NZ212097A

NZ212097A - Parenteral pharmaceutical composition comprising metoclopramide (4-amino-5-chloro-n-((2-diethylamino) ethyl)-2-methoxybenzamide) and optionally sodium metabisulphite

Info

Publication number: NZ212097A
Application number: NZ212097A
Authority: NZ
Inventors: R D Pathak; I P O'brien
Original assignee: Beecham Group Plc
Priority date: 1984-05-17
Filing date: 1985-05-15
Publication date: 1988-11-29
Also published as: GB2158714B; GB8412585D0; AU4260785A; AU623694B2; AU4362489A; GB8510115D0; ZA853671B; CA1262686A; AU591631B2; GB2158714A

Description

i-a- ©?7- Pnont/ D3+e(s) S>A}*- Corriplete Specification Filed \5~5~ C -cc PikliO \ / ( kp I K-w^> ICI i-jb' -?t'cn Date ° 0 Jc. nul No . 2 9 NOV 1988 (5/y AMENDED under Section J of the Patents Act 1953 from —. » ASSISTANT COHhlSSlONEMDF PAT NO DRAWINGS NEW ZEALAND PATENTS ACT, 1953 No. Date COMPLETE SPECIFICATION COMPOSITION We, BEECHAM GROUP p.I.e., a British Company of Beecham House, Great West Road, Brentford, Middlesex TW8 9BD, England, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) & C COMPOSITION The present invention relates to a pharmaceutical composition containing metoclopramide, and its use in medicine.

Metoclopramide is a known anti-emetic agent which is used to alleviate nausea and vomiting. Hitherto, it has been administered by oral and injection routes, and for the latter use it has conveniently been packaged into 2ml ampoules for injection, each ampoule containing lOmg metoclopramide in saline solution. It has also been found necessary to include an effective level of the antoxidant sodium metabisulphite in the injectable composition to maintain stability.

Recently, the injectable composition has been used in association with certain types of cancer chemotherapy in which an anti-cancer agent such as Cisplatin is administered, and where a side effect of such treatment is severe nausea and vomiting. However, Cisplatin has been found to be incompatible with sodium metabisulphite, and this has limited the extent to which metoclopramide can be used in the chemotherapy treatment.

We have now found that, surprisingly, sodium metabisulphite can be omitted from the injectable composition without unduly affecting the stability of the composition, and that as a result larger ampoules, of up to 20ml in size, can be employed in combination with Cisplatin in infusion for the chemotherapy treatment. It is also possible to include small amounts of sodium metabisulphite, substantially less than the 0.15% by weight of metabisulphite hitherto employed in the 2ml ampoule size, without having compatibility problems with Cisplatin.

Accordingly, the present invention provides a parenteral pharmaceutical composition comprising metoclopramide or a pharmaceutically acceptable salt thereof and from 0 to 0.06% by weight of the composition of sodium metabisulphite, in combination with a pharmaceutically acceptable liquid carrier.

Preferably the amount of sodium metabisulphite present is from 0% to 0.006% by weight of the composition and most preferably 0% of sodium metabisulphite is present.

Examples of a pharmaceutically acceptable salt of metoclopramide include the hydrochloride.

Preferably, the liquid carrier comprises sterile saline solution.

The amount of metoclopramide administered to a patient should be sufficient to exert an anti-emetic effect. An anti-emetically effective amount of metoclopramide will depend on a number of factors such as the severity of the ernesis being treated and the body weight of the patient. However in general a dosage of from 0.014 mg/kg to 10 mg/kg per day will be administered to a human.

Suitably the composition is in a unit dosage form, such as an ampoule, preferably containing an anti-emetically effective amount of metoclopramide. A unit dose in excess of lmg, in particular m excess of lOmg, for a 70kg adult will have an anti-emetic effect. For the severe eraesis caused by cancer chemotherapy, such as by Cisplatin therapy, however, a unit dose of 50 to 200 mg, in particular about lOOmg, is preferred. The volume of the unit dose may be from 1ml to 40 ml, in J / 3 particular from 2ml to 20ml, the smaller volumes correlating with the smaller dosage units and the larger volumes with the larger dosage units. The larger volumes are thus most suitable for use m cancer chemotherapy such as Cisplatin therapy.

The unit dose may be administered from once a day to as many times as is necessary to give a dosage in 24 hours of from 0.014 to 10 mg/kg bodyweight. Thus for example in the aforementioned Cisplatin therapy, a lOOmg unit dose of metoclopramide may suitably be administered from 1 to 7 times in a 24 hour period to a 70kg adult.

