JP5170334B2 - Formulation for injection containing sivelestat sodium salt or its hydrate - Google Patents

Description

  The present invention relates to a compound of formula (I):

And a hydrate thereof (hereinafter sometimes referred to as “the subject compound of the present invention”) and a hydrogen carbonate salt. More specifically, the present invention relates to an injectable preparation that exhibits excellent solubility even at low temperatures, and can maintain a clear solution state without any change in composition even after a long period of time when blended with an infusion solution.

  The subject compounds of the present invention have elastase inhibitory activity and are extremely useful compounds that are used as therapeutic agents for improving acute lung injury associated with systemic inflammatory response syndrome. Since acute lung disorder patients who are in a serious state to be administered with the subject compounds of the present invention need to be treated immediately, injections are suitable as the dosage forms of the therapeutic agents used. A freeze-dried preparation for injection containing 100 mg of cyberestat sodium hydrate, 200 mg of D-mannitol and a pH adjusting agent in one vial is marketed under the name “Eraspol 100 for injection”.

  There are several dosage forms for injection, but the most frequently used dosage forms are liquid preparations for injection and freeze-dried preparations for injection. The liquid preparation for injection is provided in a state where the injection component is dissolved in an injectable liquid medium in advance, and is administered as it is or when it is used as an injection after diluting into an appropriate infusion solution. On the other hand, the lyophilized preparation for injection is provided in a solid state where the injectable component is a lyophilized body, and once dissolved, the solution is once dissolved using a dissolving solution at the time of use, and the solution is diluted as it is or into an appropriate infusion solution before injection. It is administered as a liquid.

  If it takes time to dissolve the lyophilized preparation for injection in the solution, or if the solution is dissolved but the solution is mixed with the infusion, mixing changes such as white turbidity, precipitation, precipitation, etc. If it cannot be administered to the patient promptly and the patient's condition contends for a moment, a serious situation may occur. In the case of liquid preparations for injection, there is no need for a dissolution step with a dissolving solution, so it does not take time to dissolve. However, problems such as white turbidity, precipitation, precipitation, etc. due to mixing with infusion solutions are not freezing for injection. It is a matter of concern as with dry formulations.

  As described above, since the compound of the present invention is a drug to be administered to patients with acute lung injury, its lyophilized preparation for injection contains water (for example, purified water, distilled water for injection, sterilized water, etc.), physiological saline It can be easily and quickly dissolved in a solution such as water and glucose solution. Furthermore, the prepared solution does not change its composition even when mixed with any infusion solution, and a clear solution solution is prepared. It is required to be able to.

  The lyophilized preparation for injection of the subject compound of the present invention currently on the market is usually a preparation which is easy to handle without any problem when handled at a room temperature of about 15 ° C. or more and about 35 ° C. or less. Under conditions where the room temperature is about 15 ° C. or lower, such as in the medical field, the solubility in the solution may be reduced. In addition, when the infusion is formulated, it will precipitate when the pH value becomes about 6 or less after mixing, and it may become cloudy or precipitated. There was a problem to be solved, such as a change in the composition.

  The subject compound of the present invention is a known compound, and many documents related to the subject compound of the present invention have been reported so far.

  For example, in JP-A-3-20253, the following formula (II) which is a carboxylic acid form (free form) of the subject compound of the present invention:

Is described in Example 2 (63) (see Patent Document 1).

  JP-A-5-194366 discloses a compound corresponding to its sodium salt and tetrahydrate in Example 3 and also describes a production method thereof (see Patent Document 2).

  Furthermore, JP-A-2002-80361 discloses N- [o- (p) containing at least one pH adjusting agent selected from trisodium phosphate, hydrates thereof, sodium hydroxide, and potassium hydroxide. -Pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate solution and a preparation using the same are described (see Patent Document 3).

  Furthermore, WO 2002/007724 pamphlet describes N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt / 4 water dissolved in a mixed solvent of water and ethanol. It is described that a lyophilized preparation is produced by freeze-drying a Japanese product, and that a high-dose lyophilized preparation can be obtained by the method (see Patent Document 4).

  In addition, Chinese Patent Application No. 1456772 describes acute lung injury, acute lung injury characterized by aseptic lyophilized powder for injection made with active ingredient civerestat and filling support, solubilizer and pH adjuster. An injection for treating respiratory distress syndrome has been described (see Patent Document 5).

  However, although these prior art documents have a description regarding the subject compound of the present invention, the solubility of the injectable preparation containing the subject compound of the present invention as an active ingredient in a low temperature solution and the blending change with an infusion solution There is no description or suggestion.

JP-A-3-20253 JP-A-5-194366 JP 2002-80361 A International Publication No. 2002/007724 Pamphlet Chinese Patent Application No. 1456772

  The lyophilized preparation for injection of the subject compound of the present invention that has been conventionally used may have reduced solubility in a solution at low temperatures, for example, in medical practice in winter (room temperature is about 15 ° C. or lower). Therefore, there is a problem in that white turbidity, precipitation, and / or precipitation may occur when the pH value becomes about 6 or less in the formulation with the infusion solution.

  An object of the present invention is to provide an injectable preparation that can be prepared as a clear injection solution with improved solubility at low temperatures and / or without causing a change in formulation with an infusion solution.

  As a result of intensive studies to solve the above problems, the present inventors have found that an injectable preparation containing the compound of the present invention and a hydrogen carbonate salt achieves the object.

