FR2531861A1 - SYNERGISTIC PHARMACEUTICAL PREPARATION BASED ON DDS AND BRODIMOPRIM, FOR THE TREATMENT OF LEPROSY - Google Patents

Abstract

THE INVENTION CONCERNS A NEW PHARMACEUTICAL PREPARATION, WHICH IS CHARACTERIZED BY THE FACT THAT IT CONTAINS AS ACTIVE SUBSTANCE A MIXTURE OF DIAMINODIPHENYLSULFONE (DDS) AND 2,4-DIAMINO-5- (4-BROMO-3,5-DIMETHOXYBENZYL) -PYRIMIDINE (BRODIMOPRIM).

Description

The invention relates to a new pharmaceutical preparation which is

  characterized in that it contains as active substance a mixture of diaminodiphenylsulfone (DDS) and 2,4-diamino-5- (4-bromo-3,5dimethoxybenzyl) -pyrimidine (brodimoprim). The invention further relates to the use of such an association

  active for the treatment of leprosy and / or other Other yeast infections.

  We know the use of DDS for the treatment of leprosy.

  We were surprised to find that a mixture of DDS and

  brodimoprim exerts an action on the leprosy bacilli

  energetically increased compared to the action of the separate constituents.

  In its preferred embodiment, the preparation according to the invention contains the active substances in the

  molar ratio DD St brodimoprim I: I & T: 10.

  The marked synergistic effect of the association in accordance with the invention of DDS and brodimoprim with respect to the leprosy bacilli is illustrated by the tests described below:

  A Dubos-Davis culture broth modified by 0.25% mass / vol.

  of beef serum albumin (fraction V) was inoculated with Mycobacterium lufu from a culture on agar Inclined from Gottsacker 4 to 6 weeks old In order to obtain a uniform suspension, the bacteria were homogenized in 5 ml of the medium, then the suspension was diluted with 15 ml of medium and centrifuged at 150 g for 4 minutes Part of the upper layer was used for electronic counting and the rest for the preparation of cultures The suspension was diluted to approximately cells / ml and 50 ml fractions introduced into

  Erlenmeyer flasks for culture containing a magnetic stirrer.

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  The inhibitor was added and the cultures maintained at 31 C.

  Before taking the samples for counting, the cultures were subjected for 1 minute to vigorous agitation.

  magnetic The counting was carried out using a Coulter-

  Counter To determine the total number of germs, culture samples were diluted with a solution free of coarse salt particles (0.85%) - formaldehyde (0.2%), so as to obtain a number of 500 to 20,000 organisms For the determination of the number of live germs, samples of 0.5 ml were taken from time to time, placed in ml of fresh culture broth and incubated at 3 I Co The cultures spread out after 8 days like

  described above in counting using the Coulter-Counter.

  The variation in the growth rates of the cultures in the presence of the various inhibitors was determined. To this end, the speed constant kap lsec IJ was calculated for the first order multiplication speed observed, in the absence and in the presence of the inhibitors, at from the slope of the growth curves according to the equation log N = kapp t / 2 303 + log NO, where N is the number of microorganisms in a determined volume of culture, t the time in seconds and N the number of germs to the instant t = O.

  The results are collated in Table I for mycobacteria

  ries (M lufu) sensitive to DD 5 and in Table II for

  DDS resistant mycobacteria ('IOO t M DDS) are indi-

  the constants of the observed continuous multiplication speed (steady state generation rate) for ti lufu at 3 I C,

  in the presence of different inhibitors, at different concentrations

tions:

Table I

  Inhibitor Control value DDS (0.2 el / ml) Broâimoprim (Io O -M / ml) DDS (0.2 e M / ml) + Brodimoprim (I O 'M / ml) Test I

k Eseo IO-

  7.69, 76 7.70 o (total number of germs) Trial 2

k lsec-I IO-

  8.98 6.22 8.90 0.50 (number of live germs)

Table II

  K isecl inhibitor I 076 Control value 7 k 75 DDS 50 Lh M / ml 7.22

I 00 7.6 I

4.88

Brodimoprim 5 w M / ml 7,77

7.83

  DDS + Brodimoprim I O + I O tx / ml 2.55

+ 5 1.27

I O + 5 0.7

I 00 + IO 0.224

  The values in the tables show that in the presence of the associations of active substances which are the subject of the invention, not only is there no increase in microorganisms, but even that there is a reduction in the number of living germs in the culture, then that the growth of the culture progressed although in a slower way when the active substances were present separately Even the DDS-resistant cultures are

  totally inhibited by the DDS-brodimoprim combination

appropriate trations.

  The pharmaceutical preparations according to the invention are

  hold the combination of active substances mentioned combined with a compatible pharmaceutical support This support can be

  an organic or inorganic product allowing an administration

  entally, percutaneously or parenterally like water,

  gelatin, gum arabic, lactose, starch, ster-

  magnesium arate, talc, vegetable oils, poly-

  glycols, petroleum jelly and other similar products In addition, pharmaceutical preparations may contain other

  0 valuable pharmaceutical products such as antipyretic agents

  ques, analgesics, anti-inflammatory drugs and others Pharmaceutical preparations can be administered by oral route, for example in the form of capsules capsules, pills, powder, granules, solutions, syrups, suspensions, elixirs and others But the administration can also be parenterally, for example in the form of sterile suspension solutions or emulsions, or locally in the form of solutions,

  suspensions, ointments, powders, aerosols and others The prepa-

  pharmaceutical rations can be sterilized and / or contain

  constituents such as preservatives, sta-

  bilisants, wetting agents, emulsifiers, salts

  to modify the osmotic pressure, and buffers.

  The preparations according to the invention can find their

  used for the treatment of leprosy, even of leprosy DDS-

  resistant The preparations are particularly suitable for the treatment of leprosy without medical supervision and for

  avoid the development of resistance phenomena in monothe-

rapie by DDS.

  For the therapeutic application, the preparations in accordance with the invention can be administered to adults in daily doses of 50 to 100 mg of DDS accompanied by an amount

appropriate from brodimoprim.

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  The dose can be administered in a single dose or in several partial doses distributed throughout the day.

give one tablet a day.

  The following example is a typical dosage form 2 DDS IOO mg tablets Brodimoprim 200 PRIMOJEL (starch derivative) 6 Povidone K 30 (polyvinylpyrrolidone) o 8 Magnesium stearate 6 Total weight 420 mg

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Claims (1)

Claims   I Pharmaceutical preparation containing diaminodiphenyl-   sulfone and 2,4 diamino-5- (4-bromo-395-dimethoxy-   benzyl) -pyrimidine. 2 Preparation according to claim I for the treatment of leprosy and / or other yeast infections. 3 Preparation according to claim 1, characterized by   fact that the diaminodiphenylsulfone: 2,4-dia- molar ratio   mino-5- (4-bromo-3,5-dimethoxybenzyl) -pyrimidine is included between I: I and I: IO.