AU747596B2 - Aqueous pharmaceutical composition - Google Patents

Description

S&FRef: 508011

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

4 *4 *r 4 4*s* .r *4 4 4 Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Actelion Pharmaceuticals Ltd Gewerbestrasse 16 CH-4123 Allschwil Switzerland Peter Loeliger Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Aqueous Pharmaceutical Composition The following statement is a full description of this invention, including the best method of performing it known to me/us:- IP Australia Documents rerpi"" nr: 1 9 MAY 2000 Batch No: 5845c ACTELION1F1 Aqueous Pharmaceutical Composition The invention relates to a stable aqueous pharmaceutical composition comprising containing 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2-methoxy-phenoxy)2-(2-1 H- 15 tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide in form of the water soluble disodium salt, a buffer and a metal complex forming agent, the liquid having a pH of over and above 8,2 but not Shigher than Some of the salts of 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2-methoxyphenoxy)2-(2-1H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide are water soluble and the preparation of an aqueous pharmaceutical composition containing the disodium salt appeared to be without any problems.

Vials for clinical testing of 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2methoxy-phenoxy)2-(2-1 H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide have been prepared S: by dissolving the compound in water containing as buffer 2-amino-2-hydroxymethyl-1,3propandiol and very small amounts of ethylene diaminetetraacetic acid disodium salt as a competitive metal complex forming agent and thereafter heating the mixture in an autoclave for 20 minutes at about 121°C in order to sterilize the mixture in the vials (compare General Example which can be considered to correspond to a usual way of preparing such a water soluble formulation).

After storage of the vials at room temperature for about a year the inspection thereof revealed that the liquid contains in a number of vials visual particles which is not the case in a stable pharmaceutical composition. The number of such undesired visual particles increased with time of storage. This fact rendered these vials unsuitable for clinical trials and commercial purposes because already after some months of storage particles were visible and hence the storage time and consequently the expiration date of a given batch was much too short.

Since for practical purposes it is not feasible to run real time experiments with different parameters like different buffers, different metal complex forming agents, different origins of the ingredients, different filter media, different stopper types, different glass types of the vials, different sterilizing times etc. because for each such experiment the results would only be available after at least a year of storage, a model experiment was therefore developed in form of stress heating the vials. The assumption was made that after prolonged heating at 121oC a simulation of a long storage time is achieved. It was further expected that the results obtained after cooling of the vials to room temperature will correspond to the results of a storage time of at least one year i.e. formation of small visual particles will occur. However, even with up to 12 hours of stress heating at 121oC no particles could be seen after cooling the vials to room temperature. Even after hours and/or days the solution in the vials was still clear.

It happened that in a repetition of stress experiments vials were used from a batch presumably prepared identical to the vials from the batch used in an earlier experiments. However this .batch behaved differently inasmuch as after 12 hours of heating at 121oC a precipitate formed after cooling to room temperature. Direct comparison of the two batches confirmed the 20 different behaviour.

Itl* By means of HPLC it could be shown that this precipitate consisted mainly of a single substance (single HPLC-peak) which is called hereinafter compound X. Beside compound X number of other completely soluble decomposition products in more or less similar amounts as compound X can be detected in the HPLC chromatogram.

Careful examination of the two batches revealed that in the batch with the precipitate the pH by mistake had been adjusted to 7,58 instead to 8,0. Therefore the investigation of the influence of the pH on precipitate formation in a number of stress heating experiments was now performed. It was found that the formation of compound X and the other decomposition products was depending on the pH of the formulation and this formation was very small if at all at a pH over and above pH 8,2. For further verification and demonstration stress heating experiments were performed in a time range up to 64 hours. In the following Table 1 the results of representative experiments which are described in detail in the experimental part) are outlined: 3 Table 1 Experiment pH Stress heating time(121 0 C) Educt found Compound X found 1 7,0 12 hrs 96,02 1,00 2 8,0 12 hrs 98,06 0,38 3 8,5 12 hrs 98,63 0,20 4 9,0 12 hrs 98,93 0,12 7,0 64 hrs 78,62 4,99 6 8,0 63 hrs 96,06 1,17 7 8,5 63 hrs 98,24 0,45 8 9,0 63 hrs 98,76 0,21 O. SIn addition to the figures outlined in Table 1 it may be stated that the content of Educt and Compound X after 20 min. of sterilizing the vials at 121°C i.e. under "normal sterilization conditions" but applying the pH- conditions given in Table 1 were 20 99,30% to 99,33% Educt to 0,09% Compound X.

