KR101461271B1 - Formulations for injection containing sivelestat sodium salt or hydrate thereof - Google Patents

Abstract

It has been found that the injectable preparation containing the sivelestat sodium salt or the hydrate thereof does not change the formulation even when stored for a long period of time when it is mixed with the liquid and / Providing a formulation capable of maintaining a clear solution state.
The injectable preparation containing siberestat sodium salt, its hydrate and the hydrogencarbonate salt is a preparation having improved solubility in a dissolving solution at a low temperature. It is also an agent for improving the solubility in a dissolving solution at a low temperature, It is a preparation that maintains a solution state, and is a preparation that is very easy to handle in a medical field.

Description

TECHNICAL FIELD [0001] The present invention relates to a formulation for oral administration containing a sodium salt of siberestat or a hydrate of the same. BACKGROUND OF THE INVENTION < RTI ID = 0.0 >

The present invention relates to a compound represented by the following formula (I):

(Hereinafter sometimes referred to as a compound of the present invention) and a hydrogencarbonate salt represented by the following formula (1): " (1) " More specifically, the present invention relates to a injectable preparation which exhibits excellent solubility even at a low temperature, and which can maintain a clear solution state without accompanying a change in formulation even after mixing with a liquid for a long period of time.

The compound of the present invention has an elastase inhibitory activity and is a very useful compound which is used as a therapeutic agent for improving acute lung injury accompanied by systemic inflammatory response syndrome. In acute lung injury patients who are to be administered with the compound of the present invention, acute lung injury patients need to be urgently treated. Thus, injectable preparations are suitable for the form of the therapeutic agent to be used. In Japan, 100 mg A lyophilized injectable preparation containing berestart sodium hydrate, 200 mg of D-mannitol and a pH adjuster is sold under the name "Elaspol 100".

There are several formulations for injections, but the most frequently used formulations are injectable liquid formulations and injectable lyophilized formulations. The injectable liquid preparation is provided in a state in which the injectable component is dissolved in a liquid medium which can be injected in advance, and is administered as it is, or diluted in an appropriate liquid or the like, and then administered as an injectable solution. On the other hand, the injectable freeze-dried preparation for injection is provided in a solid state called a lyophilized product. It is dissolved once in the solution using the solution, and the solution is directly diluted in an appropriate solution or the like, do.

If it takes a long time to dissolve the lyophilized preparation for injection use in the dissolving liquid or if it causes dissolution of the lyophilized preparation, but when the solution is mixed with the liquid and causes a change in composition such as opacity, precipitation, precipitation, etc., If you can not do it, the patient's condition may lead to serious situations. In the case of injectable liquid preparations, there is no need for a dissolution step because dissolving does not require a step of dissolving. However, the problem of mixing changes such as opacity, precipitation, precipitation, etc., As in the case of pharmaceuticals, this is a concern.

As described above, since the compound of the present invention is a drug to be administered to a patient suffering from an acute lung injury, the lyophilized preparation for use in the present invention can be used as a lyophilized preparation in the form of a liquid (for example, purified water, distilled water for injection and sterilized water), physiological saline, It is required that the prepared solution can prepare an injectable solution in a clear solution without causing a change in formulation even when mixed with any liquid.

The lyophilized preparations for injectable use of the presently-marketed compounds of the present invention, which are currently sold, are generally easy to handle without any problems when they are handled at room temperature of about 15 ° C or higher and about 35 ° C or lower. , The solubility in the dissolving solution may be lowered under the condition that the room temperature is lower than about 15 占 폚. In addition, in the mixing of the solution, precipitation occurs when the pH value after mixing becomes about 6 or less, There was also a case that there was a problem to be solved.

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

For example, JP-A-3-20253 discloses a compound represented by the following formula (II), which is a carboxylate (free form)

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

Further, in Japanese Patent Application Laid-Open No. H05-194366, a compound corresponding to the sodium salt · tetrahydrate thereof is described in Example 3, and a production method thereof and the like are also described (see Patent Document 2).

Japanese Patent Application Laid-Open No. 2002-80361 discloses a process for producing a salt of N- [o- (p-pivaloyloxy) thiophene containing at least one kind of pH regulator selected from trisodium phosphate, a hydrate thereof, sodium hydroxide, Benzenesulfonylamino) benzoyl] glycine monosodium salt, tetrahydrate, and a preparation using the same. (Patent Document 3).

