| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 10, 1987 |
| PATENT TITLE |
Method of improving resorption of injected antibacterially active substances or combinations |
| PATENT ABSTRACT |
This invention relates to a method of improving the resorption of injected antibacterially active substances or combinations. More specifically, this invention relates to a method of increasing the resorption of an antibacterially active substance or combination which does not have optimum resorbability and which is administered parenterally into tissue, which comprises administering to a host at least one benzylamine derivative of the formula ##STR1## wherein R.sub.1 is a hydroxyl group in the 2- or 4-position or an amino group in the 2-position; R.sub.2 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; and R.sub.3 is a cyclohexyl group optionally substituted by a hydroxyl group, or a non-toxic, pharmacologically acceptable acid addition salt thereof with an inorganic or organic acid, in conjunction with said antibacterially active substance or combination. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 3, 1986 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Chemical Abstracts 77: 773u (1972). Chemical Abstracts 83: 65377m (1975). Chemical Abstracts 97: 115227z (1982). The Merck Index, 9th Ed., 1976, Merck & Co., Inc., Rahway, N.J., pp. 1260 and 1261. Chemical Abstracts 95: 73109p (1981). Chemical Abstracts 100: 12644j (1984). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A method of increasing the resorption of tylosin in an animal host, which comprises parenterally administering to said host (a) N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexlamine in combination with (b) an effective antibacterial amount of tylosin, the weight ratio of component (a) to component (b) being from about 2:100 to 12:100. 2. An antibacterial pharmaceutical composition for parenteral administration into the tissue of an animal host in need of such administration which comprises (a) N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexylamine and (b) an effective antibacterial amount of tylosin, the weight ratio of component (a) to component (b) being from about 2:100 to 12:100. 3. A method of increasing the resorption of tylosin in an animal host, which comprises parenterally administering to said host (a) N-(3,5-dibromo-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamine in combination with (b) an effective antibacterial amount of tylosin, the weight ratio of component (a) to component (b) being from about 4:100 to 12:100. 4. An antibacterial pharmaceutical composition for parenteral administration into the tissue of an animal host in need of such administration which comprises (a) N-(3,5-dibromo-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamine and (b) an effective antibacterial amount of tylosin, the weight ratio of component (a) to component (b) being from about 4:100 to 12:100. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to a method of improving the resorption of injected antibacterially active substances or combinations. More specifically, this invention relates to the use of benzylamine derivatives in combination with injected antibacterially active substances or combinations to improve the resorption of said antibacterially active substances after injection. BACKGROUND OF THE INVENTION It is known from the literature that benzylamine derivatives are useful as bronchosecretolytics in human and veterinary medicine. The best known examples of these benzylamine derivatives are N-(2-amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine hydrochloride (generic name: bromhexine) and N-(2-amino-3,5-dibromobenzyl)-trans-4-hydroxycyclohexylamine hydrochloride (generic name: ambroxol). These compounds result in a significant increase in the quantity of secretion, but it has been found that there are a decrease in the viscosity of the secretion and a reduction in the concentration of solids in the fluid of the respiratory tract and in their specific weight, which characterize the benzylamine derivatives as secretolytics. In addition, it is known from the literature that when the above-mentioned benzylamine derivatives are administered orally together with an antibiotic, particularly oxytetracycline and erythromycin, or with a sulfonamide such as sulfadiazine, there is an increase in the infiltration of these substances into the bronchial secretion. The same also applies to the body's own immunoglobulins, that is, immunoglobulins which have not been administered. However, this increase in the concentration of the contents of bronchial secretion is not caused by any increased resorption from the intestines induced by the above-mentioned benzylamine derivatives or by any delay in execretion through the kidneys, since there is no detectable increase in blood level values after oral or intravenous administration. OBJECTS OF THE INVENTION It is an object of the invention to provide a method of improving the resorption of injected antibacterially active substances or combinations. It is also an object of this invention to provide a combination of an antibacterially active substance or combination and a benzylamine derivative. It is a further object of this invention to provide a method of improving the resorption of an