DE3034975C2 - Drug combination used to treat infectious respiratory diseases - Google Patents

Description

Ampicillin + 23%

Erythromycin + 27%
Amoxycillin + 27%

In addition, it should be mentioned here that the active substances used according to the invention are practically non-toxic, for example the DL ₅₀ for on the mouse

Ambroxol 2720 mg / kg po,

Doxycycline 1650 mg / kg po,

Cephalexin 1600-6200 mg / kg po,

Ampicillin 3340 mg / kg po,

Erythromycin 3000 mg / kg p.o. and

Amoxycillin> 1000 mg / kg p.o.

The drug according to the invention is administered to adults in a single dose before 100-750 mg Antibiotic + 2-100 mg, but preferably 7.5-75 mg, Ambroxol Ibis applied 4 times a day. The daily dose is therefore 0.1 to 3.0 g antibiotic + 7.5 to 150 mg ambroxol. In children the respective dose is % to 1/2 of the adult dose. In adults, for example, the single dose is consisting of a drug combination according to the invention

from ambroxol / doxycycline

75 mg ambroxol + 100 mg doxycycline once a day (but double the dose on the 1st day of treatment),

from Ambroxol / Cephalexin

15-30 mg AmbroxoJ + 250-500 mg Cephalexin 2-4 X daily,

from ambroxol / ampicillin

15-30 mg ambroxol + 250-500 mg ampicillin 2-4 times a day,

from ambroxol / erythromycin

15-30 mg ambroxol + 300-600 mg erythromycin 2-4 times a day,

from ambroxol / amoxycillin

15-30 mg ambroxol + 500-750 mg amoxycillin 2-4 times a day.

The medicament combination according to the invention can be used for medical use with the aid of conventional galenic auxiliaries such as B. lactose, mannitol, corn starch, methyl cellulose, hydroxyethyl cellulose, Polyethylene oxide, highly dispersed aluminum oxide, magnesium aluminum silicate, magnesium oxide, magnesium stearate, Sodium lauryl sulfate, sodium citrate, tartaric acid, sodium pyrosulfite, dioctyl sodium sulfosuccinate, p-Hydroxybenzoic acid methyl ester, sodium salt, p-Hydroxy-benzoic acid propyl ester, sodium salt, saccharin sodium, Flavorings and defoamers in the usual galenic preparation forms such as tablets, Film-coated tablets, oblong tablets, coated tablets or capsules as well as their sustained-release forms, ampoules, dry ampoules, Incorporate dry granules or dry juices.

The following examples are intended to explain the invention in more detail:

20 Example 1

Film-coated tablets of 30 mg Ambroxol + 500 mg Cephalexin composition

The film-coated tablet contains:

Ambroxol (1) 30.0 mg

Cephalexin (2) 500.0 mg

Milk sugar (3) 100.0 mg

Corn starch sep. (4) 80.0 mg

maiaaiaiiic g & u. ν. ν uvj «m &

Polyvinylpyrrolidone (5) 16.0 mg

Magnesium stearate (6) 4.0 mg

730.0 mg

35 Manufacturing

1, 2, 3 and 4 are mixed and moistened with a 10% solution of 5 in 70% ethanol. the wet mass is beaten through a sieve with a mesh size of 1.5 mm, dried and passed through the same sieve given. Then 6 is mixed in and tablets are made from the mixture on a tablet press manufactured.

coating

A coating of a solution of ethyl cellulose in ethanol is applied to the compacts. Through this Film coating increases the weight by 1.5%.

