U.S. patent application number 10/354136 was filed with the patent office on 2003-07-10 for method for prophylaxis and treatment of diabetic complications with 4[alpha-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid and derivatives.
Invention is credited to Goto, Nobuharu, Hayashi, Yoshiharu.
Application Number | 20030130332 10/354136 |
Document ID | / |
Family ID | 18334321 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030130332 |
Kind Code |
A1 |
Hayashi, Yoshiharu ; et
al. |
July 10, 2003 |
Method for prophylaxis and treatment of diabetic complications with
4[alpha-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid and derivatives
Abstract
The present invention relates to an agent for the prophylaxis
and treatment of diabetic complications comprising, as an active
ingredient,
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid, an optically active compound thereof or a pharmaceutically
acceptable salt thereof. The present invention further relates to a
method for the prophylaxis and treatment of diabetic complications
comprising administering an effective amount of this compound. The
medicament of the present invention is useful for the prophylaxis
and treatment of diabetic complications, namely, diabetic
neuropathy, nephropathy, ophthalmopathy, arteriosclerosis and the
like. The action of the drug is long-lasting for very small doses
and a single administration a day is sufficient.
Inventors: |
Hayashi, Yoshiharu;
(Iruma-shi, JP) ; Goto, Nobuharu; (Iruma-shi,
JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
18334321 |
Appl. No.: |
10/354136 |
Filed: |
January 30, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10354136 |
Jan 30, 2003 |
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10080660 |
Feb 25, 2002 |
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10080660 |
Feb 25, 2002 |
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09850000 |
May 8, 2001 |
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09850000 |
May 8, 2001 |
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09498481 |
Feb 4, 2000 |
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6258834 |
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09498481 |
Feb 4, 2000 |
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09091993 |
Jun 26, 1998 |
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6060496 |
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09091993 |
Jun 26, 1998 |
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PCT/JP96/03776 |
Dec 24, 1996 |
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Current U.S.
Class: |
514/396 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
3/00 20180101; C07D 233/56 20130101; A61P 27/00 20180101; A61K
31/4164 20130101; A61P 25/00 20180101; C07D 249/08 20130101; A61P
13/00 20180101; A61P 25/02 20180101; C07D 231/12 20130101; C07D
233/54 20130101; A61P 3/10 20180101 |
Class at
Publication: |
514/396 |
International
Class: |
A61K 031/4164 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 1995 |
JP |
340161/1995 |
Claims
What is claimed is:
1. A method for the prophylaxis and treatment of diabetic
ophthalmopathy, comprising administering an effective amount of
4-[.alpha.-hydroxy-2-meth-
yl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid, an optically
active compound thereof or a pharmaceutically acceptable salt
thereof.
2. A method for the prophylaxis and treatment of diabetic
ophthalmopathy, comprising administering an effective amount of
sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate
dihydrate.
3. A method for the prophylaxis and treatment of diabetic
ophthalmopathy, comprising administering an effective amount of
(S)-(-)-4-[.alpha.-hydrox-
y-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid or a
pharmaceutically acceptable salt thereof.
4. A method for the prophylaxis and treatment of diabetic
ophthalmopathy, comprising administering an effective amount of
sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoate 2/3 hydrate.
5. A method for the prophylaxis and treatment of diabetic
arteriosclerosis, comprising administering an effective amount of
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid, an optically active compound thereof or a pharmaceutically
acceptable salt thereof.
6. A method for the prophylaxis and treatment of diabetic
arteriosclerosis, comprising administering an effective amount of
sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate
dihydrate.
7. A method for the prophylaxis and treatment of diabetic
arteriosclerosis, comprising administering an effective amount of
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoic acid or a pharmaceutically acceptable salt thereof.
8. A method for the prophylaxis and treatment of diabetic
arteriosclerosis, comprising administering an effective amount of
sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoate 2/3 hydrate.
9. The method of claim 1, wherein the diabetic ophthalmopathy is
cataract.
10. The method of claim 1, wherein the diabetic ophthalmopathy is
glaucoma.
11. The method of claim 1, wherein the diabetic ophthalmopathy is
retinopathy.
12. The method of claim 1, wherein the diabetic ophthalmopathy is
iritis.
13. The method of claim 2, wherein the diabetic ophthalmopathy is
cataract.
14. The method of claim 2, wherein the diabetic ophthalmopathy is
glaucoma.
15. The method of claim 2, wherein the diabetic ophthalmopathy is
retinopathy.
16. The method of claim 2, wherein the diabetic ophthalmopathy is
iritis.