In addition, International Publication No. 2002/007724 discloses a method of freezing N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt and tetrahydrate dissolved in a mixed solvent of water and ethanol A lyophilized preparation which is dried, and a method of producing the lyophilized preparation by a method disclosed in Japanese Patent Application Laid-Open (kokai) No. 2001-328756 (Patent Document 4).

In addition, Chinese Patent Application Publication No. 1457772 discloses an acute lung injury, acute respiratory distress syndrome, acute respiratory distress syndrome syndrome, acute respiratory distress syndrome syndrome, acute respiratory distress syndrome syndrome characterized by sterile injectable lyophilized powder produced by active ingredient siberestat and filler, (See Patent Document 5).

However, these prior art documents disclose the compound of the present invention. However, the solubility of the injectable preparation containing the compound of the present invention as an active ingredient in a dissolving solution at low temperature and the change in compounding with the solution Not at all.

Patent Document 1: JP-A-3-20253 Patent Document 2: JP-A-5-194366 Patent Document 3: Japanese Patent Application Laid-Open No. 2002-80361 Patent Document 4: International Publication No. 2002/007724 pamphlet Patent Document 5: Chinese Patent Application Publication No. 1457772

In the lyophilized preparations for injectable use of the compound of the present invention which have been heretofore used, the solubility in a dissolving liquid may deteriorate in medical practice at a low temperature, for example, during winter (room temperature is about 15 ° C or less) Precipitation and / or precipitation may occur when the pH value is reduced to about 6 or less in the combination regimen with the surfactant.

It is an object of the present invention to provide a injectable preparation capable of improving the solubility under low temperature and / or preparing an injectable liquid without causing a change in formulation with the liquid.

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

That is,

(1) injectable preparations containing siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt,

(2) The agent according to (1) above, wherein the hydrogencarbonate is contained in an amount of 0.25 mol or more per mol of the siberestat sodium salt or the hydrate thereof,

(3) The preparation according to (2), wherein the hydrogencarbonate is 0.25 to 10 molar sodium hydrogencarbonate per 1 mol of the siberestat sodium salt or the hydrate thereof,

(4) The preparation according to (3), wherein the hydrogencarbonate is sodium hydrogencarbonate in an amount of 0.25 to 0.95 mol per mol of the siberestat sodium salt or the hydrate thereof,

(5) The preparation according to (1) above, wherein the hydrogencarbonate is sodium hydrogencarbonate and / or potassium hydrogencarbonate,

(6) The agent according to (5) above, wherein the hydrogencarbonate is sodium hydrogencarbonate,

(7) a preparation according to (5), which further contains a pH adjusting agent and optionally contains excipients and / or inorganic salts,

(8) The preparation according to (7), wherein the pH adjuster is sodium hydroxide,

(9) The preparation according to (7) above, wherein the excipient is mannitol,

(10) The agent according to (7), wherein the inorganic salt is sodium chloride,

(11) The pharmaceutical composition according to (1) above, which is a freeze-

(12) The preparation according to (11), which is low-temperature soluble,

(13) The preparation according to (12) above, wherein the low temperature is 5 ° C to 15 ° C,

(14) The agent according to (12), wherein the solution is water, physiological saline, and / or glucose solution,

(15) The pharmaceutical composition according to (1) above, which is a liquid preparation for injection,

(16) The preparation according to (15) above, which is a solution obtained by dissolving a lyophilized preparation for injection,

(17) The preparation according to (15) above, which is a solution obtained by diluting a solution obtained by dissolving a lyophilized preparation for injection use as a dissolution solution in a low pH solution,

(18) Low pH fluid is injected in the same way as Solita T3, Sotta T2, Sotta T1, KNMG 3, Physiosol 3, Actit injections and / or Veen ) The preparation according to (17) above, which is a 3G injection solution,

(19) the preparation according to (15) above, which is a solution for preparing a freeze-dried preparation for injection,

(20) The preparation according to (19) above, wherein the solvent of the solution for preparing the injectable lyophilized preparation is water,

(21) 4.3 to 7.3 mols per mol of sodium hydrogencarbonate, sibelestat sodium salt or hydrate thereof in an amount of 0.25 to 0.95 mol based on 1 mol of the siberestat sodium salt or its hydrate, siberestat sodium salt or its hydrate Mannitol, and 0.27 to 0.9 mol of sodium chloride per 1 mol of siberestat sodium salt or hydrate thereof,