o: The results set forth in Table 1 illustrate that the increase of the formation of Compound X after 12 hrs at 121°C in the pH 9 formulation as compared to the "normal sterilization conditions" is almost negligible, i.e. 0,03%, whereas e.g. at pH 8 the increase is 10 times higher, i.e. 0,3%.

It could further be shown, by filtering a large number of vials originally prepared ("normal sterilization conditions") and stored longer than one year at room temperature and investigating the tiny amounts of particles (residue) sitting on the filter by dissolving them with Ethanol in order to perform HPLC analysis, that these particles did also contain as a major component compound X.

This fact is not understood since compound X is rather readily water soluble.

However this finding allows the conclusion that although even after 12 hours of stress heating at pH 8,0 a clear solution is obtained a normal formulation prepared without stress heating can form such very small but sometimes visible particles maybe together with 4 another carrier?) after a long time (several months) of storage at room temperature. This, in spite of the fact that the main component of the particles is compound X which is readily water soluble.

These findings allowed us to conceive a drastically improved and stable pharmaceutical composition which is assumed to be and to remain free of visible particle.

This assumption turned out to be so far correct, even after 14 months of storage at room temperature.

Therefore, in accordance with a first embodiment of the invention there is provided a stable aqueous pharmaceutical composition (not forming visible particles on storage) comprising 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide in the form of the water soluble disodium salt, a buffer, and preferably, a metal complex forming agent, the liquid having a pH of over and above 8.2 but not higher than eq S. According to a second embodiment of the invention there is provided a process for 15 the preparation of a stable aqueous pharmaceutical composition (not forming visible particles on storage) comprising dissolving 5-isopropyl-pyridine-2-sulfonic acid 6-(2hydroxyethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4ylamide in the form of the water soluble disodium salt in water, adding to the solution a buffer, preferably a metal complex forming agent and titrating the mixture obtained with S• 20 an acid until a pH over and above 8.2 but not higher than 10 is reached.

A preferred acid for adjusting the pH of the mixture is 2N hydrochloric acid. A preferred range of the pH is between 8.5 and 9.5. The preferred pH is 9.

A preferred buffer is 2-amino-2-hydroxymethyl-1,3-propanediol (TRIS) and a preferred metal complex forming agent is ethylenediaminetetraacetic acid disodium salt (EDTA). A preferred mixture consists of 0.01 to 0.1% EDTA and 0.1 to 1.0% of TRIS.

Experimental Part The following experiments describe in detail how the results set forth in experiments 1 to 8 in Table 1 have been obtained. The experiments are illustrating the invention but do not limit the scope thereof.

[R:\LJBH]01 General Experiment illustrating the Preparation of Formulations 1. In a glass or stainless steel container place a volume of Nitrogen-gassed water for injection equal to approximately 90% of the final volume to be manufactured (according to the following amounts specified for about 1 liter).

2. Add and dissolve the following excipients in the water while mixing: 1,21 g 2-Amino-2-hydroxymethyl-1,3-propanediol (TRIS) 0,1 g Ethylene diaminetetraacetic acid disodium salt (EDTA) 7,2 g Sodium chloride 15 3. With strong mixing, slowly add 26,81 g of 5-lsopropyl-pyridine-2-sulfonic acid 6-(2- .o* hydroxy-ethoxy)-5(2-methoxy-phenoxy)2-(2-1 H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4- Sylamide disodium salt by stewing it on the water surface. The formation of clots of substance is avoided.

20 4. Check and record the pH of the solution. Adjust to the desired pH with freshly prepared 2 N Hydrochloric Acid Solution.

