CS220306B2 - Method of manufacturing tablets having short breakdown period - Google Patents

Abstract

2,4-Diamino-5-benzylpyrimidines of the accompanying formula I, in which R<1>, R<2> and R<3> have the meaning given in the Patent Claim, which are contained as a potentiator for sulphonamides in tablets in which a mixture of sulphonamide and potentiator is present in an amount of 80 to 95% by weight, the mixture having a particle size of less than 40 mu m, and which additionally contain a granulating agent and a disintegrating agent which has a swelling capacity of more than 5 ml/g, the total amount of the two agents being not more than 20% by weight, are prepared by reacting a compound of the accompanying formula II, in which X, Y and Z have the meaning given in the Patent Claim, with guanidine and purifying and isolating the process product. <IMAGE>

Description

^{Pla d} m6tem vynátezu the tableting process with short-lived content 2.4minmino 5 benzylpyrlmidinu. and sulfonamide, granulating agent and disintegrant, characterized in that the particle size of _2), 4-diamino-'5-beezylppri> clonidine with a sulfonamide is lowered ZS resulting particles have a size less than 40 microns, is then wound ^{g l} U is the mixture of ^b to ^h EM 80 and ^of 08 ° / o ^h motnostních active ingredients of the granulating agent in a solution followed by mixing and drying, ^PRICE em ^z is užje ilesintegraemho agent swelling greater than 5 ml / g before or after the granulation, e.g. calcium SOH ^to arboxymeth ^{y l} LCE ^role algteátu solution, vegetable rubber or sodium starch glycollate and the total amount of granulating and disintegrating agent is no more than 20 weight percent, then the resultant granules compressed into tablets.

The present invention relates to a process for the manufacture of a tablet comprising a mixture of 2,4-dlaminopyrimidine with a sulfonamide suitable for oral administration.

2,4 diaminopyrimidines are well known not only as folic acid and folinic acid antagonists in microorganisms in need of these nutrients, but also as inhibitors of the dihydrofolate reductase enzyme in Streptococcus faecalis. When these substances were used in combination with sulphonamides, is observed a strong potentiating effect on - if a broad spectrum of microbes as a result of the sequential blocking pathways leading to - novzsyntéze coenzyme F. Therefore, the 2,4-diammopyгimidiny often referred to as a substance potentiating effect sulfonamido ^Importan . This potency can be demonstrated as well as in drip-infected mice infected with Staphylococcus or Proteus. In stotečno ^ is ^ zpštěný tencujmí ^- úcineik 'such that there has been considerable success in Lece mitoobmlnich MTO-KRN in animals and humans.

Nejbežn ^ Cry ^2.4 - daminopyrimtoin trimethoprim, which is 2,4-diamino 5- (3,4,5-trimethoxybenzyljpyrimidin that ^ob y ^kl tombinuje e ^{- f} salt amethoxazolem ^{that Z} is 3- (4 -aminobenzenesulfonamido-5-methyl-moxazole in a 1: 5 aid (trimetooprim: sulfametho-azazole) For example, tablets containing 400 mg sulfamethoxazole and 80 mg trimethoprim have been available for several years.

Ačkoh ^D and in ^the OC ^and m tombinace ^ a-diaminopyrimidine with a sulfonamide (hereinafter, such a combination will be referred to as "akttvrn composition ^for a") depends ^d of jteté MFR ^y T ^ype in in ^f e ^to CE is ^Z has ^b ý ^{t treated,} from ^p ules are used ^d AVEKO of ^{d 100 d} of ⁰⁰⁰ m ^g per ^{the example, five} 00 mg ^EXAMPLE ICEM ^F, this ^can vKA in some at ^p and ^d all ^p o ^d RECOGNITION ctospielým ^p acient ^u m ^d va even more times a day. Such amount of the active stožky about the ^{YKL b} e ^p o This ^gives purposes such as the size in which the active ingredient me.u 60 to 80 weight%. The remainder of the tablet is usually constituted by conventional carriers such as a disintegrant, a granulating agent, a binder, a glidant and an inert filler.

At present the application of such tablets often meets with difficulties caused by their ^{necessarily -} Veltem vehkostí, ^although the amount of active ingredient Y ^YC is just ⁴⁰⁰ m ^g, and constitute 89% pentamethyl hmotnostrnch. ^N and ^D to these difficulties zvěttojg aphtováno if more than ⁶ ° 0 m ^ which is often necessary, and it often happens that the patient is not willing to swallow such tablets if their size is not reduced.