That is, the present invention
(1) An injectable preparation containing sivelestat sodium salt or a hydrate thereof, and a bicarbonate,
(2) The preparation according to (1) above, containing a hydrogen carbonate salt in an amount of 0.25 mol or more per 1 mol of cyberestat sodium salt or a hydrate thereof,
(3) The preparation according to (2) above, wherein the bicarbonate is sodium bicarbonate in an amount of 0.25 to 10 moles relative to 1 mole of sivelestat sodium salt or a hydrate thereof,
(4) The preparation according to the above (3), wherein the bicarbonate is sodium bicarbonate in an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof,
(5) The preparation according to the above (1), wherein the bicarbonate is sodium bicarbonate and / or potassium bicarbonate,
(6) The preparation according to the above (5), wherein the bicarbonate is sodium bicarbonate,
(7) The preparation according to the above (5), further containing a pH adjuster and optionally containing an excipient and / or an inorganic salt,
(8) The preparation according to (7), wherein the pH adjuster is sodium hydroxide,
(9) The preparation according to (7), wherein the excipient is mannitol,
(10) The preparation according to (7), wherein the inorganic salt is sodium chloride,
(11) The preparation according to the above (1), which is a freeze-dried preparation for injection,
(12) The preparation according to (11), which is low-temperature soluble,
(13) The preparation according to (12), wherein the low temperature is 5 ° C to 15 ° C,
(14) The preparation according to (12), wherein the solution is water, physiological saline, and / or glucose solution,
(15) The preparation according to the above (1), which is a liquid preparation for injection,
(16) The preparation according to the above (15), which is a solution obtained by dissolving a freeze-dried preparation for injection with a dissolving solution,
(17) The preparation according to the above (15), which is a solution obtained by diluting a solution obtained by dissolving a freeze-dried preparation for injection with a dissolving solution into a low pH infusion solution,
(18) The preparation according to the above (17), wherein the low pH infusion is Solita T3, Solita T2, Solita T1, KNMG3, Physiozol 3, Actit Injection, and / or Vein 3G Injection,
(19) The preparation according to (15), which is a solution for producing a freeze-dried preparation for injection,
(20) The preparation according to the above (19), wherein the solvent of the solution for producing the lyophilized preparation for injection is water,
(21) Sodium bicarbonate, sivelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 moles per mole of sivelestat sodium salt or hydrate thereof, or sivelestat sodium salt or hydrate thereof Freezing for injection containing 4.3 to 7.3 moles of mannitol per mole, and 0.27 to 0.9 moles of sodium chloride per mole of sivelestat sodium salt or hydrate thereof Dry formulation,
(22) A lyophilized preparation for injection containing sivelestat sodium salt or a hydrate thereof, and a bicarbonate, wherein the liquid preparation after mixing with a dissolving solution can maintain a clear solution state at low temperature ,
(23) A liquid preparation for injection containing sivelestat sodium salt or a hydrate thereof, and a bicarbonate, wherein the liquid preparation after combination with a low pH infusion solution can maintain a clear solution state,
(24) Freezing for injection for producing a freeze-dried preparation for injection containing cibelestat sodium salt or a hydrate thereof, which can maintain a clear solution state at a low temperature after mixing with a lysis solution A method of using (adding) hydrogen carbonate to a solution for producing a dry preparation,
(25) An injectable lyophilized preparation for producing an injectable liquid preparation containing cibelestat sodium salt or a hydrate thereof, which can maintain a clear solution state after blending with a low pH infusion solution A method of using (adding) bicarbonate to the solution for producing
(26) A freeze-dried preparation for injection produced using a solution containing sivelestat sodium hydrate and bicarbonate,
(27) The lyophilized preparation for injection according to the above (26), wherein the bicarbonate is sodium bicarbonate and / or potassium bicarbonate,
(28) The lyophilized preparation for injection according to the above (27), wherein the hydrogen carbonate is sodium hydrogen carbonate in an amount of 0.25 mol to 1.2 mol with respect to 1 mol of sivelestat sodium hydrate,
(29) The lyophilized preparation for injection according to the above (27), wherein the hydrogen carbonate is sodium hydrogen carbonate in an amount of 0.5 mol to 0.95 mol with respect to 1 mol of sivelestat sodium hydrate,
(30) The freeze-dried preparation for injection according to the above (27), wherein the hydrogen carbonate is 0.25 mol to 1.2 mol of potassium hydrogen carbonate relative to 1 mol of sivelestat sodium hydrate,
(31) The freeze-dried preparation for injection according to the above (27), wherein the bicarbonate is 0.5 to 0.95 mole of potassium bicarbonate relative to 1 mole of sivelestat sodium hydrate,
(32) A freeze-dried preparation for injection according to the above (26) to (31), produced using a solution further containing an excipient,
(33) The lyophilized preparation for injection according to the above (32), wherein the excipient is a sugar alcohol,
(34) The freeze-dried preparation for injection according to the above (33), wherein the sugar alcohol is mannitol, xylitol, and / or sorbitol,
(35) A freeze-dried preparation for injection according to the above (26) to (34), which is produced using a solution further containing an inorganic salt,
(36) The lyophilized preparation for injection according to the above (35), wherein the inorganic salt is sodium chloride,
(37) A freeze-dried preparation for injection manufactured using a solution containing sodium cyberestat hydrate, bicarbonate, mannitol, and sodium chloride,
(38) The lyophilized preparation for injection according to the above (37), wherein the bicarbonate is sodium bicarbonate and / or potassium bicarbonate,
(39) The freeze-dried preparation for injection according to the above (26) to (38), wherein the pH value of the solution is 7.5 to 8.5,
(40) The lyophilized preparation for injection according to the above (41), wherein the solvent of the solution is water,
(41) The freeze-dried preparation for injection according to the above (39), wherein the pH value of the solution is adjusted with a pH adjuster,
(42) The lyophilized preparation for injection according to the above (41), wherein the pH adjuster is an alkali metal hydroxide and / or an alkaline earth metal hydroxide,
(43) The lyophilized preparation for injection according to the above (42), wherein the alkali metal hydroxide is sodium hydroxide,
(44) The freeze-dried preparation for injection according to the above (26) to (38), wherein the pH value of the solution when the freeze-dried preparation is dissolved in water is 7.5 to 8.5,
(45) When the lyophilized preparation produced using a solution containing 100 mg of sivelestat sodium hydrate is dissolved at a low temperature in a solution of 5 to 10 mL, the solution becomes a clear solution (26) to (38) The freeze-dried preparation for injection according to the above,
(46) The freeze-dried preparation for injection according to the above (45), wherein the low temperature is 5 ° C to 15 ° C,
(47) The lyophilized preparation for injection according to the above (45), wherein the solution is water, physiological saline, and / or glucose solution,
(48) A clear solution when a low pH infusion of 60 mL to 85 mL is mixed with a solution dissolved in 10 mL of water per lyophilized preparation for injection manufactured using a solution containing 100 mg of sivelestat sodium hydrate The lyophilized preparation for injection according to the above (26) to (38),
(49) The freeze-dried preparation for injection according to the above (48), wherein the low pH infusion is Solita T3, Solita T2, Solita T1, KNMG3, Physiozol 3, Actit Injection, and / or Vein 3G Injection ,
(50) An aqueous solution of sivelestat sodium hydrate containing sodium hydrogen carbonate and / or potassium hydrogen carbonate,
(51) The aqueous solution according to (50), wherein the pH value of the aqueous solution is 7.5 to 8.5, and (52) a preparation produced using the aqueous solution according to (50).

  An injectable preparation (hereinafter sometimes abbreviated as “the injectable preparation of the present invention”) containing cibelestat sodium salt or a hydrate thereof, and a bicarbonate is unprecedented with respect to a solution. Very good solubility, especially at low temperatures, especially below about 15 ° C., and / or infusions, especially low pH infusions (infusions with a pH value of about 7 or less: eg Solita T3, Solita T2, Solita T1, KNMG3, Physiozol 3, Actit Injection, and Vein 3G Injection, etc.) and blending changes such as white turbidity, precipitation, precipitation, etc. even after a long time after mixing It has the characteristic that a clear solution state can be maintained without it.

  In other words, the injectable preparation of the present invention can be used not only when the room temperature is about 15 ° C. to about 35 ° C. but also when the room temperature is about 5 ° C. to about 15 ° C. Even when it is carried out, it is a preparation that is easily dissolved in a dissolving solution and is very easy to handle. In addition, the injectable preparation of the present invention, in combination with infusions other than the above-mentioned low pH infusion solution, of course, maintains a clear solution state without any change in the composition without problems, and further, low pH infusion solution and In this formulation, it is a formulation that maintains a clear solution state without any change in formulation and is very easy to handle.

  Therefore, the injectable preparation of the present invention can be quickly prepared as a clear solution in an acute lung disorder patient who is in a serious state even at low temperatures and can be quickly administered to the patient. Or a formulation that can be stored in the form of an injection solution because it does not change its composition even after a long time, and is very easy to handle in the medical field.

  Furthermore, the injectable preparation of the present invention (particularly, an injectable lyophilized preparation) has a feature that the stability of cyberestat is excellent when dissolved in a dissolving solution. Specifically, it is possible to prevent degradation of the purity by suppressing the decomposition of the cibelestat when dissolved in the solution.

  Hereinafter, the present invention will be described in detail.

  The compounds of the present invention can be obtained by known methods, for example, the method described in Patent Document 1 and JP-A-9-40692, and Comprehensive Organic Transformations (2nd edition) (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed.) (Richard C. Larock, John Wiley & Sons Inc. (1999)). In addition, the produced compound of the present invention can be obtained by ordinary purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography or washing. It can be purified by a method such as recrystallization. In addition, the carboxylic acid form (free form) of the subject compound of the present invention represented by the above formula (II), that is, cibelestat can also be produced and purified according to the production method of the subject compound.

  In the present invention, the compound of the present invention may be crystalline, amorphous, or any form of solid (for example, a mixture of crystal and amorphous in any proportion), or substantially different from the compound of the present invention. May be equivalent. For example, the equivalent of the subject compound of the present invention is, for example, 1 equivalent or more with respect to the aqueous solution of the carboxylic acid form (free form) of the subject compound of the present invention represented by the formula (II). With respect to a carboxylic acid form (free form) of the compound of the present invention represented by the above formula (II) having a sodium donor (for example, sodium hydroxide aqueous solution, sodium hydroxide etc.) added, for example, 1 Examples include those obtained by adding an aqueous solution of sodium hydroxide in an equivalent amount or more, or those obtained by adding water to the monosodium salt of the carboxylic acid form (free form) of the compound of the present invention represented by the above formula (II). .

