Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-06-23
2002-07-30
Stucker, Jeffrey (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S003100, C514S893000, C930S120000
Reexamination Certificate
active
06426329
ABSTRACT:
TECHNICAL FIELD
This invention relates to an immunosuppressant agonists and finds application in the field of health care. More particularly, this invention relates to a pharmaceutical composition for improving the action of an immunosuppressant which comprises insulin-like growth factor I (IGF-I) or its analog as an active ingredient and to the use thereof. Furthermore,.the invention relates to enhancement of IGF-I production with a macrolide compound.
DISCLOSURE OF INVENTION
The inventors of this invention found after intensive research that insulin-like growth factor I (IGF-I) inclusive of its analog has a strong effect for improving an action of immunosuppressants and that the immunosuppressive macrolide compound has a potent IGF-I production enhancing action, and have accordingly developed this invention.
IGF-I or its analog for use in this invention includes native IGF-I's , products resulting from the fractional purification thereof, and IGF-I's produced by recombinant DNA (c f. EP-A-155655, for instance), peptide synthesis, cell culture or other technology, for example those derived from the human, bovine or other mammal. The analog of IGF-I includes various IGF-I-active muteins available upon partial change, i.e. insertion, substitution, deletion and/or addition, in the amino acid sequence of IGF-I and chemical modification products such as O-glucosylated IGF-I (WO 90/02198). As a preferred example of such analog of IGF-I, there can be mentioned the muteins resulting from the deletion or omission of 1~5 amino acids from the N-terminus of the sequence as disclosed in WO 89/05822. To avoid undesirable immune responses, the use of IGF-I of the human origin or an analog thereof is preferred.
The “action of an immunosuppressant” in the context of this invention means the action that is expressed when a substance generally called immunosuppressant is administered to animals inclusive of man, specifically the immunosuppressive action, prophylactic/therapeutic action on diseases of the liver as described in U.S. Pat. No. 5,196,437, and/or liver anagenesis accelerating action.
More particularly, the “action of an immunosuppressant” includes the therapeutic or prophylactic action on the following conditions or diseases.
(1) The rejection of transplanted organs or tissues such as heart, kidney, liver, bone marrow, skin, etc.
(2) The graft-versus-host reaction in a bone marrow transplantation.
(3) Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, insulin-dependent diabetes mellitus, uveitis, etc.
(4) Postoperative complications in partial hepatectomy.
(5) Acute hepatonecrosis caused by toxins, viral hepatitis, shock or anoxia, or of unknown origin.
(6) Immunogenic diseases of the liver, e.g. chronic autoimmune diseases of the liver such as autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, etc.
(7) Chronic diseases of the liver other than autoimmune hepatitis, such as virus B hepatitis, non-A, non-B hepatitis, cirrhosis (e.g. alcoholic cirrhosis, cirrhosis of unknown origin, etc.) and so on.
As a corollary, the preferred “action improving the action of an immunosuppressant” is the improvement and/or enhancement of the therapy or prophylaxis in the above-mentioned conditions or diseases.
The preferred other “action of an immunosuppressant” to be improved is the side effect of any substance known as an immunosuppressant and the “improvement of its action” is the alleviation or inhibition of the side effect. By way of illustration, immunosuppressants classed as “cyclosporins”, particularly cyclosporin A (CsA), are known to cause various adverse reactions such as bone loss, suppression of choleresis, suppression of bile acid secretion, and cholestatic symptoms, and the immunosuppressant agonists of this invention alleviates or inhibits such side effects.
The “composition for improving an action of immunosuppressant” of this invention can be administered, either together with an immunosuppressant at one and the same time or independently at a different time, by an administration route judiciously selected from among the conventional routes (intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, nasal, etc.). The amount of the active ingredient IGF-I or IGF-I analog in the composition for improving an action of the immunosuppressant need only be just enough to bring about the expected effect and is dependent on the patient's age and the route of administration, among other conditions. Usually, however, the daily dose-of about 1~100 mg/kg, preferably about 1~20 mg/kg, as IGF-I, on an adult basis, can be administered in a single dose or in divided doses.
Regarding the dosage form of said “composition for improving an action of an immunosuppressant”, a suitable dosage form can be selected with reference to the route of administration to be used, from among various solid forms such as tablets, capsules, powders, granules, fine granules, troches, pills and suppositories, various semisolid forms such as ointments and creams, liquid forms such as solutions, suspensions, syrups and elixirs, and liposomes. Such pharmaceutical preparations can be manufactured by the routine procedures optionally employing a pharmaceutical carrier, excipient, stabilizer and other pharmaceutically acceptable additives. For use as an injection, the composition can be provided in the form of a solid preparation (e.g. lyophilized product) for extemporaneous reconstitution. Among such pharmaceutical preparations, there can be reckoned the freeze-dried preparation described in EP-A-440989 and the nasal. preparation described in JP Kokai H5-58877.
When the composition for improving an action of an immunosuppressant of this invention is to be administered together with an immunosuppressant at the same time, the IGF-I or IGF-I analog and the immunosuppressant may be formulated together, optionally with the aid of a pharmaceutical carrier, excipient, stabilizer and/or other pharmaceutically acceptable additives, in the routine manner and the resulting composition be put to use.
The immunosuppressant whose action is to be improved by this invention and the immunosuppressant to be used for the production of said composition comprising an IGF-I or its analog and an immunosuppressant may each be any substance having immunosuppressive activity.
Macrolide compound such as FK506, ascomycin derivatives, rapamycin derivatives, and so on; cyclosporins; and so on can be exemplified as the preferable examples.
More particular examples of the macrolide compounds, the tricyclic compound of the following formula (I) or pharmaceutically acceptable salts thereof can be exemplified.
(wherein each of adjacent pairs of R
1
and R
2
, R
3
and R
4
, and R
5
and R
6
independently
(a) is two adjacent hydrogen atoms, but R
2
may also be an alkyl group or
(b) may form another bond formed between the carbon atoms to which they are attached;
R
7
is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R
1
;
R
8
and R
9
are independently a hydrogen atom or a hydroxy group;
R
10
is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;
X is an oxo group, (a hydrogen atom and a hydroxy group) (a hydrogen atom and a hydrogen atom), or a group represented by the formula —CH
2
O—;
Y is an oxo group, (a hydrogen atom and a hydroxy group) (a hydrogen atom and a hydrogen atom), or a group represented by the formula N—NR
11
R
12
or N—OR
13
;
R
11
and R
11
are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
22
and R
23
are independently a hydrogen atom or an alkyl group;
R
24
is an optionally substituted ring system which may contain one or more heteroatoms;
n is an integer of 1 or 2; and
in addition to th
Kawamura Ikuo
Ohta Mariko
Takeshita Shigeru
Fujisawa Pharmaceutical Co. Ltd.
Seharaseyon Jegatheesan
Stucker Jeffrey
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