17. The method of claim 3, wherein the diabetic ophthalmopathy is
cataract.
18. The method of claim 3, wherein the diabetic ophthalmopathy is
glaucoma.
19. The method of claim 3, wherein the diabetic ophthalmopathy is
retinopathy.
20. The method of claim 3, wherein the diabetic ophthalmopathy is
iritis.
21. The method of claim 4, wherein the diabetic ophthalmopathy is
cataract
22. The method of claim 4, wherein the diabetic ophthalmopathy is
glaucoma.
23. The method of claim 4, wherein the diabetic ophthalmopathy is
retinopathy.
24. The method of claim 4, wherein the diabetic ophthalmopathy is
iritis.
Description
TECHNICAL FIELD
[0001] This is a divisional of Ser. No. 09/091,993, filed Jun. 26,
1998, which is a 371 of PCT/JP96/03776, filed Dec. 24, 1996.
[0002] The present invention relates to an agent for the
prophylaxis and treatment of diabetic complications, namely, to an
agent for the prophylaxis and treatment of diabetic neuropathy,
nephropathy, ophthalmopathy and arteriosclerosis. More
particularly, the present invention relates to an agent for the
prophylaxis and treatment of diabetic complications comprising, as
an active ingredient,
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid, an optically active compound thereof or a pharmaceutically
acceptable salt thereof. The present invention further relates to a
method for the prophylaxis and treatment of diabetic
complications.
BACKGROUND ART
[0003] The discovery of insulin and its clinical application
resulted in drastic progress in the treatment of diabetes. Life
sustention of the patients with diabetes--which had been a deadly
disease until then--was strikingly improved. However, the therapy
of chronic complications of diabetes has become a new problem.
[0004] The therapy of diabetes aims at prevention of such chronic
complications, and practically consists of a further control of
blood glucose and a direct therapy of complications. The major
chronic complications of diabetes are known to be neuropathy,
nephropathy, ophthalmopathy, arteriosclerosis and the like (David
M. et al., N. Engl. J. Med., 328, p. 1676-1685 (1993)).
[0005] Various factors have been considered to be responsible for
the onset and progression of chronic complications of diabetes. For
example, there are known an abnormal sorbitol metabolism theory
wherein activity promotion of sorbitol-producing polyol metabolitic
pathway is the cause (Gabbay K. H. et. al., N. Engl. J. Med. 288,
p. 831-837 (1973)), a circulatory disorder theory wherein causative
factor is a decreased blood flow due to angiopathy (Dyck P. J. et.
al., Proc. Natl. Acad. Sci. USA, 82, p. 2513-2517 (1985)), a theory
attributing the disease to a compound produced by non-enzymatic
binding reaction of protein and reducing glucose (AGE: advanced
glycation endproduct) (Brownlee M. et. al., N. Engl. J. Med. 318,
p. 1315-1321 (1988)) and the like. Based on each hypothesis, an
aldose reductase inhibitor and lipoprostaglandin E1 have been
developed, and an AGE production inhibitor is under
development.
[0006] The diabetic patients show promoted platelet aggregation,
and the mechanism thereof has been known to be the promotion of
biosynthesis of thromboxane (hereinafter abbreviated as TX) A2 due
to hyperglycemia. This is considered to be one of the pathogens of
diabetic chronic complications (Giovanni Davi M. D. et al., N.
Engl. J. Med. 322, p. 1769-1774 (1990)). Thus, lipoprostaglandin E1
(hereinafter sometimes to be referred to as Lipo PGE1) having
peripheral circulation improving action or platelet aggregation
inhibitory action, 6-[4-(1-cyclohexyl-1,2,-
3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl (cilostazol) and
6-[4-(R)-chlorophenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl)--
5-(Z)-hexenoic acid.hydrochloride (investigational numer: KDI-792)
having TXA2 receptor antagonistic/synthesis inhibitory activity
have been under development as agents for the prophylaxis and
treatment of diabetic complications.
[0007] On the other hand, Japanese Patent Examined Publication No.
41143/1993 discloses
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]--
3,5-dimethylbenzoic acid having pharmacological activities such as
strong TXA2 biosynthesis inhibitory activity, platelet aggregation
inhibitory action, vasodilating action and the like, which is
useful for the prophylaxis and treatment of thrombosis, cerebral
hemorrhage, myocardial infarction, acute cardiac death, angina
pectoris, hypertension, asthma, naphritis and the like, an
optically active compound and a pharmaceutically acceptable salt
thereof. Nevertheless, it is not known that these compounds act as
agents for the prophylaxis and treatment of diabetic
complications.
