Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-06-18
2003-04-22
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S013000
Reexamination Certificate
active
06552082
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a solution of N-[o-(p-pivaloyloxybenzenesulfonylamino)benzoyl]glycine monosodium salt tetra-hydrate of formula (I)
comprising a specific pH adjuster, and a drug product using the solution.
BACKGROUND ART
As to the compound used in the present invention, a free compound thereof, i.e. N-[o-(p-pivaloyloxybenzene-sulfonylamino)benzoyl]glycine of formula (II)
is described in example 2 (63) of JP kokai hei 3-20253 (i.e. EP 0 347 168) and a monosodium salt tetra-hydrate thereof, i.e. the compound of formula (I) is described in example 3 of JP kokai hei 5-194366 (i.e. EP 0 539 223) and reference example of JP kokai hei 9-40692 (no EP publication).
The compound (I) has an inhibitory activity against elastase and is a very useful compound which is expected to be used for the treatment of acute pulmonary disorders etc. Since those patients suffering from acute pulmonary disorders are in a serious condition, it is necessary to administer a drug parenterally, preferably as an injection for a long time (from 24 hours to several days) continuously. Therefore the compound (I) is preferably formulated as an injection or a solid composition to be dissolved before administration, more preferably formulated as a freeze-dried drug product.
However, the solubility of the compound (I) in water is less than 0.4 mg/mL and its solubility in ethanol is less than 6 mg/mL, and so it was hard to prepare a clear solution thereof for injection using normal solvents.
On the other hand, JP kokai hei 9-40692 discloses a method for the preparation of the compound (I) by suspending a compound of formula (II) to a mixture of water and ethanol, adding sodium hydroxide thereto and heating and then cooling. This operation shows a method for the preparation of a sodium salt tetra-hydrate from a free carboxylic form of formula (II) but does not intend to improve the solubility of sodium salt tetra-hydrate of formula (I).
DISCLOSURE OF INVENTION
The object of the present invention consists in improving the solubility of the compound (I), and thereby providing a solution thereof and some kinds of drug products using the solution, moreover providing a solution of higher concentration and a high-dosage drug product using the solution.
Considering the effective dose of the compound (I) and the volume of suitable closed containers (vials, ampoules, etc.), the required solubility of the compound (I) is estimated to be more than 15 mg/mL.
As a result of energetic investigations in order to improve the solubility of the compound (I), surprisingly, the present inventors have found that the purpose was accomplished by adding at least one pH adjuster selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide to the solution.
As a result of another investigation to obtain a solution of higher concentration of the compound (I), the object is accomplished by using a kind of organic solvent except water in addition to using pH adjusters.
That is, the present invention relates to a solution of N-[o-(p-pivaloyloxybenzenesulfonylamino)benzoyl]glycine monosodium salt tetra-hydrate of formula (I)
comprising at least one pH adjuster selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide and a drug product using the solution.
More particularly, the present invention relates to a solution of N-[o-(p-pivaloyloxybenzenesulfonylamino)-benzoyl]glycine monosodium salt tetra-hydrate of formula (I) comprising at least one pH adjuster selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide in which the solvent is exclusively water, a solution wherein the solvent is a mixture of water and an organic solvent or a novel drug product using the solution optionally comprising excipients.
Besides, the present invention includes a novel freeze-dried drug product comprising the compound (I) and at least one pH adjuster selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide.
As the present inventors first considered that the solubility of the compound (I) was greatly subject to the pH of the solution, the relationship between the solubility and pH was investigated.
On the other hand, since the compound (I) has an ester bond in its structure and it was assumed to be unstable in a basic aqueous solution, the present inventors investigated the influence of pH on the stability of the compound (I) at the same time.
(1) The Measurement of Solubility and Stability
Aqueous solutions of di-sodium hydrogen phosphate and tri-sodium phosphate were mixed in various ratios to prepare buffers of various pH. To the prepared buffers was added sodium chloride in order to fix the ionic strength of the buffers to be 0.2. At 25 degrees Centigrade condition, to each buffer was added the compound (I), and then according to the method of solubility test of Japan pharmacopoeia, a saturated solution was prepared by stirring for 30 seconds every 5 minutes for 30 minutes. Each solution was centrifuged and the supernatant was filtrated. The concentration of the filtrate was calculated by liquid chromatography and was defined as the solubility (mg/mL) and the measured value was defined as the initial value of the stability test. The results of measurement of the solubility are shown in
FIG. 1
(open circles in the figure).
After each filtrate was incubated at 25 degrees Centigrade for eight hours, the residual rates, or amount of residue as a percentage, of the compound (I) were measured by liquid chromatography. The residual rate after eight hours was defined as the parameter for judging the stability. The results are shown in
FIG. 1
(triangles in the figure).
FIG. 1
shows that the higher the pH is, the better the solubility of the compound (I) is, while it shows that the higher the pH is, the more decomposed the compound is. Therefore in order to use the compound (I) as a pharmaceutical product, it is necessary to keep it in the optimal range of pH in terms of solubility and stability.
That is, in terms of solubility, the solution should remain clear without eduction of the compound (I); on the other hand in terms of stability, the residual rate must be more than 98% that is acceptable for pharmaceuticals. It proved that the optimal range of pH for the condition was between 7.0 and 8.5 from FIG.
1
.
On the other hand, the specification of JP kokai hei 5-194366 discloses a drug product given by admixing N-[o-(p-pivaloyloxybenzenesulfonylamino)benzoyl]glycine monosodium salt tetra-hydrate (10 g), distilled water (500 mL), sodium chloride (7 g) and sodium carbonate (anhydrous) (1.5 g), filled 5 mL portion into each vial and freeze-dried by a conventional method.
However, it proved that the pH of the freeze-dried product manufactured according to the formulation example was ascended in the time course and gave a large amount of a decomposition product. The results are shown below.
(2) The Change of pH in the Time Course on Freeze-dried Product of the Compound (I) Comprising Sodium Carbonate
The pH was measured on aqueous solutions prepared by admixing each component in the ratios described in the above specification of JP kokai hei 5-194366 at the following three points.
(a) when the aqueous solution was prepared,
(b) when the prepared aqueous solution was filled in each vial (5 mL), freeze-dried and then dissolved in water (10 mL),
(c) when the prepared aqueous solution was filled in each vial (5 mL), freeze-dried and the formulation obtained was left at 60 degrees Centigrade for two weeks and dissolved in water (10 mL).
The result was that the pH was (a) 7.80, (b) 8.11 and (c) 8.44.
When the freeze-dried product was left at 60 degrees Centigrade for two weeks, the residual rate of the compound (I) was 91.4%.
These results show that addition of sodium carbonate in the formulation ascends the pH in the time course and long-term storage accelerates the decomposition of the compound (I) though the pH was in the range between 7.0 and 8.
Sudoh Masao
Takada Akira
Ono Pharmaceutical Co. Ltd.
Richter Johann
Stevens Davis Miller & Mosher L.L.P.
Zucker Paul A.
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