Tablet weight: 730 mg
Stamp: 13 mm

Example 2

Dry granules for juice at 15 mg ambroxol + 250 mg cephalexin per 5 ml

Composition ml contain:

Ambroxol 15.0 mg

Cephalexin 250.0 mg

Sodium citrate 50.0 mg, dioctyl sodium sulfosuccinate 1.0 mg

Polyvinylpyrrolidone 50.0 mg

MägneSiurfimürniinüfnsiiikai 10.0 ITIg

Saccharin Sodium 5.0 mg

p-Hydroxy-benzoic acid methyl ester, sodium salt 6.0 mg

Propyl p-hydroxy-benzoate, sodium salt 1.5 mg

Powder flavor 10.0 mg

Silicone defoamer 0.25 mg

Mannitol ad 2.0 g

production method

Granulating solution:

Dioctyl sodium sulfosuccinate, silicone defoamers and a subset of polyvinylpyrrolidone dissolved or dispersed in an amount of water required for granulation.

Powder mix:

With the exception of the aroma, the remaining components are mixed homogeneously.

Granulation:

The powder mixture is evenly moistened with the granular liquid. The wet mass is on Sieved max. 2 mm, dried and sieved again.

Final mix:

The aroma is added to the granulate and distributed homogeneously.

40 g granules + 75 ml water result in approx. 100 ml ready-to-use juice.

ml (= 1 dose) contain 15 mg ambroxol and 250 mg cephalexin.

Example 3

Dry granules for drops of 15 mg ambroxol + 250 mg cephalexin per 1 ml

ml contains:

Ambroxol 15.0 mg

Cephalexin 250.0 mg

Sodium citrate 30.0 mg

Methyl cellulose 2.0 mg

Polyethylene oxide 2.0 mg

p-Hydroxy-benzoic acid methyl ester, sodium salt 1.2 mg

Propyl p-hydroxy-benzoate, sodium salt 0.3 mg

Powder flavor 3.0 mg

Silicone defoamer 0.05 mg

Icing sugar ad 0.4 g

production method

Granulating solution:

Polyethylene oxide, silicone defoamer and a subset of methyl cellulose are in one for the Granulation required amount of water dissolved or dispersed. The rest of the production is carried out in the same way Example 2.

g granulate + 75 ml water result in approx. 100 ml ready-to-use drip suspension. ml (a I dose) contains 15 mg ambroxol and 250 mg cephalexin.

Example 4

Oblong tablets of 15 mg ambroxol + 500 mg ampicillin

Tablet contains:

Ambroxol (1) 15.0 mg

Ampicillin (2) 500.0 mg

Powdered milk sugar (3) 380.0 mg

Corn starch sep. (4) 180.0 mg

Polyvinylpyrrolidone (5) 21.0 mg

Magnesium stearate (6) 4.0 mg

1100.0 mg

Manufacturing

1, 2, 3 and 4 are mixed and moistened with a 10% solution of 5 in 70% ethanol. the fcuclitc mass is anaiog example i Weiierbehandeii.

Tablet weight: 1100 mg

Shape: 8x17 mm oblong

Example p

Ampoules of 15 mg ambroxol + 500 mg ampicillin per 5 ml

Solution ampoule contains: ₅ ι

Ambroxol 15.0 mg

Sodium hydroxide solution 2.5 mg

Tartaric acid 5.0 mg

Polyethylene oxide 75.0 mg 4

Water for injections ad 5 ml IO &,

Drying ampoule ||

Ampicillene Sodium 500.0 mg

$ 15,

Manufacturing

Dissolve ambroxol and tartaric acid while stirring, then dissolve polyethylene oxide and adjust to pH 4.0 with sodium hydroxide solution .

to adjust. The solution is sterile-filtered through a membrane filter, filled into ampoules and sterile-filtered at 120 ^° C. for 10 minutes. 20 §

> ■ / ■ example 6 %;

Ampoules of 75 mg ambroxol + 100 mg doxycycline per 5 ml

25th 30th

Manufacturing

Dissolve substances one after the other in water and filter them through a membrane filter. When filling into ampoules gassing with nitrogen. Solution cannot be sterilized.

