AU610183B2

AU610183B2 - Stable 5-fluorouracil compositions

Info

Publication number: AU610183B2
Application number: AU17328/88A
Authority: AU
Inventors: James B. Johnson
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1987-06-03
Filing date: 1988-06-03
Publication date: 1991-05-16
Anticipated expiration: 2008-06-03
Also published as: EP0293708A1; JPH0645544B2; EP0293708B2; EP0293708B1; ATE64852T1; AU1732888A; NZ224860A; CA1309026C; ZA883888B; IE881658L; JPS649977A; IE63972B1; DK301288D0; DE3863492D1; DK301288A; PH24212A

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

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AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE This document con'ains the amendments made under bection 49 and is correct for printing Application Number: Lodged: Complete Specification Lodged: Accepted: SPublished: SPriority: SRelated Art: TO BE COMPLETED BY APPLICANT /T.

p. Heo PPMA I-c Name of Applicant: HOFFMANN-LA ROCHE CO.

AKTIENGESELLSCHAFT

Address of Applicant: 124-184 Grenzacherstrasse, Basle, Switzerland Actual Inventor: James B. Johnson Address for Service: ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

Complete Specification for the invention entitled STABLE

COMPOSITIONS.

The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 II I ~ilxI- la RAN 4060/144 5-Fluorouracil (5FU) is a fluorinated pyrimidine exhibiting antimetabolite activity and is a known antineoplastic agent.

has long been used as a drug for the palliative management of various carcinomas including carcinoma of the colon, rectum, breast, stomach, and pancrsz. It is frequently used in patients who are considered incurable by surgery or other means.

This compound is thought to interfere with the synthesis of DNA and to a lesser extent inhibits the formation of RNA.

Since DNA and RNA are essential for cell growth and division, the effect of 5FU may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on cells such as carcinoma cells which grow most rapidly.

is an article of commerce and is generally supplied for intravenous injection in 10 ml ampuls at a concentration of 50 mg/ml. The current 5FU formulations are colorless to faint yellow aqueous solutions which are at a pH of about 8.8. The current fluorouracil formulations are also temperature sensitive and must be stored at a temperature of above about 15 0 C (60 0 F) in order to avoid precipitation. Often, during shipment of the drug from supplier to user they are exposed to temperatures below this range. The ampuls may arrive at their destination with the 5FU precipitated into large agglomerates which render the product unsuitable for use in that form.

Nt/26.4.88 4. The basic application(s) referred to in paragraph 2 of th' Declaration was/were the first application(s) made in a Convention country in respect of the invention the subject of the application.

To: Declared at Basle this 28th day of April, 1988 The Commissioner of Patents, I 1.

COMMONWEALTH OF AUSTRALIA 4 Signature of Declarant(s) -2- The precipitate formation at low temperatures during winter shipment is a statistical phenomenon and occurs frequently. This necessitates the inconvenience of resolubilizing by heating to 60 0 C (140 0 F) with vigorous shaking. The solution must then slowly be cooled to body temperature before administration.

Heretofore, it has not been possible to distribute a formulation in a sealed container suitable for administering an injectable unit dose where the contents do not precipitate upon exposure to the low temperatures which often occur during shipment. With vial formulations, precipitation at lower temperatures is particularly problematic, and may occur at temperatures and conditions where the corresponding ampul formulations whould remain stable.

Accordingly, there has long been a need for a stable formulation suitable for storage in a sealed container suitable for administering an injectable unit dose where the contents do not precipitate at the temperatures below about 0 C (60 0 F) which often occur during shipment.

The instant invention comprises a composition of which remains stable at temperatures down to 0 0 C (32 0 F) when stored in a sealed container suitable for administering an injectable unit dose.

The instant invention also comprises a method for the manufacture of a 5FU composition which remains stable down to a temperature of 0 C (32 0 F) when stored in a sealed container suitable for administering an injectable unit dose.

The 5FU composition of the instant invention comprises a solution of 5FU and a base. The 5FU solution is manufactured according to current production methods known to one skilled in the art. Base is added so that the pH of the finzl composition is greater than 9 and less than 9.4 and, parti-

~II_

3 cularly is about 9.1 to 9.3.

Particularly preferred is a 5FU solution manuactured according to current production methods to which a base, particularly sodium hydroxide base, has been added so that the pH of the final composition is about 9.1 to 9.3 and the concentration of 5FU is 50 mg/ml.

Although the pH range of the composition may vary between greater than 9 up to 9.4, as the pH of the composition increases the 5FU itself begins to lose activity. Hence it is most desirable to keep the pH of the composition between 9.1 to 9.3.

0 15 This composition will remain stable down to OOC (32 0

F)

when the sealed container suitable for administering an injectable unit dose is an ampul. This composition will also remain stable down to temperatures of OOC (32 0 F) in vials Swhich are closed with the following rubber closures washed according to standard sodium phosphate washing procedures known in the art: 1. Nitrile Butadiene rubber closures; 2. Halo Butadiene rubber closures; 3. Any rubber closure which is coated with a fluorinated hydrocarbon polymer.

