JPH0128005B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention uses 3-(4-aminophenylsulfonamide)-5-methylisoxazole (sulfamethoxazole) and 2,4-diamino-5-(3, 4,5-trimethoxybenzyl)pyrimidine (trimethoprim) in a weight ratio of 5:
It relates to a long-acting injectable pharmaceutical composition containing the following: The injectable pharmaceutical composition of the present invention is suitable for gastrointestinal tract, respiratory tract,
It can be used as veterinary medicine for the treatment of urinary and surgical trauma infections. (Prior Art and Problems to Be Solved) It is well known that the action of sulfonamides such as sulfamethoxazole is enhanced by trimethoprim (UK Patent No. 1176395).
The injectable solution described in this patent is composed of a salt formed from a sulfonamide and a base. The pH value of this known solution is therefore as high as 11. Such basicity can have an adverse effect on the tissues surrounding the injection site, and therefore the application of this known injection solution is rather limited. In order to avoid the above-mentioned drawbacks, attempts have also been made to adjust the pH value of the solution to 4-6 by adding acid (UK Patent No. 1469521). However, such a low acidic PH is not preferred for intravenous administration. PH4-6 is the physiological PH value of blood (7.35-7.45)
This is because it is much lower than A common property of known injectable pharmaceutical compositions consisting of sulfonamides and trimethoprim is that their therapeutic efficacy declines 6-8 hours after administration, requiring further injections to maintain therapeutic concentrations necessary for complete recovery. It may happen. Three to four injections per day are not advantageous in human therapy, but are particularly undesirable in the field of animal therapy. (Means for solving the problem) Therefore, the development of an injectable pharmaceutical composition containing sulfamethoxazole and trimethoprim at a weight ratio of 5:1 and having a long-lasting effect is of particular interest. . The present invention was completed based on the discovery that the therapeutic effects of sulfamethoxazole and trimethoprim can be sustained by adding oleic acid ethyl ester. The injectable pharmaceutical composition of the present invention comprises 1 to 35 parts by weight of 3-(4-aminophenylsulfonamide)-5-methylisoxazole and 2,4-diamino-
It contains 0.2 to 7 parts by weight of 5-(3,4,5-trimethoxybenzyl)pyrimidine in a weight ratio of 5:1, and further contains 50 to 97 parts by volume of N,N-dimethylacetamide and poly(ethylene glycol). )1
~48 parts by volume, 2 to 4 parts by volume of oleic acid ethyl ester, and 0 to 10 parts by weight of additives. The pharmaceutical composition of the present invention comprises sulfamethoxazole.
Preferably it consists of 20g/100ml and trimethoprim 4g/100ml. The concentration of oleic acid ethyl ester is preferably 3% by volume. Poly(ethylene glycol) used
(PEG) has various molecular weights. For example, PEG 200, 300, 400 or 600 or mixtures thereof can be used (this number indicates the number of ethylene glycol units). Preferably PEG300
For example, use 60% capacity. Examples of additives include sodium sulfite,
Sodium bisulfite, sodium pyrosulfite,
Antioxidants such as potassium sulfite, potassium bisulfite, potassium pyrosulfite, etc.: surfactants such as sodium dioctyl sulfosuccinate, polyvinylpyrrolidone, water, etc. are used. The present invention is based on the discovery that prolonged therapeutic action is achieved by using 2-4% by volume of oleic acid ethyl ester in a 5:1 weight ratio formulation of sulfamethoxazole and trimethoprim. . The persistence of this effect was tested in piglets using the following pharmaceutical composition. Control composition without ethyl oleate Trimethoprim 4.0g Sulfamethoxazole 20.0g N,N-dimethylacetamide 63.6ml PEG300 19.1ml 100.0ml Invention composition containing ethyl oleate Trimethoprim 4.0g Sulfamethoxazole 20.0 g N,N-dimethylacetamide 60.6ml PEG300 19.1ml Oleic acid ethyl ester 3.0ml 100.0ml Inject 30mg/Kg intramuscularly, injections 1, 2, 3, 4,
trimethoprim (TMP) and sulfamethoxazole (SMX) after 6, 8, 10 and 24 hours
The blood concentration of was measured. In the case of trimethoprim, the blood concentration was measured using the method of WFRehm et al. [Berl.