(22) A freeze-dried preparation for injectable use containing a siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt, wherein the liquid preparation after mixing with the dissolution liquid is capable of maintaining a clear solution state at a low temperature,

(23) A liquid preparation for injectable use containing a siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt, wherein the liquid formulation after mixing with a low pH liquid solution is capable of maintaining a clear solution state,

(24) A freeze-dried preparation for injectable use containing a siberestat sodium salt or a hydrate thereof, which is capable of maintaining a clear solution state at a low temperature after mixing with a dissolution liquid, A method of using (adding) a bicarbonate salt to the solution,

(25) A liquid preparation for injectable use containing a siberestat sodium salt or a hydrate thereof, which is capable of maintaining a clear solution state after mixing with a low pH liquid solution, comprising a solution for preparing a lyophilized preparation for injection A method of using (adding) a bicarbonate salt,

(26) a freeze-dried preparation for injectable use prepared using a solution containing siberestat sodium hydrate and bicarbonate salt,

(27) The lyophilized preparation for injection use according to (26), wherein the hydrogencarbonate is sodium hydrogencarbonate and / or potassium hydrogencarbonate,

(28) The lyophilized preparation according to (27), wherein the hydrogencarbonate is sodium hydrogen carbonate in an amount of 0.25 to 1.2 mol based on 1 mol of sodium cibestradate hydrate,

(29) The lyophilized preparation for injection use according to (27), wherein the hydrogencarbonate is sodium hydrogencarbonate in an amount of 0.5 mol to 0.95 mol based on 1 mol of sodium cibestradate hydrate,

(30) The pharmaceutical composition according to (27), wherein the hydrogencarbonate is potassium hydrogencarbonate in an amount of 0.25 to 1.2 mol based on 1 mol of sodium cibestrad sodium hydrate,

(31) Hydrogen carbonate salt The freeze-dried preparation for injectable use according to the above (27), which is potassium hydrogencarbonate in an amount of 0.5 mol to 0.95 mol based on 1 mol of sodium cibestrad sodium hydrate,

(32) The freeze-dried preparation for injectable use according to any one of (26) to (31), which is prepared using a solution further containing an excipient,

(33) The lyophilized preparation for injection use according to (32), wherein the excipient is a sugar alcohol,

(34) The lyophilized preparation for injection use according to (33), wherein the alcohol is mannitol, xylitol and / or sorbitol,

(35) A lyophilized preparation for injection use according to any one of (26) to (34), which is prepared using a solution further containing an inorganic salt,

(36) The lyophilized preparation for injection use according to (35), wherein the inorganic salt is sodium chloride,

(37) A freeze-dried preparation for injectable use prepared using a solution containing siberestat sodium hydrate, bicarbonate, mannitol and sodium chloride,

(38) The lyophilized preparation according to (37), wherein the hydrogencarbonate is sodium hydrogencarbonate and / or potassium hydrogencarbonate,

(39) The pharmaceutical composition according to any one of (26) to (38), wherein the solution has a pH value of 7.5 to 8.5,

(41), wherein the solvent of the solution (40) is a water,

(39), wherein the pH value of the solution (41) is adjusted with a pH adjusting agent,

(42) The lyophilized preparation according to (41), wherein the pH adjuster is an alkali metal hydroxide and / or an alkaline earth metal hydroxide,

(43) The lyophilized preparation for injection use according to the above (42), wherein the alkali metal hydroxide is sodium hydroxide,

(44) The lyophilized preparation for injectable use according to any one of (26) to (38), wherein the pH value of the solution when the lyophilized preparation is dissolved in water is 7.5 to 8.5,

(45) A solution containing 100 mg of siberestat sodium hydrate was dissolved in 5 mL to 10 mL of the lyophilized product prepared at low temperature to prepare a clear solution. ), ≪ / RTI > a freeze-

(46) The lyophilized preparation for injectable use according to (45), wherein the low temperature is 5 ° C to 15 ° C,

(47) The lyophilized preparation for injectable use according to (45), wherein the lysis solution is water, physiological saline, and / or glucose solution,

(48) Siberestat sodium hydrate (100 mg), a solution of 60 mL to 85 mL of low pH was added to a solution of 10 mL of water for the preparation of lyophilized product, which was prepared using a solution containing 100 mg of siberestat sodium hydrate (26) to (38), wherein the freeze-

(49) The main use of the low pH fluid as described in (48) above, which is Sotta T3, Sotta T2, Sotta T1, KNMG 3, Fijiazol 3, Freeze-dried preparations,

(50) An aqueous solution of sodium cibestrad sodium hydrate containing sodium hydrogencarbonate and / or potassium hydrogencarbonate,

(51) wherein the pH value of the aqueous solution is 7.5 to 8.5, and

(52) A preparation made using the aqueous solution according to (50) above.