[0008] Under the circumstances, the development of a new
therapeutic agent that acts directly on chronic complications of
diabetes for the prophylaxis and treatment of diabetes, which is
capable of providing a better quality of life has been desired.
[0009] The Lipo PGE 1, cilostazol, KDI-792 and the like, which are
under development as agents for the prophylaxis and treatment of
diabetic complications based on the above-mentioned peripheral
circulation improving activity, platelet aggregation inhibitory
activity and TXA2 receptor antagonistic/synthesis inhibitory
activity, all exhibit only a short duration of activity and require
2 to 3 times of administration a day. Considering the quality of
life of the patients with diabetes, they are remotely
sufficient.
[0010] The present inventors have confirmed that sodium ozagrel
[sodium (E)-p-(imidazol-1-ylmethyl)cinnamate] having TXA2 synthesis
inhibitory activity suppresses promotion of biosynthesis of TXA2 in
rats with diabetes, but does not improve decreased tail nerve
conduction velocity. This suggests that not every TXA2 synthesis
inhibitor is effective for diabetic complications.
DISCLOSURE OF THE INVENTION
[0011] The present inventors have conducted intensive studies from
this viewpoint and found that
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benz-
yl]-3,5-dimethylbenzoic acid, an optically active compound thereof
and a pharmaceutically acceptable salt thereof, having
pharmacological activities of TXA2 biosynthesis inhibitory
activity, platelet aggregation inhibitory activity and vasodilating
action, are useful for the prophylaxis and treatment of diabetic
complications, namely, for the prophylaxis and treatment of
diabetic neuropathy, nephropathy, ophthalmopathy and
arteriosclerosis, and that the activity thereof is long-lasting for
small doses, thus enabling a single administration a day, which
resulted in the completion of the present invention.
[0012] Accordingly, the present invention provides the
following.
[0013] 1) An agent for the prophylaxis and treatment of diabetic
complications, comprising
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)ben-
zyl]-3,5-dimethylbenzoic acid, an optically active compound or a
pharmaceutically acceptable salt thereof as an active
ingredient.
[0014] 2) An agent for the prophylaxis and treatment of diabetic
complications, comprising sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazo-
lyl)benzyl]-3,5-dimethylbenzoate dihydrate as an active
ingredient.
[0015] 3) An agent for the prophylaxis and treatment of diabetic
complications, comprising
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidaz-
olyl)benzyl]-3,5-dimethylbenzoic acid or a pharmaceutically
acceptable salt thereof as an active ingredient.
[0016] 4) An agent for the prophylaxis and treatment of diabetic
complications, comprising sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-
-imidazolyl)benzyl]-3,5-dimethylbenzoate 2/3 hydrate as an active
ingredient.
[0017] 5) The agent for the prophylaxis and treatment of the above
1) to 4), wherein the diabetic complication is at least one member
selected from the group consisting of neuropathy, nephropathy,
ophthalmopathy and arteriosclerosis.
[0018] 6) The agent for the prophylaxis and treatment of the above
1) to 4), wherein the diabetic complication is neuropathy.
[0019] 7) The agent for the prophylaxis and treatment of the above
1) to 4), wherein the diabetic complication is nephropathy.
[0020] 8) The agent for the prophylaxis and treatment of the above
1) to 4), wherein the diabetic complication is ophthalmopathy.
[0021] 9) The agent for the prophylaxis and treatment of the above
1) to 4), wherein the diabetic complication is
arteriosclerosis.
[0022] 10) A method for the prophylaxis and treatment of diabetic
complications, comprising administering an effective amount of
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid, an optically active compound thereof or a pharmaceutically
acceptable salt thereof.
[0023] 11) A method for the prophylaxis and treatment of diabetic
complications, comprising administering an effective amount of
sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate
dihydrate.
[0024] 12) A method for the prophylaxis and treatment of diabetic
complications, comprising administering an effective amount of
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoic acid or a pharmaceutically acceptable salt thereof.
[0025] 13) A method for the prophylaxis and treatment of diabetic
complications, comprising administering an effective amount of
sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoate 2/3 hydrate.
[0026] 14) The method of any one of the above 10) to 13) wherein
the diabetic complication is at least one member selected from the
group consisting of neuropathy, nephropathy, ophthalmopathy and
arteriosclerosis.
[0027] 15) The method of any one of the above 10) to 13) wherein
the diabetic complication is neuropathy.
[0028] 16) The method of any one of the above 10) to 13) wherein
the diabetic complication is nephropathy.
[0029] 17) The method of any one of the above 10) to 13) wherein
the diabetic complication is ophthalmopathy.
