Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-04-03
2001-09-25
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001650, C424S001610, C424S001110
Reexamination Certificate
active
06294151
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a tablet containing isotope-labeled urea for diagnosing the infection with urease-generating bacteria, particularly
Helicobacter pylori.
BACKGROUND ART
Because
Helicobacter pylori
has strong urease-producing activity, urea labeled with
13
C or
14
C is used for diagnosing stomach infected with
Helicobacter pylori.
Urea labeled with
13
C or
14
C is prepared as powder, particularly freeze-dried powder, containing urea alone, for oral administration in aqueous solution. The urea labeled with 13C or 14C is degraded by the urease produced by
Helicobacter pylori
in stomach into carbon dioxide gas labeled with
13
C or 14C, which is then released into expired air. By measuring the concentration of the carbon dioxide labeled with
13
C or
14
C, therefore, the presence or absence of
Helicobacter pylori
infection can be diagnosed. When the powder is orally given in aqueous solution, the urea labeled with
13
C or
14
C is degraded with urease derived from oral bacterial flora, which causes difficulty in diagnosing correctly
Helicobacter pylori
infection.
As urea formulations for, diagnosing
Helicobacter pylori
infection, a capsule of
14
C-urea [The American Journal of Gastroenterology, 91, 233 (1996)] and a substantially water-soluble composition in solid, containing urea labeled with an isotope (W096/14091), have been known.
However, urea has strong cohesion potency and therefore sticks to tableting machines and the like during the tableting process, which results in poor industrial productivity. Tablets containing urea have so poor hardness that it is difficult to produce high-quality tablets of urea.
DISCLOSURE OF INVENTION
The present inventors have found that an urea tablet with practical disintegration time and sufficient hardness can be produced by mixing urea with one or several additives among various additives of inorganic compounds and then formulating the mixture into tablet, thereby preventing the stickiness due to the cohesion potency of urea.
The present invention relates to a tablet containing isotope-labeled urea and an inorganic compound, which may further contain an organic compound or a disintegrant.
Urea with no label is generally composed of carbon atoms of a mass number of 12, oxygen atoms of a mass number of 16, nitrogen atoms of a mass number of 14 and hydrogen atoms of a mass number of 1. The term “isotope-labeled urea” in the present invention means urea labeled with an isotope of at least one of carbon atom, oxygen atom, nitrogen atom and hydrogen atom, the isotope having a different mass number from the aforementioned mass number of the corresponding atom or a mixture of urea labeled with the isotope and urea with no label. The urea labeled includes preferably urea labeled with
13
C,
14
C or
18
O, and more preferably
13
C or
14
C. In the present invention, for example, urea labeled with
13
C is represented as
13
C-urea.
The inorganic compound includes, for example, inorganic compounds containing silica such as silicic acid anhydride, silicic acid, and silicate; inorganic compounds containing calcium; and inorganic compounds containing aluminium. The silicic acid includes, for example, ortho-silicic acid, meta-silicic acid, meso-disilicic acid, meso-trisilicic acid and meso-tetrasilicic acid. The silicate includes, for example, metal salts of silicic acid. The metal forming silicate includes, for example, aluminum, zinc, potassium, calcium and sodium. The inorganic compounds containing calcium include for example calcium salts. Specific examples include, for example, calcium carbonate, calcium hydrogen phosphate, calcium hydroxide, calcium chloride, calcium sulfate, and calcium nitrate. The inorganic compounds containing aluminium include, for example, aluminium salts, specifically including, for example, aluminum hydroxide and aluminum chloride.
Among these inorganic compounds, preferred are inorganic compounds containing silica and inorganic compounds containing aluminium; and more preferred are inorganic compounds containing silica. As the inorganic compounds containing silica, preferred is silicic acid anhydride; and more preferred is light anhydrous silicic acid.
The organic compound includes, for example, sugars, amino acids, protein, nucleic acid, and organic acids. The sugars include, for example, polysaccharides such as starch, cellulose, chitin and chitosan; oligosaccharides such as lactose and sucrose; monosaccharides such as mannitol and glucose. As the cellulose, preferred is crystal cellulose. The amino acids include naturally occurring &agr;-amino acids such as glycine, glutamic acid, glutamine, lysine, aspartic acid, and asparagine. The protein includes, for example, globulin and albumin. The nucleic acid includes, for example, inosinic acid, adenylic acid, thymidynic acid, guanylic acid and cytidylic acid. The organic acids include, for example, lactic acid, acetic acid and citric acid. As the organic compound, preferred are sugars such as mannitol, lactose and crystal cellulose.
One example of the tablet of the present invention comprises the isotope-labeled urea and such inorganic compound. The content of the isotope-labeled urea is 2 to 2,000 mg, preferably 20 to 350 mg per one tablet. The content of the inorganic compound is 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, and more preferably 1 to 50 parts by weight based on 100 parts by weight of the isotope-labeled urea.
The tablet of the present invention may optionally contain the organic compound. More preferably, the tablet contains the isotope-labeled urea, the inorganic compound and the organic compound. The content of the organic compound is 0 to 1000 parts by weight, preferably 10 to 500 parts by weight, and more preferably 100 to 300 parts by weight based on 100 parts by weight of the isotope-labeled urea in the tablet.
The tablet of the present invention may optionally contain a disintegrant. In respect of the shortened disintegration time after the administration of the tablet, it is preferable that the tablet contains the isotope-labeled urea, the inorganic compound and the disintegrant or that the tablet contains the isotope-labeled urea, the inorganic compound, the organic compound and the disintegrant. The disintegration time of the tablet containing the disintegrant can be adjusted, depending on the amount of the disintegrant to be added. The disintegration time of the tablet of the present invention in stomach is 5 seconds to 10 minutes, preferably 10 seconds to 2 minutes, and particularly preferably 15 seconds to 60 seconds. The disintegration time can be measured according to the Disintegration Test of the Japanese Pharmacopoeia.
Any disintegrant for use in formulation may be used, with no specific limitation, including, for example, polyplasdone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose and the calcium salt thereof, hydroxypropyl starch and the like; preferred examples are polyplasdone and low-substituted hydroxypropyl cellulose.
The content of the disintegrant is 0 to 500 parts by weight, preferably 1 to 100 parts by weight and more preferably 3 to 20 parts by weight based on 100 parts by weight of the isotope-labeled urea in the tablet.
Additionally, the tablet of the present invention may optionally contain other additives frequently used for the formulation of other tablets, such as, lubricants, coloring agents, sweetening agents, antioxidants and binders.
The lubricants include for example magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, hydrogenated vegetable oil, and talc.
Example of the coloring agents include yellow ferric oxide, iron sesquioxide, various edible dyes, and sodium copper chlorophyllin.
Example of the sweetening agents include sucrose, saccharin, aspartame, mannitol, dextran, lemon flavor, menthol, and citric acid.
Example of the antioxidants include ascorbic acid and reduced-type glutathione.
Example of the binders include polyvinyl alcohol, polyvinyl pyrrolidone, methyl
Hayakawa Eiji
Ito Kunio
Miura Shigemitsu
Sakato Kuniaki
Antonelli Terry Stout & Kraus LLP
Jones Dameron L.
Kyowa Hakko Kogyo Co. Ltd.
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