Example 7

40

Capsules of 75 mg ambroxol + 100 mg doxycycline

1 capsule contains:

Spray pellets 20%, consisting of wax mixture and active ingredient *) 375.0 mg

Strength 50.0 mg 45

Milk sugar 50.0 mg

fumed silica 7.0 mg

Magnesium stearate 8.0 mg

490.0 mg

50

*) The active ingredient is suspended in the melt heated to 70 ° C using an Ultra-Turrax and in a suitable Sprayed plant.

Manufacturing

55

The mixture is filled on a suitable capsule machine with a tablet loading station is equipped, in gelatin capsules size O long containing 100 together with a coated 6 mm core mg of doxycycline and usual tableting excipients.

Capsule weight: 490 mg 60

1 ampoule contains: ad 100.0 mg Doxycy el i n-hydrochloride 75.0 mg Ambroxol 9.1 mg Magnesium oxide 500.0 mg Sodium Pyrosul fit 500.0 mg Polyethylene oxide 5 ml Water for injections

Example 8

Tablets of 30 mg Ämbroxol + 600 mg erythromycin

₅ 1 tablet contains:

Ambroxol (1) 30.0 mg

Erythromycin (2) 600.0 mg

Powdered milk sugar (3) 380.0 mg

Corn starch sep. (4) 265.0 mg

ίο polyvinylpyrrolidone (5) 21.0 mg

Magnesium stearate (6) 4.0 mg

1300.0 mg

15 Manufacture

1,2,3 and 4 are mixed and moistened with a 10% solution of 5 in ethanol. The wet mass is treated further as in Example 1.

20 tablet weight: 1300 mg

Shape: 8.5 18 mm oblong

Example 9

25 children's tablets of 7.5 mg Ämbroxol + 150 mg erythromycin

1 tablet contains:

Ambroxol (1) 7.5 mg

Erythromycin (2) 150.0 mg

30 powdered milk sugar (3) 95.0 mg

Corn starch sep. (4) 66.25 mg

Polyvinyl pyrrolidone (5) 5.25 mg

Magnesium stearate (6) 1.0 mg

325.0 mg

'* Manufacture

1,2,3 and 4 are mixed and moistened with a 10% solution of 5 in ethanol. The wet mass 40 is further treated analogously to Example 1.

65 Production takes place analogously to Example 3.

40 g granules + 75 mil water result in approx. 100 ml ready-to-use drip suspension. ImI (Al dose) contains 15 mg of ambroxol and 300 mg of erythromycin base equivalent.

Tablet weight: 325 mg Example 10 30.0 mg 3.0 mg Punch diameter: 10 mm for drops to 15 mg ambroxol + 300 m 1.0 mg 3.0 mg 2.0 mg 0.05 mg Dry granulate 15.0 mg 1.0 mg ad 0.4 g 1 ml of drop solution contains: Erythromycin base equivalent 300.0 mg p-Hydroxy-benzoic acid methyl ester, sodium salt 1.2 mg Manufacturing Ambroxol Sodium citrate Propyl p-hydroxy-benzoate, sodium salt 0.3 mg Sodium lauryl sulfate Polyvinyl pyrrolidone Methyl cellulose Powder flavor Sodium saccharine Silicone defoamer powdered sugar

Example 11
Dry granules for juice at 30 mg ambroxol + 600 mg erythromycin per 5 ml

ml contain:

Ambroxol 30.0 mg

Erythromycin base equivalent 600.0 mg

Sodium citrate 100.0 mg

Hydroxyethyl cellulose 15.0 mg

Magnesium aluminum silicate 15.0 mg

Alumina 15.0 mg

Saccharin Sodium 4.0 mg

p-Hydroxy-benzoic acid methyl ester, sodium salt 6.0 mg

Propyl p-hydroxy-benzoate, sodium salt 1.5 mg

Powder flavor 10.0 mg

Silicone defoamer 0.15 mg

Icing sugar ad 2.0 g

Manufacturing

10 15th 20th

In contrast to Example 2, a portion of the hydroxyethyl cellulose is used here instead of polyvinylpyrrolidone dissolved in water together with silicone defoamer. Otherwise, the production is analogous to the example 2.

g granulate + 75 ml water make approx. 100 ml ready-to-use juice.