Furthermore it is disadvantageous that the increase in the percentage of the assets on the ^{y d 80} wt. 0% vetoucí reilkm thus ^to ce ^o b ^s velikostt taWety results in deterioration - tablets times as large ^d ESINTE ^g race and expanded on ^p tδn ^{br s,} large robivos ^{d t} or TVR whom was hotdnoty ^d Ostia. These properties are obviously of utmost importance especially because it does not meet certain l ^EC and ^the tent ^of the ^d ar ^dy plating healthcare cal authorities of many countries. For example, poor property pentamethyl can sleep well VES ^{d tk} attrition and fragmentation of tablets during their transportation and the patient would therefore be unable to get the desired amount of the active ingredient.

Nyrn ^was about yji ^br Teno ^- that may be a ^{d t} ska tablet with excellent properties even St. ^YSS microns. ^p aktvní the ^piece em ^ky no stacks ^{of d} destiny. In fact, the tablet can be made containing a high proportion of the active ingredients ⁵ to 9 wt. % or ^d staples ^{- higher} . This is possible by using the active ingredient - i.e. combination 2,4- ^d diamino sulfonates yrimidinu ^p · ^d em, ^z has the size ^also part axis ^t ^ j and ^k buúe in another defined, lower than 40 μΐη. Jehkož reduction in the proportion of carriers apparently accompanies the use vyšího proportion of the active ingredient, the resultant pentamethyl elkonomktá above ^h at the ^{dy d} P ^ chozími tablets.

B ^y It 'also zjištůno that ^P asc Boblo · NaCl capacity desmtegiač.ního rea, as will be defined is associated with a decrease in odpovtoajícuii ctesinto ^ raířmm time of the tablets according to the invention. Although the size of the low ^Ca st ⁱ c alkUvrn hundred ^clippers in Van ^ ztopení tablet properties, the inclusion desíntogračního agent having a swelling capacity, as defined below, - more than 5 ml / g -. brings further improvements to these properties. In particular, it is possible to achieve surprisingly low disintegration times with tablets - having - a high content of active ingredient, for example 95 wt. °% ^{and the} holding has. ^- at the same time hardness scores of 118 N.

The invention provides a tablet comprising a ^d 8 ^{O d} of ⁹ 8 wt. % Mixture of ^ S-diaminopyrimidine with a sulfonamide, _ desmtegrační agent and a granulating agent, the total amount of both ^NO in ^id e ^l Nern ^{sentences, 20} wt. % ^{Preparations,} the particle size of the mixture is less than 40 --ma disintegrating agent has a swelling capacity, as will be defined more than 5 ml / g.

In particular, the tablet comprises at least 85 wt. Aktvrn with ^l% O ^{from alkyl, the} above TERA ^h o n ^{e p d} at present for the ratio of from 1: 20 to 20: 1, eg 1: 3 ^{(2, 4-d} iaminopyrimidinu: sulphonamide) and which has - a particle size greater than 1 nm, preferably 2 nm.

Tacet consist of 1-5 ^h mot.% From the wound ^{g of L} and ^{C, or} N ^idl whom you AAZ ^1-5 wt. % ^D esintegračního agent is also preferably formulated as a tablet, which has a swelling feeling ^ ^ j and ^k bu ^d ev al ^{width d} m ^d t ^fi NOCs ^and at ^greater than 10 ml / g.

Exact velitost Part C ^^ alktvní ingredient ^F is to be used according to this invention will depend upon the intended content of the final tablet. For example, ⁸⁵ masses are required. Aktwm% ^YC O ^{L y, p} and ^the particle size can be for example between 20 and 30 nm. On the other hand, if the requested content ^{95 h} mot.% Aktvrn SiOx ^1, it is advisable to use an even smaller particle size, e.g. ^IKL and ^{width d} smaller than ^{15 microns,} with výliotou Mem 10 / an.

The particle size of the active ingredient can be readily reduced by precipilation techniques or by milling the particles in any apparatus or other lege artis methods known and suitable for this purpose. In particular in the ^h and ^{d kl} Nu ^Di mtynek ^to AC, which can ^b used YT either solid or suspendable hammer type and is usually combined with a fan and a cyclone for collecting the material.