  In the present invention, injectable preparations include lyophilized preparations for injection and liquid preparations for injection.

  When an injectable preparation containing cibelestat sodium salt or a hydrate thereof, and a bicarbonate salt, that is, the injectable preparation of the present invention is an injectable lyophilized preparation, the following is simply referred to as “the injectable lyophilized preparation of the present invention”. May be abbreviated. Similarly, when the injectable preparation of the present invention is an injectable liquid preparation, hereinafter, it may be simply abbreviated as “the injectable liquid preparation of the present invention”.

  In the present invention, the injection solution means a liquid composition that can be directly injected into a living body.

  In the present invention, the liquid preparation for injection means a preparation provided in a state in which an injection component is dissolved in an injectable liquid medium in advance. And then administered as an injection solution. The liquid preparation for injection is not particularly limited as long as it is generally used as a liquid preparation. Specifically, (a) a preparation provided in the state of a solution prepared when producing a freeze-dried preparation for injection containing the compound of the present invention and bicarbonate, etc., (b) the compound of the present invention and A preparation provided in a state where an injectable lyophilized preparation containing bicarbonate or the like is dissolved in a solution, and (c) an injectable lyophilized preparation injectable containing a compound of the present invention and bicarbonate And a preparation provided in a state in which the solution is diluted with an infusion solution.

  The solvent for the injectable liquid preparation of the present invention is not particularly limited as long as it is generally used as an injectable preparation. In the present invention, preferable examples of the solvent for the liquid preparation for injection of the present invention include water (for example, distilled water for injection, sterilized water, and purified water), a mixed solvent of water and an organic solvent (for example, ethanol), and the like. is there. More preferably, it is water.

  In the present invention, the lyophilized preparation for injection means a preparation in which the injectable component is provided in a solid state called a lyophilized form, and once used, it is dissolved once using a dissolving solution, and the solution is directly used as an injection solution. Or, it is administered as an injection solution after dilution in an appropriate infusion solution or the like as desired. That is, it can be said that a solution obtained by adding an arbitrary dissolving solution to a freeze-dried preparation for injection and dissolving is substantially equivalent to a liquid preparation for injection.

  The lysis solution of the present invention refers to a liquid medium that is added in a small amount (approximately 10 mL or less) in a lyophilized preparation for injection (for example, a vial) to dissolve the lyophilized product using a syringe or the like. Specific examples include water (for example, purified water, distilled water for injection, and sterilized water), physiological saline, and / or glucose solution.

  The injectable preparation of the present invention exhibits excellent solubility even when blended with a low pH infusion solution as well as causing no change in blending when blended with an infusion solution that is not low pH. That is, this “low pH infusion solubility” means that even when mixed with a low pH infusion solution, it is in a clear solution state without causing a change in formulation and can be maintained for a long time. Specifically, when the injectable preparation of the present invention is an injectable liquid preparation, the preparation is in a clear solution state without causing a change in composition when mixed with various low pH infusion solutions, and the state is This means that it can be maintained for a long time, preferably 6 to 24 hours, and when the injectable preparation of the present invention is an injectable lyophilized preparation, there are various solutions prepared by adding a solution to the preparation. When mixed with a low pH infusion solution, it is a clear solution state without causing a change in composition, and the state can be maintained for a long time, preferably 6 to 24 hours. Here, the low pH infusion refers to an infusion having a pH of about 7 or less, preferably about 6 or less, and specifically, Actit, Vin 3G, Kirit, 5%, Glyceol, KN1, Solita T1. No., Soldem 1, KN3, KNMG3, Solita T3, Soldem 3A, Physiozol 3, Solita T2, low molecular dextran sugar injection, and Maltos-10.

  The lyophilized formulation for injection of the present invention is also low temperature soluble. The term “low temperature solubility” means that it exhibits excellent solubility in a solution at low temperatures. Since the freeze-dried preparation for injection of the present invention is soluble at low temperature, it can be rapidly dissolved even when a dissolution solution is added at a low temperature, preferably at about 5 ° C. or more and about 15 ° C. or less, and the solution should be prepared easily. Can do.

  In the present invention, the hydrate of sivelestat sodium salt is not particularly limited as long as an arbitrary number of water molecules are hydrated to the molecule of sivelestat sodium salt. Examples of hydrates of sivelestat sodium salt include, for example, sivelestat sodium salt monohydrate, sivelestat sodium salt dihydrate, sivelestat sodium salt trihydrate, sivelestat sodium salt tetrahydrate, and Siverestat sodium salt pentahydrate is preferred, and siverestat sodium salt tetrahydrate is particularly preferred.

  In the present invention, the bicarbonate is not particularly limited as long as it is generally used as an injectable preparation. As the hydrogen carbonate, for example, an alkali metal hydrogen carbonate is preferable, and sodium hydrogen carbonate, potassium hydrogen carbonate, and a mixture of any ratio thereof are particularly preferable. The bicarbonate is not limited to the anhydride, and may be added as a hydrate.

  The content of the hydrogen carbonate is not particularly limited as long as the function and effect of the present invention can be exhibited. The lower limit of the content of the bicarbonate is usually from the viewpoint of effectively exhibiting the above-described low pH infusion solubility and / or low-temperature soluble action effect, with respect to 1 mol of sivelestat sodium salt or a hydrate thereof, About 0.25 mol or more, further about 0.26 mol or more, further about 0.3 mol or more, further about 0.4 mol or more, particularly about 0.5 mol or more are preferable. In addition, in addition to the above-mentioned effects, the upper limit of the content of hydrogen carbonate is usually from the viewpoint of ease of formulation of a lyophilized preparation for injection, relative to 1 mol of sivelestat sodium salt or a hydrate thereof. About 10 mol or less, further about 6 mol or less, further about 4 mol or less, further about 2 mol or less, further about 1.5 mol or less, further about 1.2 mol or less, further about 1.06 mol or less, It is preferably about 1.0 mol or less, more preferably about 0.98 mol or less, further about 0.97 mol or less, further about 0.96 mol or less, particularly about 0.95 mol or less.

  Specifically, a content of about 0.25 mol to about 10 mol with respect to 1 mol of sivelestat sodium salt or hydrate thereof is preferable. More preferred bicarbonate content is from about 0.25 mol to about 6 mol, from about 0.25 mol to about 4 mol, from about 0.25 mol to about 2 mol, from about 0.25 mol to about 1.5 mol. Mole, from about 0.25 mole to about 1.2 mole, from about 0.25 mole to about 1.2 mole, from about 0.26 mole to about 1.06 mole, from about 0.25 mole to about 0.95 mole, About 0.26 mole to about 0.95 mole. The most preferable range of the content of hydrogen carbonate is a ratio of about 0.5 mol to about 0.95 mol with respect to 1 mol of cyberestat sodium salt or hydrate thereof.

  The injectable preparation of the present invention may contain one or more components selected from the group such as an excipient, a pH adjuster, and / or an inorganic salt, if necessary. In addition, one or more components selected from the group such as a stabilizer, a soothing agent, a buffering agent, and / or a preservative may be contained as necessary.

  In the injectable preparation of the present invention, the excipient used as necessary is not particularly limited as long as it is generally used as an excipient for injectable preparations. Preferred excipients include, for example, monosaccharides such as glucose (glucose), fructose, and mixtures of any proportion thereof, such as lactose (lactose), maltose (maltose), and mixtures of any proportion thereof. Disaccharides such as polyhydric alcohols such as glycerol, eg sugar alcohols such as mannitol, xylitol, sorbitol, and mixtures of these proportions, such as dextran 40, dextran 80, and any proportion thereof. Dextrans, such as mixtures, as well as mixtures of these excipients. More preferably, it is mannitol, glucose, lactose, maltose, glycerin, xylitol, sorbitol, dextran, and a mixture thereof in any proportion, and more preferably, for example, mannitol, xylitol, sorbitol, and any proportion thereof Sugar alcohols such as a mixture of mannitol, and mannitol is particularly preferable. An excipient | filler is not limited to an anhydride, You may add as a hydrate.