[0030] 18) The method of any one of the above 10) to 13) wherein
the diabetic complication is arteriosclerosis.
[0031] 19) Use of
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5--
dimethylbenzoic acid, an optically active compound thereof or a
pharmaceutically acceptable salt thereof for the production of a
medicament for the prophylaxis and treatment of diabetic
complications.
[0032] 20) Use of sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzy-
l]-3,5-dimethylbenzoate dihydrate for the production of a
medicament for the prophylaxis and treatment of diabetic
complications.
[0033] 21) Use of
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benz-
yl]-3,5-dimethylbenzoic acid or a pharmaceutically acceptable salt
thereof for the production of a medicament for the production of a
medicament for the prophylaxis and treatment of diabetic
complications.
[0034] 22) Use of sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazol-
yl)benzyl]-3,5-dimethylbenzoate 2/3 hydrate for the production of a
medicament for the prophylaxis and treatment of diabetic
complications.
[0035] 23) The use of any one of the above 19) to 22) wherein the
diabetic complication is at least one member selected from the
group consisting of neuropathy, nephropathy, ophthalmopathy and
arteriosclerosis.
[0036] 24) The use of any one of the above 19) to 22) wherein the
diabetic complication is neuropathy.
[0037] 25) The use of any one of the above 19) to 22) wherein the
diabetic complication is nephropathy.
[0038] 26) The use of any one of the above 19) to 22) wherein the
diabetic complication is ophthalmopathy.
[0039] 27) The use of any one of the above 19) to 22) wherein the
diabetic complication is arteriosclerosis.
[0040] 28) A pharmaceutical composition for the prophylaxis and
treatment of diabetic complications, which comprises an effective
amount of
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic
acid, an optically active compound thereof or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
[0041] 29) A pharmaceutical composition for the prophylaxis and
treatment of diabetic complications, which comprises an effective
amount of sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate
dihydrate and a pharmaceutically acceptable carrier.
[0042] 30) A pharmaceutical composition for the prophylaxis and
treatment of diabetic complications, which comprises an effective
amount of
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5(1-imidazolyl)benzyl]-3,5-dimethylbe-
nzoic acid or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0043] 31) A pharmaceutical composition for the prophylaxis and
treatment of diabetic complications, which comprises an effective
amount of sodium
(S)-(-)4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbe-
nzoate 2/3 hydrate and a pharmaceutically acceptable carrier.
[0044] 32) The pharmaceutical composition of any one of the above
28) to 31) wherein the diabetic complication is at least one member
selected from the group consisting of neuropathy, nephropathy,
ophthalmopathy and arteriosclerosis.
[0045] 33) The pharmaceutical composition of any one of the above
28) to 31) wherein the diabetic complication is neuropathy.
[0046] 34) The pharmaceutical composition of any one of the above
28) to 31) wherein the diabetic complication is nephropathy.
[0047] 35) The pharmaceutical composition of any one of the above
28) to 31) wherein the diabetic complication is ophthalmopathy.
[0048] 36) The pharmaceutical composition of any one of the above
28) to 31) wherein the diabetic complication is
arteriosclerosis.
[0049] 37) A commercial package comprising the pharmaceutical
composition of any one of the above 28) to 31) and a written matter
associated therewith, the written matter stating that said
pharmaceutical composition can or should be used for the
prophylaxis and treatment of diabetic complications.
DETAILED DESCRIPTION OF THE INVENTION
[0050] The action as the agent for the prophylaxis and treatment of
diabetic complications of the present invention, namely, the action
as the agent for the prophylaxis and treatment of neuropathy,
nephropathy, ophthalmopathy and arteriosclerosis, can be confirmed
through rat tail nerve conduction velocity, sciatic nerve
conduction velocity, degree of glomerular disorder, amount of
urinary albumin excretion, degree of cataract examining funduscopy,
degree of hypertrophy and the like.
[0051] Of the diabetic complications in the present invention,
neuropathy means symmetric polyneuropathy of sensory, motor and
autonomic nerves, and local or polydomous neuropathy of cerebral
nerve; and ophthalmopathy means cataract, glaucoma, retinopathy,
iritis and the like.
[0052] The compounds of the present invention can be synthesized by
the methods described in Japanese Patent Examined Publication No.
41143/1993 and Japanese Patent Unexamined Publication No.
215771/1990.