As used herein, the swelling capacity of a disintegrating agent is defined as the volume (mL) to which swells 1g tablet comprising 95 ^h mot.% Of dry ^eh of ^d ESMT ^g RACM · it mnidla and ^5h mot.% ^ Tyviny ^ yrrondonu K 30) when in contact with excess water at 21 ° C. Determine the granulation desrntegrarního CMML 2 ^g) with ^{10% p} olvvm ^yl pyrrolidone (K 30), 1 mL) and drying the resulting granules at 60 ° C. Compressing the granules to a hardness of ¹¹⁸ N is zfekap tablets rum ^{p e} r of 15 mm and an approximate weight of 900 mg. Each tablet is then accurately weighed and placed in ²⁵ ml ^D no ^d m ^of the RN ^{AL eh} o ce. ^The nyon disc of 8 mm thickness and having two grooves forms a tight but shifting fit in the measuring cylinder resting on top of the tablet. F against ^{the paw} are dying of ^BE to the ^b in the ^d u ^d is ^the uv UNU ^The Right ^E m ^{H k} is the rovrně and allowing a thin hypodermic needle was inserted between the disc and the glass wall of a measuring cylinder. A nylon disk was placed 5 g weight and water is injected one of ^{l AB} em free space only to the ^p obMoirnjmího tablet second groove serves air leakage. When the above water hladrna vrchokm dm ^ m ^of the needle is removed and water is added until it is in excess, i.e. 25 ml. The volume under the disk is then recorded at periodic intervals until there is no further increase in absorption. In some cases ό.03ί.ηΐθ £ Γυ.jící agent absorbs water to form a viscous gel which slows the rate of absorption and enforces longer intervals such as 48 hours before is achieved not ^from maximálnfro to ^b of ^bt - Nani. *

After the swelling is complete, the final volume is read and corrected to the corresponding value for 1 g of the tablet, i.e. the value for swelling capacity. The whole process is preferably carried out at approximately constant room temperature, for example 21 ° C.

Disintegrating agent having a swelling ^on apacity V ^e t ^get than 5 ml / g ^kt ns therefore grilles to be used according to the present invention includes calcium of ^ when carboxymethyl cellulose (such as ECG 505) nízkovisk: added sodium carboxymethylcellulose (such as Copagel ) rosthnná rubber ^type guar ^Star rubber (j and ^k o is SUPERCOL U and SUPERCOLU GF), alginates, sodium (such as alginate YZ) and sodium ^šk ro ^b ovýc ^{h glyco} about ^l at ^u (j and ^k o is Primojel) . The most preferred disintegrants are Supercol U and Primojel.

Granulating agents which may be used in the present invention include starch in the form of mucilage, starch derivatives such as ^SK ro ^b tončiiovto the lens ^{assembly L} ", cellulose derivatives ^{é ú} ZOV I ^to the Met-lcel.utóza, gelatin and especially ^é polyvin ^y lp ^y rolidide.

The 2,4-minoinopyrimidines that can be used in the present invention include those represented by Formula I:

R (I) wherein

X is phenyl optionally substituted, and

R is C 1 -C 4 alkyl, or is

X is a benzyl group optionally substituted, and

R is a hydrogen atom.

Preferably X is substituted with a benzyl group of formula II:

wherein ^{R1, R2} and ^R3 are the same ^e or different and ^k and ^f res m ^s that ^TT in ^row ene and ^lkyl cord for ^the u ^pi Nou having 1 to 4 carbon atoms, a hydrogen atom, or ^R1 and ^R2 together can inedstovovat and ^lendioxy groups having from 1 to 4 carbon atoms, such as methylenedioxy group4.

Examples of compounds which conform to formula I include the aforementioned trimethoprim, diaveride [1,4-diamino- ^5- ( ^3,4- dimethoxybenzyl ⁾ pyridine], ormetoprim, ie 2,4-diamino-4-methyl-d-dimethozybenzyl ) pyrimMm, 2,4toiaPΊШO- ⁵ -f ^3, 4 u ⁱ me ^th ox ^y - ^{5-bromobenzyl)} pyrimidia and pyrimethamine, i.e. 2, ⁴ - ^{р 1п} ™ ^{ю 5} - (4-O-chlorienyH ethyljtyrimh din. A particularly preferred compound is trimethoprim.