The composition of the invention may be prepared by admixing the components in conventional manner.

Further according to the present invention there is provided a method of treating nausea and vomiting which comprises administering to a patient m need thereof an anti-emetically effective amount of a composition of the invention.

The invention is now illustrated by means of the following Example.

Example The following formulations were made up as follows: Formulation 1 Metoclopramide hydrochloride BP Sodium chloride BP Water for injection BP % w/v 0.526 0.800 to 100.000 £ 4s-, 4 Formulation 2 Metoclopramide hydrochloride BP Sodium chloride BP Sodium metabisulphite Water for injection BP to 100.000 0.006 0.526 0.800 Preparation 1 The sodium chloride, sodium metabisulphite where present and the metoclopramide hydrochloride were dissolved in that order in boiled water for injection BP (about 80% final volume) at below 30°C under stirring and with nitrogen bubbled through the water. The solution was made up to the final volume with water for injection at below 30°C. The solution was filtered under nitrogen pressure through a 5nm filter, collected and filled into 20ml glass ampoules under nitrogen. The product was sterilised by heat treatment of the sealed ampoules in an autoclave.

Preparation 2 The above procedure was repeated except that the final solution was filtered through a sterilising filter, and the filling was effected in a sterile area. &CW MENDED WHAT WE CLAIM IS: 1. A parenteral pharmaceutical composition comprismc metoclopramide or a pharmaceutically acceptable salt thereof, and from 0 to 0.06% by weight of/the composition of sodium metabisulphite, in combination with a pharmaceutically acceptorle liquid carrier. 2. A composition according to claim 1 whdch contains from 0 to 0.006% by weight of the composition of sodium metabisulphite.

A composition according to clainr 1 or 2 which contains 0% of sodium metabisulphite.

/ A composition according to .any one of clainys 1 to 3 wherein the metocloprampfrle is in the fotfm of the hydrochloride salt.

/ / / A composition accordyig to any one preceding claims lia unit dosage fo/m. the A composition according to claiity5 wherein the unit dosage fo^m contains at l^ast 1 mg of metoclopramide or a pharmaceiytically acceptable salt thereof.

A composition according tgf claim 6 wherein the unit dosage /orm contains fn6m 50 to 200 mg of armaceutically acceptable salt/thereof. 8. A/composition according to claim 7 wherein the fanit dosage contains 100 mg of metoclopramide or a pharmaceuticaVly acceptable salt thereof.

A composition according to any one of claims 5 to 8 wherein^the volume of the unit dosage is from 1 ml to/40 ml.

Claims

212097 - 5 - WE CLAIM IS

A parenteral pharmaceutical composition in umt dosage torm comprising metoclopramide or a pharmaceutically acceptable salt thereof, and from 0 to 0 06% by weight of the composition of sodium metabisulphite, in combination with a pharmaceutically acceptable liquid carrier
A composition according to claim 1 which contains from 0 to 0 006% by weight of the composition of sodium metabisulphite
A composition accordmg to claim 1 or 2 which contains 0% of sodium metabisulphite
A composition according to any one of claims 1 to 3 wherein the metoclopramide is in the form of the hydrochloride salt
A composition according to any one of claims 1 to 4, containing at least 1 mg of metoclopramide or a pharmaceutically acceptable salt thereof
A composition accordmg to any one of claims 1 to 5, containing from 50 to 200 mg of metoclopramide or a pharmaceutically acceptable salt thereof
A composition accordmg to any one of claims 1 to 6, contaimng 100 mg of metoclopramide or a pharmaceutically acceptable salt thereof
A composition accordmg to any one of claims 1 to 7 wherein the volume of the umt dosage is from 1 ml to 40 ml
A composition according to claim 8 wherein the volume of the umt dosages is from 2 ml to 20 ml ROW AMENDED _ 6 _
A composition according to claim 9 whereirf the volume of the unit dosages is from 2 ml po 20 ml.
11. A parenteral pharmaceutical compositic according to claim 1 substantially as hereinbefore described with reference to the example i 212097 - 6 - 10 A parenteral pharmaceutical composition comprising metoclopramide or a pharmaceutically acceptable salt thereof, and 0% by weight of the composition of sodium metabisulphite, in combination with a pharmaceutically acceptable liquid earner 11 A composition accordmg to claim 10 wherein the metoclopramide is in the form of the hydrochlonde salt 12 A parenteral pharmaceutical composition accordmg to claim 1 substantially as hereinbefore desenbed with reference to the examples $ r a ^ c>(f J. PA ft K & SON p-q \§4>\*XK ^.FNTS FOR THE APPLICANTS END