Note: Descriptions are shown in the official language in which they were submitted.
~2S~3573
,
Finely Pulverized 2,4-diamino-6-(2,5-dichloro-
phenyl)-l,3,5-triazine and Pharmaceutically
Acceptable Acid Additic,n Salts Thereof
2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine and
various acid addition salts thereof are ~nown to exhibit strong
anti-ulcer activity (see Japanese Patent l~os. 919103 and 101~236.
However, in testing that compound for its anti-ulcer activity,
it has been found that disadvantages arise due to lack of
reproducibility of the level of anti-ulcer activity when the
compound is administered without regard to the average particle
size. In particular, it has been found that the compound lacks
a dose dependency thereby giving rise to unpredictibility as well
as lack of reproducibility of the activity levels.
The present invention is based on tne surprising discover
that a number of advantages accrue from finely pulverizing 2,4-
diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceutical Y
acceptable acid addition salt tnereof, so that the average
particle diameter is 20 microns or less. A particularly useful
average particle diameter is 5 to 10 microns and e~tremely good
results have been achieved wherein the av2rage particle diameter
is about 8 microns.
11hen 2,4-diamino-6-(2,5-dichloro~henyl)-1,3,5-triazine
or a pharmaceutically acceptable acid addition salt thereof is
finely pulverized so that the average particle diameter is 20
microns or less, a nur.lber of quite unexpected advantages result.
These advantage~ include a rmarked improver.ent in the properties
~ii and ~ c~ the activity. For ex2mple, the inhibition
activity against stress ulcer in rats showed linear dose depende Y
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In addition, quite surprisingly, investigations on the effect
on toxicity revealed that the finely pulverized particles accord-
ing to the present invention were far less toxic that those of
the prior art having an average particle diameter of about 50
microns. In addition, we have observed that body weight increase
inhibition which is a main side effect of administration of the
compound of the present invention or a pharmaceutically accep~abl~
acid addition salt thereof, is only transient and moderate and
the recovery is far faster than occurs when the prior art having
an average particle diameter of about 50 microns is administered.
The present invention, therefore, resides in the discover T
of unexpected improvement in properties and decrease in side
effects when 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine
and pharmaceutically acceptable acid addition salts thereof are
finely pulverized so that the average particle diameter is 20
microns or less. Also included within the present.invention are
pharmaceutical com,positions useful for treating peptic ulcers
in hu~ans and animals which com?rises 2,4-diamino-6-(2,5-dichloro-
phenyl)-1,3,5-triazine or a pnarmaceutically acceptable acid
addition salt thereof in finely pulverized form so that the
average particle diameter is 20 microns or less, preferably 5-10
microns, in combination with a pharmaceutically acceptable
carrier, Accordi.ng to a further embodiment of the present inven-
tion, the compound may be used in the form of its maleate salt.
Both the compound andpharmaceutically acceptable acid addition
salts thereof have been found to be particularly useful when the av2rage
particle diameter is about ~ microns. Also included within the
present invention is the method of treating peptic ulcers in
humans and animals which comprises administering to a human or
animal in need thereof a therapeutically effective amount of
2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a
pharmaceutically acceptable acid addition salt thereof, in
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finely pulverized form, so that the average particle diameter is
20 microns or less, preferably 5 to 10 microns, in combination
with a pharmaceutically acceptable carrier, The compound may be
administered as such or in the form of a pharmaceutically
acceptable acid addition salt. The maleate salt has been found
to be particularly useful. The compounds and the pharmaceuticall ,
acceptable acid addition salts thereof, having an average
particle diameter of about ~ microns, have been sho~n to be
useful according to the present invention.
The advantages of the present invention are demonstrated
when 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine is
administered orally to rats and its activity on ulcer formation
induced by stress is measured by the immobilization water
imrnersion method. According to that test, when the compound of
the present invention is administered, a dosage of 1 mg/kg is
effective, whereas when the co~pound has an average particle
diameter of about 50 microns, a dosage of 5 mg/kg was shown to
be ineffective. Similar results were obtained using the maleate
salt according to the present inventi.on. Table 1 below shows
the lack of uniformity of result and linear dose dependency
when the compound as known in the art havin~ an average particle
diameter of abou~ S0 microns was ad~inistered to rats, as above
described.