[0053] The pharmaceutically acceptable salts of the compounds of
the present invention include, for example, salts with inorganic
acid such as hydrochloric acid, hydrobromic acid and sulfuric acid;
acid addition salts with organic acid such as fumaric acid, maleic
acid, mandelic acid, citric acid, tartaric acid, salicylic acid and
the like; salts with metal such as sodium, potassium, lithium,
calcium, magnesium, zinc and aluminum and salts with amino acid
such as lysine. Further, hydrates, such as 1/2 hydrate, 1/3
hydrate, 2/3 hydrate, monohydrate, {fraction (3/2)} hydrate and
dihydrate, are also encompassed.
[0054] Preferable compounds of the present invention include sodium
4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate
dehydrate (hereinafter sometimes referred to as compound A-1),
sodium
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylb-
enzoate 2/3 hydrate (hereinafter sometimes referred to as compound
A-2), sodium
(R)-(+)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-di-
methylbenzoate 2/3 hydrate (hereinafter sometimes referred to as
compound A-3),
(S)-(-)-4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dim-
ethylbenzoic acid (hereinafter sometimes referred to as compound
A4), and
(R)-(+)-4[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbe-
nzoic acid (hereinafter sometimes referred to as compound A-5).
Compound A-1 is crystals having a melting point of 271-285.degree.
C. Compound A-2 has an optical rotation off
[.alpha.].sub.D.sup.23.5-149.50.degree. (c=1.0, water), an optical
rotation of compound A-3 is [.alpha.].sub.D.sup.24+147.2.degree.
(c=1.0, water) and compound A-4 has a melting point of
286-288.degree. C. (decomposition) and an optical rotation of
[.alpha.].sub.D.sup.21-261.5.degree. (c=1.0, dimethylformamide),
and compound A-5 has a melting point of 286-287.degree. C.
(decomposition) and an optical rotation of
[.alpha.].sub.D.sup.21+260.5.degree. (c=1.0,
dimethylformamide).
[0055] The agent for the prophylaxis and treatment of diabetic
complications according to the present invention is formulated as a
general pharmaceutical preparation. For example, the compound of
the present invention is formulated into a dosage form suitable for
oral or parenteral administration; such as a pharmaceutical
composition or tablet, pill, powder, granule, capsule, troche,
syrup, liquid, emulsion, suspension, injection (liquid,
suspension), suppository, inhalant, percutaneous absorber, eye
drop, eye ointment and the like, which is produced by admixing the
compound with a pharmaceutically acceptable carrier (e.g.,
excipient, binder, disintegrator, corrective, corrigent,
emulsifier, diluent, solubilizer and the like). When a solid
preparation is prepared, an additive is used, such as sucrose,
lactose, cellulose, D-mannitol, maltitol, dextran, starch, agar,
arginates, chitins, chitosans, pectin, tragacanth gums, gum arabic,
gelatins, collagens, casein, albumin, calcium phosphate, sorbitol,
glycine, carboxymethylcellulose, polyvinylpyrrolidone,
hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerol,
polyethylene glycol, sodium hydrogencarbonate, magnesium stearate,
talc and the like. Where necessary, tablets are prepared to have an
ordinary tablet coating to give, for example, sugar-coated tablet,
enteric-coated tablet, film-coated tablet or two-layer tablet or
multi-layer tablet.
[0056] When a semi-solid preparation is to be produced, animal and
plant fats and oils (e.g., olive oil, corn oil, castor oil and the
like), mineral oil and fats (e.g., petrolaturm, white petrolatum,
solid parafin and the like), wax (e.g., jojoba oil, carnauba wax,
yellow bees wax and the like), partially synthesized or entirely
synthesized glycerol fatty acid ester (e.g., lauric acid ester,
myristic acid ester, palmitic acid ester and the like) and the like
are used. Examples of commercially available products thereof
include Witepsol (manufactured by Dynamite Novel), Pharmasol
(manufactured by NOF Corporation) and the like.
[0057] When a liquid preparation is to be produced, an additive
such as sodium chloride, sorbitol, glycerol, olive oil, propylene
glycol, ethyl alcohol and the like is used. Particularly when an
injection is to be produced, a sterile aqueous solution (e.g.,
physiological saline and isotonic solution) or oily liquid (e.g.,
sesame oil and soy bean oil) is used. Where necessary, an adequate
suspending agent (e.g., sodium carboxymethylcellulose), non-ionic
surfactant, solubilizer (e.g., benzyl benzoate and benzyl alcohol)
and the like may be also used. When an eye drop is to be produced,
an aqueous liquid or aqueous solution is used, which is
particularly a sterile aqueous solution for injection. This eye
drop liquid may contain various additives as appropriate, such as
buffer (preferably, borate buffer, acetate buffer, carbonate buffer
and the like are used for reducing irritation), isotonizing agent,
solubilizer, preservative, thickener, chelating agent, pH adjusting
agent preferably, pH is generally adjusted to about 6-8.5),
aromatic and the like.
