DD154802A5 - PROCESS FOR PREPARING AN INJECTABLE PHARMACEUTICAL PREPARATION OF PROLONGED EFFECT - Google Patents

Abstract

The invention relates to the preparation of a prolonged-duration injectable pharmaceutical preparation comprising from 1 to 35 parts by weight of 3- (4-aminophenylsulfonamido) -5-methylisoxazole and from 0.2 to 7 parts by weight of 2,4-diamino-5- (3,4,5 -trimethoxybenzyl) -pyrimidine in a weight ratio of 5: 1, further 50 to 97 parts by volume of N, N-Dimethylessigsaeureamid, 1 to 48 parts by volume of polyethylene glycol, 2 to 4 parts by volume Aethyloleat and 0 to 10 parts by weight of additive or additives contained. The injectable pharmaceutical preparation prepared according to the invention also has a therapeutic effect 24 hours after the administration. The ph value of the solution is close to the ph value of the blood.

Description

14 231 55

225492

Procedure for. Preparation of an Injectable Pharmaceutical Preparation with Extended Duration of Action

Field of application of the invention:

The invention relates to a process for the preparation of an injectable pharmaceutical preparation with prolonged warming.

The preparation according to the invention can be used in veterinary medicine to treat infections of the gastrointestinal tract, the respiratory system, the Urogenitalien and wounds.

Characteristic of the known technical solutions:

It is known that the effect of the various sulfonamides, for example, of the sulfamethoxazole is potentiated by the trimethoprim (GB-P 1 176 395). The cited publication describes injectable solutions containing salts formed with bases, which solutions can reach a pH of 11. The basic reaction can lead to tissue damage at the site of the injection, thereby making limited use of these known injectable solutions can be.

- 2 -

-Z-

2'Z ο 4 az

Attempts were made to eliminate the disadvantages associated with using the basic solution by adjusting the pH of the pharmaceutical preparation to 4 to 6 by adding an acid (GB-P 1 469 521). However, working with an acidic pH is also unfavorable in intravenous injections because the pH of 4 to 6 is quite remote from the physiological value of the blood (7.35 to 7.45).

A common feature of the known injectable sulfonamide Lind trimethoprim containing pharmaceutical preparations is that the therapeutic effect ceases 6 to 8 hours after injection. Thus, the therapeutic concentration level required for healing can only be secured by a further injection.

Target aer invention:

The aim of the invention is therefore to remedy the disadvantages mentioned, ie the provision of an injectable pharmaceutical preparation consisting of sulfamethoxazole and trimethoprim in a weight ratio of 5: 1, which ensures a prolonged therapeutic effect, wherein the pH in the vicinity the pH of the blood is.

The genius of the creature is de

The new injectable pharmaceutical preparation contains 1-35 parts by weight of 3- (4-aminophemylsulfonamido) -5-methyl isoxazole and 0.2-7 parts by weight of 2/4-diamino-5- (3,4-S-trinethoxybonzyl) -pyrimidine a weight ratio of 5: 1, further 50-97 parts by volume of M, N-dimethylacetic acid amide, 1 - 48 parts by volume of polyethylene glycol, 2-4 parts by volume of ethyl oleate and Q to 10 parts by weight of additives / additives.

- 3

22 54 92

Suitably, the pharmaceutical preparation contains 20 g / 100 ml sulfamethoxazole and 4 g / 100 ml trimethoprim.

Polyethylene glycol (PEG) of different molecular weight can be used: e.g. PEG 200, 300, 400 or 600 or the mixtures of these products. The number indicates the number of A'thylenglykol units. Preferably, PEG 300 is suitably used in an amount of 60% by volume.

Suitably, the pharmaceutical preparation to be created contains 3% by volume of ethyl thyloleate.

As additives can be used e.g. Antioxidants such as sodium sulfite, sodium bisulfite, sodium pyrosulfite, potassium sulfite, potassium bisulfite, potassium pyrosulfite, etc., surface-active and dissolution promoting agents such as dioctylsuccinic acid sodium, polyvinylpyrrolidone, etc., water, etc. may be used.

The invention is based on the finding that a prolonged therapeutic effect for the combination of SuIfQfiiethoxazoi and trimethoprim in a weight ratio of 5: 1 by the presence of 2 to 4 percent by volume of Äthyloieat is secured.