(Hereinafter may be abbreviated as " injectable preparation of the present invention ") containing a sodium salt of siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt has excellent solubility to the dissolution liquid, Especially those having a solubility at or below about 15 ° C and / or having a solubility in water, especially a low pH solution (sap having a pH value of less than about 7, such as Sotta T3, Sotta T2, Sotta T1, KNMG 3 , Fijiazol 3, Arctitide Injection and Empty 3G Injection), and even after a long period of mixing, it is possible to maintain a clear solution state without any change in formulation such as opacity, precipitation, and precipitation I have.

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, for example, It is easy to dissolve in the dissolution solution and is very easy to handle. In addition, the injectable preparation of the present invention, in combination with the liquid other than the low-pH liquid solution, not only maintains a clear solution state without involving any change in formulation without any problem, and further, It is a very easy-to-handle formulation that maintains a clear solution state without accompanying formulation changes.

Therefore, the injectable preparation of the present invention can be prepared into an injectable solution quickly in a clear state when urgently treating a patient suffering from an acute lung injury, which is in a critical state even at low temperatures, and can be rapidly administered to a patient, or Which is characterized in that it can be preserved in the form of an injection solution because it does not cause a change in formulation even when it is left for a long time.

In addition, the injectable preparation of the present invention (particularly, a lyophilized preparation for injection) has a characteristic that stability of siberestart is excellent at the time of dissolution with a dissolution liquid. Concretely, when dissolving in a dissolving solution, degradation of siberestat can be suppressed, and deterioration of purity can be prevented.

Hereinafter, the present invention will be described in detail.

The compound of the present invention can be produced by a known method such as the methods described in the above-mentioned Patent Document 1 and Japanese Patent Application Laid-Open No. 9-40692, and Comprehensive Organic Transformations (Second Edition) Methods described in Transformations: A Guide to Functional Group Preparations, 2nd Ed.) (Richard C. Larock, John Wiley & Sons Inc. (1999)) can be suitably modified and combined. The produced compound of the present invention can be purified by conventional purification means such as distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography or column chromatography or washing or recrystallization And the like. The carboxylic acid form (free form) of the compound of the present invention represented by the formula (II), that is, siberestat, can also be produced and purified according to the method for producing the compound of the present invention.

In the present invention, the compound of the present invention may be in the form of crystals, amorphous form, or any solid form (for example, a mixture of crystals and amorphous forms in any ratio) or may be substantially equivalent to the compound of the present invention . Substantially equivalent to the compound of the present invention is, for example, 1 equivalent or more of a sodium donor (for example, an aqueous sodium hydroxide solution (for example, an aqueous solution of sodium hydroxide , Sodium hydroxide and the like), one obtained by adding one equivalent or more of an aqueous solution of sodium hydroxide or the like to the carboxylate (free form) of the compound of the present invention represented by the formula (II) (I) wherein the monosodium salt of the carboxylic acid derivative (free form) of the compound of the present invention is added with water.

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

When the injectable preparation containing the siberestat sodium salt or its hydrate and the hydrogencarbonate salt, that is, the injectable preparation of the present invention is a lyophilized preparation for injection, hereinafter simply referred to as " lyophilized preparation of the present invention " There is a case. Likewise, when the injectable preparation of the present invention is a liquid preparation for injectable use, there may be simply referred to as " liquid preparation for injectable use of the present invention "

In the present invention, an injection liquid means a liquid composition capable of being injected into a living body as it is.

In the present invention, the injectable liquid preparation means a preparation in which the injectable component is dissolved in a liquid medium which can be injected in advance, and when it is in use, it is injected as it is, ≪ / RTI > The liquid formulation for injection is not particularly limited as long as it is generally used as a liquid formulation. Concretely, there are provided (a) a preparation provided in the form of an adjusted solution when preparing a lyophilized preparation for injection for use containing a compound of the present invention and a hydrogencarbonate salt, (b) a compound containing the compound of the present invention, (C) dissolving a lyophilized preparation for injection containing a compound of the present invention and a bicarbonate salt as a dissolving solution, and then dissolving the lyophilized preparation in an aqueous solution A preparation provided in a diluted state, and the like.

