IE881658L

IE881658L - Stable 5-fluorouracil compositions

Info

Publication number: IE881658L
Application number: IE881658A
Authority: IE
Inventors: James B Johnson
Original assignee: Hoffmann La Roche
Priority date: 1987-06-03
Filing date: 1988-06-02
Publication date: 1988-12-03
Also published as: DK301288D0; NZ224860A; PH24212A; EP0293708B2; DK301288A; JPS649977A; AU1732888A; DE3863492D1; EP0293708B1; ATE64852T1; JPH0645544B2; CA1309026C; AU610183B2; ZA883888B; EP0293708A1; IE63972B1

Abstract

5-Fluorouracil products with a pH greater than 9.0 and less than 9.4, which essentially consist of a solution of 5-fluorouracil and of a base, are stable to temperatures of 0 DEG C (32 DEG F).

Description

65^ / Z 2 5-Fluorouracil (5FU) is a fluorinated pyrimidine which exhibits antimetabolite activity and which is a known antineoplastic agent. 5FU has been used for a long time as an agent for the 5 palliative treatment of various carcinomas including carcinoma of the colon, of the rectum, of the breast, of the stomach and of the pancreas. It is frequently used in patients who are considered to be incurable by surgery or by other means.

It is believed that this compound interferes with the io synthesis of DNA and to a lesser extent inhibits the formation of RNA. Since DNA and RNA are essential for cell growth and cell division, the effect of 5FU may be to create a thymine deficiency which leads to an uncontrolled growth and to the death of the cell. The effects of DNA and RNA defficiency are most marked in 15 the case of cells such as carcinoma cells which grow very rapidly. 5FU is an article of commerce and is generally supplied for intravenous injection in the form of 10 ml ampoules having a concentration of 50 mg/ml. The known 5FU formulations are 20 colourless to faint yellow aqueous solutions having a pH of about 8.8 (see Martindale, The Extra Pharmacopoea, The Martindale Press, London, 1982). The known fluorouracil formulations are sensitive to cold and must be stored at temperatures above about 15°C (60°F) in order to prevent precipitation. During shipment 25 from the manufacturer to the consumer these formulations are often exposed to temperatures which lie below this range. When the ampoules arrive at the destination, they contain the 5FU in the form of a precipitation consisting of large agglomerates. The product in this form is unsuitable for further use. 30 The formation of precipitates at low temperatures during shipment in the winter is a statistical phenomenon and occurs frequently. This has the inconvenient consequence that the precipitate must be re-dissolved by heating to 60°C (140°F) with vigorous shaking. The solution must then be cooled slowly to body temperature before it can be used.

It has hitherto not been possible to make available a 5FU formulation in a sealed container which is suitable for the administration of an injectable unit dose and from which the 5FU does not precipitate upon exposure to low temperatures, which often occur during shipment. The precipitation at low temperatures is a particular problem in the case of formulations in the form of vials. In this case, precipitations may already occur at temperatures and conditions at which the corresponding ampoule formulations remain stable.

Accordingly, there has for a long time been a need for a stable 5FU formulation which is suitable for storage in a sealed container and which is suitable for the administration of an injectable unit dose and from which the 5FU does not precipitate at temperatures below 15°C (60°F), which often occur during shipment.

The stabilization of aqueous 5FU solutions by the addition of ethylene glycol, propylene glycol or polyethylene glycol is described in Chemical Abstracts £2., 168466u (1975).

The present invention is concerned with 5FU preparations, which remain stable at temperatures up to 0°C (32°F) when they are stored in sealed containers, which are suitable for the administration of an injectable unit dose.

The present invention is also concerned with a process for the manufacture of 5FU preparations, which remain stable at temperatures up to 0°C (32°F) when they are stored in sealed containers, which are suitable for the administration of an injectable unit dose.

The 5FU preparations in accordance with the invention contain a solution of 5FU and a base. The 5FU solution can be 4 manufactured using conventional methods which are known to a person skilled in the art. A base is then added thereto so that the pH of the finished preparation is 9.2.

Particularly preferred is a 5FU solution manufactured using t 5 conventional methods to which a base, especially sodium hydroxide, has been added so that the pH of the finished * preparation is 9.2 and the concentration of 5FU is 50 mg/ml.

These preparations remain stable at temperatures up to 0°C 10 (32°F) when the sealed container suitable for the administration of an injectable unit dose is an ampoule. These preparations also remain stable up to temperatures of 0°C (32°F) in vials which are provided with the rubber closures which are set forth hereinafter and which, in turn, have been washed using standard sodium 15 phosphate washing procedures known per se: 1. Nitrile-butadiene rubber closures; 2. Halo-butadiene rubber closures; 3. Any rubber closure which is coated with a fluorinated hydrocarbon polymer. 20 Nitrile-butadiene rubber closure means rubber closures from nitrile butadiene elastomers which have been reinforced with an inert mineral and vulcanized with an organic peroxide (such as West* 2212).