The sulfonamides that can be used in accordance with the present invention include those represented by Formula III:

/ -L N S θ £ N W - G.

(III) where

Q is substituted or unsubstituted pyrimidin-2-yl, pyrimidin-4-yl, substituted isoazolyl, quinoxalinyl or acyl, wherein the alkyl group has from 1 to 4 carbon atoms.

Examples of preferred sulfonamides corresponding to Formula III include the aforementioned sulfamethosazole, sulfadimethoxin, i.e. 6- (4-aminobenzenesulfonamido-2,4-dimethoxypyrimidine, sulfadiazine, e.g.

2- (4-aminobenzenesulphonamido) pyrimidine, sulfadoxine, i.e.

4- (4-aminobenzenesulfonamido) -5,6-dimethoxy-yrimidine, sulfoquinoraline, i.e. 2-sulfonamidinoquinoline, sulfadimidine, i.e. 2- (4-aminobenzenesulfonamido) 4,6, dimethylpyrimidine, sulfafurazole, e.g.

5- (4-amino-benzenesulfonamido) -dimethylisoxazole, and with acetic acid, ^i.e. , N-sulfanilylacetamide.

A particularly preferred compound is sulfamethoxazole.

^{2, 4d} iaminopyrimi ^d sulfonam'd ins and ^y may be made by any suitable method described in the literature. For example, ^ l-Amino-dtoenz ^ p ^ I ^ ^b MIDI yl generally made by methods described in British patent no. 1,261,455, for example as sulfamethoxazole can be produced as described in British patent application no. 814 · 276th

It may also be useful to hold tablets small part of a suitable lubricant in ^the middle, such as magnesium ^ the latter is then protected by the adhesion of the tablet to the punches and dies of automatic tableting equipment. Colorants and preservatives may also be added if desired.

According to the invention there is provided a method of manufacturing a tablet, which consists in being compressed on a standard machine, the product contains about ^{2 8} 0 ² for ^{98 h} mot.% ^Of a mixture ^{of 2,4} diaminopyrimidine with a sulfonamide, a disintegrating agent and a granulating agent, the total the amount of both reagents is not more than ^{20 h} mot%. pnpravku, directly vehkost ^CA stic mixture is less than 4θ ^ m disintegrating agent has a swelling capacity as has been in the PIO-chozrn (teHnovtoa in ^greater not ^from 5 ml ^{/ g.} The active ingredient and a disintegrating agent are mixed in the dry state at slow speed for example about 15 rpm in a planetary agitator, the mixture is wet-mixed for about 30 minutes with the granulating solution and, if necessary to maintain consistency, together with another solvent. The dried material is sieved and the lubricant is added to the granules so obtained. Compressing the granules in a standard machine to a specified hardness yields tablets of the desired size and shape.

It is noted that the advantageous properties of the tablets prepared according to this invention for ^{D eV} mz ^p eny rnterakcemí ^b uso. between the disintegrating agent and one or each of the 2,4-diaminopyrimidine ^yl pyrimidines, sulphonamides granulator 'agent.

Disintegration time can be determined by the method described in British Pharmacopoeia 1988 that the rapid movement of the tablet in water at standard conditions, when not already žtoné zlzyt of ^ky ^ tovapri for ^d ≤ t ≤ urn wire loop (see pages 1366-1367).

The British Pharmacopoeia 1968 also requires that the disintegration time for any tablet should not exceed 15 minutes, but it is desirable that these times be less than 10 minutes, especially less than 5 minutes, for safety reasons in view of the inevitable variation between tablets. Insults to this basic requirement is generally recommend ^{and well,} and ^{would have} a ^b-SAH vtokostt in anuhch of rnchž is Tomette vyoo ^{b ENA, the} MZM not ^of 2%.

Tablet hardness is the amount of force required for its fragmentation, or is specifically the compressive strength, and although it can be measured accurately by ^{dl e p} e ^M onsantova stantaráů different method is convenient and suitable for testing the tablets produced according to the present invention. Essentially, the method consists in using a Monsant tablet hardness tester, a spring-loaded device capable of exerting a radial pressure on the edge of the tablet, and the shattering force is subtracted from the scale on the device housing. Tablet Friability is a measure of weight loss, which tablet suffer abrasion or impact am ^already e ^b YT test ^and on to ^"R oche" fria ^{bi pacemakers,} in which the weighted · sample tablets, for example, 6 g, is subjected in the machine for some time, should 4 minutes · abrasion caused re ^clop en ⁱ z srovnateteým toernm with the ^{BL t} e ^r between themselves or their _ impinging on the walls of their containers in common use, and to shock induced free fall 'of the 15.25 cm, with which the the tablets may meet during various packaging, handling and transport procedures.

