JPH0234922B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a respiratory disease therapeutic agent containing a respiratory disease therapeutic agent and a specific hydroxycyclohexylamine or a salt thereof. Respiratory diseases, such as acute tract infections, acute bronchitis, chronic bronchitis, bronchopneumonia, bronchiectasis, diffuse panbronchiolitis, pneumonia, pulmonary suppuration,
One indicator of the usefulness of drugs such as antibiotics for pulmonary tuberculosis is the intralesional concentration in the airways and lungs at the time of antibiotic administration.Clinically, the intralesional concentration is higher than the antibiotic concentration in sputum. is estimated.
The concentration of antibiotics in the airways and lung lesions is
It is known that this can be increased by co-administering bromhexine hydrochloride, an airway mucolytic agent represented by the following formula, during administration. For example, bromhexine hydrochloride can be used to treat chronic bronchitis.
Twice (8 times each) for patients with bronchiectasis and bronchopneumonia.
mg) After oral administration, administration of ampicillin, cephalothin, cephalolidine, and oxytetracycline increases the antibiotic concentration in the patient's sputum approximately twice, and in some cases even more, than when antibiotics are administered alone. It has been reported that there has been an increase in
1972; Pharmacotherapy, Volume 8, No. 2, Nos. 33-38
p. 1975). It is also known that when bromhexine hydrochloride and rifampicine were administered orally to rats at the same time, the intraalveolar concentration of the antibiotics increased by 23% compared to when they were used alone (Rossi et al.
Rass, Med. Sper. vol. 21, pp. 3-8, 1974). Combination drugs of bromhexine hydrochloride and ampicillin, amoxicillin, oxytetracycline, or erythromycin are already in clinical use in West Germany, Spain, and other countries. On the other hand, metabolites of bromhexine such as trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol (ambroxol) and 6,8-dibromo-3-trans-4
-Hydroxycyclohexyl-1,2,3,4-
The following general formula () containing tetrahydroquinazoline
Hydroxycyclohexylamine represented by is superior to bromhexine. [In formula (), R ₁ represents hydrogen or a methyl group, and R ₂ represents hydrogen. Or again,
R ₁ and R ₂ together represent a single bond. ] It is known to have an effect of promoting the secretion of airway secretions and lung surface active substances, and is also excellent in expectorant effects and improving effects on lung function. Therefore, it is expected that if the compound of general formula () is used in combination with a drug to treat respiratory diseases such as antibiotics, the concentration of the drug in the airways and lung lesions will be higher than when bromhexine is used. and research has been conducted. However, in experiments using rats, when the antibiotics ampicillin, erythromycin, or amoxicillin were used in combination with ambroxol hydrochloride, the concentration of antibiotics in the alveoli was 23% higher than when they were used alone.27 % and increased by 27%, which is not significantly different from that of bromhexine hydrochloride (Wiemeyer, Drug Res. 31
(1), 6, pp. 974-976, 1981). The present inventors have conducted extensive research on the combined effects of various known expectorants or airway mucolytic agents and respiratory disease therapeutics, and have found that hydroxycyclohexylamines represented by the general formula (), in particular, discovered that hydroxyl is more effective at secreting drugs into the airways and alveoli than, for example, bromhexine, carbocysteine, or serratiopeptidase, and that this effect is best when both are administered simultaneously. The present invention was completed by confirming that an excellent therapeutic agent for respiratory diseases can be obtained by using cyclohexylamines and a therapeutic agent for respiratory diseases as a combination drug. That is, the present invention is a respiratory disease therapeutic agent containing a respiratory disease therapeutic drug and a hydroxycyclohexylamine represented by the following general formula () or an acid addition salt thereof. (In formula (), R ₁ represents hydrogen or a methyl group, and R ₂ represents hydrogen. Alternatively,
R ₁ and R ₂ together represent a single bond. ) Specific examples of hydroxycyclohexylamines represented by the general formula () include trans-4
- [(2-amino-3,5-dibromobenzyl)
Amino]cyclohexanol (ambroxol), N-(trans-P-hydroxy-cyclohexyl)-N-methyl-(2-amino-3,5
-dibromo-benzyl)-amine, N-(trans-m-hydroxy-cyclohexyl)-(2-
Amino-3,5-diglomo-benzyl)-amine, N-(trans-m-hydroxy-cyclohexyl)-N-methyl-(2-amino-3,5-
dibromo-benzyl)-amine, N-(trans-O-hydroxy-cyclohexyl)-(2-amino-3,5-dibromo-benzyl)-amine,
