Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from eucalypti
Reexamination Certificate
2001-01-23
2002-09-10
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from eucalypti
C424S078050, C424S725000, C424S747000, C435S166000, C435S410000, C514S474000, C514S168000
Reexamination Certificate
active
06447817
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an anti-inflammation analgesic preparation. More specifically, it relates to an anti-inflammation analgesic preparation which exhibits an excellent anti-inflammation analgesic effect on pains involving a swelling of a muscle, a joint or a bone and a fatigue involving lassitude and which is excellent in a shelf life, safety to a skin and endermic absorptivity of an effective ingredient.
TECHNICAL BACKGROUND
It has been found that a cyclooxygenase inhibitor is useful in an anti-inflammation analgesic preparation, and since then, a variety of anti-inflammation analgesic preparations containing a cyclooxygenase inhibitor have been proposed. At present, however, on the basis of any cyclooxygenase inhibitor, there has been obtained no satisfactory anti-inflammation analgesic preparation which is free from side effects and useful against lumbago, bruise, sprain, stiff shoulder, arthralgia, myalgia, a swelling and a pain after muscle fatigue or bone fracture, shoulder periarthritis, tendon-thecitis, peritendinitis, inflammation of lateral epicondyle of humerus, a swelling after injury, an ache, a swelling and a pain from rheumatism or osteoarthritis and a pain and fatigue of a leg and loins from excess exercise or labor.
Meanwhile, ascorbic acid has been studied with regard to its various physiological activities and is well recognized to be a vitamin indispensable for keeping health. It is clear from many reports that it is useful for strengthening a blood vessel wall due to promotion of the biosynthesis of glucocorticoids which are distributed in adrenal gland to a greater extent and are anti-inflammation factor in oroganisms or the synthesis of collagen. However, there has been completed no technique to utilize ascorbic acid in an anti-inflammation analgesic preparation, since ascorbic acid is readily decomposed upon contact to light, heat, water and metal ion or has a problem on endermic absorptivity.
Clearly, prostaglandins derived from cyclooxygenase play a great part in proceeding of an inflammation and are useful for an effect on relieving some pains and decreasing some inflammations. However, a typical cyclooxygenase inhibitor, indomethacin, fails to satisfy an expectation regardless of whether it is orally administered or endermicly applied. In treatment of a rheumatic patient in particular, it is used as a supplementary drug for avoiding side effects caused by a gold preparation or a steroid preparation, or it is used for a patient whose disease condition is moderate. Nonsteroidal anti-inflammation preparations typified by indomethacin and mefenamic acid are orally used for decreasing inflammation and relieving pains after surgical treatments of bone fracture or tooth extraction. However, they are not satisfactory since they are recognized not only to have side effects such as disorders on a stomach or duodenum but also to have side effects such as rubefaction, itching, eruption, irritation and the like.
DISCLOSURE OF THE INVENTION
Under the circumstances the present inventors have made diligent studies and as a result have found that a drug containing a specific ascorbic acid derivative as an active ingredient has remarkably high anti-inflammation analgesic activities and is excellent in stability and safety and that such a drug is further excellent in endermic absorptivity. While it has been already pointed out that an ascorbic acid has an anti-inflammation analgesic effect, there is no example of practical use thereof for a reason that it is poor in stability, safety and endermic absorptivity as described above.
Further, the present inventors have also made studies concerning how to apply the active ingredient and have found that therapy by external use of the specific ascorbic acid derivative is more useful for attaining the object, and the present invention has been accordingly completed.
It is an object of the present invention to provide an anti-inflammation analgesic preparation useful against lumbago, bruise, sprain, stiff shoulder, arthralgia, myalgia, a swelling and a pain after muscle fatigue or bone fracture, rheumatism or osteoarthritis and a swelling, edema and stiffness from exercise or physical fatigue.
The anti-inflammation analgesic preparation of the present invention for achieving the above object comprises an ascorbic acid derivative of the following formula (I) or a salt thereof,
wherein at least one of R
1
, R
2
and R
3
is a linear or branched alkyl group having 1 to 20 carbon atoms, an alkylcarbonylmethyl, an alkoxycarbonylmethyl, an allylalkyl, an acyl, a sulfonic acid group or a phosphoric acid group, and the rest represents hydrogen.