For example, the tablet start time may be determined according to US Pharmacopoeia XVIII using an apparatus consisting of a 1680 cylindrical basket (µm stainless steel mesh, a 1000 ml glass jar with a cap, a constant temperature water bath and a variable speed motor). , PMZ ^MU e ^b e such ^t ^ M ^{0, 6% alkyl} Selma HCl pH 1.2, is poured into a vessel which had been immersed in a constant temperature bath and the dissolution medium is heated at 37 · C. tablet The basket is rotated at, for example, 120 rpm and samples are taken at regular intervals by syringe and analyzed, for example, by absorption in ultraviolet light.

Other advantages of the invention will now be apparent from the following examples which describe preferred embodiments of the methods of the invention but are not intended to limit the invention in any way.

Example 1

The swelling capacity of the various disintegrants was determined according to the method described above at 21 ^° C. Each disintegrant tested was then included in the formulation:

Weight (g) sulfametho 'azole800.0 trimethoprim160.0 disintegrant19.0 polyvinylpyrrolidone (K30) 20.8 dioctylsulfosuccinate sodium0.8 magnesium stearate10.0

Sulfamethoxazole and trimethoprim form a mixture having a particle size of 11.6 µm and this mixture is dry blended with a disintegrant in a Morton mixer before adding 260 mL of a solution containing polyvinylpyrrolidone (K 30) and dioctylsulfosuccinate sodium in equal parts of alcohol and water An additional 200 ml of a solution containing only the same portion of alcohol and water is added before the wet mass is passed through a 1000 mesh screen. The resulting granules are dried on the fluidized bed for 20 minutes at 70 ° C before sieving through. sieve with a mesh diameter of 1000 δ.

Magnesium stearate, pre-screened through a 125 mesh screen, is added to the granules, and the resulting mixture is compressed on a Manest D3 rotary compression machine to form tablets having a hardness value of about 118 N (Montanto). The properties, in particular the disintegration time, were then determined for each tablet formulation.

Disintegrant

Swelling capacity (ml / g)

Disintegration time (minutes)

guar resin (Supercol U) 23.1 1.08 sodium starch glycolate (Přímojel) 14.8 1.42 Calcium alginate (Alfinate YZ) 10.2 2.17 low-viscosity sodium carboxymethyl- pulp (Copagel) 5.2 3.17 guar resin polysaccharide (Super- col G. F.) 7.4 3.17 carboxymethylcellulose calcium (E. C. G. 505) 6.0 7.67 bleached cellulose, type а (Серо cellulose) 4.8 > 15 alginic acid 4.6 > 15 microcrystalline cellulose (Avicel PH 101) 3.4 > 15 colloidal aluminum magnesium silicate (Vee- gum regular) 2.3 > 15 dehydrated oil (Crodamix U 35) 1.6 > 15 cornstarch 1.3 > 15

These results confirm that by using a disintegrant having a swelling capacity of more than 5 ml, the prescription yields a tablet having the best properties, particularly as regards its disintegration time.

Example 2

Sulfamethoxazole (800.0 g) and trimethoprim (160.0 g) are mixed and then passed through an Apex friction grinder coupled to sieve B. 1762. The mill is operated at medium speed with cutting blade blades facing forward to obtain the active ingredient having a particle size of 10 μιη. The resulting mixture of sulfamethoxazole and trimethoprim was dry blended on a Morton blender with sodium starch glycolate (Primojel) (20.0 g) dry.

Dissolve 20.0 g of gelatin in 100 ml of water and make up to 200 ml with alcohol. The resulting solution is then added to the dry mixture to effect granulation. The resulting wet mass is passed through a 1000 μηι sieve and dried on the fluidized bed for 20 minutes at 60 ^° C. Dried granules having a moisture content of 0.4 ° / o are passed through a 1000 g sieve. magnesium stearate, pre-sieved through a 125 µm sieve, is added to the granules, and the resulting mixture is compressed on a Manesto D3 rotary compression machine to give tablets having a hardness value of 12030 rather 118 N (Monsant), a disintegration time of 45 seconds and a toobwosti of ^less than 0.2%.