5 ml (= 1 dose) contain 30 mg ambroxol and 600 mg erythromycin base equivalent. 25th

Example 12

Tablets of 15 mg ambroxol + 750 mg amoxycillin

Tablet contains:

Ambroxol

Amoxycillin

Milk sugar

Corn starch sep.

Polyvinyl pyrrolidone

Magnesium stearate

(D
(2)
(3)
(4)
(5)
(6)

15.0 mg 750.0 mg 400.0 mg 305.0 mg

25.0 mg 5.0 mg

1500.0 mg

Manufacturing

1,2,3 and 4 are mixed and moistened with a 10% solution of 5 in ethanol. The wet mass is treated further as in Example 1.

30th

40 45

Tablet weight:
Shape:

1500 mg

8 X 17 mm oblong.

50

55

Claims (1)

Claim: Medicines for the treatment of infectious respiratory diseases containing erythromycin, doxycycline, Cephalexin, ampicillin or amoxycillin, characterized in that it also contains trans-4 - [(2-amino-3,5-dibromobenzyl) -amino] cyclohexanol or contains its physiologically acceptable acid addition salt In British patent i 1 78 034 the compound trans-4 - [(2-amino-3,5-dibromobenzyl) amino] -cyclohexanol is used and their physiologically compatible acid addition salts with inorganic and organic Acids described, which have expectorant properties. The above compounds, in particular However, the hydrochloride (generic name: Ambroxol) are therefore used to treat acute and chronic problems Respiratory diseases associated with pathologically altered secretion formation, as well as in the Intensive care medicine used to avoid pulmonary complications. In the fight against bacterial diseases of the respiratory tract antibiotics such. B. Erythromycin, Doxycycline, Oxytetracycline, Chloramphenicol, Cephalexin, Ampicillin and Amoxycillin, proven. _s Surprisingly, it has now been found that with simultaneous administration of erythromycin, doxycycline, Cephalexin, ampicillin and amoxycillin and of trans-4 - [(2-amino-3,5-dibromobenzyl) -amino] cyclohexanol or the physiologically acceptable acid addition salts of which the bronchopulmonary antibiotic concentrations of the antibiotic used are increased by more than 20%. The ones that can be achieved with the new combination Antibiotic active levels thus guarantee a therapeutic success even in severe acute clinical pictures. It is of particular importance here, however, that even after the acute disease state has subsided with a relatively low dose of antibiotics, a sufficiently high level of antibiotic action in the bronchopulmonary region Area can be sustained, so recurrences are extremely rare. The subject of the present invention is thus a new synergistically acting drug combination for the treatment of infectious respiratory diseases, containing erythromycin, doxycycline, cephalexin, Ampicillin and amoxycillin and trans-4 - [(2-amino-3,5-dibromobenzyl) amino] cyclohexanol or its physiological compatible acid addition salts in addition to optionally one or more inert carriers and / or diluents. For example, the influence of trans-4 - [(2-amino-3,5-dibromobenzyl) amino] cyclohexanol hydrochloride on the bronchopulmonary antibiotic concentrations of ampicillin, erythromycin and amoxycillin examined as follows: All substances were administered once to Wistar rats weighing between 300 and 400 g, once via an esophageal probe. The dose of the antibiotics to be examined was 50 mg / kg each and that of ambroxol 10 mg / kg each. The rats were fed with pellets from Cargill Dieta RR and water; the animals were kept at a temperature between 20 and 24 ^° C. under test conditions. In each case groups of 20 rats were compared with the antibiotic to be examined + ambroxol treated a control group (same antibiotic without ambroxol). The animals were each 90 minutes killed after substance administration and both lungs removed. The lungs were homogenized and at Centrifuged 5000 r. The respective concentration of the antibiotics was determined microbiologically in the supernatant. The administration of Ambroxol caused the measured antibiotic levels to rise as follows: