JPS5936624A - Method for stabilizing solid pharmaceutical - Google Patents

Abstract

PURPOSE:To prevent the coloring and stabilize a solid pharmaceutical useful as a carcinostatic agent, by using a disoxidizing agent or an agent for disoxidizing or generating gaseous carbon dioxide present in the solid pharmaceutical consisting essentially of 4-carbamoyl-imidazolium-5-oleate. CONSTITUTION:The coloring of a solid pharmaceutical consisting essentially of 4-carbamoyl-imidazolium-5-oleate expressed by the formula or a salt thereof or a hydrate thereof is prevented by using a disoxidizing agent or an agent for disoxidizing or generating gaseous carbon dioxide, e.g. a sulfite, present in the solid pharmaceutical. The disoxidizing agent or the agent for disoxidizing or generating gaseous carbon dioxide is usually used by packaging in an air-permeable bag, e.g. a packaging material having Japanese paper laminated on a prous polyethylene. The amount of the disoxidizing agent to be used is such an amount as to remove about 50-100cc minimal oxygen if the oxygen in the packaging material is 50cc to stabilize the compound expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides guccarbamoyl-imidazolium-! - This invention relates to a method for stabilizing a solid preparation containing oleate, 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 4 (J.
Am, Ohem, Sac, ), 741 volumes (/
9j, 2nd year).

, p. 2192.

Recently, it has been found that this compound has a strong anticancer effect (1987-321JQ), and it has become clear that it is extremely meaningful medically. This compound is an anticancer agent with purine antimetabolite effect, and is a highly safe anticancer agent with few side effects.It is particularly effective against solid cancers, which have traditionally been difficult to treat with chemical treatments. .

Clinical applications in a wide range of dosage forms such as injections, ointments, and suppositories are highly anticipated.@This compound itself has the property of easily becoming colored by oxygen, heat, light, etc. For example, when applied to oral preparations, there is a tendency for the interaction of coexisting excipients and more complex reaction paths to cause more pronounced coloring. As a means to prevent such coloring,
As shown in Publication No. 10321, H803,803
", Methods using sulfur compounds that generate E12052-ions are known. However, although the use of these sulfur compounds is very effective in preventing coloration of this compound, it is difficult to use when the preparation is taken internally.・A unique odor of sulfur-based compounds can be felt, which is not necessarily satisfactory for use in solid preparations. Therefore, the present inventors have determined that the present compound can be stabilized without adding a stabilizer to the formulation. As a result of extensive research on methods that can be used to achieve this goal, we have found that coloring of this compound can be significantly prevented by coexisting a solid preparation of this compound with a deoxidizing agent and a deoxygenating carbon gas generating agent in a sealed container. The present invention was completed based on the discovery that the prevention effect is sufficiently useful as a preparation and does not impair the feeling of taking it. Generators include sulfite, bisulfite, thiosulfate, dithionite, oxalate, pyrogallol, longaliy l'
s-gulose, copper amine complex, 7-scorpic acid, iron powder,
Stones of any composition can be used, with main ingredients being iron carbide, zinc powder, ferrous salts, and other famous reducing substances.

Oxygen scavengers and deoxygenated carbon dioxide gas generating agents are usually packaged in air-permeable packaging materials, such as Japanese paper laminated with perforated polyethylene, which is preferable. A packaging material with an oxygen permeability as small as Sθθcc~・24t hrs-atm, preferably 100cc/m”・ko44 hrs・
Packaging materials below ATM are used ◇For example, stretched nylon,
Polyester, moisture-proof cellophane, vinylidene chloride, M
x Nylon, vinyl chloride, and various vinylidene chloride coated films (Kop-KoN).

(KPET, KDT, etc.), vinylon, ethylene/vinyl alcohol copolymer, aluminum foil, aluminum vapor-deposited film, glass bottles, etc., and those having an oxygen permeability within the above range are preferably used.