  The content of the excipient is not particularly limited. The content of the excipient is preferably in a ratio of about 0.3 mol to about 29 mol with respect to 1 mol of sivelestat sodium salt or hydrate thereof. More preferably, it is a ratio of about 0.6 mol to about 23 mol, and more preferably a ratio of about 1.45 mol to about 14.5 mol, with respect to 1 mol of sivelestat sodium salt or hydrate thereof. Particularly preferred is a ratio of about 2.9 mol to about 8.7 mol, and particularly preferred is a ratio of about 4.3 mol to about 7.3 mol. When the content is within the above range, it is easy to prepare a cake-like lyophilized product when a lyophilized preparation for injection is prepared.

  In the injectable preparation of the present invention, the inorganic salt used as necessary is not particularly limited as long as it is generally used as an injectable preparation. Examples of the inorganic salt include alkali metal chloride salts, alkaline earth metal chloride salts, alkali metal bromide salts, alkaline earth metal bromides, alkali metal sulfate salts, alkaline earth metal sulfate salts, and any of these. Such as a mixture of proportions. Preferably, for example, an alkali metal chloride salt, an alkaline earth metal chloride salt, and a mixture thereof in any proportion, more preferably, for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and these It is a mixture in an arbitrary ratio, and sodium chloride is particularly preferable. The inorganic salt is not limited to an anhydride and may be added as a hydrate.

  The content of the inorganic salt is not particularly limited. The content of the inorganic salt is preferably about 0.045 mol to about 4.5 mol with respect to 1 mol of sivelestat sodium salt or hydrate thereof. More preferably, it is a ratio of about 0.068 mol to about 3.6 mol, more preferably about 0.09 mol to about 2.7 mol, relative to 1 mol of sivelestat sodium salt or its hydrate. The ratio is particularly preferably about 0.18 mol to about 1.8 mol, and particularly preferably about 0.27 mol to about 0.9 mol.

  In the injectable preparation of the present invention, the pH adjuster used as necessary is not particularly limited as long as it is generally used as an injectable preparation. Preferred pH adjusters are inorganic bases such as, for example, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures of these in any proportion. More preferred are, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, and mixtures of these in any proportion, and sodium hydroxide is particularly preferred. These pH adjusting agents may be added as salts (for example, monovalent alkali metal salts such as sodium salt and potassium salt, divalent alkaline earth metal salts such as calcium salt, etc.) and hydrates thereof. Moreover, you may add as aqueous solution (For example, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, calcium hydroxide aqueous solution, etc.).

  When the injectable preparation of the present invention is an injectable liquid preparation, the pH value is preferably 7.0 to 8.5. More preferably, it is 7.5-8.5.

  When the injectable preparation of the present invention is an injectable lyophilized preparation, the pH value of a solution obtained by dissolving it with a dissolving solution is preferably 7.0 to 8.5. More preferably, it is 7.5-8.5.

  As a method for preparing the liquid preparation for injection of the present invention, the operation of adding or mixing the above-mentioned bicarbonate (for example, sodium bicarbonate, potassium bicarbonate, etc.) This is done by conventional pharmaceutical methods. If necessary, excipients (for example, mannitol, glucose, lactose, maltose, glycerin, xylitol, sorbitol, dextran, etc.), pH adjusters (for example, aqueous sodium hydroxide, potassium hydroxide, etc.), inorganic The operation of further adding or mixing a salt (for example, sodium chloride, etc.), a stabilizer, a soothing agent, a buffering agent, a preservative and the like is a method in which the following methods are appropriately combined, and a method shown in the examples. And by conventional pharmaceutical procedures.

  As a method for preparing the liquid preparation for injection of the present invention, for example, the compound of the present invention and bicarbonate are weighed, mixed and then dissolved in water, and the solution is weighed into an aqueous solution containing the compound of the present invention. And a method of dissolving the weighed compound of the present invention in an aqueous solution containing a bicarbonate. There is also a method in which an aqueous solution containing the compound of the present invention and an aqueous solution containing a hydrogen carbonate are prepared, and then these aqueous solutions are mixed to prepare. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing two components of the subject compound of the present invention and a bicarbonate.

  In addition, as a method for preparing the liquid preparation for injection of the present invention further containing a pH adjuster in the subject compound and bicarbonate, for example, the subject compound, bicarbonate and pH adjuster are weighed, respectively. The method of dissolving in water after mixing, the method of dissolving the bicarbonate and pH adjuster weighed in the aqueous solution containing the compound of the present invention, and the aqueous solution containing the compound of the present invention and bicarbonate were weighed. A method for dissolving a pH adjuster, a method for dissolving a hydrogen carbonate salt weighed in an aqueous solution containing the compound of the present invention and a pH adjuster, a compound of the present invention weighed in an aqueous solution containing a hydrogen carbonate and a pH adjuster A method of dissolving, a method of dissolving a target compound of the present invention weighed in an aqueous solution containing a bicarbonate and a pH adjuster, and a method of the present invention weighed in an aqueous solution containing a pH adjuster Such compounds and methods for dissolving bicarbonate salt. There is also a method of preparing an aqueous solution containing the compound of the present invention, an aqueous solution containing a bicarbonate, and an aqueous solution containing a pH adjuster, and then mixing these aqueous solutions. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing three components of the subject compound of the present invention, a bicarbonate, and a pH adjuster.

  In addition, as a method for preparing the liquid preparation for injection of the present invention further containing an inorganic salt in the subject compound and bicarbonate of the present invention, for example, the present compound and bicarbonate further containing a pH adjuster In the same manner as the method for preparing a liquid preparation for injection according to the invention, a method using an inorganic salt in place of a pH adjusting agent can be mentioned. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, a bicarbonate and an inorganic salt.

  Moreover, as a method for preparing the liquid preparation for injection of the present invention further containing an excipient in the subject compound and bicarbonate, for example, the subject compound and bicarbonate further contain a pH adjuster. The method of using an excipient | filler instead of a pH adjuster similarly to the method of preparing the liquid formulation for injection of this invention is mentioned. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, a bicarbonate, and an excipient.

  In addition, as a method for preparing the liquid preparation for injection of the present invention further containing a stabilizer in the subject compound and bicarbonate of the present invention, for example, the present subject compound and bicarbonate further containing a pH adjuster. In the same manner as the method for preparing a liquid preparation for injection according to the invention, a method using a stabilizer instead of a pH adjuster and the like can be mentioned. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, a bicarbonate, and a stabilizer.

  Moreover, as a method for preparing the liquid preparation for injection of the present invention that further contains a soothing agent in the subject compound and bicarbonate, for example, the subject compound and bicarbonate further contain a pH adjuster. In the same manner as the method for preparing the liquid preparation for injection of the present invention, a method using a soothing agent instead of a pH adjuster, and the like can be mentioned. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, a bicarbonate, and a soothing agent.

  Moreover, as a method for preparing the liquid preparation for injection of the present invention further containing a buffer in the subject compound and bicarbonate of the present invention, for example, the present compound further comprising a pH adjuster in the subject compound and bicarbonate. In the same manner as the method for preparing a liquid preparation for injection according to the invention, a method using a buffering agent instead of a pH adjusting agent can be mentioned. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, bicarbonate and buffer.

  In addition, as a method for preparing the liquid preparation for injection of the present invention further containing a preservative in the subject compound of the present invention and bicarbonate, for example, the present compound further comprising a pH adjuster in the subject compound of the present invention and bicarbonate. In the same manner as the method for preparing a liquid preparation for injection according to the invention, a method using a preservative in place of a pH adjusting agent can be used. In addition to these preparation methods, any method may be used as long as it is a liquid preparation for injection containing the three components of the subject compound of the present invention, a bicarbonate, and a preservative.

