DE3326165A1 - PHARMACEUTICAL PREPARATION - Google Patents

Description

10

clock. Str.;: Ί. it ,. ifetS) 472947
F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

2 July 0, 883

RAN 4440/159

Pharmaceutical preparation

The invention relates to a new pharmaceutical Preparation, which is characterized in that it is called Active ingredient a mixture of diaminodiphenyl sulfone (DDS) and 2,4-diamino-5- (4-bromo-3,5-dimethoxybenzyl) pyrimidine (Brodimoprim) contains.

20th

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

DDS is known to be used to treat leprosy. Surprisingly, it was found that a mixture of DDS and brodimoprim against leprosy pathogens is synergistic compared to the action of the individual components increased effect unfolds.

30th

In a preferred embodiment, the invention contains Preparation of the active ingredients in the molar ratio DDS: Brodimoprim = 1: 1 to 1:10.

The pronounced synergistic effect of the inventive combination of DDS and brodimoprim against leprosy

Me / 5/30/83

y _

The pathogen becomes clear from the experiments described below:

One with 0.25 w / v -% bovine serum albumin (Fraction V) modified Dubos-Davis nutrient solution was inoculated with Mycobacterium lufu from a 4-6 week old Gottsacker slant culture. In order to obtain a uniform suspension, the bacteria were homogenized in 5 ml of medium, the suspension was then diluted with 15 ml of medium and centrifuged for 4 minutes at 150 g. Part of the supernatant was used for electronic counting and the remainder for making cultures. The suspension was diluted to about 10 cells / ml and 50 ml portions were added to 300 ml Erlenmeyer culture flasks containing a magnetic stirrer. The inhibitor was added and the cultures kept at 31 ^° C. The cultures were vigorously magnetically stirred for 1 minute prior to taking samples for enumeration. The count was made with a Coulter Counter. To determine the total bacterial count, culture ^{samples were diluted with particle-free common salt (0.85 0} formaldehyde ( 0.2%) solution, so that a number of 500-20,000 organisms were obtained removed at a time, placed in 50 ml of fresh nutrient solution and incubated at 31 ° C. The cultures were counted after 8 days - as described above - with the Coulter Counter.

The change in the growth rates of the cultures in the presence of the individual inhibitors was determined. In addition the rate constant k [sec. ] for the observed rate of growth of the first order, in Absence and presence of the inhibitors, from the slope of the growth curves according to the equation

log N = kt / 2,303 + log N _n

el MP J

determined, where N is the number of microorganisms in a defined culture volume, t is the time in seconds and N _n

V y (if y ι y ν

the number of germs at time t = 0.

The results are summarized in Table I for DDS-sensitive and in Table II for DDS-resistant (= 100 μΜ DDS) mycobacteria (M. lufu). The constants for the observed steady state generation rate for M. lufu at 31 ⁰ C in the presence of various inhibitors at different concentrations are given:

Table I.

Inhibitor Attempt 1 Attempt 2 k [sec ~ ¹ .10 ~ ⁶ ] k CSek ~ ¹ .10 ~ ⁶ ] Control value 7.69 8.98 DDS (0.2 μΜ / ml) 5.76 6.22 Brodimoprim (10 μΜ / ml) 7.70 8.90 DDS (0.2 µΜ / ml) + 0 -0.50 Brodimoprim (Total germ count) (Live germ (10 μΜ / ml) number)

Table II

Inhibitor k CSek ~ ¹ .10 ~ ⁶ ] Control value 7.75 DDS 50 μl / ml 7.22 100 " 7.61 30 200 " 4.88 Brodimoprim 5 μl / ml 7.77 10 7.83 DDS + brodimoprim 10 + 10 µΜ / ml 2.55 35 50 + 5 1.27 100 + 5 0.7 100 + 10 0.24

The values in the table show that in the presence of the Combination of active ingredients no growth of the microorganisms and even a reduction in the number of living bacteria was observed in the culture, whereas the culture growth - albeit at a slower rate - progress if the active substances were individually present. Also DDS-resistant Cultures are created by combining DDS-Brodimoprim Completely inhibited at appropriate concentrations.

The pharmaceutical preparations according to the invention contain the mentioned active ingredient combination together with an acceptable pharmaceutical carrier. This carrier can be one for enteral, percutaneous or parenteral

■ J5 administration suitable organic or inorganic Carrier material such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable Oils, polyalkylene glycols, petrolatum and the like. In addition, the pharmaceutical preparations can provide additional contain pharmaceutically valuable substances, such as antipyretic agents, pain relievers, anti-inflammatory agents Means and the like. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, capsules, Pills, powders, granules, solutions, syrups, suspensions. Elixirs and the like can be administered. The administration can also be parenteral, 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 can be sterilized and / or components contain, such as preservatives, stabilizers, wetting agents, emulsifiers, salts, in order to reduce the osmotic pressure vary, and buffer substances

The preparations according to the invention can be used for treatment leprosy, including DDS-resistant leprosy, are used. The preparations are particularly suitable for those who do not medically supervised therapy of leprosy and prevention

-JS -

the development of resistance in DDS monotherapy.

For therapeutic use, the inventive Preparations in daily doses of 50-100 mg DDS and a corresponding amount of brodimoprim in adults administered.

The dose can be administered as a single dose or in several divided doses distributed over the day. Preferably one tablet is administered daily.

An example of a typical dosage form is the following:

Tablet :

DDS 100 mg

Brodimoprim 200 PRIMOJEL (starch derivative) 6

Povidone K 30 (polyvinylpyrrolidone) 8

Magnesia stearate 6

Total weight 420 mg

Claims (3)

Claims 1. Pharmaceutical preparation containing diaminodiphenyl sulfone and 2, 4-diamino-5- (4-bromo - 3, 5-dimethoxy- 5 benzyl) pyrimidine. 2. Preparation according to claim 1 for the treatment of leprosy and / or other mycobacterioses. "10 3. Preparation according to claim 1, characterized in that that the molar ratio of diaminodiphenyl sulfone: 2,4-diamino-5- (4-bromo-3,5-dimethoxybenzyl) pyrimidine Is 1: 1 to 1:10. 15 ***