Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-09
2002-06-04
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S635000, C514S922000, C514S936000
Reexamination Certificate
active
06399658
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof as an active ingredient. The composition of the present invention has the effect of reducing lactic acid levels in blood, and is useful, for example, for reducing side effect caused by a drug which has lactic acidosis as a side effect.
BACKGROUND ART
Lactic acidosis is a state in which the lactic acid level in blood is 45 mg/dL or more, and pH of arterial blood is 7.25 or less. As to clinical symptoms, though lactic acidosis usually does not result in any symptoms in the early stage, later there appear, for example, low blood pressure, unconsciousness, nausea, vomiting, stomach ache, diarrhea, muscular ache, the state of hyperventilation and circulatory disorder etc. These symptoms often occur especially severely in elderly persons and patients with cardiac or renal disease etc.
Certain kind of drugs and medical supplements are known to cause lactic acid levels to increase in blood as a side effect and to induce lactic acidosis. After lactic acidosis occurs, usage of the drugs and the medical supplements may be restricted, because of the possibility that they might worsen renal failure etc.
Biguanide compounds have excellent activity in reducing blood sugar levels. Therefore they have long been used as a medicament for treating diabetes, as have sulfonylureas (SU). Since some biguanide compounds have recently been found to have a unique pharmaceutical profile that they do not promote insulin secretion, do not induce fatness, and improve insulin resistance, biguanide compounds such as metformin (1,1-dimethylbiguanide hydrochloride) have been paid attention. However, biguanide compounds are known to cause hyperlactatemia (Brit.Med.J., 5794/1, 205-206(1972)) and lactic acidosis (Acta.Med.Scand., 191, 203-208 (1972)) as a side effect by inducing accumulation of lactic acid. In fact, phenformin (1-(2-phenethyl)biguanide), a biguanide, is known to cause often serious lactic acidosis as a side effect.
A dichloroacetic acid salt of a biguanide compound is reported as a safer drug (JP 51-125718 (A)). However, dichloroacetic acid has comparatively strong toxicity (LD
50
/rat oral: 2820 mg/kg), so the salt is not a satisfactorily safer drug.
PROBLEM TO BE SOLVED
The problem to be solved is to provide a medicament for reducing lactic acid levels in blood, and to provide a pharmaceutical composition or a compound with a reduced side effect, which contains a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effect.
SOLUTION OF THE PROBLEM
The inventors of the present invention have intensively carried out research on pharmaceutical compositions or compounds for reducing side effect caused by a drug or the like which causes lactic acid levels in blood to increase as a side effect, and found that L-ascorbic acid or the like can reduce lactic acid in blood. Thus, the present invention has been accomplished.
That is, the present invention is as follows.
[1] A medicament for reducing lactic acid levels in blood containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof as an active ingredient.
[2] A medicament according to [1] for treating lactic acidosis.
[3] A medicament according to [1] or [2] containing L-ascorbic acid as an active ingredient.
[4] A method for reducing lactic acid levels in blood comprising administrating L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof.
[5] A pharmaceutical composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof, and a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effect.
[6] A pharmaceutical composition according to [5] wherein the drug or the medical supplement which causes lactic acid levels in blood to increase as a side effect is amoxapine, theophylline, metformin, phenformin, buformin, nalidixic acid, hopantenic acid, azidothymidine or dideoxycytidine or a salt of any of these; or high caloric transfusion, propylene glycol, ethylene glycol, xylitol, lactose or sorbitol.
[7] A pharmaceutical composition according to [5] containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof; and a biguanide represented by formula 1:
wherein
R
1
is hydrogen or lower alkyl;
R
2
is lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aryloxy-lower alkyl; or R
1
and R
2
are taken together with the nitrogen atom to form saturated heterocyclic ring, or a salt thereof.
[8] A pharmaceutical composition according to [5], [6] or [7] wherein L-ascorbic acid, the L-ascorbic acid derivative or the salt thereof is L-ascorbic acid.
[9] A pharmaceutical composition according to any one of [5] to [8] wherein the dose of L-ascorbic acid, the L-ascorbic acid derivative or the salt thereof is in the range between about 50 mg/day and about 10 g/day.
[10] A salt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect.
[11] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is a biguanide represented by formula 1:
wherein R
1
and R
2
are as defined above.
[12] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is metformin, phenformin or buformin.
[13] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is metformin.
[14] A salt according to any one of [10] to [13] wherein L-ascorbic acid, the L-ascorbic acid or the salt thereof is L-ascorbic acid.
[15] A medicament containing a salt according to any one of [10] to [14].
[16] A medicament for treating diabetes containing a salt according to any one of [10] to [14].
[17] A method for treating diabetes comprising administrating a salt according to any one of [10] to [14].
“L-Ascorbic acid derivative” includes any L-ascorbic acid derivatives which have a pharmacological effect as Vitamin C, such as esters, stereoisomers, glycosides, aminated derivatives, ethers and the like of L-ascorbic acid (“Unknown Abilities of L-Ascorbic Acid” Kumao Ebihara, ed. by Maruzen (1992)).
“Ester of L-ascorbic acid” includes esters esterified at one or more of 2-, 3-, 5- or 6-hydroxyl group of L-ascorbic acid or stereoisomers thereof, for example, esters of phosphoric acid, sulfuric acid, straight or branched C
2
-C
20
alkanoic acid or aryl carboxylic acid, and esters esterified by straight or branched C
2
-C
6
alkoxycarbonyl and the like. Examples of the straight or branched C
2
-C
20
alkanoic acid are acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid and the like. Preferred example are the straight C
12
-C
20
alkanoic acids. Examples of the aryl carboxylic acid include benzoic acid and the like. Examples of the straight or branched C
2
-C
6
alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and the like. Preferred examples of the esters of phosphoric acid or sulfuric acid are ones esterified at the 2-hydroxyl group. Preferred examples of the esters of straight or branched C
2
-C
20
alkanoic acid or aryl carboxylic acid, and the esters of straight or branched C
2
-C
6
alkoxycarbonyl are those esterified at the 5- and/or 6-position(s).
“Stereoisomer of L-ascorbic acid” includes eryt
Ichihara Junji
Itakura Yasushi
Noguchi Hiroshi
Taiji Mutsuo
Yamaga Hiroshi
Jagoe Donna
Krass Frederick
Sumitomo Pharmaceuticals Co. Ltd.
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