injected antibacterially active substance or combination by admixing said substance or combination with an effective amount of a benzylamine derivative of the formula ##STR2## wherein R.sub.1 is a hydroxyl group in the 2- or 4-position or an amino group in the 2-position; R.sub.2 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; and R.sub.3 is a cyclohexyl group optionally substituted by a hydroxyl group, or a non-toxic, pharmacologically acceptable acid addition salt thereof with an inorganic or organic acid. These and other objects of the invention will become more apparent in the discussion below. DETAILED DESCRIPTION OF THE INVENTION It has now been surprisingly found that when a benzylamine derivative of the formula ##STR3## or a non-toxic, pharmacologically acceptable acid addition salt thereof with an inorganic or organic acid is administered parenterally, the resorption of an antibacterially active substance or combination which has been administered parenterally into the tissues and which, on its own, does not have optimum resorbability, is speeded up. Thus, according to the invention, as a result of the higher blood levels with the same dosage of the antibacterially active substance or combination, better and safer therapeutic results are obtained or--if higher blood levels are not wanted--the quantity administered can be reduced by comparison with the quantity required when the substance in question is administered on its own, and consequently a significant saving is achieved. Moreover, the problem of residues is solved since the injection site for the antibacterial substances and combinations in question is usually the tissue, which contains measurable residues of these substances longest. Therefore, the present invention relates to the novel use of the benzylamine derivatives of Formula I and of the non-toxic, pharmacologically acceptable acid addition salts thereof, preferably in veterinary medicine, for increasing the resorption of antibacterially active substances or combinations which have been administered parenterally into the tissue and are not readily resorbable, preferably by parenteral administration of the benzylamine derivatives at the same time. In Formula I, R.sub.1 is a hydroxyl group in the 2- or 4-position or an amino group in the 2-position; R.sub.2 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; and R.sub.3 is a cyclohexyl group optionally substituted by a hydroxyl group. The preferred benzylamine derivatives of Formula I are, however, those compounds wherein R.sub.2 and R.sub.3 together with the nitrogen atom between them represent an N-methyl-cyclohexylamino, N-ethyl-cyclohexylamino, trans-4-hydroxy-cyclohexylamino, or cis-3-hydroxy-cyclohexylamino group. A particularly preferred benzylamine derivative of Formula I is the compound N-(3,5-dibromo-2-hydroxybenzyl)-trans-4-hydroxycyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof with an inorganic or organic acid, especially the hydrochloride salt. Examples of antibacterial substances used according to the invention, optionally in the form of the esters or salts thereof, including the following: an antibiotic of the tetracycline group, such as oxytetracycline, oxytetracycline hydrochloride, rolitetracycline, or doxycycline; a difficultly soluble antibiotic of the .beta.-lactam group, such as procaine penicillin, benethamine penicillin, benzathine penicillin, the benzathine salts of oxacillin, cloxacillin, or ampicillin, and of the cephalosporins; erythromycin and the derivatives thereof, such as 9-deoxy-11-deoxy-9,11-{imino-[2-(2-methoxyethoxy)-ethylidene]-oxy}-(9F)-er ythromycin, erythromycin lactobionate, erythromycin ethylsuccinate, erythromycin glucoheptonate; spiramycin, spiramycin adipate; tylosin, tylosin tartrate; oleandomycin; chloramphenicol, chloramphenicol succinate; thiamphenicol, or thiamphenicol glycinate; a sulfonamide or a sodium salt thereof, such as sulfadiazine, sulfadoxine, sulfamethoxazole, sulfadimethoxine, sulfadimidine, or sulfathiazole; a sulfonamide together with an agonist such as trimethoprim, for example, the sulfdimidine/sulfathiazole/trimethoprim combination, or the sodium salts thereof; and, optionally, the delayed-release forms thereof. The invention further relates to the new combinations which are suitable for parenteral administration into the tissue, containing a benzylamine derivative of Formula I and an antibacterial substance or combination which, on its own, does not have optimum resorbability, together with one or more conventional inert diluents or carriers, preferably those forms which are suitable for intramuscular administration. The preferred combinations are those containing (1) a benzylamine derivative of Formula I wherein R.sub.1 represents a hydroxyl group and R.sub.2 and R.sub.3 together with the nitrogen atom between them are as defined above, but preferably represent the N-ethyl-cyclohexylamino, trans-4-hydroxycyclohexylamino, or cis-3-hydroxy-cyclohexylamino group, although especially preferably R.sub.1 in the 2-position represents a hydroxyl group and R.sub.2 and R.sub.3 together with the nitrogen atom between them represent the trans-4-hydroxycyclohexylamino group, and (2) one of the above-mentioned antibacterial substances or combinations. A particularly preferred embodiment of the invention is directed to a combination of (1) N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof and (2) a delayed-release oxytetracycline preparation, a delayed-release oxytetracycline hydrochloride preparation, rolitetracycline, or doxycycline; a difficultly soluble antibiotic of the .beta.