Of ascorbic acid derivatives of the formula (I), a 3-0-substituted ascorbic acid of the formula (II) in particular is excellent in effectiveness, stability, safety and endermic absorptivity and is suitable for use as an anti-inflammation analgesic preparation for external application.
wherein R
1
is a linear or branched alkyl group having 1 to 20 carbon atoms, an alkylcarbonylmethyl or an alkoxycarbonyl methyl.
The 3-0-substituted ascorbic acid of the formula (II) used in the present invention is a known ascorbic acid derivative which generally has anti-oxidative activity and is recognized to have carcinogenesis inhibition activity, cancer-metastasis prevention activity, fair skin making activity. Further, WO91/03471 refers to an organ-disorder inhibition activity based on inhibition activity against a lipid peroxidation.
The 3-0-substituted ascorbic acid of the formula (II) includes 3-0-alkylascorbic acid (R
1
=alkyl), 3-0-alkylcarbonylmethylascorbic acid (R
1
=alkylcarbonylmethyl) and 3-0-alkoxycarbonylmethylascorbic acid (R
1
=alkoxycarbonylmethyl).
First, the 3-0-alkylascrobic acid includes L-3-0-methylascorbic acid, L-3-0-ethylascorbic acid, D-3-0-ethylascorbic acid, L-3-0-propylascorbic acid, L-3-0-isopropylascorbic acid, L-3-0-butylascorbic acid, L-3-0-isobutylascorbic acid, L-3-0-pentylascorbic acid, L-3-0-hexylascorbic acid, L-3-0-octylascorbic acid, L-3-0-decylascorbic acid, L-3-0-dodecylascorbic acid, L-3-0-tetradecylascorbic acid, L-3-0-hexadecylascorbic acid, L-3-0-octadecylascorbic acid and L-3-0-didecylascorbic acid.
The 3-0-alkylcarbonylmethylascorbic acid includes L-3-0-methylcarbonylmethylascorbic acid, L-3-0-ethylcarbonylmethylascorbic acid, L-3-0-butylcarbonyl-methylascorbic acid, L-3-0-hexylcarbonylmethylascorbic acid, L-3-0-octylcarbonylmethylascorbic acid, L-3-0-decylcarbonylmethylascorbic acid, L-3-0-dodecylcarbonyl-methylascorbic acid, L-3-0-tetradecylcarbonlmethylascorbic acid, L-3-0-hexadecylcarbonylmethylascorbic acid, L-3-0-octadecylcarbonylmethylascorbic acid and L-3-0-didecylcarbonylmethylascorbic acid.
The 3-0-alkoxycarbonylmethylascorbic acid includes L-3-0-methoxycarbonylmethylascorbic acid, L-3-0-ethoxycarbonylmethylascorbic acid, L-3-0-butoxycarbonyl-methylascorbic acid, L-3-0-hexyloxycarbonylmethylascorbic acid, L-3-0-octyloxycarbonylmethylascorbic acid, L-3-0-decyloxycarbonylmethylascorbic acid, L-3-0-dodecyloxycarbonylmethylascorbic acid, L-3-0-tetradecyloxycarbonylmethylascorbic acid, L-3-0-hexadecyloxycarbonylmethylascorbic acid, L-3-0-octadecyloxycarbonylmethylascorbic acid and L-3-0-didecyloxycarbonylmethylascorbic acid.
These ascorbic acid derivatives can be synthesized by a known method described in JP-A-1-228977 or the like.
The present invention may use L-ascorbic acid-2-phosphate ester and a salt thereof, ascorbic acid-2-sulfate ester, L-ascorbic acid-2-pyrophosphoric acid, L-6-0-stearylascorbic acid, L-6-0-palmitoylascorbic acid, L-2,6-0-dipalmitoylascorbic acid or L-ascorbic acid-2-glycoside included in the ascorbic acid derivative of the formula (I).
Together with the above ascorbic acid derivative, the anti-inflammation analgesic preparation of the present invention may contain at least one secondary ingredient selected from a salicylic acid derivative, indomethacin, piroxicam, flurbiprofen, felbinac, ketoprofen, menthol, camphor, thymol, crotamiton or eucalyptus oil. The secondary ingredien
Koda Shigeru
Niyiro Yasunori
Sugiyama Satoru
Davis Ruth A.
Lankford , Jr. Leon B.
Nippon Hypox Laboratories Inc.
Nixon & Vanderhye P.C.
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