The prolonged effect was investigated on young pigs. The pharmaceutical preparations used were composed as follows:

I. Comparative preparation without Äthyloleat

Trimethoprim 4.0 g

Sufamethoxazole 20.0 g

N, N-Dimethylacetic acid amide 63.6 ml PEG 300 _l 19.1 ml

100.0 ml

ΊΙ. Prepared according to the invention with Athylolcat trimethoprim 4.0 g

Sulfamethoxazole. 20.0 g of Ν, Ν-dimethylacetic acid amide 60.6 ml of PEG 300 19.1 ml

Ethyl oleate, J-L-'J? ... l,

100.0 ml

Both of the two preparations were given intra-muscularly at a dose of 30 mg / kg. After 1, 2, 3, 4, 6, 8, 10 or 24 hours, the concentration of trimethoprim (TMP) and sulfamethoxazole (SMX) in the blood was determined. The determination of the concentration was carried out in the case of trimethoprim according to the method of WF Rehnr and coworkers (Borl Hünen, Veterinary Wschr., 8J3, 223/1972 /) and SuIfamethoxazol according to the method of CA. Bratton and coworkers (0th Biol »Chern», - 1_2_8, 537/1939 /). The results obtained are given in Table I.

Table I Comparison test on young pigs

Preparation was given in ·, a dose of 30 mg / kg im.

Concentration (, μg / ml) in the blood

4 6 8 10 24 hours after entering

I. Without ethyloleate TMP

SMX

1.00 1.05 - 0.63 0.35 0.20 0.10 31.9 26.4 19.4 15.5 6.2 1.2.

II. With ethyloleate

TMP

SMX

1.80 1.60 1.25 1.25 0.85 0.52 0.40 0.10 26.6 27.3 24.0 22.7 14.9 8.5 6.5 2.0

From the information compiled in Tafeelle I, it is possible that the concentration of sulfamethoxazole ~

2 25 4 9 2

actual therapeutic effect ensures - in the case of the comparative preparation without Äthyloleat in the eighth hour after the input is so low that it is no longer sufficient for the therapeutic effect. (To achieve a therapeutic effect, a sulfamethoxazole concentration of at least 2.0 μg / ml is required.

When using the new ethyloleate preparation containing the therapeutic effect is also 24 hours after the typing. So it is sufficient to give the sick animals only one injection daily. It was also investigated in young pigs how the pharmezeutische preparation according to the invention is tolerated by the animals. The preparation was administered / kg intramuscularly in doses of 30 mg / kg, 90 mg / kg, 150 mg / kg or 300 mg, and the eventual formation of a local or systemic reaction was studied on the first, second and third day after administration ,

At the therapeutic dose, neither local nor systemic reactions could be detected. At a triple therapeutic dose (ie, 90 mg / kg), a small swelling was detected at the site of injection the following day. On the second day, the swelling had disappeared. At five times the therapeutic dose (ie, 150 mg / kg), massive swelling was observed at the site of injection. She was also gone on the second day. Finally, at ten times the therapeutic dose (ie, 300 ^m gA9), a conspicuous swelling occurs which has disappeared on the third day. Even at this extremely high dose no systemic reaction was detected.

From the above examination it can be seen that the new pharmaceutical preparation is well tolerated by the animals.

6 - 2 2 5 4 9 2

The novel injectable pharmaceutical preparation is prepared according to the invention by adding from 1 to 35 parts by weight. Sulfamethoxazole and 0.2 to 7 parts by weight of trimethoprim in a weight ratio of 5: 1 with 50 to 97 parts by volume of N, N-dimethylacetic acid amide, 1 to 48 parts by volume of polyethylene glycol, 2 to 4 parts by volume of methyl thyloleat and 0 to 10 parts by weight of additives or admixtures , And the mixture in a known per se in an injectable pharmaceutical preparation transferred.

The pharmaceutical preparation according to the invention having a prolonged duration of action is expediently prepared as follows:

The active ingredients, namely trimethoprim and sulfamethoxazole are dissolved in three quarters of the total amount of the N, \ Dime'chyl ~ acetic acid amide with gentle warming. Then, nitrogen is bubbled through the solution which is cooled to room temperature. After admixing the remaining portion (a quarter) of the N, N-dimethylacetic acid amide, the solution is filtered under a nitrogen atmosphere and filled in bottles, which were previously flushed with nitrogen. The air is removed from the room above the liquid level, then the bottles are capped and sterilized at a temperature of 12O ° C for 20 minutes.

Of course, the mixture may also be sterilized in another known manner and filled into ampoules.

If additives are still used, you can proceed as follows:

The surfactant (s) and dissolution promoting agent (s), sulfamethoxazole and trimethoprim are dissolved in N ₁ N-

mm ξ am

22 54 92

Dimethylacetic acid amide dissolved, and to the obtained and cooled liquid is added a mixture of polyethylene glycol, ethyl oleate, water and antioxidants). Thereafter, the resulting solution is sterilized and filled in bottles.