-lactam group, such as procaine penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt of oxacillin, cloxacillin, or ampicillin, and of the cephalosporins, erythromycin or a derivative thereof, such as 9-deoxy-11-deoxy-9,11-{imino-[2-(2-methoxyethoxy)-ethylidene]-oxy}-(9F)-et hromycin, erythromycin lactobionate, erythromycin ethylsuccinate, erythromycin glucoheptonate; spiramycin, spiramycin adipate; tylosin, tylosin tartrate; oleandomycin; thiamphenicol, or thiamphenicol glycinate, or a sulfonamide or a sodium salt thereof, such as sulfadiazine, sulfadoxine, sulfamethoxazole, sulfadimethoxine, sulfadimidine, or sulfathiazole, or a sulfonamide combination with an agonist such as trimethoprim, for example, the sulfadimidine/sulfathiazole/trimethoprim combination, or a combination of (1) N-(2-amino-3,5-dibromo-benzyl)-trans-4-hydroxy-cyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof and (2) an antibiotic of the tetracycline group, such as oxytetracycline, oxytetracycline hydrochloride, rolitetracycline, or doxycycline, a difficultly soluble antibiotic of the .beta.-lactam group, such as procaine penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt of oxacillin, cloxacillin, or ampicillin, and of the cephalosporins, erythromycin or one of the derivatives thereof, such as 9-deoxy-11-deoxy-9,11-{imino-[2-(2-methoxyethoxy)-ethylidene]-oxy}-(9F)-er ythromycin, erythromycin lactobionate, erythromycin ethylsuccinate, erythromycin glucoheptonate; spiramycin, spiramycin adipate; tylosin, tylosin tartrate; oleandomycin; chloramphenicol, chloramphenicol succinate; thiamphenicol, or thiamphenicol glycinate, or a sulfonamide or a sodium salt thereof, such as sulfadiazine, sulfadoxine, sulfamethoxazole, sulfadimethoxine, sulfadimidine, or sulfathiazole, or a combination of a sulfonamide with an agonist such as trimethoprim, for example, the sulfadimidine/sulfathiazole/trimethoprim combination, or, optionally, a corresponding delayed-release form. The following combinations are, however, particularly preferred: (a) combinations of (1) N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof or N-(3,5-dibromo-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof with (2) erythromycin, erythromycin lactobionate, erythromycin ethylsuccinate, erythromycin glucoheptonate, 9-deoxy-11-deoxy-9,11-{imino-[2-(2-methoxyethoxy)-ethylidene]oxy}-(9F)-ery thromycin, tylosin, tylosin tartrate, spiramycin, spiramycin adipate, oleandomycin, benethamine penicillin, benzathine penicillin, ampicillin, oxacillin, cloxacillin, rolitetracycline, doxycycline, or a salt thereof, or a sulfonamide or a salt thereof, optionally in combination with trimethoprim, and (b) combinations of (1) N-(3,5-dibromo-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamine or a non-toxic, pharmacologically acceptable acid addition salt thereof with oxytetracycline or a salt thereof, chloramphenicol, chloramphenicol succinate, thiamphenicol, or thiamphenicol glycinate. To demonstrate the efficacy of the invention, the resorption-promoting effect of the following benzylamine derivatives: A=N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexylamine hydrochloride; B=N-(2-amino,3,5-dibromo-benzyl)-trans-4-hydroxy-cyclohexylamine hydrochloride; and C=N-(3,5-dibromo-2-hydroxy-benzyl)-trans-4-hydroxycyclohexylamine hydrochloride, was tested in the following manner: Cattle, pigs, and sheep (with the same ten animals per group) were treated once with only the antibacterial substance or combination in question and once with the combination of the benzylamine derivative together with the same antibacterial substance or combination, administered by intramuscular route. The two treatments were given at an interval of eight days to ensure that the substance or substances administered in the first treatment had been totally eliminated. The order of treatment varied, that is, in some cases the antibacterial substance or combination (control) was administered first and in some cases the combination including the benzylamine derivative was administered first (test group). In some cases the tests were carried out as "cross-over" tests, that is, on the first occasion five animals were given the antibacterial substance or combination while five animals were given the combination including the benzylamine derivative. When the test was repeated eight days later, the treatments were reversed. Blood samples were taken during the day at one and two hour intervals and after 24 hours, and in some cases after 32 hours as well, and in two cases (delayed-release preparations) after 48 and 72 hours also. The levels of antibiotics or sulfonamide in the blood serum were determined using conventional microbiological methods with test pathogens specific to each substance. In each case, the areas under the blood level curves obtained were compared, as an overall measurement of antibacterial activity. This comparison showed increases in blood level for the combination of benzylamine derivatives with the antibacterial substance or