WO1995010274A1

WO1995010274A1 - Aqueous pharmaceutical composition

Info

Publication number: WO1995010274A1
Application number: PCT/AU1994/000615
Authority: WO
Inventors: Alan Duncan Robertson; Clive John Blower
Original assignee: F.H. Faulding & Co. Limited
Priority date: 1993-10-14
Filing date: 1994-10-11
Publication date: 1995-04-20

Abstract

A pharmaceutical composition including an aqueous formulation of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; and a buffer including an organic acid salt; and a supplementary buffering component, in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5.

Description

AQUEOUS PHARMACEUTICAL COMPOSITION The present invention relates to an aqueous pharmaceutical composition including ranitidine, and a process for preparing same. Ranitidine is a pharmaceutical useful in the short term treatment of duodenal ulcers and gastric ulcers, including intravenous use for prophylaxis against recurrent haemorrhage. Ranitidine and its pharmaceutically acceptable salts have the chemical formula [N-[2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]-thio]ethyl]-N'-methyl-2-nitro- 1 ,1-ethenediamine. Ranitidine and its pharmaceutically acceptable salts were first described in British Patent No. 1 ,565,966. Whilst formulations known in the prior art containing ranitidine are therapeutically effective, they suffer from the disadvantage of having a relatively short shelf life due to the breakdown of the ranitidine. This is particularly so with aqueous formulations.

One solution offered by the prior art is described in United States Patent 4,585,790 to Glaxo Group Ltd., which discloses an aqueous based ranitidine formulation that is buffered so that it has a pH in the range of 6.5 to 7.5. Citrate and phosphate salts are used as buffers. Whilst such a system has improved the stability of ranitidine formulations somewhat, the Glaxo patent still suffers some stability problems and has the disadvantage that during sterilisation of the formulation approximately 4% to 8% of the ranitidine degrades.

Accordingly, it is an object of the present invention to overcome, or at least alleviate, one or more of the difficulties related to the prior art.

Accordingly, in a first aspect there is provided a pharmaceutical composition including an aqueous formulation of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; and a buffer including an organic acid salt; and a supplementary buffering component, in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5.

It has surprisingly been found that the buffered aqueous pharmaceutical composition according to this aspect of the present invention exhibits excellent stability and extended shelf life. The ranitidine or its pharmacologically acceptable salts may be present in the pharmaceutical composition in any suitable concentration. The ranitidine may be present in a concentration of from approximately 1 to 40 mg/ml, preferably 20 to 30 mg/ml, more preferably approximately 25 to 30 mg/ml (base equivalent) of water for injection. The ranitidine may be present as the ranitidine hydrochloride.

The buffer according to this aspect of the present invention may be present in any suitable amounts to provide a pH of the composition in the range of approximately 5.5 to 6.5, preferably approximately 5.9 to 6.25. The buffer may be present at concentrations in the range of approximately 5 to 20 mg/ml, preferably approximately 5 to 12 mg/ml.

The organic acid salt in the buffer may be of any suitable type. A citric acid, tartaric acid or succinic acid salt may be used. A succinic acid salt is preferred. The organic acid salt may be present in amounts of from approximately 50 to 95% by weight, based on the total weight of the buffer components, preferably approximately 75 to 90% by weight.

Thus the pharmaceutical composition desirably includes an aqueous formulation of a ranitidine salt in a concentration of from approximately

1 to 40 mg/ml; and a buffer including approximately 50 to 95% by weight, based on the total weight of the buffer components, of an organic acid salt selected from citric acid, tartaric acid or succinic acid, or mixtures thereof; and approximately 5 to 50% by weight, based on the total weight of the buffer components of a supplementary buffering agent selected from organic acids and organic acid salts and mixtures thereof.

The supplementary buffering component may be of any suitable type. The supplementary buffering component may be selected from organic acids and organic acid salts. The organic acid may be the same as or different from those present in the organic acid salt of the buffer. A succinic acid component may be used. Desirably, a succinic acid component is used in combination with a succinic acid salt. Alternatively, an organic acid salt such as sodium hydrogen tartrate may be used as the supplementary buffering component. The supplementary buffering component may be present in amounts of from approximately 5 to 50% by weight, based on the total weight of the buffer, preferably approximately 10 to 25% by weight.

The buffered aqueous pharmaceutical composition may, where required, include a pH modifier. The pH modifier may be an acid or base. An inorganic acid such as hydrochloric acid or an alkali metal hydroxide such as sodium hydroxide may be used as the pH modifier. The pH modifier may be included in concentrations of approximately 0.25 to 2.5 mg/ml, preferably approximately 0.25 to 0.75 mg/ml. The pharmaceutical composition according to the present invention may further include supplementary excipients or conventional pharmaceutical additives such as lactose, dextrose, sodium carbonate, hexitols such as mannitol, C12 sugars, dextrans or mixtures thereof. Supplementary excipients may be present in amounts of from 0 to approximately 10% by weight based on the total dry weight of the pharmaceutical composition, more preferably approximately 4.0% by weight to 7.5% by weight.