The pH of the injectable pharmaceutical preparation of the invention is generally between 7.5 and 8, i. not far from the physiological value of the blood. In addition to the prolonged therapeutic effect, the preparation prepared according to the invention is relatively concentrated, so that even quite heavy animals can be treated by the injection of a not too large amount of solution.

EXAMPLES

The invention will be explained in more detail with reference to the following examples.

example 1

4.0 g of trimethoprim and 20.0 g of sulfamethoxazole are dissolved in 45.0 ml of Ν, Ν-dimethylacetic acid amide. The resulting solution is (300 PEG) was added 3.0 mL of ethyl oleate and 19.1 ml polyethylene glycol, and the volume of the solution is adjusted by admixing further 15.6 ml Ν, Ν-Dimethylessigsäureamid to 100 ml. The solution is filtered under nitrogen and filled into ampoules, the ampoules are sealed and sterilized.

Example 2

An injectable solution is prepared from the following components according to Example 1:

Trimethoprim. 4.0 g

Sulfamethoxazole 20.0 g

Ethyl oleate 2.5 ml

PEG 200. 19.1 ml

N, N-dimethylacetic acid amide J§u-Ei.

100.0 ml

An injected solution is prepared from the following components in the manner described in Example 1: '

Trimethoprim 4.0 g

Sulfamethoxazole 20.0 g

Ethyl oleate 3.5 ml

PEG 600 19.1 ml "

Ν, Ν-dimethylacetic acid amide .J§HiJLJiii>

100.0 ml

Ex iel. 4

An injectable solution is prepared from the following components as in Example 1:

Trimethoprim 4.0 g

Sulfamethoxazole, 20.0 g of ethyloleate 3.0 ml

PEG 400 17.7 ml

N, N-Dimethylessigsäureamid _i 62.0 ml

100.0 ml

22 54 92

Example 5

An injectable solution is prepared from the components below in the manner described in Example 1:

Tirmethoprim '4.0 g

Sulfamethoxazole 20.0 g

Ethyloleate. 3.0 ml

Mixture of PEG 300 and PEG 400 20.5 ml

N, N-dimethylacetic acid amide 59.2 ml

Example 6

4 g of polyvinylpyrrolidone, 0.2 g Dioktylbernsteinsäurenatrium, 20.0 g SuIfamethoxazol and 4.0 g of trimethoprim are dissolved at about 40 ⁰ C in 63.0 ml. Ν, Ν-Dimethylessigsäureamid. To the resulting liquid is added 10 ml of polyethylene glycol (PEG 300), a solution of 0.1 g of sodium bisulfite in 1.0 g of distilled water and then 2.3 ml of ethyl oleate with stirring The solution is filtered under nitrogen and filled into ampoules, the ampoules are sealed and sterilized at 100 ⁰ C for 30 minutes.

- 10 -

Claims (4)

- ίο - 9 2 5 4 9 invention claim 1. A process for the preparation of an injectable prolonged-release pharmaceutical preparation containing 3 ~ (4-aminophenylsulfonamido) -5-methylisoxazole and 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine a weight ratio of 5: 1, characterized in that 1 to 35 parts by weight of 3 ~ (4-Äminophenylsulfonamido) ~ ~ ~ ~ ethylalazoxazol and 0.2 to 7 parts by weight of 2,4-diamino-5 ~ (3 _t 4 , 5-trimethoxybenzyl) -pyrimidine mixed with 50 to 97 parts by volume of N, N-dimethylacetic acid amide, 1 to 48 parts by volume of polyethylene glycol, 2 to 4 parts by volume A'thyloleat and 0 to 10 parts by weight of additive or additives, and the mixture in a conventional manner into an injectable pharmaceutical preparation. 2. The method according to item 1, characterized in that 1-35 parts by weight of 3- (4-Aminophenylsulfonamideo) · - 5-mothylisoxa2ol and 0.2 to 7 parts by weight of 2,4-diamino ~ 5 ~ (3,4,5 -trimethoxabenzyl) -pyrimidine with SO to 97 parts by volume of N, N ~ dimethylacetamide, 1 to 48 parts by volume of polyethylene glycol and 2 to 4 parts by volume of ethyl oleate. 3. The method according to item 1 or 2, characterized in that the 3- (4-Aminophenylsulfonamido) -5-methylisoxazol in an amount of 20 parts by weight and the 2,4 ~ diamino ~ 5 »- (3,4,5-trimethoxybenzyl ) -pyrimidine is used in an amount of 4 parts by weight. 4. 'method according to item 3, characterized in that the Ethyl oleate is used in an amount of 3 parts by volume.