Halo-butadiene rubber closure means rubber closures from 25 halo-butadiene elastomers which have been reinforced with an inert mineral and vulcanized with a phenolic resin (such as West* PH 703/VII).

Fluorinated hydrocarbon polymer means all compositions which contain fluorinated hydrocarbon polymers and which are 30 used as a coating material.

♦Trade Mark All West products are manufactured by the West Company, Phoenixville, PA 19469.

The 5FU preparations obtained represent a significant improvement over the known preparations with regard to increased resistance to precipitation.

The present invention is illustrated in more detail in connection with the following Example which serves for the purpose of illustration only.

Example West PH 703/VII or West 2212 rubber closures, manufactured by West Company, are washed according to the following procedure. 1. Place the rubber closures to be washed in a clean, stainless steel or glass vessel. Cover the closures with a 1 percent solution of tetrasodium pyrophosphate in distilled water. 2. Autoclave the container for half an hour at 121°C. 3. Decant the still hot liquid from the closures and thoroughly rinse the closures with distilled water while agitating. 4. Immerse the closures in distilled water and autoclave for half an hour at 121°C. 5. Repeat steps 3 and 4. 6. Inspect the rinse water for clarity. If the rinse water is not clear, repeat the autoclaving with distilled water until the decanted water appears clear. 7. Sterilize the washed closures by autoclaving in suitable, air-pervious containers (e.g. autoclave bags) at 121°C for 45 minutes. A drying cycle of at least 5 minutes should be used after completion of this sterilization in order to guarantee dryness of the sterile closures. The closures should be used within 48 hours of the sterilization.

The 5FU preparation is prepared starting from a 5FU solution which has been manufactured according to conventional methods which are known to a person skilled in the art. This solution is then brought to pH 9.2 with sodium hydroxide. The volume is adjusted with water so that the concentration of 5FU is 50 mg/ml at the end.

The preparation is subsequently filled into vials which are sealed with the washed rubber closures.

Table I illustrates comparative tests of the 5FU preparations in accordance with the Application in vials and ampoule formulations.

Table 1 Precipitation Study in the case of Refrigerated Storage (5°C) Dav on which precipitation Units precipitated after $ first observed weeks Amooule/vial Stationary Shaking Stationary Shaking PH 9,2 (HQ 5FU excess) Ampoule (1) 0/45 0/25 Vial - West 2212 0/25 0/25 Vial - West PH 703/VII 0/25 0/25 pH 8.8 (no 5FU excess) Ampoule (1) Vial - West 2212 1 10 3 3 6/50 10/25 10/50 17/25 Vial - West PH 703/VII 12/25 23/25 pH 8.8 (5% 5FU excess) Ampoule 19/25 18/25 8 (1) Data are the results of two studies. Ampoules were used controls for the vials fitted with the West PH 703/VII and West 2212 closures.

Claims

1. A 5-fluorouracil preparation having a pH of 9.2, which consists essentially of a solution of 5-fluorouracil and a base.

2. A preparation according to claim 1, wherein the concentration of 5-fluorouracil is 50 mg/ml.

3. A preparation according to claim 1 or 2, wherein the base is sodium hydroxide.

4. A preparation according to claim 1, wherein the concentration of 5-fluorouracil is 50 mg/ml and the pH is 9.2 and the base is sodium hydroxide.

5. A pharmaceutical dosage form suitable for administering an injectable unit dose of 5-fluorouracil, consisting of a sealed container containing a preparation according to any one of claims 1-4.

6. A pharmaceutical dosage form according to claim 5, characterized in that the sealed container is an ampoule.

7. A pharmaceutical dosage form according to claim 5, characterized in that the sealed container is a vial which is sealed with a sodium phosphate-washed rubber closure selected from the group consisting of nitrile-butadiene rubber closures, halo-butadiene rubber closures and any rubber closures which are coated with a fluorinated hydrocarbon polymer.

8. A process for the manufacture of 5-fluorouracil preparations according to any one of claims 1-4, characterized by adjusting the pH of a 5-fluorouracil solution to 9.2 with a base and adjusting the desired concentration of 5-fluorouracil with water. 10

9. A process for the manufacture of pharmaceutical dosage forms according to any one of claims 5-7, characterized by adjusting the pH of a 5-fluorouracil solution to 9.2 with a base, adjusting the desired concentration of 5-fluorouracil with water and filling the desired amount of the thus-obtained preparation into a sealed container.

10. A preparation according to claim 1, substantially as hereinbefore described and exemplified.

11. A pharmaceutical dosage form according to claim 5, substantially as hereinbefore described and exemplified. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.