[0058] The amount of the active ingredient of these preparation is
0.1-100 wt % , suitably 1-50 wt %, of the preparation. The dose
varies depending on the symptom, body weight, age and the like of
patients. In the case of oral administration, the dose is generally
about 0.01-50 mg/kg body weight/day for an adult, which is
preferably administered in a single dose or several doses.
EXAMPLES
[0059] The agent for the prophylaxis and treatment of diabetic
complications of the present invention is explained more
specifically by way of Formulation Examples and pharmacological
activity. It should be noted that the present invention is not
limited to these exemplifications.
Formulation Example 1
Film-Coated Tablet
[0060]
1 Compound A-1 50.0 mg D-mannitol 70.5 mg Corn starch 16.0 mg
Sodium hydrogencarbonate 15.0 mg Hydroxypropylmethylcellulose 3.0
mg Talc 5.0 mg Magnesium stearate 0.5 mg
[0061] Compound A-1, D-mannitol, corn starch and sodium
hydrogencarbonate were mixed and an aqueous solution of
hydroxypropylmethylcellulose was sprayed for flow granulation. The
granules were passed through a 24-mesh sieve, and talc and
magnesium stearate were added. The mixture was processed in a
rotary compressor Kikusui Seisakusho) to give tablets each weighing
160 mg. Then, a film coating agent comprising
hydroxypropylmethylcellulose as a film coating base was applied at
6 mg per tablet.
Formulation Example 2
Fine Granules
[0062]
2 Compound A-1 10% D-mannitol 89.5% Hydroxypropylcellulose 0.5%
[0063] Compound A-1 and D-mannitol were mixed and an aqueous
solution of hydroxypropylcellulose was added. The mixture was
kneaded, which was followed by granulation and drying at 50.degree.
C. The granules were passed through a 32-mesh sieve to give fine
granules.
Formulation Example 3
Tablets
[0064]
3 Compound A-1 50.0 mg D-mannitol 30.0 mg Corn starch 19.0 mg
Sodium hydrogencarbonate 15.0 mg Hydroxypropylmethylcellulose 1.5
mg Talc 4.0 mg Magnesium stearate 0.5 mg
[0065] Compound A-1, D-mannitol, corn starch and sodium
hydrogencarbonate were mixed and an aqueous solution of
hydroxypropylmethylcellulose was sprayed for flow granulation. The
granules were passed through a 24-mesh sieve, and talc and
magnesium stearate were added. The mixture was processed in a
rotary compressor (Kikusui Seisakusho) to give tablets each
weighing 120 mg.
Formulation Example 4
Fine Granules
[0066]
4 Compound A-2 5% D-mannitol 92% Hydroxymethylpropylcellulose
3%
[0067] Compound A-2 and D-mannitol were mixed and an aqueous
solution of hydroxypropylmethylcellulose was added. The mixture was
kneaded, which was followed by granulation and drying at 50.degree.
C. The granules were passed through a 32-mesh sieve to give fine
granules.
[0068] The pharmacological activity of the pharmaceutical agent of
the present invention is explained by way of Experimental
Examples.
Experimental Example 1
[0069] Diabetes was induced by intravenous administration of
streptozotocin (65 mg/kg) to 6-week-old male Sprague-Dawley rats.
Starting from 2-4 weeks after the onset of diabetes, a 0.5%
hydroxypropylmethylcellulose suspension containing the compound of
the present invention was orally administered once a day. At 4-7
weeks from the administration, tail nerve conduction velocity was
measured with an induction potential test device (Neuropack 2,
manufactured by Nihon Kohden) according to a modification of the
method of Miyoshi (Fukuoka Medical Journal, vol. 62, pp. 588-603
(1971)). To be specific, subcutaneous temperature at the tail was
maintained at 37.degree. C. and the tail nerve was percutaneously
stimulated electrically at 2 stimulation points (interval 6 cm).
The distance between stimulation points was divided by the
difference between latencies in electromyogram induced to give
nerve conduction velocity. As to the test group in Table 1, blood
glucose was measured at 6 weeks after administration. At 7 weeks
after administration, urinary excretion of TXB2, which is a stable
metabolite of TXA2, was measured.