M″anch.Tier″arztl.Wschr., 85 , 228 (1972)], in the case of sulfamethoxazole, CA
Bratton et al.'s method [J.Biol.Chem., 128 , 537
(1939)]. The results obtained are shown in Table 1.

[Table] As is clear from the data shown in Table 1, in the case of compositions that do not contain oleic acid ethyl ester, the concentration of sulfamethoxazole that provides the actual therapeutic effect is extremely low at 8 hours after administration; There is no therapeutic effect at all. A concentration of sulfamethoxazole of at least 2.0 μg/ml is required for therapeutic efficacy. The pharmaceutical composition of the present invention has a therapeutic effect even 24 hours after administration. Thus, one injection per day is sufficient to treat sick animals. The injectable compositions of the present invention were also tested for tolerability in animals. 30mg/Kg, 90mg/ for piglets
Kg, administered intramuscularly at doses of 150 mg/Kg and 300 mg/Kg;
The appearance of local or systemic reactions was observed on days 1, 2 and 3 of administration. At the therapeutic dose, 30 mg/Kg, no local or systemic reactions were observed. 3 times the therapeutic dose, 90mg/
After administering Kg, mild swelling was observed at the injection site the next day, but it disappeared the next day. 5 times the amount of 150mg/
Kg had a hard swelling at the injection site the next day, but it disappeared the next day. 10x dose i.e. 300mg/Kg
Significant swelling developed and continued until the third day. However, even at this significantly high dose, no systemic reaction occurred. The above tests show that the pharmaceutical compositions of the invention are well tolerated by animals. The pharmaceutical composition for injection of the present invention comprises 1 to 35 parts by weight of 3-(4-aminophenylsulfonamide)-5-methylisoxazole and 2,4-diamino-5
0.2 to 7 parts by weight of (3,4,5-trimethoxybenzyl)pyrimidine in a weight ratio of 5:1, and further 50 to 97 parts by volume of N,N-dimethylacetomide,
Manufactured by blending 11 to 48 parts by volume of poly(ethylene glycol), 2 to 4 parts by volume of oleic acid ethyl ester, and 0 to 10 parts by weight of additives, and preparing the resulting mixture into a pharmaceutical composition for injection. . The injectable pharmaceutical composition of the present invention is preferably produced by the following method. That is, trimethoprim and sulfamethoxazole are mixed with about 3/3 of the total amount of N,N-dimethylacetamide while being heated gently.
Dissolve in 4. Add oleic acid ethyl ester and poly(ethylene glycol) to the resulting solution,
Burge the mixture with nitrogen while cooling to room temperature. After adding the remaining N,N-dimethylacetamide,
The solution is passed under a nitrogen atmosphere and filled into containers previously flushed with nitrogen. The air in the upper part of the liquid is removed, the container is sealed and sterilized at 120°C for 20 minutes. Of course, the mixture may be sterilized and then filled into ampoules by any known method. When adding additives, the injectable pharmaceutical composition of the present invention is manufactured by the following method. The surfactant, solubilizing agent is dissolved in N,N-dimethylacetamide along with suluamethoxazole and trimethoprim. Poly(ethylene glycol), oleic acid ethyl ester, water and additives are added to the cooled solution, and the resulting solution is then sterilized and filled into containers. The PH value of the injectable pharmaceutical composition of the present invention is generally between 7.5 and 8, ie, around the physiological PH value of blood. In addition to long-lasting action, the compositions of the present invention are relatively concentrated so that even animals with large body weights can be treated by injecting a suitable amount of solution. Next, the present 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 were mixed with 45.0 g of N,N-dimethylacetamide.