5. Bring the solution to the final 1,0 liter volume with water for injection and mix thoroughly.

Check and record the final pH of the solution as desired 6. Sterilize solution by filtration through a sterile 0,2 um-rated filter into a sterile receiving flask.

7. Aseptically fill the solution into clean, sterile, depyrogenated glass vials and insert a sterile serum stopper onto each vial.

8. Seal the stopper with a cap.

9. Sterilize the filled and closed vials in a circulating water autoclave 20 min. at 121 C.

6 Experiment 1 The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 7; stress heating time (at 121°C) 12 hours.

Experiment 2 The General Example is repeated using the adjustments of pH and stress heating time as set 15 forth in Table 1, i.e.

pH 8; stress heating time (at 121°C) 12 hours.

Experiment 3 SThe General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 8,5; stress heating time (at 121C) 12 hours.

Experiment 4 The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 9; stress heating time (at 121C) 12 hours.

Experiment The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 7; stress heating time (at 121°C) 64 hours.

Experiment 6 The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 8; stress heating time (at 121°C) 63 hours.

Experiment 7 The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 8,5; stress heating time (at 121°C) 63 hours.

0: 0: Experiment 8 The General Example is repeated using the adjustments of pH and stress heating time as set forth in Table 1, i.e.

pH 9; stress heating time (at 121°C) 63 hours.

Result: 8 The formulations illustrated by Experiments 1, 2, 5 and 6 when performed without stress heating do form visible particles after storage of several months at room temperature.

The formulations illustrated by Experiments 3, 4, 7 and 8 when performed without stress heating do not form visible particles after storage of several months at room temperature.

Claims (15)

1. A stable aqueous pharmaceutical composition comprising pyridine-2-sulfonic acid 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5- yl-pyridin-4-yl)-pyrimidin-4-ylamide in form of the water soluble disodium salt and a buffer, the liquid having a pH of over and above 8.2 but not higher than

2. The stable aqueous pharmaceutical composition according to claim 1, comprising a metal complex forming agent.

3. The aqueous pharmaceutical composition according to claim 2, comprising as metal complex forming agent ethylenediaminetetraacetic acid disodium salt.

4. The aqueous pharmaceutical composition according to any one of claims 1, 2 and 3, comprising as the buffer 2-amino-2-hydroxymethyl-1,3-propanediol.

The aqueous pharmaceutical composition according to any one of claims 1 to 4, comprising a mixture of 2-amino-2-hydroxymethyl-l,3-propanediol and ethylene S" diaminetetraacetic acid disodium salt. 15

6. The aqueous pharmaceutical coniposition according to any one of claims 1 and 5, comprising a mixture of 0.1 to 1.0% 2-amino-2-hydroxymethyl-l,3-propanediol and 0.01 to 0.1% ethylene diaminetetraacetic acid disodium salt.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 6, comprising a liquid, the pH of which is in between 8.5 and

8. The aqueous pharmaceutical composition according to any one of claims 1 to 7, comprising a liquid, the pH of which is o

9. The stable aqueous pharmaceutical composition according to any one of claims 1 to 8 when administered to patients.

10. An aqueous pharmaceutical composition, substantially as hereinbefore described with reference to any one of the examples.

11. A process for the preparation of a stable aqueous pharmaceutical composition comprising dissolving 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide in the form of a water soluble disodium salt in water, adding to the solution a buffer and titrating the mixture obtained with an acid until a pH over and above 8.2 but not higher than 10 is reached.

12. The process according to claim 10, comprising adding to the mixture a metal complex forming agent. [R:\LIBH]01175.doc:ljg

13. The process according to claim 10, comprising titrating the mixture with 2 N hydrochloric acid until a pH of 9.0 is reached.

14. A process for the preparation of a stable aqueous pharmaceutical composition, substantially as hereinbefore described with reference to any one of the examples.

15. A stable aqueous pharmaceutical composition prepared according to the process of any one of claims 11 to 14. Dated 18 March, 2002 Actelion Pharmaceuticals Ltd Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S f i f* *o if ifS if. S. 1 if i S. if i 0 oif if if *ift if if if* S. 0 if if if- 00 S i *f ft f ft *tfft [R:\LIBH]OI 175.doc:ljg