CA1250573A - Finely powdered 2,4-diamino-6-(2,5-dichloro-phenyl)-1, 3,5-triazine and pharmaceutically acceptable acid addition salts - Google Patents
Finely powdered 2,4-diamino-6-(2,5-dichloro-phenyl)-1, 3,5-triazine and pharmaceutically acceptable acid addition saltsInfo
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- CA1250573A CA1250573A CA000420582A CA420582A CA1250573A CA 1250573 A CA1250573 A CA 1250573A CA 000420582 A CA000420582 A CA 000420582A CA 420582 A CA420582 A CA 420582A CA 1250573 A CA1250573 A CA 1250573A
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- particle diameter
- pharmaceutically acceptable
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Abstract
ABSTRACT OF THE DISCLOSURE
2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine and pharmaceutically acceptable acid addition salts thereof in finely pulverized form so that the average particle diameter is 20 microns or less have been found to be particularly useful for the treatment of peptic ulcers.
2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine and pharmaceutically acceptable acid addition salts thereof in finely pulverized form so that the average particle diameter is 20 microns or less have been found to be particularly useful for the treatment of peptic ulcers.
Description
~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
~@
~ZS(~573 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 ~25V~73 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~;
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
~@
~ZS(~573 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 ~25V~73 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_ lZS(~S73 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 ~Z~73 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.
i~S~i73 / 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
_3_ lZS(~S73 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 ~Z~73 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.
i~S~i73 / 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.
lZ~73 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, ~q~573 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.
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.
lZ~73 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, ~q~573 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.
Claims (16)
- Claim 1. 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceutically acceptable acid addition salt thereof in finely pulverized form so that the average particle diameter is 20 microns or less.
- Claim 2. A compound according to claim 1 in the form of the maleate salt.
- Claim 3. The compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein the average particle diameter is 5 to 10 microns.
- Claim 4. The maleate salt according to claim 2 wherein the average particle diameter is 5 to 10 microns.
- Claim 5. The compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein the average particle diameter is about 8 microns.
- Claim 6. The maleate salt according to claim 2 wherein the average particle diameter is about 8 microns.
- Claim 7. 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine according to claim 1 wherein the average particle diameter is about 8 microns.
- Claim 8. A pharmaceutical composition useful for the treatment of peptic ulcers in humans and animals which comprises a therapeu-tically effective amount of 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceutically acceptable acid addition salt thereof in finely pulverized form so that the average particle diameter is 20 microns or less, in combination with a pharmaceutically acceptable carrier.
- 9. A composition according to claim 8 wherein the compound is in the form of the maleate salt.
- 10. A composition according to claim 8 wherein the average particle diameter is 5 to 10 microns.
- 11. A composition according to claim 9 wherein the average particle diameter is 5 to 10 microns.
- 12. A composition according to claim 8 wherein the average particle diameter is about 8 microns.
- 13. A composition according to claim 9 wherein the average particle diameter is about 8 microns.
- 14. A composition according to claim 8 wherein the compound is 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine and the average particle diameter is about 8 microns.
- 15. A composition according to claim 8 in oral administration form.
- 16. A composition according to claim 8 in rectal administ-ration form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000420582A CA1250573A (en) | 1983-01-31 | 1983-01-31 | Finely powdered 2,4-diamino-6-(2,5-dichloro-phenyl)-1, 3,5-triazine and pharmaceutically acceptable acid addition salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000420582A CA1250573A (en) | 1983-01-31 | 1983-01-31 | Finely powdered 2,4-diamino-6-(2,5-dichloro-phenyl)-1, 3,5-triazine and pharmaceutically acceptable acid addition salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1250573A true CA1250573A (en) | 1989-02-28 |
Family
ID=4124458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000420582A Expired CA1250573A (en) | 1983-01-31 | 1983-01-31 | Finely powdered 2,4-diamino-6-(2,5-dichloro-phenyl)-1, 3,5-triazine and pharmaceutically acceptable acid addition salts |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1250573A (en) |
-
1983
- 1983-01-31 CA CA000420582A patent/CA1250573A/en not_active Expired
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| MKEX | Expiry |