Nitrile Butadiene rubber closure means rubber closures with a Nitrile Butadiene elastomer reinforced with an inert mineral and cured with an organic peroxide (such as West 2212).

Halo Butyl rubber closure means rubber closures with a Halo Butyl elastomer reinforced with an inert mineral and cured with a phenolic resin (such as West PH 703/VII).

4 Fluorinated hydrocarbon polymer means any composition containing fluorinated hydrocarbon polymers and used as a coating material.

All West products are manufactured by West Company, Phoenixville, PA 19469.

The resulting composition of 5FU represents a significant improvement over the current compositions for increased resistance to precipitation.

The present invention will be further described in connection with the following Example which is set forth for the purposes 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 rubber closures to be washed in a clean, stainless steel pot ur glass receptacle. Cover closures with a 1% solution of tetrasodium pyrophosphate in distilled water.

2. Autoclave container for 1/2 hour at 121 0

C.

3. Decant the liquid from the closures while still hot and then thoroughly rinse the closures with distilled water while agitating.

4. Immerse the closures in distilled water and autoclave for 1/2 hour at 121 0

C.

Repeat steps 3 and 4.

5 6. Inspect 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 washed stopppers by autoclaving in suitable breathable containers autoclave bags) at 121°C for minutes. A drying cycle of at least 5 minutes should be used at the end of this sterilization to assure dryness of the sterile closure. Closures should be used within 48 hours of sterilization.

The 5FU composition is prepared by beginning with a solution manufactured according to current production methods known to one skilled in this art. This solution is then brought to a pH of 9.1 to 9.3 with sodium hydroxide.

The volume is adjusted with water so tht the final concentration of 5FU is 50 mg/ml.

The composition is then dispensed into vials which are sealed with the washed rubber closures.

Table I illustrates comparative studies of the instant composition in the vial and ampul formulations.

6 Table I Refrigerated Storage (5 0 C) Precipitation Study Injectable 500 mg/10 ml Ampuls/Vials with West 2212 or PH 703/VII Stoppers pH 9.2 or pH 8.8 Day Precipitate First Observed Stationary Shaking Units Precipitated After 5 Weeks Stationary Shaking Ampul/Vial Ampul(l) pH 9.2 (no 5FU excess) 0/45 0/25 Vial West 2212 Vial West PH 703/VII 0/25 pH 8.8 (no 5FU excess) 6(50 Ampul(l) 0/25 0/25 0/25 10/50 17/25 23/25 18/25 Vial West 2212 Vial West PH 703/VII Ampul 10/25 12/25 pH 8.8 5FU excess) 19/25 were set up as controls for Data are totals compiled from two studies. Ampuls vials with both West PH 703/VII and 2212 stoppers.

7 While the invention has been described in connection with the preferred embodiment, it is not intended to limit the scope of the invention to the particular form set forth, but, on the contrary, it is intended to cover such alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Claims

1. A 5-fluorouracil composition of pH greater than and less than 9.4 consisting essentially of a solution of

5-fluorouracil and a base. 2. A composition according to claim 1, wherein the pH is Shmt 9.1 to 9.3. 3. A composition according to claim 1 or 2, wherein the concentration of 5-fluorouracil is 50 mg/ml. 4. A composition according to any one of claims 1 to 3, wherein the base is sodium hydroxide. A composition according to claim 1, wherein the concentration of 5-fluorouracil is 50 mg/ml, the pH is

9.1 to 9.3 and the base is sodium hydroxide. 6. A pharmaceutical dosage form suitable for administering an injectable unit dose of which dosage form consists of a sealed container containing a composition according to any one of claims 1 to 7. A pharmaceutical dosage form according to claim 6, wherein the sealed container is an ampul. 8. A pharmaceutical dosage form according to claim 6, wherein the sealed container is a vial sealed with sodium phosphate washed rubber closures selected from the group consisting of a nitrile butadiene rubber closure, a halo butadiene rubber closure and any rubber closure which is coated with a fluorinated hydrocarbon polymer. c _i Q I: CI C 9 9. A method for the manufacture of a composition according to any one of claims 1 to 5, which comprises adjusting the pH of a 5-fluorouracil solution to greater than 9.0 and less than 9.4 with a base and adjusting to the desired concentration of 5-fluorouracil with water. A method for the manufacture of pharmaceutical dosage forms according to any one of claims 6 to 8, which comprises adjusting the pH of a 5-fluorouracil solution to greater than 9.0 and less than 9.4 with a base, adjusting to the desired concentration of 5-fluorouracil with water and placing the desired volume of the composition thus obtained in sealed containers.

11. Any novel composition or dosage form or com o t- thereof set forth herein, or any nov od or method step set forth her e said composition, dosage form, _cimp~Tf, method or step being substantially as herein ,AJ i DATED this 2nd day of June, 1988. F-;HOFFMANN-LA ROCHE :CO. AKTIENGESELLSCHAFT By Its Patent Attorneys, ARTHUR S. CAVE CO.