5TABLE 1 tail nerve conduction velocity urinary TXB2 m/sec dose
excretion 7 wks after mg/kg/ blood glucose ng/day/100 g admini-
test group day mg/dl body weight stration Control group 0 122.0
.+-. 3.8** 4.1 .+-. 0.4** 44.6 .+-. 0.5** Diabetes group 0 870.3
.+-. 78.5 16.9 .+-. 1.7 41.3 .+-. 0.5 Compound A-1 0.03 718.3 .+-.
50.7 10.6 .+-. 1.4** 42.0 .+-. 0.5 Administered group Compound A-1
0.1 772.1 .+-. 32.4 6.9 .+-. 0.8** 43.4 .+-. 0.4** Administered
group Compound A-1 0.3 791.9 .+-. 65.5 5.1 .+-. 0.5** 43.7 .+-.
0.3** Administered group Compound A-1 1.0 718.4 .+-. 64.1 3.4 .+-.
0.3** 44.8 .+-. 0.4** Administered group
[0070] The data was shown by mean.+-.standard error of 11-12 rats
per group. Each group was compared to diabetes group by Dunnett's
test (**P<0.01).
[0071] From the above-mentioned results of Experimental Example,
the compound A-1 of the present invention decreased urinary TXB2
excretion that had been increased by diabetes, and increased tail
nerve conduction velocity which had been decreased by diabetes, in
a dose-dependent manner without affecting the blood glucose.
6TABLE 2 dose tail nerve conduction velocity test group mg/kg/day
m/sec 5 wks after administration Control group 0 43.7 .+-. 0.4**
Diabetes group 0 39.4 .+-. 0.2 Compound A-2 0.03 40.7 .+-. 0.5**
Administered group Compound A-2 0.1 42.6 .+-. 0.4** Administered
group Compound A-2 0.3 43.0 .+-. 0.3** Administered group Compound
A-2 1 42.6 .+-. 0.5** Administered group
[0072] The data was shown by mean.+-.standard error of 10 rats per
group. Each group was compared to diabetes group by Dunnett's test
(**P<0.01).
7TABLE 3 dose tail nerve conduction velocity test group mg/kg/day
m/sec 4 wks after administration Control group 0 43.0 .+-. 0.5
Diabetes group 0 38.8 .+-. 0.5 Compound A-4 0.3 40.9 .+-. 0.5**
Administered group Compound A-4 1 41.3 .+-. 0.4** Administered
group Compound A-4 3 41.7 .+-. 0.5** Administered group
[0073] The data was shown by mean.+-.standard error of 10 rats per
group. Each group administered with the compound was compared to
diabetes group by Dunnett's test (**P<0.01).
[0074] From the above-mentioned results of Experimental Examples,
the compound A-2 and compound A-4 of the present invention
suppressed decrease in tail nerve conduction velocity in a
dose-dependent manner.
Experimental Example 2
[0075] A 0.5% hydroxypropylmethylcellulose suspension containing
the compound of the present invention was orally administered to
9-week-old male spontaneously diabetic mice (db/db) once a day. At
4-5 weeks from the administration, sciatic nerve conduction
velocity was measured with an induction potential test device
(Neuropack 2, manufactured by Nihon Kohden) according to a
modification of the method of Yasuda (Diabetes, 38, p. 832-838
(1989)). To be specific, rectal temperature was maintained at
37.degree. C. and two points of sciatic notch and ankle were
percutaneously stimulated electrically. The distance between the
stimulation points was divided by the difference between latencies
in induced electromyogram to give nerve conduction velocity.
8TABLE 4 dose sciatic nerve conduction velocity test group
mg/kg/day m/sec 4 wks after administration Diabetes group 0 44.3
.+-. 1.1 Compound A-2 0.05 46.6 .+-. 1.5 Administered group
Compound A-2 0.5 51.9 .+-. 1.2** Administered group Compound A-2 5
51.7 .+-. 1.4** Administered group
[0076] The data was shown by mean.+-.standard error of 7-9 mice per
group. Each group was compared to diabetes group by Dunnett's test
(**P<0.01).
9TABLE 5 dose sciatic nerve conduction velocity test group
mg/kg/day m/sec 5 wks after administration Diabetes group 0 39.6
.+-. 1.2 Compound A-4 0.3 45.2 .+-. 1.2** Administered group
Compound A-4 1 45.9 .+-. 0.7** Administered group Compound A-4 3
45.3 .+-. 0.8** Administered group
[0077] The data was shown by mean.+-.standard error of 8-9 mice per
group. Each group was compared to diabetes group by Dunnett's test
(**P<0.01).
[0078] From the above-mentioned results of Experimental Examples,
the compound A-2 and compound A-4 of the present invention
increased sciatic nerve conduction velocity of spontaneous diabetic
mice.
