NL8302579A - PHARMACEUTICAL PREPARATION. - Google Patents

Description

N.0. 31926

* V

Pharmaceutical preparation

The invention relates to a new pharmaceutical preparation »which is characterized» in that the active substance is a mixture of diaminodiphenylsulfone (DDS) and 2-diamino-5- (k-bromo-3,5-d-imethoxybenzyl) pyrimidine (Brodimoprim) contains.

The invention further relates to the use of such a combination of active substances for the treatment of leprosy and / or other mycobacterioses.

It is known to use DDS for the treatment of leprosy. Surprisingly, it has been found that a mixture of DDS and 1Q Brodimoprim develops a synergistically increased effect over leprosy pathogens compared to the action of the individual components.

In a preferred embodiment, the preparation according to the invention contains the active substances in the molar ratio of 15 DDS: Brodimoprim = 1: 1 to 1:10.

The pronounced synergistic effect of the inventive combination of DDS and Brodimoprim on leprosy pathogens is evident from the experiments described below: 20 Dubos-Davis modified with 0.25% (w / v) bovine serum albumin (fraction V) nutrient solution was contaminated with mycobacterium lufu from an oblique Gottsacker culture.

To obtain a uniform suspension, the bacteria were homogenized in 25 µl medium, the suspension was then diluted with 15 ml medium and centrifuged at 150 g for k minutes. Some of the supernatant was used for electronic counting and the rest was used to start the cultures. The suspension was diluted to approx

C

30 cells / ml and 50 ml portions were placed in 300 ml Erlenmeyer flasks containing culture stirrers. The inhibitor was added and the cultures were kept at 31 ° C. To take samples for counting, the cultures were vigorously stirred for 1 minute.

Counting was performed with a Coulter Counter. To determine the total plate count, culture samples were diluted with particulate-free table salt (0.85 wt. 5%) formaldehyde (0.2 wt. #) Solution 8302579 2 to give a number of 500-20,000 organisms. For the live bacterial count, 0.5 ml samples were taken from time to time, placed in 50 ml of fresh nutrient solution and incubated at 31 ° C. The cultures were counted after 8 days - as described - with the Coulter-Counter.

The change in the growth rates of the cultures in the presence of the individual inhibitors was determined. To this end, the rate constant k & pp [sec. ] for the observed first-order multiplication rate, in the absence and presence of the inhibitors, from the increase in the growth curves according to the equation log N = k & pp t / 2.303 + log Nq, where N is the number of microorganisms in a defined culture volume, t is the time in seconds and Nq is the number of germs at time t = 0.

The results are summarized in Table A for DDS sensitive and Table B for DDS resistant (A (^, ηΜ DDS) mycobacteria (M. lufu). The constants for the observed sustained multiplication rate (steady state 20 generation rate) for M. lufu at 31 ° C in the presence of different inhibitors are indicated at different concentrations.

Table A

Inhibitor Trial 1 Trial 2 k [sec \ l0 k [sec ”\ lo“ ^]

Control value 7 69 69.98 DDS (0.2 µM / ml 5.76 6.22

Brodimoprim (10 µm / ml) 7.70 8.90 DDS (0.2 ^ rUM / ml + 0 -0.50

Brodimoprim (total plate count) (live plate count)

(Um / ml) 8302579 3 '

Table B

1 ^

Inhibitor k [sec .10]

Control value 7 * 73 DBS 50 yuM / znl 7 »22 100» 7.61 200 »if, 88

Brodimoprim 5yuM / ml 7.77 10 »7.83 DDS + Brodimoprim 10 + 10yUM / ml 2.55 50 + 5" 1.27 100 + 5 »0.7 100 + 10« 0.24

The values in the table show that in the presence of the active compound combination according to the invention, no growth of the microorganisms and even a reduction of the live bacterial count in the culture was observed, while the growth of the culture - albeit in a delayed manner - progresses when the active substances are present separately. Cultures resistant to DDS were also completely inhibited by the combination of DDS and Brodimoprim at suitable concentrations.

The pharmaceutical preparations according to the invention contain said active compound combination together with a tolerable pharmaceutical carrier. This carrier can be an organic or inorganic carrier material suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum and the like. In addition, the pharmaceutical preparations may contain other pharmaceutically valuable substances, such as fever reducers, analgesics, anti-inflammatory agents and the like.

The pharmaceutical preparations can be administered orally, for example, in the form of tablets, capsules, pills, powders, granules, solutions, syrups, suspensions, elixirs and the like. However, the administration can also take place parenterally, for example in the form of sterile solutions, suspensions or emulsions or locally in the form of solutions, suspensions, ointments, powders, aerosols and the like. The pharmaceutical preparations may be sterilized and / or contain ingredients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts to vary the osmotic pressure and buffering agents.

The compositions according to the invention can be used for the treatment of leprosy, also with respect to DDS resistant leprosy. The formulations are particularly useful in non-physician controlled leprosy therapy and in avoiding the development of resistance in DDS monotherapy.

For the therapeutic application, the compositions of the invention may be administered in daily doses of 50-100 mS DDS and an appropriate amount of Brodimoprim in adults.

The dose can be administered as a single dose or in several divided doses throughout the day. Preferably, one tablet is administered per day.

4

An example of a typical dosage form is the following: 15 Tablet: DDS 100 mg

Brodimoprim 200 PRIMOJEL (starch derivative) 6

Povidone K 30 (polyvinylpyrrolidone) 8 20 magnesium stearate 6

Total weight if20 mg 8302579

Claims (3)

5 s “* Pharmaceutical preparation, characterized in that it contains diaminodiphenylsulfoa and 2, diamino-5- (4-broom-3, 5-dimethyl-benzyl) -pyrimidine, A composition according to claim 1 for the treatment of leprosy and / or other Mycobacterioses. Preparation according to claim 1 or 2, characterized in that the molar ratio diaminodiphenylsulfone: 2,4-di-amino-5 "(4-bromo-3,5-dimethoxybenzyl) -pyrimidine is 1: 1 to 1:10. ****** 8302579 - - ^