In a preferred aspect, the aqueous pharmaceutical composition may be formulated for parenteral administration. The parenteral composition may conveniently be prepared by dissolving ranitidine and/or one or more of its pharmaceutically acceptable salts and the excipients in water suitable for injection. The solution, which conveniently is sparged with an inert gas such as nitrogen, is sterilised preferably by filtration and then aseptically packed into suitable containers, e.g. ampoules, vials or containers for infusion, under an atmosphere of nitrogen. Alternatively the formulation may be terminally sterilised, for example by heating.

In a further preferred aspect, an aqueous pharmaceutical composition may be formulated for oral administration. The oral composition may include ranitidine and/or one or more of its pharmaceutically acceptable salts dissolved in water, together with buffer, a preservative and a viscosity enhancing agent. Optionally the composition may also contain other conventional excipients such as a sweetener, a flavour and/or flavouring aids.

Examples of suitable viscosity enhancing agents include Xanthan gum, sorbitol, glycerol, sucrose or a cellulose derivative such as carboxymethyl cellulose or an ether thereof such as an alkyl and/or a hydroxyalkyl ether of cellulose as for example hydroxypropylmethylcellulose.

Suitable preservatives include the alkyl hydroxybenzoates, such as methyl, ethyl, propyl and/or butyl hydroxybenzoates. Suitable sweeteners include saccharin sodium, sodium cyclamate, sorbitol and sucrose.

Accordingly, in a still further aspect of the present invention there is provided a process for preparing a pharmaceutical composition as described above, which process includes providing an effective amount of ranitidine and/or its pharmaceutically acceptable salts; a buffer including an organic acid salt and a supplementary buffer component in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5; water; and a mixing vessel; adding approximately 30 to 80% by volume of the water to the mixing vessel; dissolving the ranitidine and/or salt therein; and sequentially adding the supplementary buffering component, organic acid salt and residual water thereto.

The process may further include sparging the solution so formed; and subjecting the solution to a sterilisation step. Sparging of the solution may be conducted with nitrogen. The sterilisation step may include a filtration step.

The solution thus formed may then be aseptically packed in ampoules or vials under an atmosphere of nitrogen.

Where a pH modifier is required, the pH modifier may be added before or after the ranitidine or salt is added to the water.

The pharmaceutical compositions according to the present invention may be utilised in the treatment of ulcers and the like in a similar manner to standard Ranitidine formulation. Accordingly, in a further aspect, there is provided a process for the therapeutic or prophylactic treatment of ulcers and related indications which process includes administering to a patient requiring such treatment a therapeutically or prophylactically effective amount of a pharmaceutical composition including an aqueous formulation of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; and a buffer including an organic acid salt; and a supplementary buffering component, in an amount sufficient to provide a pH of the composition in the range of approximately 6.0 to 6.5.

Preferably the pharmaceutical composition includes an aqueous formulation of a ranitidine salt in a concentration of from approximately 1 to 40 mg/ml; and a buffer including approximately 50 to 95% by weight, based on the total weight of the buffer components, of an organic acid salt selected from citric acid, tartaric acid or succinic acid, or mixtures thereof; and approximately 5 to 50% by weight, based on the total weight of the buffer components of a supplementary buffing agent selected from organic acids and organic acid salts and mixtures thereof; in a concentration of approximately 5 to 20 mg/ml.

The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the description following is illustrative only and should not be taken as a restriction on the generality of the invention described above.

EXAMPLE 1 Ranitidine hydrochloride 28 mg (25 mg base equivalent)

Sodium citrate 5.0 mg

Sodium hydrogen tartrate 1.1 mg Water 1.0 mL pH = 6.06

Mixing Instructions

To a clean mixing vessel was added 80% of volume of water for injection. Ranitidine hydrochloride was added followed by sodium hydrogen tartrate. Sodium citrate was then added followed by the required amount of water for injection to make up to volume. The solution was sparged with nitrogen, sterilised by filtration and then aseptically packed into ampoules under an atmosphere of nitrogen.

Stability Information

Tartrate formulation stability data:

40°C Potency (%) Impurities (%) PH

Initial 103.8 - 6.06

2 weeks 102.7 0.23 6.08

4 weeks 101.0 0.71 6.4

EXAMPLE 2

Ranitidine hydrochloride 28 mg (25 mg base equivalent) Succinic acid 1.04 mg

Sodium succinate 6.0 mg Sodium hydroxide (1.ON) 0.5 mg

Water 11..00 mmLL pH = 6.06

Mixing Instructions To a clean mixing vessel was added 80% of volume of water for injection.