To carry out the present invention, a packaged oxygen absorber and a deoxidizing carbon dioxide gas generating agent are placed in the packaging material for the solid preparation of the present compound, or if the solid preparation packaging material is a sealed container such as a bottle. This can be carried out by loading the inside of the stopper, etc.〇(3) Use of the de-#xing agent and deoxidizing carbon dioxide gas generating agent according to the method of the present invention is the dosage form of the solid preparation of the present compound, it And so on! 141, but for example, if the oxygen in the packaging material is jθ00, stabilization of this compound can be expected with a porcelain that can remove at least Sθ~/θθω, and Sθθ~jθθOC.
As long as it is enough to remove a certain amount of oxygen, you will get guaranteed results.

Next, the usefulness of the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example / Granules [Formulation] / Medium lactose
qjθ Cape Toumon: I Shidenbun
330 Misaki Hydroxypropyl Cellulose
λL~Goocarba moi imidazo Uumuu! -Oleide hydrate, lactose, corn starch (4t) Mix the starch with an all-purpose mixer, add an aqueous solution of hydroxypropyl cellulose and knead, then create a basket-type wet process a.
After granulation, the mixture was dried and sized to obtain granules.

[Storage test]

Ageless 0z, an oxygen absorber whose main ingredients are granules sy and iron powder.
-10 (Mitsubishi Gas Chemical System) was placed in a glass bottle with an inner volume of 0 (+) and stored tightly at 30°C for 7 months, and the coloring of the granules was visually observed [7◇No oxygen scavenger was used as a control. Exactly the same material was used outside the dot plate. As a result, coloration of the granules was observed when no oxygen absorber was used, but no coloration was observed when an oxygen absorber was used.@ Example Cocapsules [Prescription]
/Glucarbamoyl imidazolium in capsule-j
- Olate - □〇 Misaki's hydrated corn starch
/θθ Magnesium stearate
Hydrate of imidazolium-5-oleate, corn starch.

Magnesium stearate was mixed and filled into Japanese Pharmacopoeia No. 7 capsules.

[Storage test]

Oxygen absorber Tamotsu 0 whose main ingredient is 70 capsules and reactivation
A-10θ (manufactured by Toyo Valve) was stored in an aluminum pillow package (inner volume jθ Tsukuda) at 50°C for several months, and the coloring of the contents of the capsule was visually observed. 0 As a control, no oxygen scavenger was used. was completely In2-like.

As a result, coloration of the capsule contents was observed when an oxygen absorber was not used, but no coloration was observed when an oxygen absorber was used.Example 3 Tablets [Formulation] 7 tablets of medium milk
Sugar /S
■Corn starch
73 ■ Carboxymethyl cellulose calcium
/θ■Hydroxypropylcellulose /θ■Magnesium stearate -2machi Gucarbamoyl-imidazolium-S-oleate hydrate, lactose, corn starch, and carboxymethylcellulose calcium are mixed in a multipurpose mixer, and an aqueous solution of hydroxypropylcellulose is added. The mixture is kneaded, granulated using a power mill, dried, sized, mixed with magnesium stearate, compression molded, and! So my diameter? , j■ tablets.

[Storage test]

Tablet-0 tablet and L-7 Trapan, a deoxygenating carbon dioxide gas generator based on sodium scorbate ■ Freshness preserving agent 0-/θ
θ (Toppan Printing III) was placed in a glass bottle with an internal volume of 2jeO and stored in SOoC in a tightly closed state for 7 months, and the coloring of the tablet was visually observed. As a control, the same product was used except that no deoxygenating carbon dioxide gas generating agent was used. As a result, when the oxygen deoxidizing carbon dioxide gas generating agent was not used, coloring of the tablets was observed. No coloring was observed when the generator tl was used. RO-/jθ (Diachemifa If') was placed in a 5 AA glass bottle and stored tightly at jθ°0 for several months, and the coloring of this compound was visually observed. Oxygen scavenger was used as a control. 90 As a result, when using an oxygen absorber, coloring of this compound was observed, but when using an oxygen absorber, no coloring was observed.

Claims (1)

[Scope of Claims] A solid preparation mainly containing goocarbamoyl imidazolium-j-oleate, a salt thereof, or a hydrate thereof represented by the following formula, and an oxygen scavenger or a deoxygenated carbon dioxide gas generating agent coexist. A method for stabilizing solid preparations that is specially designed to improve