Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-13
2003-02-25
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06525058
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a stable pharmaceutical composition for oral use of 1-ethyl methylester 4-[[3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]-1-piperazineacetate or a pharmaceutically acceptable salt thereof and also to a method for manufacturing the composition thereof. The present invention further relates to a method for stabilization of a pharmaceutical composition comprising 1-ethyl methylester 4-[[3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]-1-piperazineacetate or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
In the Japanese Laid-Open Patent Hei-08/301857 (corresponding to the European Patent 741,133), there is a report that a series of amidine derivatives is able to suppress particularly the interaction of integrin receptor with a ligand, to particularly suppress a binding of fibrinogen, fibronectin and a von Willebrand factor with fibrinogen receptor (glycoprotein IIb/IIIa) of platelets, to suppress a binding of adhesion protein such as vitronectin, collagen and laminine with the corresponding receptor on the surface of various cell species and to particularly suppress the expression of platelet thrombin and accordingly that it can be used for the treatment of thrombosis, apoplexy, cardiac infarction, angina pectoris, osteolytic diseases (particularly osteoporosis), recurrent stricture after angiogenesis, ischemic disease, inflammation, arteriosclerosis and acute renal failure. Particularly, 1-ethyl methylester 4-[[3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]-1-piperazineacetate or a pharmaceutically acceptable salt thereof (hereinafter, referred to as “compound A”), especially a 5R substance which is an optical isomer thereof (generic name: gantofiban; hereinafter, referred to as “gantofiban”) and, more especially, a citrate of the said 5R substance (gantofiban citrate) has a good activity and is a compound which has now been in a stage of research and development and expected to be provided as a pharmaceutical agent.
However, in the above-mentioned laid-open patent, there is neither disclosure nor suggestion that the compound A including gantofiban citrate has a property by which manufacture of a stable preparation for oral use is made difficult and also about the stabilization of the said preparation for oral administration.
or a pharmaceutically acceptable salt thereof (Compound A)
DISCLOSURE OF THE INVENTION
With an object of providing a pharmaceutical agent where the compound A, particularly gantofiban citrate, is an active ingredient, the present inventors have designed a pharmaceutical agent for oral use and have found that, although gantofiban citrate per se is a stable substance, gantofiban citrate is decomposed with a lapse of time in a preparation containing the same. As a result of an intensive study for its cause, it has been found that gantofiban citrate is changed when compounded with fillers, binders and disintegrating agents which are commonly added for oral preparations such as, particularly, lactose, D-mannitol, finely crystalline cellulose, corn starch, calcium hydrogen phosphate, light anhydride silicic acid and cross-carmellose sodium whereupon decomposition with a lapse of time takes place.
Accordingly, an object of the present invention is to provide a stable pharmaceutical composition for oral use comprising the compound A, particularly gantofiban or, more preferably, gantofiban citrate. Another object of the present invention is to provide a method for the manufacture of a stable pharmaceutical composition for oral use comprising the compound A, particularly gantofiban or, more preferably, gantofiban citrate. Still another object of the present invention is to provide a method for the stabilization of a pharmaceutical composition for oral use comprising the compound A, particularly gantofiban or, more preferably, gantofiban citrate.
In view of the above, the present inventors have carried out an intensive investigation for the stabilization of a pharmaceutical composition comprising the compound A and have unexpectedly found that, although coating of the pharmaceutical with an oily base usually results in a retardation of the pharmaceutical because the oily base is hydrophobic and the pharmaceutical is hardly wetted with water, a quick release of the pharmaceutical is not deteriorated giving a stable pharmaceutical composition if an oily base is compounded with the compound A whereupon the present invention has been accomplished.
Thus, the present invention relates to a stable pharmaceutical composition for oral use comprising 1-ethyl methylester 4-[[3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]-1-piperazineacetate or a pharmaceutically acceptable salt thereof and an oily base; particularly to the said pharmaceutical composition for oral use in which the oily base is selected one or more from the group consisting of higher saturated fatty acid, ester of fatty acid with alcohol, higher alcohol, phospholipid, sterol or its ester, and hydrocarbon; preferably to the said pharmaceutical composition for oral use in which the oily base is selected one or more from the group consisting of higher saturated fatty acid, ester of fatty acid with alcohol, and higher alcohol; more preferably to the said pharmaceutical composition for oral use in which the compound A is gantofiban in a 5R form or, particularly, a citrate thereof; further to the said pharmaceutical composition for oral use in which 0.001-1000 part(s) by weight of the oily base is/are contained to 1 part by weight of the compound A; and still further to the said pharmaceutical composition for oral use in which the compound A is coated with the oily base. The present invention further relates to a method for the manufacture of a pharmaceutical composition for oral use in which the compound A is compounded with an oily base; particularly to the method for the manufacture of a pharmaceutical composition for oral use in which the compound A is coated with an oily base; particularly to the method for the manufacture of a pharmaceutical composition for oral use in which the oily base is selected one or more from the group consisting of higher saturated fatty acid, ester of fatty acid with alcohol, higher alcohol, phospholipid, sterol or its ester, and hydrocarbon; and preferably to the method for the manufacture of a pharmaceutical composition for oral use in which the compound A is gantofiban in a 5R form or, particularly, a citrate thereof. The present invention furthermore relates to a method for the stabilization of a pharmaceutical composition comprising the compound A in which the compound A is compounded with an oily base; particularly to the method for the stabilization of a pharmaceutical composition comprising the compound A in which the compound A is coated with an oily base; particularly to the method for the stabilization of a pharmaceutical composition comprising a compound A in which the oily base is selected one or more from the group consisting of higher saturated fatty acid, ester of fatty acid with alcohol, higher alcohol, phospholipid, sterol or its ester, and hydrocarbon; and preferably to the method for the stabilization of a pharmaceutical composition comprising a compound A in which the compound A is gantofiban in a 5R form or, particularly, a citrate thereof.
The compound A which is used in the present invention includes a pharmaceutically acceptable salt thereof and, usually, the salt is produced from a pharmaceutically acceptable inorganic or organic acid. With regard to the acid used for producing such a salt, examples of the inorganic acid are sulfuric acid, nitric acid, hydrohalo acid such as hydrochloric acid and hydrobromic acid, phosphoric acid such as orthophosphoric acid and sulfamic acid while examples of the organic acid are aliphatic, alicyclic, aromatic-aliphatic, aromatic or heterocyclic monocarboxylic acids, polycarboxylic acids, sulf
Ito Akira
Sugiura Hiroshi
Yamazaki Shigeru
Reamer James H
Sughrue & Mion, PLLC
Yamanouchi Pharmaceutical Co., LTD
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