JPH0129769B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a long-term stable pharmaceutical preparation containing 4-carbamoyl-5-hydroxyimidazole, a salt thereof, or a hydrate thereof (hereinafter referred to as "the present compound") as a main component. This compound is a known compound, for example, Journal of the American Chemical Society (J.Am.Chem.Soc.), Vol. 74 (1952), 2892.
Although it can be synthesized by the method described on the page, it has recently been found that this compound has a strong anticancer effect (Japanese Patent Application Laid-open No. 53-32124), and it is clear that it is extremely meaningful medically. It became. This compound is an anticancer agent with purine antimetabolite action, and is particularly effective against solid cancers that are difficult to treat with conventional chemical treatments. It is also a highly safe anticancer agent with few side effects. Clinical applications in a wide range of dosage forms such as tablets, ointments, and suppositories are highly anticipated. The present compound itself has the property of easily being colored by oxygen, and this coloring tends to be further accelerated by the influence of heat and light. Therefore, difficulties are expected in formulating various dosage forms, especially when preparing an aqueous injection, not only the effects of dissolved oxygen in the aqueous solution and oxygen in the container space, but also the catalytic effects of various coexisting additives. As a result, the coloring is more noticeable than in other dosage forms. Generally, a method of removing oxygen from the preparation is used as a means of preventing coloration due to oxidation. However, even when the present compound is prepared by such a method, an oxidation reaction is initiated by a very small amount of oxygen remaining in the solution, and the compound gradually becomes colored. In such cases, addition of an antioxidant becomes effective. We have already found that the addition of sulfur compounds, which produce one of the ions SO ₃ ^2- , HSO ₃ ^- , S ₂ O ₅ ^2-, among various antioxidants, is useful in preventing the coloration of this compound. . Although this effect is certainly useful in a wide range of dosage forms in general, there have been some concerns about ensuring long-term stability in dosage forms that are particularly susceptible to oxidation reactions, such as aqueous injections. That is, the addition of only a small amount of a sulfur compound that generates these ions alone is not sufficient, and the effect was only observed when it was added in an amount that was somewhat undesirable from a safety standpoint. Therefore, we conducted various studies on methods that would have a sufficient effect of preventing coloration by adding only trace amounts of sulfur compounds that generate these ions, and we conducted experiments with the idea that this might be possible by combining with other antioxidants. Ivy. As a result, it was quite surprising that although the effect of sodium pyrosulfite and L-cysteine hydrochloride was small when each was added alone, the expected additive effect was exceeded when they were combined. A remarkable anti-coloration effect was observed. This effect can be called synergistic, compared to other combinations that remain additive, and is a completely new finding. Furthermore, as shown in Experimental Example 2, the aqueous injection of this compound containing this combination, that is, a trace amount of sodium pyrosulfite and L-cysteine hydrochloride, showed no coloring at all even under severe conditions and during long-term storage at room temperature. Nakatsuta. From these facts, this compound has SO ₃ ^2- , HSO ₃ ^- ,
Knowledge that it is possible to obtain a stable injection that does not show coloration over a long period of time by adding a trace amount of a sulfur compound that produces one type of ion selected from S ₂ O ₅ ^2- in combination with L-cysteine hydrochloride. This led to the completion of the present invention. Although the present invention has been described with a focus on aqueous injections, which are the most difficult to stabilize, the content of the present invention can also be applied to a wide range of pharmaceutical preparations in general, such as oral preparations, ointments, and suppositories. Examples of sulfur compounds include hydrogen sulfite {alkali metal hydrogen sulfite such as sodium hydrogen sulfite (NaHSO ₃ ) and potassium hydrogen sulfite (KHSO ₃ );
Ammonium bisulfite (NH ₄ HSO ₃ )}, sulfite water or sulfite {sodium sulfite (Na ₂ SO ₃ ),
Alkali metal sulfites such as potassium sulfite (K ₂ SO ₃ ), alkaline earth metal sulfites such as calcium sulfite (CaSO ₃ ), barium sulfite (BaSO ₃ )}, pyrosulfite {sodium pyrosulfite (Na ₂ S ₂ O _{5 )} ),
Alkali metal pyrosulfites such as potassium pyrosulfite (K ₂ S ₂ O ₅ ), etc. The amounts of sulfur compounds that generate HSO ₃ ^- , SO ₃ ^2- or S ₂ O ₅ ^2- ions and L-cysteine hydrochloride present in the preparation of the present invention are determined by considering the stabilizing effect and the safety of the additive. Sulfur compound 0.001-0.100, L-cysteine hydrochloride 0.01-0.01 in weight ratio to compound 1
0.50 is preferred. Pharmaceutical preparations of the present compound may include pharmaceutically acceptable solvents, solubilizing agents, tonicity agents, buffers,
Adds preservatives, PH adjusters, excipients, binders, disintegrants, coating agents, lubricants, flavoring agents, thickeners, moisture-proofing agents, coloring agents, flavoring agents, bases, antifoaming agents, etc. hand,
Tablets, troches, capsules, granules, pills, elixirs, syrups,
It can be made into emulsions, ointments, creams, and suppositories. Next, the present invention will be illustrated by experimental examples and examples, but the scope of the present invention is not limited thereto. Experimental Example 1 Various stabilizers were added at a concentration of 0.2% singly or in combination to an aqueous L-arginine solution containing 10 mg of the present compound per ml. Transfer 5 ml of this solution to a 18 ml vial, stopper it tightly, and store at 50℃ for 24 hours.
The degree of coloring was measured by absorbance at a layer length of 10 mm and a wavelength of 420 mm after storage for a time. Also, the color is JIS Z8102−
1957 "Color name book" based on "Industrial color name book" Displayed by Nippon Shikisha Co., Ltd.

[Table] Experimental Example 2 Aqueous injections were prepared with the following prescription amount per ampoule and stored under severe conditions of 50° and 1000 Lux and at room temperature, and the degree of coloring was compared by absorbance at a layer length of 10 mm and a wavelength of 420 mm. However, degassed water is used for preparation, and the space inside the ampoule is purged with nitrogen. Formula 4-carbamoyl-5-hydroxyimidazole in 1 ampoule
100mg L-arginine 200mg Sodium pyrosulfite 4mg L-cysteine hydrochloride 10mg Benzyl alcohol 50mg Sterile distilled water for injection Total 5ml

[Table] Example 1 4 g of sodium pyrosulfite and 10 g of L-cysteine hydrochloride were gently dissolved in 55 degassed sterile distilled water for injection, and 100 g of 4-carbamoyl-5-hydroxyimidazole, 200 g of L-arginine and 50 g of benzyl alcohol were added. Dissolve gently. After sterilization, take 5 ml of this solution, fill it into a 5 ml ampoule, replace the air in the container with nitrogen, and then seal it to obtain a long-term stable aqueous injection of 4-carbamoyl-5-hydroxyimidazole. .

Claims (1)

[Claims] 1. The following formula 4-carbamoyl-5-hydroxyimidazole or a salt thereof or a hydrate thereof represented by
A trace amount of sulfur compounds that produce S ₂ O ₅ ^2- ions and L-
A method for producing a long-term stable pharmaceutical preparation, characterized by adding cysteine hydrochloride in combination.