FINELY PULVERIZED 2,4-DIAMINO-6-(2,5-DICHLOROPHENYL)-1,3,5-TRIAZINE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF

Abstract: 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: Finely Pulverized 2,4-diamino-6-(2,5-dichloro phenyl)-1,3,5-triazine and Pharmaceutically Acceptable Acid Addition Salts Thereof 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine and various acid addition salts thereof are known to exhibit strong anti-ulcer activity (see Japanese Patent Nos. 919103 and 1017236. 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 ant 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 the surprising discover that anur:Der of advantages accrue fro2 finely pulverizing 2,4- fy diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceurical acceptable acid addition salt thereof, so that the average particle diameter is 20 microns or less. A particularly useful average particle diameter is S to 1C microns and extremely good results have been achieved wherein the average particle diameter is about 8 microns. Wnen 2,4-diemino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceuticallv acceptable acid addition salt thereof is finely pulverized so that the average particle diarneter is 20 microns or less, a n-sher of quite unexpected advantages result. These advantages include a marked improvement in the properties and reducibility of the activity. For example, the inhibition activity against stress ulcer in rats showed linear dose dependency. In addition. quite surprisingly, investigations on the effect on toxicity revealed that the finely pulverized particles according to the present invention were far less toxic that those of the prior art having an average particle diameter o 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 acceptable acid addition salt thereof, is only transient anc -oderate and the recovery is far faster than occurs when the prior art having an average particle diameter of about 50 microns is administered. The presence invention, therefore, resides in the discovery 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 diemeter is 20 microns or less. Also included within the present invention are pnarraceutical compositions useful for treating peptic ulcers in humans and enimals which comprises 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine or a pharmaceurically acceptable acid addition salt thereof in finely pulverized forx so that the average particle diameter is 20 microns or less, preferably 5-10 microns, in combination with a pharmaceutically acceptable carrier. According to a further embodiment of the present invention, the compound ray be used in the iorm of its r--leate salt. Both the compound and pharmaceutically acceptable acid addition salts thereof have bean found to be particularly usefd when the averege particle diameter is about 8 microns. Also inched within the present invention is the method of treating peptic ulcers in nans and animale which comprises aeministering 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 phartaceutically acceptable acid addiction salt thereof, in finely pulverized form, so that the average particle diatte-er 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 pharmaceuricall | acceptable acid addition salts thereof, having an average particle diameter of about 8 microns, have been shown to a 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 immersion method. According to that test, when the compord of the present invention is administered, a dosage of 1 mg/kg is effective, whereas when the compound has an average particle diameter of about 50 microns, a dosage of 5 rng/kg was sho.-.. to be ineffective. Similar results were obtained using the maleate salt according to the present invention. Table 1 below shows the lack of uniformity of result and linear dose dependent when the compound as known in the art having an average perticle diameter of about 50 microns was administered to rats, as above described. Table 1 Dosages Inhibition Rate (mg/kg; per os) 0.37 37% 46% 29% 1.12 - 9% 29% 422 3.72 62. 47Z 33X Since 50 microns is a common particle diameter in pharmaceutical preparations, it as 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 pharmaceutically acceptable acid additio salts in the finely pulverized form of the present invention are set forth in Table 2. T a b l e 2 I n h i b i t i o n R a t e 0.3 1.0 3.0 10 30 mg/kg Substente (I) 33% 45% 63% 70% 85% Substance (II) 35Z 51i; 70Z 85Z The data shows linear dose dependency. ED50 values can be determined as 1.22 mg/kg (per os) and 0.90 mg/kg (per os), respectively, for substance I - 2,4-diamino-6-(2,5-dichloro- phenyl)-1,3,5-triazine and 10 sus stance II which is the maleate salt thereof. It was further quite unexpected to find that when 2,4-diemino-6-(2,5-dichlorophenyl)-1,3,5-triazine having an average particle diameter of about 8 microns was tested for toxicity, that on intraperitoneal injection, no rats were killed with dosages up to 3000 mg/kw 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 effect as observed with the maleate salt according to the present invention. While the LD50 of the maleat salt having an average particle diameter of 50 microns was determine to be 495 mglkg (406 to 604), the maleate salt according to the present invention had an LD50 of 835 mg/kg (696 to 1002). This decrease in toxicity is totally unexpected and represents a significant and 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 toxicity because the mechanism for achieving pharmacological 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 cor,-.pound 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 consumption and body weight is generally restored upon cessation of administra- tion of the compound. However, when the compound or a pharma ceutically acceptable acid addition salt thereof according to the present invention having an average particle diameter of about 8 microns was a =..nistered, 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. 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-100NP (Nippon Nev.matic MEG Co.). The pulverization is carried out by feeding 2 kg or less of the substance per hour. An average particle diameter of about 8 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-dO with the aid of an ultrasonic homogenizer for 30 seconds and measure by Coleter Counter T*.-II (Coulter Electronics Co., U.S.A.) equipped with aperture tube of 100 microns. ine compound and pharmaceutically acceptable acid addition 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 day be administered one or more daily as needed. Examples of auxiliary materials include: (1) Fillers and diluents such as starch, lactose, and mannitol (2) Binding agents such as microcrystalline cellulose, methyl cellulese, other cellulose derivetives, gum arabic, gelatine, polyethylene glycol, polyvinyl alcohol, anc polyvinyl pyrrolidone (3) Wetting agents such as glycerol (4) Disintegrating agents such as carboxylmethyl cellulose (except sodium salt), microcrystalline cellulose, polyethyleneglycol (5) Solubilization retarding agents such as carboxylmethyl cellulose sodium salt (6) Absorption accelerating agents such as qua ternary ammonium compounds (7) Surface active agents such as cetyl alcohol, glycerine fatty acid esters (6) Fluidizing agents such as anhydrous silicic acid, synthetic aluminum silicate (9) Lubricants such as talc, r.agneslu-. ste-rate, calcium stearate, solid polyethylene glycol (10) Coating agents such as AEA (Trade...±rX - Sankyo), MPM (Traderark Tanabe), shellac, TC-5 (Tradenark - Shin-Etsu) Tablets, sugar coated tablets, capsules, trouches, pills, etc. made from the present invention drugs nay contain usual coating agents, etc. which possess untransparent agents therein. Such materials can, for example, be manufactured from polymers or from wax. The pharmaceutical compositions of the present invention may be formulated into a sustained release form, either by micro-incapsulation or by other techniques knows per se in the pharmaceutical industry. Examples of suitable additives to prcpare suppositories are Water soluble bases such as polyethyione glycol and oil bases such as cacao butter, Witepsol (Trademark-Dynamite Nobel AG). Such bases may contain surface active agents therein. Examples of materials used for the manufacture of suspension injections, emulsions, suspensicns, sirups, etc. are as follows: (1) Eaulslfication and suspensing agents such as water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils/fats, glycol, tetrahydrofurfuryl alcohol, polyethylene glycol (2) Surface active agents such as sorbitan fatty acid esters, polycxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithine (3) Suspension agents such as carboxymethylcellulose sodium salt, methyl cellulose, other cellulose derivatives, tragacanth, gum arabic, other natural rubbers (4) Preservatives such as para-hydro-:ybenzoic 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 like. The pharmaceutical compositions according to the present invention contain from about 0.1 to 99.5% and more preferably from about 0.5 to 957. 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 ay contain other therapeutic agents such as digestive enzymes, antacids, inhibitants for stomach secretion, aromatic stomach agents, bitter stomach agents, protective agents for stomach mucous, anti-cholinic 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 from about 0.5 to 100 mg/kg but the precise dosage may vary according to the severity of the condition, 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 following non-limitative example more particularly illustrates the present invention: EXAMPLE 2,4-Diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine is powdered by supplying it at rate of not e.ore than 2 kg/hour to a Jet Mill PJM- 100 NP (Nippon Newmatic Mfg Co). Ene pulverized pharrr.accutical is dispersed in z physiological saline solution containing one drop of Tween-80 by the use of ultrasonic ho.o.enizer for 30 seconds and their particle diameter in average is measured by Coulter Counter TA-II (Coleter Electronics Co, U. S. A.) and the result is about S microns. EMI10.1 The axis of abscissa and the ordinate are administration dates and body weights, respectively. . . means control groups, x----x means finely powdered groups according to this invention, and o----o means the ordinary conventional powder groups.