T a b 1 e 1
Dos2~es I~ibition Rate
( mg/~; per os)
0.37 37% 46% 29%
1.12 - 9% 29% 42~;
3.72 6~ 47% 33%
_3_
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Since 50 microns is a common particle diameter in
pharmaceutical preparations, it was most surprising that such
significant and important advantages accrued according to the
present invention. Inhibition activity against stress ulcer in
rats of the compound and pharmaceutieally acceptable aci.d additio
salts in the finely pulverized form of the present invention are
set forth in Table 2.
T a b 1 e 2.
I n h i b i t i o n R a t e
O 3 1. 0 3 . O 10 30 mg /li g
Substance (I) 33% 45% 63% 70% 85%
Substance (II) 35Y. 51% 70% 85%
The data shows linear dose de?endency. ED50 values can be
determined as 1.22 mg/kg (per os) and 0.90 mg/~g (per os),
respectively, for substance I - 2,4~diamino-6-(2,5-dichloro-
phenyl)-1,3,5-triazine and for substanee II whieh is the maleate
salt thereof.
It was further quite unexpected to find that when
2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine having an
average partiele diameter of about 8 microns was tested for
toxieity, that on intraperitoneal injeetion, no rats were l;illed
with dosages up to 3000 mg/kg while the same compound having an
average particle diameter of about 50 microns showed an LD50 of
1740 mg/kg (1614 to 1876) when injected intraperitoneally in
male rats. A similar effeet was observed with the maleate salt
according to the present invention. ~hile the LD50 of the maleat
salt having an average particle diameter of 50 microns was
determined to be 495 mg/kg (406 to 604), the maleate salt
according to the present invention had an LD50 of 835 mg/kg (696
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to 1002). This decrease in toxicity is totally unexpected and
represents a significantand important advance in the art.
The finely pulverized compound and pharmaceutically
acceptable acid addition salts according to the present invention
would appear to show decreased toxiciey because the mechanism
for achieving p'narmacological and therapeutic activity and
toxicity are quite distinct. The therapeutic results are achieved
due to improved absorption, but the side effects most likely
result from retention in the digestive tract.
A further advantage results from body weight increase
inhibition which is one of the main side effects of the compound
and salts of the present invention~ When 10 mg/kg or more per
day of either the cormpound or maleate salt is chronically
administered to rats orally, body weight increase is inhibited.
This is a side effect of triazines of this type. The inhibition
is believed to be due to a decrease in food consu~ption and
body weight is generally restored upon cessation of administra-
tion of the compound. ~o~ever, when the compound or a pharTaa-
ceutically acceptable acid addition salt thereof according to
the present invention having an average particle diameter of
about 8 microns was administered, the appearance of the side
effect was only transient and moderate and the recovery of body
weight was far faster as compared to that occurring when the
compound was administered having an average particle diameter of
about 50 microns. The improvement was particularly dramatic
when the maleate salt according to the present invention was
compared with a maleate salt having an average particle diameter
of about 50 microns, in accordance with the usual micron size
for pharmaceuticals.
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/ Figure 1 shows a change in body weights which occurs on
administration of 15 mg/kg per day to male rats (10 rats in one
group) over a continuous 12 day period. The average particle
sizes were 8 microns for the compound according to the present
invention as compared to the same compound having an average
particle diameter of 50 microns.
2,4-diamino-6-(2,5-dichlorophenyl~-1,3,5-triazine and
pharmaceutically acceptable acid addition salts thereof may be
finely pulverized to achieve the average particle diameter of
20 microns or less by using jet Mill PJM-lOO`~P (l~ippon Newmatic
MEG Co.). The pulverization is carried out by feeding 2 kg or
less of the substance per hour. An average particle diameter of
about S microns may be prepared in that manner. If necessary,
auxiliary pulverizing agents such as starch, anhydrous silicic
acid, etc. may be used. In measuring average particle size, the
powder is dispersed in physiological saline solution containing
one drop of Tween-~0 with the aid of an ultrasonic homogenizer
for 30 seconds and measured by Coleter Counter TA-II (Coulter
Electronics Co., U.S.A.) equipped with aperture tube of 100
microns.
The compound and pharmaceutically acceptable acid additio
salts according to the present invention may be formulated into
tablets, sugar coated or otherwise, capsules, troches, pills,
granules, powders, suppositories, emulsions, suspensions, sirups,
and the like, using conventional pharmaceuticaly techniques.