  As a method for preparing the solution for producing the lyophilized preparation for injection of the present invention, a method for adjusting the above-mentioned method for preparing the liquid preparation for injection of the present invention as appropriate, a method shown in Examples, and a normal preparation Such as scientific methods.

  In the present invention, the method for producing the lyophilized preparation for injection of the present invention includes freezing by an ordinary pharmaceutical method using the solution for producing the lyophilized preparation for injection of the present invention obtained by the above method. Can be produced by drying.

  Examples of the solvent used when dissolving the freeze-dried preparation for injection of the present invention include a solution. Examples of the solution include water (eg, purified water, distilled water for injection, and sterilized water), physiological saline, glucose solution (eg, 5% glucose solution), and the like. The injection solution obtained by this method may be administered as it is, or it may be further diluted as a suitable infusion solution and then administered as an injection solution. Examples of infusion solutions include Actit Note (Kowa; standard pH 4.3 to 6.3; Actit is a registered trademark of Kowa) and Vin 3G Note (Kowa; Standard pH 4.3 to 6.3; Vin is a registered trademark of Kowa. Glyceol injection (such as xylitol injection) that is 5% (Otsuka Pharmaceutical Factory; standard pH 4.5-7.5; Kirit is a registered trademark of Otsuka Pharmaceutical Factory). Chugai Pharmaceutical; Standard pH 3-6; Glyceol is a registered trademark of Chugai Pharmaceutical Co., Ltd. Concentrated glycerin / fructose injection solution, etc. KN1 (Otsuka Pharmaceutical Factory; Standard pH 4-7.5), Solita T1 (Ajinomoto; Standard) pH 3.5-6.5; Solita is a registered trademark of Ajinomoto, and Soldem 1 (Terumo; standard pH 4.5-7; Soldem is a registered trademark of Terumo), etc. KN3 (Otsuka Pharmaceutical Factory; standard pH 4-7.5), KNMG3 (Otsuka Pharmaceutical Factory; standard pH 3.5-7; KNMG is a registered trademark of Otsuka Pharmaceutical Factory), Solita T3 (Ajinomoto; Standard pH 3. Solita is a registered trademark of Ajinomoto), Soldem 3A (Terumo; standard pH 5-6.5; Soldem is a registered trademark of Terumo) and Physizol 3 (Otsuka Pharmaceutical Factory; standard pH 4- 5.2; Dehydration supplement that is Sorita T2 (Ajinomoto; standard pH 3.5-6.5; Sorita is a registered trademark of Ajinomoto), such as maintenance solution that is Physiozole is a registered trademark of Otsuka Pharmaceutical Factory) Liquid, dextran sugar injection (Otsuka Pharmaceutical Factory; standard pH 3.5 to 6.5), etc., and Maltos-10 (Otsuka Pharmaceutical Factory; standard pH 4) 6; Martos is like maltose Injection is a is) registered trademark of Otsuka Pharmaceutical Factory.

  In the present invention, the temperature for preparing the liquid preparation for injection of the present invention is about 0 ° C. or more and about 35 ° C. or less, more preferably 3 ° C. or more and 35 ° C. or less, and further preferably 3 ° C. or more and 30 ° C. or less. Yes, particularly preferably 5 ° C. or higher and 30 ° C. or lower, particularly preferably 5 ° C. or higher and 27 ° C. or lower.

  In the present invention, as a storage of the liquid preparation for injection of the present invention, the liquid preparation itself may be stored as an injection solution, or the injection solution may be added to various infusions and stored as a diluted injection solution. May be.

  In the present invention, the liquid preparation for injection of the present invention has a clear solution state with no problem even at room temperature of about 5 ° C. or more and about 15 ° C. or less, as well as at room temperature of about 15 ° C. or more and about 35 ° C. or less. Is kept.

  In the present invention, the temperature for storing the liquid preparation for injection of the present invention is about 0 ° C. or more and about 35 ° C. or less, more preferably 3 ° C. or more and 35 ° C. or less, and further preferably 3 ° C. or more and 30 ° C. or less. Yes, particularly preferably 5 ° C. or higher and 30 ° C. or lower, particularly preferably 5 ° C. or higher and 27 ° C. or lower.

  In the present invention, the liquid preparation for injection according to the present invention can be used with various infusion solutions (for example, Solita T3, Solita T2, Solita T1, KNMG3, Physiozol 3, Actit Injection, and Vein 3G Injection). It is a formulation that maintains a clear solution state over a long period of time with respect to the formulation.

  In the present invention, as a preparation for using the lyophilized preparation for injection of the present invention as an injection solution, a solution obtained by dissolving the lyophilized preparation for injection in a dissolution solution may be prepared as an injection solution, and further the injection The solution may be added to various infusions to prepare a diluted solution as an injection solution.

  In the present invention, the freeze-dried preparation for injection of the present invention can be used without any problem at room temperature of about 5 ° C. to about 15 ° C. For example, water, physiological saline, glucose solution, etc.) can be quickly and clearly dissolved to maintain the clear solution state.

  In the present invention, the temperature for preparing the injectable lyophilized preparation of the present invention as an injection solution is about 0 ° C. or more and about 35 ° C. or less, more preferably 3 ° C. or more and 35 ° C. or less, and further preferably 3 ° C. The temperature is 30 ° C. or lower, particularly preferably 5 ° C. or higher and 30 ° C. or lower, and particularly preferably 5 ° C. or higher and 27 ° C. or lower.

  In the present invention, the lyophilized preparation for injection according to the present invention is prepared by dissolving various kinds of infusion solutions (for example, Solita T3, Solita T2, Solita T1, KNMG3, Physiozol 3, When formulated with Actit Injection, Vein 3G Injection, etc.), it is a preparation that maintains a clear solution state even after a long time.

  In the present invention, as a storage after preparing the lyophilized preparation for injection of the present invention in an injection solution, a solution obtained by dissolving the lyophilized preparation for injection in a solution may be stored as an injection solution, Further, the injection solution may be added to various infusion solutions, and the diluted solution may be stored as an injection solution.

  In the present invention, the injection solution obtained by dissolving the freeze-dried preparation for injection of the present invention in a solution, or the injection solution obtained by further diluting the solution dissolved in the solution with an infusion solution has a room temperature of about 15 ° C. or more and about 35 ° C. In the following, as a matter of course, even when the room temperature is about 5 ° C. or more and about 15 ° C. or less, the solution remains clear even after a long time without any problem.

  In the present invention, the temperature at which the freeze-dried preparation for injection of the present invention is prepared after being prepared as an injection solution is about 0 ° C. or more and about 35 ° C. or less, more preferably 3 ° C. or more and 35 ° C. or less, and still more preferably It is 3 to 30 ° C, particularly preferably 5 to 30 ° C, and particularly preferably 5 to 27 ° C.

  In the present invention, the low temperature means 0 ° C. or more and 15 ° C. or less. More preferably, it is 3 degreeC or more and 15 degrees C or less, Most preferably, they are 5 degreeC or more and 15 degrees C or less.

  In the present invention, the term “long time in which the formulation for injection of the present invention does not cause a change in formulation even for a long time due to the formulation with an infusion solution” means 3 to 72 hours. More preferably, it is 6 hours-72 hours, More preferably, it is 6 hours-48 hours, Especially preferably, it is 6 hours-36 hours, Especially preferably, it is 6 hours-24 hours.

  In the present invention, as an injectable preparation containing the compound of the present invention and a hydrogen carbonate salt, an injectable preparation containing the three components of the compound of the present invention, a hydrogen carbonate, and a pH adjuster is preferred. More preferable is an injectable preparation containing 4 components of a bicarbonate, a pH adjuster and an excipient, and it contains 5 components of the subject compound of the present invention, a bicarbonate, a pH adjuster, an excipient and an inorganic salt. Injectable preparations are particularly preferred.