N-(trans-O-hydroxy-cyclohexyl)-N-methyl-(2-amino-3,5-dibromo-benzyl)-amine and each cis form, and 6,8-dibromo-3-trans-4
-Hydroxycyclohexyl-1,2,3,4-
Tetrahydroquinazoline, 6,8-dibromo-3
-Trans-3-hydroxycyclohexyl-
1,2,3,4-tetrahydroquinazoline, 6,
Examples include 8-dibromo-3-trans-2-hydroxycyclohexyl-1,2,3,4-tetrahydroquinazoline and the respective cis forms. Particularly preferred is ambroxol. These hydroxycyclohexylamines can be converted into pharmaceutically acceptable acid addition salts by known methods, eg, by reaction with an alcoholic solution of an inorganic or organic acid in equivalent amounts. Suitable acids include hydrochloric, hydrobromic, sulfuric, phosphorous, lactic, citric, tartaric or maleic acid. The therapeutic drug for respiratory diseases in the present invention may be any drug that acts on the trachea or lungs, for example,
Antibiotics, anti-inflammatory agents, antiallergic agents, chemotherapeutic agents, and anticancer agents are available, but antibiotics effective against respiratory infections are preferred, and among these, rifampicin is the most suitable. If ambroxol and rifampicin are used as a combination, a particularly excellent therapeutic agent for respiratory infections can be obtained. In the present invention, the dosage of the drug for treating respiratory diseases varies depending on the drug, but for example, when the drug is rifampicin, the dose for adults is 50 to
500mg is appropriate. The compound of general formula () is 10
~200mg is appropriate. In the present invention, both are used as a combination, but the dosage form may be any form such as tablets, granules, powders, capsules filled with granules or powder, syrups, and injections. Capsules are particularly preferred. Known techniques can be employed for formulation. Hereinafter, the present invention will be explained in detail with reference to Examples. Example 1 Rifuampicin (RFP) was administered to three patients with pulmonary tuberculosis.
Antibiotic concentrations in serum, urine, and sputum were measured after oral administration of 450 mg alone and in combination with 15 mg of ambroxol hydrochloride. Subtilis as a test bacterium for concentration measurement
ATCC6633 and Triptoroy Agar (BBL) as medium
This was carried out using the thin layer cup method using Nippon Chemical's 1. The relationship between the concentration of rifampicin in serum and the elapsed time after administration is shown in Figures 1 to 3. Tables 1 to 3 show the relationship between the concentration of rifampicin in sputum and the elapsed time after administration. In addition, in the case of sputum, 1/5 times the amount of acetylcysteine was added thereto, and the mixture was stirred with a vibrator at room temperature for 15 minutes, and the concentration of rifampicin was measured. It can be seen that when rifampicin and ambroxol hydrochloride are used together, the amount of sputum increases and the concentration of rifampicin in the sputum increases 4 to 6 times compared to the case when rifampicin is used alone. This indicates that the therapeutic agent of the present invention is effective in treating respiratory infections. Figures 4 to 6 show the amount of rifampicin excreted in the urine. When used together, the amount of rifampicin excreted increased by 20 to 30%, which indicates that the combined use of ambroxol hydrochloride increases the absorption of rifampicin from the intestinal tract. In addition, Figures 1 and 4 are for TM, a 43-year-old female;
Figures 3 and 5 are SM 37-year-old male, Figures 3 and 6 are
KO is a 46-year-old male patient. Example 2 225 parts of rifampicin and ambroxol hydrochloride
60 parts were mixed uniformly. Then, capsules having the following composition were prepared. 1 capsule {rifampicin 225mg ambroxol hydrochloride 60mg}

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FIGS. 1 to 3 are diagrams showing changes in rifampicin concentration in patient serum over time. Fourth
Figures 6 to 6 are diagrams showing changes in the amount of rifampicin excreted in the patient's urine (ratio to the dose) over time.

Claims (1)

[Scope of Claims] 1. A therapeutic agent for respiratory diseases, which contains a therapeutic agent for respiratory diseases and a hydroxycyclohexylamine represented by the following general formula () or an acid addition salt thereof. [In formula (), R ₁ represents hydrogen or a methyl group, and R ₂ represents hydrogen. Or again,
R ₁ and R ₂ together represent a single bond. 2. The therapeutic agent for respiratory diseases according to claim 1, wherein the therapeutic agent for respiratory diseases is rifampicin. 3 Hydroxycyclohexylamine of general formula () is trans-4-[(2-amino-3,
The therapeutic agent for respiratory diseases according to claim 1, which is 5-dibromobenzyl)amino]cyclohexanol. 4 Claim 1 whose dosage form is a capsule
A therapeutic agent for respiratory diseases described in Section 1.