Claims: lrAAT IS CLAIMED IS: 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-diemino-6-(2,5-dichlorophenyl)-1,3,5triazine according to claim 1 wherein te average particle diameter is about 8 microns. Claim 8. A pharmaceutical composition useful for the treatment of peptic ulcers in humans and enimals which nonprises 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 finely pulverized form so that the average particle diameter is 20 microns or less, in combination with a pharmaceutically acceptable carrier. Claim 9. A composition according to claim 8 wherein the compound is in the form of the maleate salt. Claim 10. A composition according to claim 8 wherein the average particle diameter is 5 to 10 microns. Claim it. A composition . according to claim 9 wherein the average particle diameter is 5 to 10 microns. Claim 12. A composition according to claim 8 wherein the average particle diameter is about 8 microns. Claim 13. A composition according to claim 9 wherein the average particle diameter is about 8 microns. Claim 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. Claim 15. A composition according to claim 8 in oral administration form. Claim 16. A composition according to claim 8 in rectal administration form.

Inventors: AOYAGI, YOSHIAKI, ENOMOTO, HIROSHI, KAWAMATA, MASANOBU, NOMURA, AKIRA, UEDA, FUSAO
Applicants: NIPPON SHINYAKU COMPANY, LIMITED
Application year: 1983
Main classification: A61K31
IPC codes: A61K31, C07D251