  In the present invention, an injectable preparation containing three components of the subject compound of the present invention, bicarbonate and sodium hydroxide is preferred, and contains four components of the subject compound of the present invention, bicarbonate, sodium hydroxide and mannitol. An injectable preparation is more preferable, and an injectable preparation containing 5 components of the subject compound of the present invention, bicarbonate, sodium hydroxide, mannitol, and sodium chloride is particularly preferable.

  In the present invention, a lyophilized preparation for injection containing sivelestat sodium salt or a hydrate thereof, sodium hydrogen carbonate, mannitol, and sodium chloride is particularly preferred, and the proportion of each component is cyberestat sodium salt or its 0.25 to 0.95 molar amount of sodium bicarbonate, 4.3 to 7.3 molar amount of mannitol, and 0.27 to 0.9 molar amount of sodium chloride with respect to 1 mol of hydrate It is preferable that

  The injectable preparation of the present invention contains the compound of the present invention and a hydrogen carbonate, but here "contains" means the effect of the present invention in addition to the compound of the present invention and the hydrogen carbonate. It is used to mean that other components may be contained within a range that does not adversely affect the components. Furthermore, the “containing” includes a more limited meaning that it basically consists of the compound of the present invention and a hydrogen carbonate. As used herein, “consisting essentially of” includes the essential components of the present invention compound and bicarbonate as main components, and other trace components within a range that does not adversely affect the effects of the present invention. Used to mean good. The meaning of the above “containing” includes all of the injectable preparations described in the present specification, for example, an injectable preparation containing the above-mentioned three components, an injectable preparation containing four components, and a five-component preparation. The same applies to any case of injectable preparations.

  In the present invention, hydrogen carbonate ions derived from hydrogen carbonate can be measured by an analysis method known so far. This analysis method is not particularly limited. Specific analysis methods include, for example, neutralization titration method, ion component measurement method (ion chromatograph method) and the like. An injectable preparation containing cyberestat sodium salt or a hydrate thereof, and when hydrogen carbonate ions are detected by any of these analytical methods, the preparation is included in the present invention.

  In the present invention, the cation (for example, sodium ion, potassium ion, etc.) in the hydrogen carbonate can be measured by a conventionally known analytical method. This analysis method is not particularly limited. As a specific analysis method, for example, there is an ion component measurement method (ion chromatography method) and the like.

In the present invention, when the inorganic salt used as desired is, for example, sodium chloride, the chloride ion (Cl ⁻ ) in sodium chloride can be measured by a conventionally known analysis method. This analysis method is not particularly limited. Specific analysis methods include, for example, silver nitrate titration methods (for example, Fajans method (Fajans method), Mole method (Mohr method), etc.), ion electrode method, ion component measurement method (ion chromatograph method), gravimetric analysis method and so on. In addition, cations (for example, sodium ions, potassium ions, calcium ions, magnesium ions, etc.) and anions (for example, bromine ions (Br ⁻ ), sulfate ions (SO ₄ ²⁻ ), etc.) in inorganic salts used as desired. Can be measured by known analytical methods. This analysis method is not particularly limited. Specific analysis methods include, for example, an ion component measurement method (ion chromatographic method), a gravimetric method, an absorptiometric method, a gas chromatographic method, a activation analysis method, and an ion electrode method.

  In the present invention, the injectable preparation of the present invention satisfactorily fulfilled the characteristics (for example, stability, industrial productivity, safety, etc.) of a pharmaceutical suitable as a preparation produced using the subject compound of the present invention.

  EXAMPLES Hereinafter, although an Example is given and this invention is explained in full detail, this invention is not limited to these.

  Moreover, you may change in the range which does not deviate from the range of this invention.