Time ^p ot ^of ebný к extended ^p ustení ⁵ 0% pentamethyl ^0.6 HC1 pH ^1.2 in the ^LSI and ^d m I ^{DESIGNATION to} the T50 ^and time required ^to dissolve ^80% pentamethyl-in ^0, 6% HC ^1, dateím ^dESIGNATION I ^to about Tao was 7 and 20 minutes.

Thickness is 5.5 mm and diameter 11 mm, tablet weight 505 mg and contain 400 mg sulfamethoxazole and 80 mg trimethoprim.

Example d 3

Sulfamethoxazole (4000.0 g) and trimethoprim (800.0 g), the mixture has a size ^{and part} C for ^{11.6 h} and Suc Mikhaylovna with direct jele (0 ^5, 0 ^g] in crates mixer for ¹⁰ minutes ^p Dissolve 100.0 g of gelatin in 500.0 ml of water and make up the solution to 1000.0 ml with alcohol and add the resulting solution to the dry mixture together with 250 ml of a solution containing an equal volume of alcohol and water and stir for 20 minutes. the wet mix then passes through Apexův friction grinder coupled to the A9 sieve 6.35 mm and the granules are dried on trays overnight at 50 ° C. the granules having a moisture content ^{of 0.47} '% ^í further sift RZE with ^the sieve of mesh vehkostt 1000 μΊΏ.

50.0 g of magnesium stearate pre-sieved through a 125 µm sieve are added to the granules and the resulting mixture is compressed on a Manesto D3 rotary compression machine to form tablets having a hardness of 118 N (Monsant), a disintegration time of 46 seconds and friability values less than 0.2 percent.

The values T50 and Tao were 4 minutes and 11 minutes of ^W and K is pentamethyl tíouštau ^{5.56 mm,} diameter 11.0 mm, weight 505 · mg and contains 400 mg sulfamethoxazole and 80 mg trimethoprim.

Example 4

Sulfamethoxazole (4000.0 g) and trimethoprim (800.0 g), the mixture has a size stic ^Ca 1 ¹ 6 ^ μη is dry mixed with ^p rimojelem (95.0 g) in Bekenově mixer for 10 minutes. 1300.0 ml solution of 104.0 g polyvinylpyrrohdonu ⁽³ ° ^K] and ⁴ 0 ^g of ^Copper SOH MoU tylsulfosukcinátu in equal parts of alcohol and water was added to the dry mix together with a further 100 ml of a solution containing only equally alcohol and water . the wet mass is m ^s CH ^{and 1} 0 minutes: and ^p and ^the proc ^ ne of ^the RZE Apexův friction grinder associated with networking A9. the granules are dried on trays overnight at 50 ° C. the dried granules have a moisture content ^{of 0, 70%} is passed ^to the ^s RZE sfto ^to a size of 1000 microns.

50.0 g of magnesium stearate, pre-sieved through a sieve with a mesh size of 125 / ml, is added to the granules and the mixture is compressed on a Manest D3 rotary compression machine so as to produce a tablet of hardness value of 1 ² 0

N, disintegration time of 1 minute 31 seconds and ^h o ^{d t} u no smaller ^width droMvosta not ^of 0.2%.

^H odnoty ^T 50 and ^T with the ⁷ and ²⁹ minutes, and each pellet has a thickness of 5.33 mm, diameter ^{11 mm, h t ENGINE} nose and ^308.8 mg ^b sahuj sultametaoxazolu ⁴⁰⁰ milligrams and ⁸⁰ mg trimethoprim.

Furthermore, if the mixture is compressed to a maximum hardness of> 195 N, the disintegration time is 9 minutes.

Example 5

The process of Example ³ is repeated except that the sodium starch glycolate (Primojel) is replaced by guar gum (Supercolem Uj.

Compression of the mixture yields tablets having a hardness value of 121 N, a disintegration time of 1 minute 45 seconds and a friability value of ^less than ^0.2 %.

The T50 and Teo values are 8 and 31 minutes, and each tablet has a thickness of 5.42 mm, a diameter of 11 mm, a weight of 503.8 mg and contains 400 mg of sulfamethoxazole and 80 mg of triethoprim.

