DE3326165C2 - - Google Patents

Description

The invention relates to a new pharmaceutical A preparation which is characterized in that it is known as Active ingredient a mixture of diaminodiphenylsulfone (DDS) and 2,4-diamino-5- (4-bromo-3,5-dimethoxybenzyl) pyrimidine (Brodimoprim) contains.

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

From GB-A-20 82 063 is an antibacterial effective formulation known that a sulfone and a pyrimidine derivative, namely Trimethoprim contains.

In DE-OS 24 52 889 a variety of benzylpyrimidines disclosed. Furthermore, it is also mentioned that the disclosed benzylpyrimidines have a synergistic effect with sulfonamides can.

It is known to use DDS for the treatment of leprosy. Surprisingly, it has been found that a mixture of DDS and brodimoprim compared to leprosy pests one in comparison synergistic to the effect of the individual components increased effect unfolds.

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

The pronounced synergistic effect of the invention Combination of DDS and Brodimoprim against Leprosy  becomes from the experiments described below clear:

One with 0.25% w / v bovine serum albumin (fraction V) Modified Dubos-Davis broth was mixed with Mycobacterium lufu from a 4-6 week old Gottsacker slant culture inoculated. To a uniform suspension too were obtained, 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 for the electronic counting and the rest used for the preparation of the cultures. The suspension was diluted to about 10⁵ cells / ml and 50 ml portions were placed in 300 ml Erlenmeyer culture bottles containing contained a magnetic stirrer. The inhibitor was added and kept the cultures at 31 ° C. Before taking samples for counting, the cultures became 1 minute stirred magnetically. The counting was done with a Coulter counter made. To determine the total germ count were culture samples with particle free saline (0.85%) - formaldehyde (0.2%) - diluted solution so that a number of 500: 20,000 organisms were obtained. To determine the Live germ counts were taken from 0.5 ml samples from time to time, in 50 ml of fresh nutrient solution and at 31 ° C incubated. The cultures became after 8 days - as above described - counted with the Coulter Counter.

The change in the growth rates of the cultures in the presence of the individual inhibitors was determined. For this, the rate constant k _app [sec. ^-1 ] for the observed first-order propagation rate, in the absence and presence of the inhibitors, from the slope of the growth curves according to the equation

log N = k _app t / 2.303 + log N₀

determined, where N is the number of microorganisms in one defined culture volume, t is the time in seconds and N₀  the number of germs at time t = 0.

The results are in Table I for DDS sensitive and in Table II for DDS-resistant (= 100 μM DDS) Mycobacteria (M. lufu). It will be the Constants for the observed rate of propagation (steady state generation rate) for M. lufu at 31 ° C in the presence of different inhibitors, at different Concentrations indicated:

Table I

Table II

The table values show that in the presence of the inventive Drug combinations no growth of Microorganisms and even a reduction in the number of living germs was observed in culture, whereas culture growth - albeit in a slower way - progressed, if the active ingredients were present individually. Also DDS resistant Cultures are produced by combining DDS-Brodimoprim completely in appropriate concentrations inhibited.

Comparative tests A) Comparative experiment in vitro

The efficacy of a diaminodiphenylsulfone (DDS) and Brodimoprin (BDP) containing preparation compared to a preparation containing DDS and trimethoprim (TMP).

In the tests, the constants were observed for the Continuous growth rate (steady state generation rate) for DDS-sensitive mycobacteria (M. lufu). The Results are given in the table below:

Table III

B) In vivo test

There were the efficacies of the combination of one hand DDS and TMP and on the other hand DDS and BDP in the mouse paw test, (described in Lepr. Rev. 49, 1978, 7).  

In this test showed a combination of 0.0001% DDS and 0.1% TMP no inhibitory effect.

A combination of 0.0001% DDS and 0.03% BDP caused on the other hand a delay of bacterial multiplication (M. leprae) of 120 days.

This shows that the combination according to the invention is significant is more effective than the combination of DDS and TMP though at the combination according to the invention a significantly lower Concentration of BDP used as TMP (prior art) has been.

The pharmaceutical preparations according to the invention contain the mentioned drug combination together with a compatible pharmaceutical carrier. This carrier can be one for enteral, percutaneous or parenteral Administration suitable organic or inorganic Be carrier material, such as. As water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, herbal Oils, polyalkylene glycols, petrolatum and the like. In addition, the pharmaceutical preparations can further contain pharmaceutically valuable substances, such as antipyretic Means, painkillers, anti-inflammatory Means and the like. The pharmaceutical Preparations can be administered orally, eg. In the form of tablets, capsules, Pills, powders, granules, solutions, syrups, suspensions, Elixiren and the like can be administered. The Administration may also be parenteral, z. B. in the form of sterile solutions, suspensions or emulsions, or locally, in the form of solutions, suspensions, ointments, powders, Aerosols and the like, take place. The pharmaceutical Preparations may be sterilized and / or ingredients such as preservatives, stabilizers, wetting agents, Emulsifiers, salts to increase the osmotic pressure vary, and buffer substances.

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

The dose may be given as a single dose or in several divided doses are administered throughout the day. Preferably One tablet is given daily.

An example of a typical dosage form is the the following:

tablet DDS | 100 mg Brodimoprim 200 mg PRIMOJEL (starch derivative) 6 mg Povidone K 30 (polyvinylpyrrolidone) 8 mg magnesium stearate  6 mg Total weight 420 mg

Claims (3)

1. Pharmaceutical preparation containing diaminodiphenylsulfone and 2,4-diamino-5- (4-bromo-3,5-dimethoxy-benzyl) -pyrimidine. 2. Preparation according to claim 1, characterized that the molar ratio diaminodiphenylsulfone: 2,4-diamino 5- (4-bromo-3,5-dimethoxybenzyl) -pyrimidine 1: 1 to 1:10 is. 3. Use of a preparation according to claim 1 or 2 for the treatment of leprosy and / or other mycobacteriosis.