The required amount of sodium hydroxide was added followed by the ranitidine hydrochloride. Succinic acid was added, followed by sodium succinate and finally the required amount of water for injection to make up to volume. The solution was sparged with nitrogen, sterilised by filtration and then aseptically packed into ampoules under an atmosphere of nitrogen. Stability Information Succinic acid/sodium succinate buffered formulation stability data:

40°C Potency % Impurities % PH Colour

Initial 104.6 N/R 6.04 Colourless

1 month 100.7 0.69 6.24 Colourless

2 months 100.6 0.89 6.18 Colourless

3 months 101.0 1.1 6.23 Faint yellow In a separate study, the following trends at 25°C and 40°C were observed:

Test Point Temp (°C) Potency Impurities PH Colour (%) (%)

Initial 2 - 8 104.0 0.04 6.13 Colourless

6 months 25 104.7 0.49 6.34 Colourless

6 months 40 101.8 2.23 6.40 Pale straw yellow

Finally, it is to be understood that various other modifications and/or alterations may be made without departing from the spirit of the present invention as outlined herein.

Claims

1. A pharmaceutical composition including an aqueous formulation of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; and a buffer including an organic acid salt; and a supplementary buffering component, in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5.

2. A pharmaceutical composition according to Claim 1 , wherein the supplementary buffering component is present in an amount sufficient to provide a pH of the composition in the range of approximately 5.9 to 6.25.

3. A pharmaceutical composition according to Claim 2, wherein the buffer includes approximately 50 to 95% by weight, based on the total weight of the buffer components, of an organic acid salt selected from citric acid, tartaric acid or succinic acid, or mixtures thereof; and approximately 5 to 50% by weight, based on the total weight of the buffer components of a supplementary buffering agent selected from organic acids and organic acid salts and mixtures thereof.

4. A pharmaceutical composition according to Claim 3, wherein the supplementary buffering agent is a succinic acid salt or tartaric acid salt.

5. A pharmaceutical composition according to Claim 1 , further including a pH modifier.

6. A pharmaceutical composition including an aqueous formulation of a ranitidine salt in a concentration of from approximately 1 to 40 mg/ml; and a buffer including approximately 50 to 95% by weight, based on the total weight of the buffer components, of an organic acid salt selected from citric acid, tartaric acid or succinic acid, or mixtures thereof; and approximately 5 to 50% by weight, based on the total weight of the buffer components of a supplementary buffing agent selected from organic acids and organic acid salts and mixtures thereof; in a concentration of approximately 5 to 20 mg/ml.

7. A pharmaceutical composition according to Claim 1 , further including 0 to approximately 10% by weight, based on the total dry weight of the pharmaceutical composition of a supplementary excipient or conventional pharmaceutical additive selected from the group consisting of lactose, dextrose, sodium carbonate, hexitols such as mannitol, C12 sugars, dextrans or mixtures thereof.

8. A pharmaceutical composition according to Claim 1 , formulated for parenteral administration.

9. A pharmaceutical composition according to Claim 1 , formulated for oral administration and further including a preservative and a viscosity enhancing agent.

10. A pharmaceutical composition according to Claim 9, wherein the viscosity enhancing agent is selected from the group consisting of Xanthan gum, sorbitol, glycerol. sucrose or a cellulose derivative or an ether; and the preservative is an alkyl hydroxybenzoate.

11. A process for preparing a pharmaceutical composition, which process includes providing an effective amount of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; a buffer including an organic acid salt; and a supplementary buffer component in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5; water; and a mixing vessel; adding approximately 30 to 80% by volume of the water to the mixing vessel; dissolving the ranitidine and/or salt therein; and sequentially adding the supplementary buffering component, organic acid salt and residual water thereto.

12. A process according to Claim 11 , further including sparging the solution so formed; and subjecting the solution to a sterilisation step.

13. A process according to Claim 10 wherein a pH modifier is added before or after the ranitidine or salt is added to the water.

14. A process for the therapeutic or prophylactic treatment of ulcers and related indications which process includes administering to a patient requiring such treatment a therapeutically or prophylactically effective amount of a pharmaceutical composition including an aqueous formulation of a pharmaceutically active ingredient including ranitidine and/or its pharmaceutically acceptable salts; and a buffer including an organic acid salt; and a supplementary buffering component, in an amount sufficient to provide a pH of the composition in the range of approximately 5.5 to 6.5.

15. A process according to Claim 14 wherein the pharmaceutical composition includes an aqueous formulation of a ranitidine salt in a concentration of from approximately

1 to 40 mg/ml; and a buffer including approximately 50 to 95% by weight, based on the total weight of the buffer components, of an organic acid salt selected from citric acid, tartaric acid or succinic acid, or mixtures thereof; and approximately 5 to 50% by weight, based on the total weight of the buffer components of a supplementary buffing agent selected from organic acids and organic acid salts and mixtures thereof; in a concentration of approximately 5 to 20 mg/ml.

16. A pharmaceutical composition according to Claim 1, substantially as hereinbefore described with reference to Example 1 or 2.