Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-12-11
2001-08-21
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S458000, C514S474000
Reexamination Certificate
active
06277834
ABSTRACT:
BACKGROUND ART
It is known that adrenocortical hormones, though not having a direct inhibitory effect on phospholipase A
2
, secondarily exhibits anti-inflammatory effects by inducing production of an anti-inflammatory protein within the cells. However, there is a problem of great clinical importance that an extended use of adrenocortical hormones at high doses causes serious side effects including reduction of glucose tolerance, aggravation of infections, delayed healing of wounds, formation of steroid cataract and induction of glaucoma. Thus, to separate the side effects of adrenocortical hormones from their therapeutic effects is highly desired.
In order to separate the side effects from the therapeutic effects, which are both aspects of the adrenocortical hormonal effects, therefore, agents with adrenocortical hormonal effects must not be overdosed. It is thus considered important to find an adjuvant molecule that can augment adrenocortical hormonal effects, in particular, an adjuvant molecule that can augment adrenocortical hormones-mediated gene expression.
No agent, however, has been known so far to serve as as an adjuvant molecule that is safe and capable of augmenting adrenocortical hormones-mediated gene expression, and there has been a need for an agent that can augment adrenocortical hormonal effects.
Thus, a study was carried out that was directed to reducing the side effects of adrenocortical hormones by combining them with another, adjuvant molecule, thereby allowing to lower the concentration of adrenocortical hormones. The study revealed that a certain group of phosphodiester compounds were capable of augmenting adrenocortical hormonal effects (Japanese Unexamined Patent Publication No. H09-194376).
Upon the above background, however, the present inventors, from a different viewpoint, pursued a study in search of an agent that can directly reduce the side effects of adrenocortical hormones not by reducing their dose (or their concentration in a preparation). In the process, the above phosphodiester compounds were further studied on their interaction with adrenocortical hormones. As a result, it was surprisingly found by the present inventors that those phosphodiester compounds and adrenocortical hormones, when concurrently administered, exhibit a synergism of the antiinflammatory effects of the respective agents, as opposed to simple addition of their effects. At the same time, it was also unexpectedly found that the side effects of the adrenocortical hormones were directly and remarkably reduced. The present invention was made upon this findings.
DISCLOSURE OF INVENTION
The present invention relates to:
(1) a medicament for reducing side effects of adrenocortical hormones comprising a phosphodiester compound of the following formula or a pharmacologically acceptable salt thereof
wherein R
1
and R
2
are the same or different and each denotes hydrogen or methyl (hereinafter referred to as “the present compound”),
(2) the medicament for reducing side effects of adrenocortical hormones according to (1) above, wherein the ratio of doses or concentrations in a preparation is 1 mg-100 mg of the phosphodiester compound or a pharmacologically acceptable salt thereof to 1 mg of an adrenocortical hormone,
(3) the medicament for reducing side effects of adrenocortical hormones according to (1) or (2) above, wherein the adrenocortical hormone is a compound selected from the group consisting of betamethasone valerate, hydrocortisone, sodium dexamethasone meta-sulfobenzoate, triamcinolone acetonide, alclometasone propionate, and fluocinolone acetonide, and
(4) the medicament for reducing side effects of adrenocortical hormones according to (1) to (3) above, wherein the preparation form thereof is ointment or eye drops.
DETAILED DESCRIPTION OF THE INVENTION
The medicament for reducing side effects of adrenocortical hormones of the present invention can be used as a medicament for reducing side effects of adrenocortical hormones, which have a wide variety of effects including, e.g., antiinflammatory effect and adrenal cortex dysfunction treatment effect. Examples of adrenocortical hormones include, but are not limited to, betamethasone valerate, hydrocortisone, sodium dexamethasone meta-sulfobenzoate, triamcinolone acetonide, alclometasone propionate, and fluocinolone acetonide.
The present compound used for a medicament for reducing side effects of adrenocortical hormones can be synthesized by or according to the method described in, e.g., Japanese Patent Publication No. H02-44478 or Japanese Unexamined Patent Publication No. S62-205091.
A variety of uses are already known for the present compound used for a medicament for reducing side effects of adrenocortical hormones, including uses as anticataract medicaments, medicaments for prevention and treatment of climacteric disturbance, cosmetics having skin-beautifying effect [Japanese Patent Publication No. H02-44478], anti-ulcer medicaments [Japanese Unexamined Patent Publication No. S63-270626], and medicaments for prevention and treatment of ischemic disorders of organs [Japanese Unexamined Patent Publication No. H02-111722].
In addition, the present compound is known to directly inhibit an enzyme, phospholipase A
2
, to thereby exhibit anti-inflammatory effects (Japanese Patent Publication Nos. H01-27044 and H05-23274). As noted above, a further use is also known for the present compound as a medicament for augmenting adrenocortical hormonal effects (Japanese Unexamined Patent Publication No. H09-194376). However, this Japanese Unexamined Patent Publication has as its objective to reduce the side effects of adrenocortical hormones by lowering their doses (or their concentration in a preparation) by combining them with another, adjuvant molecule, and it does not describe a method of directly reducing the side effects of adrenocortical hormones not by reducing their dose (or their concentration in a preparation).
In contrast, the present inventors surprisingly found that those two compounds, when concurrently administered, exhibit synergism of the antiinflammatory effects of the respective agents as opposed to simple addition of their effects and simultaneously found unexpectedly that the side effects of the adrenocortical hormones are directly reduced remarkably without requiring to lower their dose (or their concentration in a preparation). No agent has been known before that can directly and remarkably reduce the side effects of adrenocortical hormones without altering the doses (or the concentration in a preparation) of adrenocortical hormones, as opposed to reducing their side effect by lowering their doses (or their concentration in a preparation) by combining them with another, adjuvant molecule. Thus, the invention is an epoch-making discovery.
For the purpose of the present invention, the present compound used for a medicament for reducing side effects of adrenocortical hormones may be used in its free form or in the form of a pharmacologically acceptable salt thereof. Examples of such pharmacologically acceptable salts include, but are not limited to, alkaline metal salts such as sodium salt, potassium salt and the like, and alkaline earth metal salts such as calcium salt, magnesium salt and the like. Other salts may be used insofar as they are pharmacologically acceptable.
The medicament for reducing side effects of adrenocortical hormones of the present invention may contain one species of the present compound or two or more of its species in combination, according to a given purpose and need.
As it has very low toxicity and thus is highly safe, the present compound for the medicament for reducing side effects of adrenocortical hormones of the present invention can be used advantageously for the purpose of the present invention. [For example, a potassium salt of phosphodiester of L-ascorbic acid and DL-&agr;-tocopherol (a compound wherein both R
1
and R
2
denote methyl, hereinafter referred to as “EPC-K”), a representative species of the present compound, has LD
50
values
Iemura Masahito
Ogata Kazumi
Sakaue Takahiro
Henley III Raymond
Merchant & Gould P.C.
Senju Pharmaceutical Co. Ltd.
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