A.
Kim Vickie
Welfide Corporation
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