In addition, if the mixture is compressed to a maximum hardness (> 195 N), the disintegration time is 9 minutes.

Example 6

The process of Example 4 is repeated except that Primojel is replaced by YZ Alginate.

Mixture compression to give tablets having Tvrdos ^{t 118} N ^d ESINTE ^g ra ^c m time 1 minute 53 seconds, friability values of less than 0.2 percent.

The values T50 and Teo are 9 and 31 minutes, and each of the ^bl e ^t has tlouštau ^5.40 μπι, remeasure И HMO nose ^{t t 504.0} mg and contain ⁴⁰⁰ mg of sulfamethoxazole and 80 mg trimethoprim.

In addition, if the mixture is compressed to a maximum hardness (> 195 N), the disintegration time of 5 minutes is ²⁵ s ^k un ^d .

Example 7

Sulfamethoxazole (400.0 g) and trimethoprim ^(80.0 g ^ jejmhž with a mixture ^{of Ca} velteost stic 11.8 μιη is dry blended with the Primojel ^(24.0 g] after ¹⁰ minutes Zmepelovém mteéru. Prepare solution containing 16.0 g to ^1.0 g of ^{n e} ^ dioMylsuhosu salts inate, 57.0 g of alcohol and 80.0 g of purified water. the solution is using the slow speed for the ^lhk am ⁱ s ^{≤ 10} with ^p Minmi r ew ^ASK matertalem. wet mass is forced through a sieve mesh size of 1000 microns. the resulting granules are dried in a fluidized bed at 60 ° C for 30 minutes ^{to the} ostium moisture content of ^0, 86%.

The dried granules are passed through a 1000 µm sieve and 4.8 g of sieved magnesium stearate on a 125 µm sieve are compressed on a Manesto D3 rotary machine to produce tablets having a hardness value of 142 N (Monsant), disintegration time 58 seconds and friability value ^0.4 6%.

22030В

The T 50 and T 50 values are 2 and 3 minutes and each tablet has a thickness of 5.8 mm, a diameter of 11 mm, a weight of 526.0 mg and contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 8

400.0 g of sulfamethoxazole and 80.0 g of trimethoprim, the mixture of which has a particle size

11.8 μπι, 80.0 g sodium starch glycolate (Primojel) and 30.0 g lactose are granulated as in Example 7. The granules are dried to a moisture content of 1.43%.

After sieving through a 1000 µm sieve, it is mixed with magnesium stearate sieved through a 125 µm sieve and compressed on a Manest D3 rotary compression machine to produce tablets having a hardness value of 145 N (Monsant), 1 minute disintegration time. 53 seconds and a friability value of 0.34%.

The T 50 and T 50 values are 2 and 4 minutes and each tablet has a thickness of 6.3 mm, a diameter of 11 mm and a weight of 572.0 mg and contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 9

80.0 g of sulfamethoxazole and 400.0 g of trimethoprim, the mixture of which has a particle size of 28.4 μπι, 96 g of pregelatinized starch and 16.0 g of sodium starch glycolate (Prlmojel), are dry blended for 10 minutes on a Z-blade mixer. . 200.0 g of purified water are mixed with the powdered material for a minute. The wet mass is passed through a 1000 μπι sieve and the granules are then dried to a moisture content of 1.25%.

Magnesium stearate (4.8 g), previously sieved through mesh 125 _t um was added к dried granules and the mixture is compressed on a rotary Manestově D3 compression machine to give tablets having a hardness value of 97 N (by Monsanto), a disintegration time of 6 minutes 10 seconds and friability 0.30%.

The T 50 and T 50 values are 5 and 11 minutes and each tablet has a thickness of 6.69 mm, a diameter of mm, a weight of 597 mg and contains 80 mg of sulfamethoxazole and 400 mg of trimethoprim.

Example 10

400.0 g of sulfamethoxazole and 40.0 g of trimethoprim, whose mixture has a particle size of 11 μΐη and 32.0 g of sodium starch glycolate (Primojel), are mixed for 10 minutes in the dry state. A solution is prepared containing 28.0 g of polyethylene glycol and 122.0 g of purified water. The solution was wet mixed with powdered material for 10 minutes. The granules are prepared as in Example 7. The granules are dried to a moisture content of 1.1%.