Dissolve in ml. Oleic acid ethyl ester 3.0ml
and poly(ethylene glycol) (PEG300)
and further N,N-dimethylacetamide
Add 15.6ml to adjust the volume to 100ml. The resulting solution is passed under a nitrogen atmosphere and filled into ampoules, which are then sealed and sterilized. Example 2 An injectable solution is prepared as described in Example 1 from the following ingredients: Trimethoprim 4.0 g Sulfamethoxazole 20.0 g Oleic acid ethyl ester 2.5 ml PEG200 19.1 ml N,N-dimethylacetamide 61.1 ml 100.0 ml Example 3 An injectable solution is prepared as described in Example 1 from the following ingredients: . Trimethoprim 4.0 g Sulfatoxazole 20.0 g Oleic acid ethyl ester 3.5 g PEG600 19.1 ml N,N-dimemethylacetamide 60.1 ml 100.0 ml Example 4 An injectable solution is prepared as described in Example 1 from the following ingredients: . Trimethoprim 4.0 g Sulfamethoxazole 20.0 g Oleic acid ethyl ester 3.0 ml PEG400 17.7 ml N,N-dimethylacetamide 62.0 ml 100.0 ml Example 5 An injectable solution is prepared as described in Example 1 from the following ingredients: . Trimethoprim 4.0g Sulfamethoxazole 20.0g Oleic acid ethyl ester 3.0ml Mixture of PEG300 and PEG400 20.5ml N,N-dimethylacetamide 59.2ml 100.0ml Example 6 Polyvinylpyrrolidone 4g, sodium dioctylsuccinate 0.2g, sulfamethoxa sol
20.0 g and 4.0 g of trimethoprim are dissolved in 63.0 g of N,N-dimethylacetamide at about 40°C. Poly(ethylene glycol) in the resulting liquid
(PEG300) 10 ml, distilled water 1.0 g, and a solution of 0.1 g sodium bisulfite dissolved in 2.3 ml oleic acid ethyl ester were added under stirring. The volume of the resulting mixture was reduced to 100.0 with N,N-dimethylacetamide.
Make it ml. After passing under a nitrogen atmosphere, the solution was packed into an ampoule, the ampoule was sealed, and the solution was heated at 100°C/30°C.
Sterilizes in minutes.

Claims (1)

[Claims] 1 3-(4-aminophenylsulfonamide)
Contains 1 to 35 parts by weight of -5-methylisoxazole and 0.2 to 7 parts by weight of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine in a weight ratio of 5:1. And then N,N-
A sustained-acting injectable pharmaceutical composition comprising 50 to 97 parts by volume of dimethylacetamide, 1 to 48 parts by volume of poly(ethylene glycol), 2 to 4 parts by volume of oleic acid ethyl ester, and 0 to 10 parts by weight of an additive. 2 3-(4-aminophenylsulfonamide)
Contains 1 to 35 parts by weight of -5-methylisoxazole and 0.2 to 7 parts by weight of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine in a weight ratio of 5:1. And then N,N-
50-97 parts by volume of dimethylacetamide, 1-48 parts by volume of poly(ethylene glycol) and 2-4 parts by volume of oleic acid ethyl ester. thing. 3 3-(4-aminophenylsulfonamide)
-5-Methylisoxazole 20 parts by weight, 2,4-
4 parts by weight of diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, 63 parts by volume of N,N-dimethylacetamide, 10 parts by volume of poly(ethylene glycol), 2 parts by volume of ethyl oleate, and 5.3 parts by volume of oleic acid ethyl ester. The sustained-acting injectable pharmaceutical composition according to claim 1, consisting of parts by weight. 4 Additives: 4 parts by weight of polyvinylpyrrolidone, 0.2 parts by weight of sodium dioctyl sulfosuccinate, 1.0 parts by weight of water, and sodium bisulfite
The sustained-acting injectable pharmaceutical composition according to claim 3, using 0.1 part by weight.