They may be administered one or more daily as needed. E~amples
lZ5~573
o~ a m liary ma~erials incl~de:
(1) Fillers and diluent5 such as starch, lactose, and mannitol
(2) binding agents such as microcrystalline cellulose, methyl-
cellulose, other cellulose deri-~atives, gum arabic, gelatine, polyethylene
glycol, polyvinyl a]cohol, and polyvinyl pyrrolidone
(3) l~etting agents such as glycerol
(4) Disin~egrating agents such zs carbo~:ylmetl-yl cellulose (except
sodium salr), microcrystalline cellulose, polycthy]eneglycol
(5) So]ubilization retarding agents such as carbo~:ylmethyl cel]ulose
sodium salt
(6) Absorption accclerating agents such as quaternary ar.-.onium
compounds
(7) Surface active agents such as cetyl a]cohol, glycerine fatty
acid esters
t8) F]uidieing agents such as anhydrous silicic acid, synthetic
aluminum silicate
t9) Lubricants such as ta]c, r..agnesium stearate, ca]cium stearate,
solid polyethylene glycol
(10) CoatiDg agents such as ~E~ (Trademar~ - San~yo), 1-~:; (Trademar~ -
Tanabe), shellac, TC-5 (Trademark - Shin-Etsu)
Tablets, sugar coated tablets, capsules, trouches, pills,
etc. made from the present invention drugs may contain usual
coating agents, etc. which possess untranspare~t agents therein.
Such materials can, for example, be manufactured from polymers
or from wax.
The pharmaceutical com?ositions of the present invention
may be for~ulated into a sustained release form, either by
micro-incapsulation or by other techniques known per se in the
pharmaceutical industry.
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E~a~7lcs o uiLable a~dlcivcs to prcp~re suppositories are ~ter
soluble bases such as polyethy]ene glycol and oil bases such as cacao
butter, l~itepsol (Tradem~rk - ~namite Nobel AG). Such bases may contain
surface active agents therein.
E--.a,,.ples of materi21s uskd for the manufacture of suspension injec-
tions, emu~sions, suspensions, sirups, etc. are as follo~s:
~ 1) E~ulsiiication and suspensing agents such 25 ~ater, eth~l alcohol,
iso?ropyl slcohol, ethyl carbonate, benzyl alcohol, benzyl b~nzoate,
propy]ene glycol, 1,3-butylene glycol, dimethyl formamide, oils/fats,
glycol, tetrahydrofurfllryl alcollol, polyethylene glycol
(2) Surface active agents such as sorbitan fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, polyo:;yethylene fatty acid
ksters, polyoxyethylene ethers of hydrogenated castor oil, lecithine
(3) Suspension agents such as carbox)~ethylcellulose sodium salt,
thyl cellulose, other cellulose derivatives, tragacanth, gum arabic,
other natural rubbers
(4) Preservatives such as para-hydroxybenzoic acid esters,
benzalconium chloride, sorbic acid salts
The pharmaceutical compositions according to the present
invention may also contain the usual coloring agents, preserva-
tives, perfumes, seasoning agents, sweetening agents and the lik .
The pharmaceutical compositions according to the present
invention contain from about 0.1 to 99.5% and more preferably
from about 0.5 to 95% of 2,4-diamino-6-(2,5-dichlorophenyl)-1,
3,5-triazine or a pharmaceutically acceptable acid addition salt
thereof.
In the compositions according to the present invention,
the compound or pharmaceutically acceptable acid addition salt
thereof may be the sole therapeutic agent or the composition
may contain other therapeutic agents such as digestive enzymes,
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antacids, inhibitants for stomach secretion, aromatic stomach
agents, bitter stomach agents, protective agents for stomach
~ n~; ~o/~e~9ic
mucous, ~-Q~ ic agents and the like. The compositions of
the present invention may also contain anti-inflammatory agents.
The route of administration is generally oral, but other
routes such as rectal administration is also suitable. Generally
the daily dosage will be fron about 0.5 to 100 mg/kg but the
precise dosage may vary according to the severity of the conditiol l,
the degree of symptoms, the past medical history of the patient
and the like. When a larger amount is administered, it is
generally desirable to divide the same into individual dosages.
The follo~ing non-limitative e~ample more particularly
illustrates the present invention:
EX~PLE
2,4-Diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine is powdereù by
supplying it at rate of not nlore than 2 ',.g/hour to a Jet Mill rJ~-
100 ~P (~ippon ~'e~atic ~Ifg Co). ~)e pulv~rizcd phnrmaccutical is
dispersed in a physiological saline solu~ion containing one drop of
Twcen-80 by the ~Ise of ultrasonic ho~ogenizer for 30 seconds
and their particle diaG.eter in a~erage is r.,easured by Coulter Counter
TA-II (Coleter Electronics Co, U. S. A.) and the result is about 8 microns.