4.8 g of magnesium stearate previously sieved through a 125 µm sieve are added to the dried granules and the resulting mixture is compressed on a Manesto D3 rotary compression machine to produce tablets having a hardness value of 141 N (Monsant), a disintegration time of 7 minutes 15 seconds and friability 0.33%.

The T 50 and T 50 values are 14 and 35 minutes and each tablet has a thickness of 5.50 mm, a diameter of 11 mm, a weight of 545 mg and contains 440 mg of sulfamethoxazole and 40 g of trimethoprim.

Example 11

400.0 g of sulfamethoazole and 80.0 g of trimethoprim, the mixture of which has a particle size

11.8 μηι, and 96.0 g of YZ alginate are mixed in the dry state for 10 minutes. A solution is prepared containing 16.0 g of polyvinylpyridone (K 30), 80.0 g of alcohol and 100.0 g of purified water, which is wet mixed with the powdered material for 10 minutes at slow speeds. The granules were prepared in the same manner as in Example 1 and dried to a moisture content of 1.0%.

The dried granules are sieved through a 1000 micron sieve and mixed with 4.8 g of magnesium stearate previously sieved on a 125 micron sieve. The resulting mixture was compressed on a Manest BB3 rotary compression machine to give tablets having a hardness value of 123 N (Monsant), a disintegration time of 6 minutes 25 seconds and a friability value of 0.2%.

The T0 value was 5 minutes and each tablet had a thickness of 6.7 mm, a diameter of 11 mm, a weight of 597 mg and contained 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 12

1000 g of sulfadiazine, trimethoprim and 200 g of a mixture of particles having a size of 15 _μΐη} is mixed with the product in an amount of Primojel

23.8 g in a mixer for 10 minutes. Then 26 g of polyvinylpyrrolidone К 30 and 1 g of sodium dioctyl sulfosuccinate are added, the mixture is dissolved in 130 ml of purified water and the solution is made up to 260 ml with alcohol.

The resulting solution is mixed with 120 ml of a solution containing only equal amounts of alcohol and water, and the resulting mixture is mixed for 10 minutes. The mixture was passed through a 1000 µm sieve and dried at 70 ° C for 20 minutes. The granules having a water content of 0.45 percent are re-passed through a sieve having a mesh diameter of 1000 µm.

5 grams of magnesium stearate, pre-sieved through a 125 mesh screen, is added to the granulated mixture, and the resulting mixture is compressed on a rotary tabletting machine to give tablets having a hardness of 101 N (Monsanto), disintegration time of 2 minutes and 25 seconds and possible size. abrasion less than 0.2%. Each of the tablets thus produced has a thickness of 4.94 mm, a tablet weight of 501 mg, and each tablet contains 400 mg of sulfadiazine and 80 mg of trimethoprim.

Claims (8)

OBJECT OF THE INVENTION A process for producing a short disintegrating tablet comprising 2,4-diamino-5 benzylpyrimidine and sulfonamide, a granulating agent and a disintegrant, characterized in that the particle size of 2,4-diamino-5-benzylpyrimidine is reduced by sulfonamide, wherein the resulting particles have a particle size of less than 40 µm and then granulated a mixture containing 80 to 98% by weight of the active ingredients, a granulating agent in solution followed by mixing and drying, using a disintegrant with a swelling greater than 5 ml / g before or after granulation, for example calcium carboxymethylcellulose, low viscosity sodium carboxymethylcellulose, sodium alginate, vegetable gums or sodium starch glycolate, and the total amount of granulating and disintegrating agent is at most 20% by weight, after which the resulting granules are compressed into tablets. 2. Process according to claim 1, characterized in that 1 to 5% by weight of the granulating agent is used. 3. A process according to claim 1, wherein from 1 to 5% by weight of a disintegrant is used. 4. A process according to claim 1, wherein the particle size of the mixture of 2,4-diaminopyridine with sulfonamide is in the range of 20 to 30 μηι and the amount of active ingredient is 85% by weight. 5. The process according to claim 4, wherein the particle size is 10 [mu] m and the amount of active ingredients is 95% by weight. 6. The process of claim 1 wherein the disintegrant has a swelling capacity of greater than 10 ml / g. ' 7. The process of claim 1 wherein the granulating agent is polyvinylpyrrolidone. 8. The method of claim 1, wherein the disintegrant is sodium starch glycolate.