The solvent for the injectable liquid preparation of the present invention is not particularly limited as long as it is generally used as a injectable preparation. In the present invention, the solvent of the injectable liquid preparation of the present invention is preferably a mixed solvent of water (for example, distilled water for injection, sterilized water and purified water), water and an organic solvent (for example, ethanol etc.). 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 the form of a solid such as a lyophilized product. In use, the lyophilized preparation is once dissolved by using the solution, Dilute it in a suitable solution or the like as desired, and administer it as an injection solution. That is, it can be said that the addition of an optional solution to the lyophilized preparation for injection and dissolution is substantially equivalent to the liquid formulation for injection.

The dissolving liquid of the present invention refers to a liquid medium in which a small amount (about 10 mL or less) is added to a container (for example, a vial or the like) of a main lyophilized preparation for dissolving the lyophilized material using a syringe or the like, (For example, purified water, distilled water for injection, sterile water, etc.), physiological saline, and / or glucose solution.

The injectable preparation of the present invention not only does not cause a compounding change in combination with a solution having a low pH but also exhibits excellent solubility in combination with a low pH solution. That is, this "low pH aqueous solubility" means that the solution is in a clear solution state without causing a change in the compounding even when mixed with a low pH aqueous solution, and the state can be maintained for a long time. Specifically, when the injectable preparation of the present invention is a liquid preparation for injection, it is in a clear solution state without causing any change in formulation when the preparation is mixed with various low-pH aqueous solutions, and the condition is maintained for a long time, preferably 6 For 24 hours. When the injectable preparation of the present invention is a lyophilized preparation for injection, the solution prepared by adding the solution to the formulation causes a change in formulation when mixed with various low-pH aqueous solutions And the state of the solution can be maintained for a long time, preferably 6 hours to 24 hours. Herein, the low pH liquid solution refers to the liquid solution having a pH of about 7 or less, preferably about 6 or less. Specifically, the solution is an aqueous solution of ACTTT, empty 3G injection, kylit injection 5%, glycerol injection , KN 1, Sotta T 1, Soldem 1, KN 3, KNMG 3, Sotta T 3, Soldem 3A, Fijiol 3, Sotta T2, low molecular weight dextran injections and Martos (Martos) -10.

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

In the present invention, the hydrate of the sodium salt of siberestat is not particularly limited as long as the molecule of the sodium salt of siberestat is water-hydrated arbitrarily. Examples of the hydrate of the sodium salt of siberestat include sodium salt of siberestat sodium salt, sodium salt of siberestat sodium salt, sodium salt of siberestat sodium salt, siberestat sodium salt tetrahydrate and siberestat sodium salt pentahydrate , And a siberestat sodium salt tetrahydrate is particularly preferable.

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

The content of the hydrogencarbonate salt is not particularly limited as far as it can exert the action and effect of the present invention. The lower limit of the content of the hydrogencarbonate salt is generally about 0.25 mol or more, preferably about 0.25 mol or more per mol of the siberestat sodium salt or the hydrate thereof from the viewpoint of effectively exhibiting the action effects of the low pH solubility and / More preferably at least about 0.26 mole, more preferably at least about 0.3 mole, even more preferably at least about 0.4 mole, especially at least about 0.5 mole. The upper limit of the content of the hydrogencarbonate salt is generally about 10 moles or less, preferably about 10 moles or less, more preferably about 10 moles or less, or about 10 moles or less, More preferably not more than about 6 mol, more preferably not more than about 4 mol, still more preferably not more than about 2 mol, still more preferably not more than about 1.5 mol, more preferably not more than about 1.2 mol, more preferably not more than about 1.06 mol, More preferably about 0.96 mol or less, particularly about 0.95 mol or less.

Concretely, a content of about 0.25 mol to about 10 mol per 1 mol of the siberestat sodium salt or hydrate thereof is preferable. More preferably, the content of hydrocyanic acid salt is from about 0.25 mole to about 6 mole, from about 0.25 mole to about 4 mole, from about 0.25 mole to about 2 mole, from about 0.25 mole to about 1.5 mole, from about 0.25 mole to about 1.2 mole, About 1.2 mole, about 0.26 mole to about 1.06 mole, about 0.25 mole to about 0.95 mole, and about 0.26 mole to about 0.95 mole. The most preferred range of the content of the hydrogencarbonate is from about 0.5 mol to about 0.95 mol per 1 mol of the siberestat sodium salt or hydrate thereof.