The production method of the lyophilized preparation for injection of the present invention is as follows.
<Example 1>
Using about 140 mL of distilled water for injection, sivelestat sodium salt tetrahydrate (4 g; 7.56 mmol), sodium bicarbonate (400 mg; 4.76 mmol), and mannitol (8 g) corresponding to the compound of the present invention 1N aqueous sodium hydroxide solution was added to the mixed solution to adjust the pH to 7.7, and a clear solution was obtained. Next, sodium chloride (200 mg) was added to the clear solution and dissolved. Water for injection was added to a final volume of 200 mL. This solution of 200 mL in total was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and freeze-dried by a conventional method to obtain 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial. .
<Example 2>
Injection containing 100 mg of the compound of the present invention per vial in the same manner as in <Example 1> using sodium hydrogen carbonate (168 mg; 2.00 mmol) instead of sodium hydrogen carbonate (400 mg) 40 vials of lyophilized formulation were obtained.
<Example 3>
Injection containing 100 mg of the subject compound of the present invention in one vial in the same manner as in <Example 1> using sodium hydrogen carbonate (336 mg; 4.00 mmol) instead of sodium hydrogen carbonate (400 mg) 40 vials of lyophilized formulation were obtained.
<Example 4>
Injection containing 100 mg of the compound of the present invention per vial in the same manner as in <Example 1> using sodium bicarbonate (504 mg; 6.00 mmol) instead of sodium bicarbonate (400 mg) 40 vials of lyophilized formulation were obtained.
<Example 5>
Injection containing 100 mg of the compound of the present invention in one vial in the same manner as in <Example 1> using sodium hydrogen carbonate (672 mg; 8.00 mmol) instead of sodium hydrogen carbonate (400 mg) 40 vials of lyophilized formulation were obtained.
<Example 6>
Injection containing 100 mg of the compound of the present invention per vial in the same manner as in <Example 1> using potassium hydrogen carbonate (400 mg; 4.00 mmol) instead of sodium hydrogen carbonate (400 mg) 40 vials of lyophilized formulation were obtained.
<Example 7>
Using about 140 mL of distilled water for injection, sivelestat sodium salt tetrahydrate (4 g; 7.56 mmol), sodium bicarbonate (400 mg; 4.76 mmol), and mannitol (8 g) corresponding to the compound of the present invention 1N aqueous sodium hydroxide solution was added to the mixed solution to adjust the pH to 7.7, and a clear solution was obtained. Water for injection was added to a final volume of 200 mL. This solution of 200 mL in total was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and freeze-dried by a conventional method to obtain 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial. .
<Example 8>
Using about 140 mL of distilled water for injection, 1N water was added to a mixed solution of sivelestat sodium salt tetrahydrate (4 g; 7.56 mmol) and sodium bicarbonate (400 mg; 4.76 mmol) corresponding to the compound of the present invention. An aqueous sodium oxide solution was added to adjust the pH to 7.7, and a clear solution was obtained. Next, sodium chloride (200 mg) was added to the clear solution and dissolved. Water for injection was added to a final volume of 200 mL. This solution of 200 mL in total was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and freeze-dried by a conventional method to obtain 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial. .
<Example 9>
Using about 140 mL of distilled water for injection, 1N water was added to a mixed solution of sivelestat sodium salt tetrahydrate (4 g; 7.56 mmol) and sodium bicarbonate (400 mg; 4.76 mmol) corresponding to the compound of the present invention. An aqueous sodium oxide solution was added to adjust the pH to 7.7, and a clear solution was obtained. Water for injection was added to a final volume of 200 mL. This solution of 200 mL in total was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and freeze-dried by a conventional method to obtain 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial. .
<Example 10>
By using glucose (8 g) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial were obtained in the same manner as in <Example 1>. It was.
<Example 11>
By using lactose (8 g) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention per vial are obtained in the same manner as in <Example 1>. It was.
<Example 12>
By using maltose (8 g) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial are obtained in the same manner as in <Example 1>. It was.
<Example 13>
Using glyceol (600 mg) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention in one vial are obtained in the same manner as in <Example 1>. It was.
<Example 14>
Using xylitol (2 g) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention per vial are obtained in the same manner as in <Example 1>. It was.
<Example 15>
Using sorbitol (8 g) instead of mannitol (8 g), 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention per vial are obtained in the same manner as in <Example 1>. It was.
<Example 16>
A lyophilized preparation 40 for injection containing 100 mg of the compound of the present invention in one vial in the same manner as in <Example 1> using dextran 40 (1.2 g) instead of mannitol (8 g) A vial was obtained.
<Comparative Example 1>
This is a freeze-dried preparation for injection obtained by the method described in the preparation example of Patent Document 2. The compound of the present invention (10 g), distilled water for injection (500 mL), sodium chloride (7 g), and sodium carbonate (anhydrous) (1.5 g) were mixed by a conventional method, and then the solution was sterile filtered by a conventional method. Each vial was filled into 5 mL vials and lyophilized by a conventional method to obtain 100 lyophilized preparations for injection containing 100 mg of the compound of the present invention in one vial.
<Comparative example 2>
This is a freeze-dried preparation for injection obtained by the method described in Example 1 (a) and Example 1 (b) of Patent Document 3.
Mannitol (20 g) was dissolved in distilled water, and the compound of the present invention (10 g) was added. While stirring the mixture with a stirrer, 1N sodium hydroxide (0.44 g) was added, and the total volume was adjusted to 500 mL with distilled water to obtain a clear aqueous solution having a pH value of 7.65. Next, this aqueous solution was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and lyophilized by a conventional method to obtain 100 vials of a lyophilized preparation for injection containing 100 mg of the compound of the present invention in one vial.
<Comparative Example 3>
It is a freeze-dried preparation for injection obtained by the method described in paragraph No. 0025 in Patent Document 3.
Mannitol (8 g) was dissolved in water (150 mL), and the compound of the present invention (4 g) was added and suspended. While stirring the suspension with a stirrer, an aqueous sodium hydroxide solution (40 mg / mL; 5.6 mL) was added to make a total aqueous solution of 200 mL with water to obtain a clear aqueous solution. Next, this aqueous solution was aseptically filtered by a conventional method, filled into vials in 5 mL portions, and lyophilized by a conventional method to obtain 40 vials of a lyophilized preparation for injection containing 100 mg of the compound of the present invention in one vial.
<Comparative example 4>
Instead of sodium hydrogen carbonate, sodium acetate was used as a commonly used buffer.
1 vial was prepared in the same manner as in <Example 1> using sodium acetate (1080 mg) (maximum actual dose used so far as an additive for injectable preparation) instead of sodium bicarbonate (400 mg). Among them, 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 5>
Instead of sodium bicarbonate, trisodium phosphate was used as a commonly used buffer.
Instead of sodium bicarbonate (400 mg), using trisodium phosphate (80 mg) (maximum actual dose used so far as an additive for injectable preparations), in the same manner as in <Example 1>, In one vial, 40 vials of the lyophilized preparation for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 6>
Instead of sodium hydrogen carbonate, dipotassium hydrogen phosphate was used as a commonly used buffer.
Instead of sodium bicarbonate (400 mg), dipotassium hydrogen phosphate (100 mg) (maximum actual dose used so far as an additive for injection preparations) was used in the same manner as in <Example 1>. In one vial, 40 lyophilized preparations for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 7>
Instead of sodium hydrogen carbonate, disodium hydrogen phosphate was used as a commonly used buffer.
Instead of sodium hydrogen carbonate (400 mg), disodium hydrogen phosphate (144 mg) (maximum dissolution dose in 200 mL of water (5 ° C., left for 24 hours)) was used in the same manner as in <Example 1>. In one vial, 40 lyophilized preparations for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 8>
In place of sodium hydrogen carbonate, citric acid monohydrate was used as a commonly used buffer.
Instead of sodium bicarbonate (400 mg), citric acid monohydrate (840 mg) (maximum dissolution dose in 200 mL of water (5 ° C., left for 24 hours)) was used in the same manner as in <Example 1>. Thus, 40 vials of lyophilized preparation for injection containing 100 mg of the compound of the present invention per vial were obtained.
<Comparative Example 9>
Instead of sodium bicarbonate, sodium citrate was used as a commonly used buffer.
Instead of sodium hydrogen carbonate (400 mg), sodium citrate (588 mg) (maximum dissolved dose in 200 mL of water (5 ° C., left for 24 hours)) was used in the same manner as in <Example 1>, In the vial, 40 vials of lyophilized preparation for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 10>
Instead of sodium bicarbonate, trometamol was used as a commonly used buffer.
Instead of sodium bicarbonate (400 mg), trometamol (292 mg) (maximum dissolved dose in 200 mL of water (5 ° C., left for 24 hours)) was used in one vial in the same manner as in <Example 1>. 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention were obtained.
<Comparative Example 11>
Instead of sodium hydrogen carbonate, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) was used as a commonly used buffer.
In the same manner as in <Example 1> using HEPES (80 mg) (maximum actual dose used so far as an additive for injectable preparation) instead of sodium bicarbonate (400 mg) in one vial 40 vials of a freeze-dried preparation for injection containing 100 mg of the compound of the present invention were obtained.
The components per vial of the freeze-dried preparation for injection in <Example 1> to <Example 16> and <Comparative Example 1> to <Comparative Example 11> obtained by the above production method are shown in Tables 1 and 2 below. Shown in
The adjustment amount (pH 7.7) in Table 1 and the pH 7.7 adjustment amount in Table 2 represent the amounts added so that the pH value of the solution before lyophilization in each experimental example was 7.7. As used herein, the compound of the present invention represents sivelestat sodium salt tetrahydrate.

  The method for producing a liquid preparation for injection of the present invention can be produced as follows.

Cibelestat sodium salt tetrahydrate and sodium bicarbonate corresponding to the compound of the present invention are dissolved in distilled water for injection, and then adjusted to pH 7.7 with an aqueous sodium hydroxide solution. The resulting solution can be sterile filtered, filled into containers (eg, vials, ampoules, etc.), capped and final sterilized for production. Alternatively, it can be produced by adding a solution such as water, physiological saline, and / or glucose solution to the lyophilized preparation for injection of <Example 1> to <Example 16> described above and dissolving them clearly. Furthermore, a solution obtained by adding a solution such as water, physiological saline, and / or glucose solution to the freeze-dried preparation for injection of <Example 1> to <Example 16> above and then dissolving the solution clearly is infusion. Can be diluted to
<Test Example 1>
Solubility test of injectable preparation at low temperature <Example 1> to <Example 16> and <Comparative Example 1> to <Comparative Example 11> Under 25 ° C.), 5 mL or 10 mL of physiological saline or 5 mL of 5% glucose solution was added and dissolved clearly. The clear solution was stored at 5 ° C. (in a refrigerator) or 15 ° C. (in a thermostat), and the appearance after 24 hours was confirmed.

  As a result, as shown in Table 3 below, <Comparative Example 1> to <Comparative Example 2> and <Comparative Example 4> to <Comparative Example 11> are injectable preparations according to the present invention. Examples 1> to <Example 16> were found to have very good solubility at low temperatures (5 ° C. and 15 ° C.). In addition, in appearance confirmation, whether the solution obtained by the above method is a clear solution, or whether it is a suspended (for example, cloudy) solution, a solution in which a solid is precipitated, or a solution in which a solid is precipitated. It was judged.

  In Table 3 below, clear experimental examples and comparative examples are indicated by ◯ marks, and suspended, precipitated, and precipitated comparative examples are indicated by X marks. The case where the solubility test was not examined was indicated by-. “Clear” means that the state of the solution is clear in the visual confirmation of the appearance of the solution. On the other hand, “suspension, precipitation, precipitation” means that, in visual confirmation of the appearance of the solution, a solid is precipitated in the solution and becomes turbid, or the solid is precipitated.

