KR820000267B1 - Method of preparation stabilized antibiotic formulations - Google Patents

Abstract

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Description

Method of Preparation of Stable Antibiotic Formulations

The present invention is a non-toxic oral administration of an amino glycoside antibiotic having a pyranose ring in which the 4 'and 5' positions are unsaturated and the 5 'position is substituted with an amino alkyl group. It is about a method.

Amino glycosides have been known as effective antimicrobials. Recently, 4 'and 5' positions are unsaturated among the series compounds, and the 5 'position is characterized by the substitution of amino alkyl groups, and attention has been focused on subclasses having excellent antibacterial effects. Some examples of these include sisomicin (US Pat. No. 3,832,286), verdamicin (UK Pat. No. 1,405,283), antibiotic G-52 (US Pat. No. 3,956,068), antibiotic 66-40B and antibiotics. Mu-1, Mu-2, Mu-4, Mu-5 and Mu-6 (5-epi), known as 66-4D (US Pat. No. 3,880,828) and mutacin (Mutamicin South African Patent No. 74/4938). -Sisomycin). Among the "antibiotics" referred to in this specification are included as synthetic derivatives, such as 1-N-alkyl or 1-N-isomers, namely 1-N-ethyl-sisomicin (netylmycin). (Note: South African Patent No. 74/4939). These antibiotics are usually administered orally as an acid addition salt, namely, sisomycin sulphate or netylmycin sulfate.

Unfortunately, however, these unsaturated aminoglycoside compounds are susceptible to degradation, especially when exposed to air for a short time or at high temperatures. This decomposition eventually results in the formation of a dark chromophoric material, reducing its efficacy, and at the same time producing unknown poisons. Thus markets with these compositions, such as sisomycin sulfate, have a relatively short lifespan. Therefore, it is necessary to increase the lifetime as these products. The term "lifetime" as the product used in this specification means a period in which the pigmentation is 1,200 APHA or less, and the pH can be maintained at 2.5 or more. (Note: APHA pigment units are a widely used standard method, for example as cited in the "Standard Methods for Water and Wastewater Testing" 13th Edition, 1971, American Public Health Association).

We have found that these unstable unsaturated aminoglycoside compounds surprisingly give an initial pH of 5.0 to 7.0, resulting in a very stable parenteral solution for pH and pigment. The preferred pH range is 5.8 to 6.8, especially 6.2 to 6.5. The lifetime of the compound thus obtained is much higher than the formulations when the initial pH is below 5.0 or above 7.0 as described above. In the case where the initial pH is in the preferred pH range of 5.8 to 6.8, the pH of the compound is stable with little change, and thus the product itself exhibits a certain characteristic. In the particularly preferred pH range 6.2 to 6.5 the product has a stable pH even in the presence of oxygen such as air. By changing these small pH ranges, the safety of pigments and pH is significantly higher. Previously, the initial pH of aminoglycoside products was around 3.5-4.5.

Particularly stable products can be obtained by adding antioxidants to the formulation in high concentrations. Preferred antioxidants include sodium metasulfite, sodium bisulfite and sodium sulfite or their complex salts, which are selected according to the initial pH of the product. These antioxidants work by oxidizing themselves as reducing agents or by inhibiting a series of oxidation reactions.

Other suitable antioxidants for such aqueous bodies include sodium thiosulfate, sodium formaldehyde sulfoxylate, acetone sodium, metabisulfite, ascorbic, isoascorbic acid, thioglycerol, thiosorbitol, thioglycolic acid and Cysteine hydrochloride.

The desired pH is adjusted by adjusting the pH by adding a base such as sodium hydroxide or by decreasing the pH by adding an acid such as hydrochloric acid. Preferably, an antioxidant or a complex antioxidant is selected and added to obtain the desired initial pH immediately without the need for other adjustments to adjust the pH.

Three preferred aminoglycoside formulations handled by the present invention are sisomycin sulfate at a concentration of 10 to 50 mg / ml, netylmycin sulfate at a concentration of 10 to 100 mg / ml and 5-epi-sisomicin at a concentration of 10 to 50 mg / ml. .

Various orally nontoxic ingredients can optionally be added to the formulation, such as preservatives such as parabens and benzyl alcohol; Electrolytes such as sodium chloride or sodium sulfate to make isotonic solution the same as body fluids; Chelating agents such as disodium EDTA.

Very stable in the pH range 6.2 to 6.5 can be seen in the following experiment. In other words, NaOH is added to the head solution containing 250 mg of netylmycin in 5 ml of water. One solution is sealed in ampoules under nitrogen gas and the solution is sealed in air. These ampoules were stored for one week at 75 ° C and their pH was

a) Nitrogen treatment solution: 6.5

b) Air treatment solution: 6.2

There was no difference.

An example of the product of the aqueous solution of sisomicin sulfate which is a conventional product as mentioned above is shown next. This solution formulation has an initial pH of 3.7 to 3.9 and a lifespan of about 18 months at 30 ° C., which is much shorter than that of the improved product shown in the Examples.

Example 1

This formulation is prepared by adjusting the pH of the above conventional product to 5.2 by adding 0.1 N sodium hydroxide. Now-type solutions have a lifespan of at least 36 months at 30 ° C.

Example 2

This formulation is manufactured by popularizing the composition shown next by the following operation method.

Operation: (per 50 liters)

About 35 liters of distilled water is placed in a stainless steel jacket and heated to 70 ° C. Methylparaben or propylparaben is added to warm water and stirred to dissolve. After the paraben has been dissolved, the contents of the tank are cooled to 25 to 30 ° C. Nitrogen gas is added to the solution, and the next operation is continued under nitrogen gas. Disodium EDTA, sodium chloride, sodium sulfite and sodium metabisulfite and sisomycin sulfate are added. The volume of the whole solution is added to distilled water so that the volume is 50 liters and stirred until uniform.

For aseptic operation, the solution is separated through a filter and the sterile filtrate is collected in a tank.

This sterile solution is sealed by addition to sterile vials, ampoules or syringes.

The product prepared according to Example 2 has a pH of about 5.2 and its lifetime is about 36 months at 30 ° C.

In the formulations listed below, 3 to 21 were prepared according to Example 2, and all had a life of at least 36 months at 30 ° C.

TABLE 1

These formulations contain inverse 10 mg benzyl alcohol / ml.

Always use NaOH or HCl to achieve the correct pH.

Claims (1)

The pH is set to 5.0 to 7.0, and the sulfite or metasulfite is added as an antioxidant, and the 4 'and 5' positions are unsaturated, and the pyranose ring having an amino alkyl substituent at the 5 'position is contained. A method for preparing an oral aqueous antibiotic formulation stable against a pH and a pigment containing a salt of an aminoglycoside antibiotic as a main component.