combination in question, compared with the control group in question, as is shown in the following table: TABLE 1 __________________________________________________________________________ Increase in Antibacterially Active Benzylamine Blood Level Substance or Combination Derivative Type of (in %, compared (Dosage: mg/kg of body weight) (Dosage: mg/kg) Animal with control) __________________________________________________________________________ Erythromycin 10 A 0.3 i.m. cattle 16.1 10 C 0.6 i.m. cattle 21.4 10 A 0.6 i.m. pig 59.1 10 A 1.2 i.m. pig 31.4 Erythromycin derivative 10 A 1.2 i.m. pig 15.3 10 C 1.2 i.m. pig 45.4 Oxytetracycline hydrochloride 10 C 0.6 i.m. cattle 16.3 Delayed-release oxytetracycline 20 A 0.6 i.m. pig 109.5 preparation* 20 C 1.2 i.m. pig 80.0 Tylosin 15 A 0.3 i.m. cattle 33.0 15 C 0.6 i.m. cattle 23.5 Tylosin 10 A 0.6 i.m. pig 19.3 10 A 1.2 i.m. pig 30.3 10 C 0.6 i.m. pig 30.5 10 C 1.2 i.m. pig 26.1 Sulfadimidine/- 24 A 0.6 i.m. pig 29.6 Sulfathiazole/- 24 A 1.2 i.m. pig 25.1 Trimethoprim 24 C 0.6 i.m. pig 29.9 Combination 24 C 1.2 i.m. pig 20.3 (10:10:4) __________________________________________________________________________ *Blood level monitored for 72 hours; after 48 hours it is 0.13 .mu.g/ml for the control but 0.35 .mu.g/ml for the test group; after 72 hours, it is 0.00 .mu.g/ml for the control but still 0.19 .mu.g/ml for the test group. The benzylamine derivatives of Formula I used according to the invention and the non-toxic, pharmacologically acceptable acid addition salts thereof with inorganic or organic acids are well tolerated. For example, the acute toxicity (LD.sub.50) in the mouse is >400 mg/kg i.p. for Compound A, 268 mg/kg i.p. for Compound B, and >800 mg/kg i.p. for Compound C. In view of the above-mentioned biological characteristics, the benzylamine derivatives of Formula I and the non-toxic, pharmacologically acceptable acid addition salts thereof are, as mentioned above, suitable for improving the resorption of antibacterial substances or combinations administered parenterally into the tissue and thus help to improve and guarantee the success of the therapy. The dosage is appropriately above 0.1 mg/kg, preferably between 0.2 and 2.0 mg/kg, while in solutions the upper limit is set by the solubility of the benzylamine derivative used. For example, in water Compounds A to C have the following maximum solubilities: ______________________________________ Compound Maximum Solubility ______________________________________ A 0.2 to 5.0 mg/cm.sup.3 B 16.6 mg/cm.sup.3 C 0.1 to 1.0 mg/cm.sup.3 ______________________________________ dependent upon the pH, in the acid range. Obviously, higher concentrations can be achieved in oily carriers, dependent upon the solubility in oil of the benzylamine derivative and also when the benzylamine derivative is suspended in suitable carriers in which it is insoluble or not sufficiently soluble. Moreover, the benzylamine derivative is preferably administered simultaneously with a therapeutic dose of the antibacterial substance or combination which is to be used. Examples of individual doses include the following: TABLE 2 ______________________________________ Active Substance Dose ______________________________________ oxytetracycline 5 to 30 mg/kg rolitetracycline 15 to 50 mg/kg doxycycline 2 to 5 mg/kg erythromycin 5 to 20 mg/kg 9-deoxy-11-deoxy-9,11-{imino- 5 to 20 mg/kg [2-(2-methoxyethoxy)-ethylidene]- oxy}-(9F)-erythromycin spiramycin 10 to 50 mg/kg tylosin 5 to 20 mg/kg chloramphenicol 10 to 50 mg/kg thiamphenicol 10 to 50 mg/kg sulfadiazine 15 to 50 mg/kg sulfadiazine/sulfathiazole/- 15 to 30 mg/kg trimethoprim sulfadoxin/trimethoprim 15 to 30 mg/kg procaine penicillin 2000 to 20,000 I.U./kg benzathine penicillin 6000 to 25,000 I.U./kg ampicillin 2 to 15 mg/kg oxacillin 5 to 15 mg/kg cloxacillin 5 to 15 mg/kg oxytetracycline hydrochloride 2 to 25 mg/kg ______________________________________ Examples of suitable forms for administration include injectable preparations of an aqueous, water-miscible or oily nature in which the antibacterial substances in question are dissolved or suspended in the desired concentration. The same also applies to the benzylamine derivatives or the salts thereof, depending on their solubility, while the same preparation may contain one substance in solution and the other in suspension. In those cases where an aqueous solution is desired but is not practicable due to insufficient stability, such as of the antibiotic, the injectable combination is prepared shortly before administration by dissolving or suspending the dry substance in the solvent containing the benzylamine derivative. The benzylamine derivatives of Formula I and the nontoxic, pharmacologically acceptable acid addition salts thereof used according to the invention are known from the literature. See, for example, U.S. Pat. Nos. 3,336,308, 3,536,713, and 4,113,777, incorporated herein by reference. The compounds of Formula I may be obtained in the form of their non-toxic, pharmacologically acceptable acid salts after reaction with inorganic or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulfuric, methylsulfuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p-toluenesulfonic, methanesulfonic, and amidosulfonic acid. |
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