<Test Example 2>
Formulation test with low pH infusion For Solita T2 (Ajinomoto), KNMG3 (Otsuka Pharmaceutical Factory), and Physizol 3 (Otsuka Pharmaceutical Factory), which are low pH infusions, <Example 1> to <Example 16> And the compounding test with the various freeze-dried preparations for injection obtained in <comparative example 1>-<comparative example 6> was implemented. Various lyophilized preparations for injection were dissolved in 10 mL of physiological saline per vial at room temperature (about 22 ° C. to about 28 ° C.). Next, 2 mL of the solution, 12.5 mL of Solita T2, 16.7 mL of KNMG3, and 12.5 mL of Physiozol 3 were placed at room temperature (about 22 ° C. to about 28 ° C.). Blended. About each compounding liquid, it stood and stored at room temperature (about 22 degreeC-about 28 degreeC), and confirmed the external appearance 24 hours after mixing | blending. The appearance confirmation method is the same method as in Test Example 1 described above. In Table 4 below, clear experimental examples and comparative examples are indicated by ○ marks, and suspended, precipitated, and precipitated comparative examples are indicated by × marks.

  The preparations for injection of <Example 1> to <Example 16> and <Comparative Example 1> were all clear solutions 24 hours after immediately after compounding. On the other hand, in the injectable preparations of <Comparative Example 2> to <Comparative Example 6>, white turbidity, precipitation, precipitation and the like were confirmed from about 1 hour after blending to about 5 hours after blending.

  As a result, as shown in Table 4 below, in comparison with <Comparative Example 2> to <Comparative Example 6>, <Example 1> to <Example 16>, which are injectable preparations of the present invention, are low. It has been found that it has extremely excellent solubility in combination with pH infusion.

  As described above, from the results of Test Example 1 and Test Example 2 described above, the injectable preparation of the present invention exhibits extremely excellent solubility in a solution at low temperatures and / or is extremely excellent in blending with a low pH infusion solution. It was found to exhibit high solubility.

  Further, from Table 3 above, the results of <Comparative Example 3> have good solubility test results at low temperatures, and from Table 4, <Comparative Example 1> has good results of combination tests with low pH infusion solutions. However, both of the preparations of <Comparative Example 1> and <Comparative Example 3> were used in stability tests (for example, a measurement test of a pH value when a freeze-dried preparation for injection was dissolved in a dissolving solution, a purity test, etc.) The preparation was slightly unstable. On the other hand, all the preparations for injection (<Example 1> to <Example 16>) were stable preparations in this stability test.

  The injectable preparation according to the present invention can be quickly prepared into a clear solution in the case of treating acute lung disorder patients who are in a serious condition, and can be quickly administered to the patient, or can be used for a long time. However, it is a formulation that is very easy to handle in the medical field, and has the feature that it can be stored in the state of an injection solution because it does not cause a change in formulation.

Claims (29)

An injectable preparation comprising cibelestat sodium salt or a hydrate thereof, and an amount of 0.25 to 0.95 mole of hydrogen carbonate per 1 mol of cibelestat sodium salt or a hydrate thereof. The preparation according to claim 1, wherein the bicarbonate is sodium bicarbonate and / or potassium bicarbonate. The preparation according to claim 2, wherein the bicarbonate is sodium bicarbonate. The preparation according to any one of claims 1 to 3, further comprising a pH adjuster and optionally containing an excipient and / or an inorganic salt. The preparation according to claim 4, wherein the pH adjuster is sodium hydroxide. The preparation according to claim 4, wherein the excipient is mannitol. The preparation according to claim 4, wherein the inorganic salt is sodium chloride. The preparation according to any one of claims 1 to 7, which is a freeze-dried preparation for injection. The preparation according to claim 8, which is soluble in a solution at low temperature. The preparation according to claim 9, wherein the low temperature is 5 ° C to 15 ° C. The preparation according to claim 9, wherein the solution is water, physiological saline and / or glucose solution. The preparation according to any one of claims 1 to 7, which is a liquid preparation for injection. The preparation according to claim 12, which is a solution prepared by dissolving a freeze-dried preparation for injection with a dissolving solution. The preparation according to claim 12, which is a solution obtained by diluting a solution obtained by dissolving a freeze-dried preparation for injection with a dissolving solution into a low pH infusion solution. Low pH infusion, Solita No. T3 (Solita is a registered trademark), Solita No. T2 (Solita is a registered trademark), Solita No. T1 (Solita is a registered trademark), No. KNMG3 (knmg is a registered trademark), physiotherapist tetrazole No. 3 (Physio 15. The preparation according to claim 14, wherein the sol is a registered trademark) , an actit injection (actit is a registered trademark) , and / or a Vin 3G injection (Vin is a registered trademark) . The preparation according to claim 12, which is a solution for producing a freeze-dried preparation for injection. The preparation according to claim 16, wherein the solvent of the solution for producing the lyophilized preparation for injection is water. Sivelestat sodium salt or hydrate thereof, 1 mole of sodium bicarbonate, sivelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof. In contrast, a freeze-dried preparation for injection containing 4.3 to 7.3 moles of mannitol and 0.27 to 0.9 moles of sodium chloride per mole of sivelestat sodium salt or hydrate thereof. Sivelestat sodium salt or hydrate thereof, 1 mole of sodium bicarbonate, sivelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof. In contrast, an injectable liquid preparation containing 4.3 to 7.3 moles of mannitol and 0.27 to 0.9 moles of sodium chloride with respect to 1 mole of sivelestat sodium salt or hydrate thereof. The liquid preparation for injection according to claim 19, which has a pH value of 7.5 to 8.5. Sivelestat sodium salt or hydrate thereof, 1 mole of sodium bicarbonate, sivelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof. It contains 4.3 to 7.3 moles of mannitol and 0.27 to 0.9 moles of sodium chloride per mole of sivelestat sodium salt or its hydrate, and pH is adjusted with sodium hydroxide. A liquid preparation for injection whose value is adjusted. The liquid preparation for injection according to claim 21, which has a pH value of 7.5 to 8.5. 23. A freeze-dried preparation for injection produced by freeze-drying the liquid preparation for injection according to claim 21 or 22. 24. The freeze-dried preparation for injection according to claim 23, wherein the pH value of the solution obtained by dissolving the freeze-dried preparation for injection with a dissolving solution is 7.5 to 8.5. Sivelestat sodium salt or hydrate thereof, 1 mole of sodium bicarbonate, sivelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof. A lyophilized preparation for injection containing 4.3 to 7.3 moles of mannitol and 0.27 to 0.9 moles of sodium chloride per mole of sivelestat sodium salt or hydrate thereof. A freeze-dried preparation for injection prepared by adjusting a pH value of a solution obtained by dissolving the freeze-dried preparation for injection with a dissolving solution to 7.5 to 8.5. A freeze-dried preparation for injection containing cyberestat sodium salt or a hydrate thereof, and a bicarbonate, and having an amount of 0.25 to 0.95 mole relative to 1 mole of sivelestat sodium salt or hydrate thereof. A preparation that contains a bicarbonate and can maintain a clear solution state at a low temperature after mixing with a solution. An injectable liquid preparation containing sivelestat sodium salt or a hydrate thereof, and a bicarbonate, wherein the amount of carbonic acid is 0.25 to 0.95 mole per mole of sivelestat sodium salt or a hydrate thereof. A preparation containing a hydrogen salt and capable of maintaining a clear solution state after liquid formulation with a low pH infusion. In order to produce a lyophilized preparation for injection containing cyberestat sodium salt or a hydrate thereof, which can maintain a clear solution state at a low temperature after mixing with a lysis solution, the lyophilized preparation for injection is prepared. A method of using a 0.25 to 0.95 mole amount of hydrogen carbonate to 1 mole of sivelestat sodium salt or hydrate thereof in the solution to be produced. Injectable lyophilized preparation for manufacturing a liquid preparation for injection containing cibelestat sodium salt or a hydrate thereof, which can maintain a clear solution state after combination with a low pH infusion solution A method of using, in the solution, 0.25 to 0.95 moles of hydrogen carbonate per mole of sivelestat sodium salt or hydrate thereof.