Experimental Example 3
[0079] Diabetes was induced by intravenous administration of
streptozotocin (65 mg/kg) to 6-week-old male Sprague-Dawley rats.
Starting from 16 weeks after the onset of diabetes, a 0.5%
hydroxypropylmethylcellulose suspension containing compound A-1 was
orally administered once a day. At 5 weeks from the administration,
tail nerve conduction velocity was measured with an induction
potential test device (Neuropack 2, manufactured by Nihon Kohden)
according to a modification of the method of Miyoshi (Fukuoka
Medical Journal, vol. 62, pp. 588-603 (1971)). To be specific,
subcutaneous temperature at the tail was maintained at 37.degree.
C. and the tail nerve was percutaneously stimulated electrically at
2 stimulation points (interval 6 cm). The distance between the
stimulation points was divided by the difference between latencies
in induced electromyogram to give nerve conduction velocity.
10 TABLE 6 tail nerve conduction velocity (m/sec) dose before 5 wks
after test group mg/kg/day administration administration Control
group 0 54.0 .+-. 0.5 54.4 .+-. 0.5 Diabetes group 0 46.4 .+-. 0.5
46.9 .+-. 0.3 Compound A-1 0.3 46.2 .+-. 0.5 48.3 .+-. 0.6
Administered group Compound A-1 1 46.1 .+-. 0.4 49.4 .+-. 0.4**
Administered group Compound A-1 3 46.0 .+-. 0.3 50.2 .+-. 0.5**
Administered group
[0080] The data was shown by mean.+-.standard error of 10 rats per
group. Each group administered with the compound was compared to
diabetes group by Dunnett's test (**P<0.01).
[0081] From the above-mentioned results of Experimental Example,
the compound A-1 increased tail nerve conduction velocity that had
been lowered by the progression of diabetes, in a dose-dependent
manner.
Experimental Example 4
[0082] Diabetes was induced by intravenous administration of
streptozotocin (65 mg/kg) to 5-week-old male Sprague-Dawley rats.
Starting from 9 weeks after the onset of diabetes, a 0.5%
hydroxypropylmethylcellulose suspension containing compound A-1 was
orally administered once a day. At 9 weeks from the administration,
kidney was removed to determine the degree of glomerular disorder
and fixed in a 10% neutral-buffered formalin solution. Tissue
sections were stained with hematoxylin/eosin. Glomerulus was
evaluated according to the degree of obstruction in 5 stages (0: no
obstruction, 1: up to 25% obstruction, 2: up to 50% obstruction, 3:
up to 75% obstruction, 4: up to 100% obstruction). Fifty glomeruli
were evaluated per sample and the total score was used as an index
of the degree of glomerular disorder. This operation was done under
a single blind condition.
11TABLE 7 dose test group mg/kg/day n glomerular disorder score
Diabetes group 0 9 90.2 .+-. 7.9 Compound A-1 Administered group
0.3 5 90.8 .+-. 10.0 Compound A-1 Administered group 1 7 65.7 .+-.
12.0 Compound A-1 Administered group 10 8 55.4 .+-. 9.2*
[0083] The data was shown by mean.+-.standard error. Each group was
compared. to diabetes group by Dunnett's test (**P<0.05).
[0084] From the above-mentioned results of Experimental Example,
the compound A-1 of the present invention suppressed glomerular
disorder due to diabetes in a dose-dependent manner.
Experimental Example 5
[0085] Diabetes is induced by intravenous administration of
streptozotocin (65 mg/kg) to 6-week-old male Sprague-Dawley rats.
Starting from 2 weeks after the onset of diabetes, a 0.5%
hydroxypropylmethylcellulose suspension containing compound A-1 is
orally administered once a day. Urine is taken with the passage of
time for 24 hours at several weeks' interval. The amount of urinary
albumin excretion is determined by enzyme immunoassay. In addition,
retina is photographed and examined by counting neogenetic blood
vessels. After the completion of the drug administration, the rats
are killed and blood vessels, such as aorta, are taken to make
tissue samples. The sample stained with hematoxylin/eosin is
observed with an optical microscope to quantitatively determine the
degree of tunica intima.
[0086] From the above-mentioned Formulation Examples and
Pharmacological Experiments, it is clear that the pharmaceutical
agent of the present invention is useful for the prophylaxis and
treatment of diabetic complications, namely, diabetic neuropathy,
nephropathy, ophthalmopathy, arteriosclerosis and the like. The
action of the drug is long-lasting for very small doses and a
single administration a day is sufficient.
* * * * *