Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-18
2001-11-13
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S970000
Reexamination Certificate
active
06316453
ABSTRACT:
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-(2-1H-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 higher than 10.
Some of the salts of 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2-methoxy-phenoxy)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(2-methoxy-phenoxy)2-(2-1H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide have been prepared by dissolving the compound in water containing as buffer 2-amino-2-hydroxymethyl-1,3-propandiol 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 121° C. 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 121° C. 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 121° C. a precipitate formed after cooling to room temperature. Direct comparison of the two batches confirmed the different behaviour.
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 a 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:
TABLE 1
Stress heating
% Compound
Experiment
pH
time (121° C.)
% Educt found
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
5
7.0
64 hrs
78.62
4.99
6
8.0
63 hrs
98.06
1.17
7
8.5
63 hrs
98.24
0.45
8
9.0
63 hrs
98.76
0.21
In 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
99.30% to 99.33% Educt
0.08% to 0.09% Compound X.
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 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 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, the invention relates to a stable aqueous pharmaceutical composition (not forming visible particles on storage) comprising containing 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2-methoxy-phenoxy)2-(2-1H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide in 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 10.
Furthermore the invention relates to a process for the preparation of a stable aqueous pharmaceutical composition (not forming visible particles on storage) comprising dissolving 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5(2-methoxy-phenoxy)2-(2-1H-tetrazol-5-yl-pyridin-4yl)-pyrimidin-4-ylamide in 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 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 2 N 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 ethylene diaminetetraacetic acid disodium salt (EDTA). A preferred mixture consists of 0.01 to 0.1% EDTA and 0.1 to 1.0% of TRIS.
REFERENCES:
patent: 6004965 (1999-12-01), Breu et al.
Actelion Pharmaceuticals Ltd.
Krass Frederick
Pennie & Edmonds LLP
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