The injectable preparation of the present invention may contain, if necessary, one or more components selected from the group of excipients, pH adjusters and / or inorganic salts. In addition, if necessary, it may contain at least one component selected from the group consisting of stabilizers, anhydrophilizing agents, buffering agents and / or preservatives.

In the injectable preparation of the present invention, the excipient to be used as needed is not particularly limited as long as it is generally used as an excipient for injectable preparations. Examples of suitable excipients include disaccharides such as glucose (glucose), fructose, and mixtures thereof in an arbitrary ratio, for example, disaccharides such as lactose (lactose), maltose (maltose) Dextrans such as dextran 40, dextran 80 and mixtures of any of these, and the like, such as polyhydric alcohols such as glycerol, for example, sugar alcohols such as mannitol, xylitol, sorbitol, And mixtures of these excipients. More preferred are mannitol, glucose, lactose, maltose, glycerin, xylitol, sorbitol, dextran and mixtures of any of these ratios, more preferably mannitol, xylitol, sorbitol, Sugar alcohol such as a mixture in an arbitrary ratio, etc., and mannitol is particularly preferable. The excipient is not limited to anhydride, and may be added as a hydrate.

The content of the excipient is not particularly limited. The content of the excipient is preferably from about 0.3 mol to about 29 mol per mol of the siberestat sodium salt or the hydrate thereof. More preferably, the ratio is about 0.6 to about 23 moles, more preferably about 1.45 moles to about 14.5 moles per mole of the siberestat sodium salt or the hydrate thereof, From about 2.9 mol to about 8.7 mol, and particularly preferably from about 4.3 mol to about 7.3 mol. When the content is within this range, preparation of the cake-like lyophilizate is facilitated when the lyophilized preparation for injection is used.

In the injectable preparation of the present invention, the inorganic salt to be used is not particularly limited as long as it is generally used as a injectable preparation. Examples of inorganic salts include alkali metal chloride salts, alkaline earth metal chloride salts, alkali metal bromide salts, alkaline earth metal bromide salts, alkali metal sulfate salts, alkaline earth metal sulfate salts and mixtures of any of these. Preferably, it is, for example, an alkali metal chloride salt, a chlorinated alkaline earth metal salt and a mixture of any of these in an arbitrary ratio, more preferably, for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, Sodium chloride is preferred. 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 per mol of the siberestat sodium salt or the hydrate thereof. More preferably, the ratio is 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 the siberestat sodium salt or hydrate thereof, Preferably from about 0.18 mol to about 1.8 mol, and particularly preferably from about 0.27 mol to about 0.9 mol.

In the injectable preparation of the present invention, the pH adjusting agent to be used if necessary is not particularly limited as long as it is generally used as a preparation for injection. Preferable examples of the pH adjuster include inorganic bases such as alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures of any of these. More preferably, inorganic bases such as sodium hydroxide, potassium hydroxide, and mixtures of any of these, and the like are preferable, and sodium hydroxide is particularly preferable. These pH adjusting agents may be added as a salt (for example, a monovalent alkali metal salt such as a sodium salt or a potassium salt, or a divalent alkaline earth metal salt such as a calcium salt) or a hydrate thereof, or as an aqueous solution (for example, an aqueous solution of sodium hydroxide , An aqueous solution of potassium hydroxide, an aqueous solution of calcium hydroxide, etc.).

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

When the injectable preparation of the present invention is a lyophilized preparation for injection, the pH value of the solution dissolved in the solution is preferably 7.0 to 8.5. More preferably, it is 7.5 to 8.5.

As the method for preparing the injectable liquid preparation of the present invention, the operation of adding or mixing the above-described hydrogencarbonate (for example, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.) or the like can be carried out by the methods shown in the examples and the conventional pharmaceutical methods . If necessary, the pH adjusting agent (e.g., sodium hydroxide solution, potassium hydroxide and the like), inorganic salt (e.g., mannitol, glucose, lactose, maltose, glycerin, xylitol, Sodium chloride, etc.), a stabilizer, an anhydrous agent, a buffering agent, a preservative and the like are further added or mixed is carried out in accordance with a suitable combination of the following methods, a method shown in the examples, and a conventional pharmaceutical method.

Examples of the method for preparing the injectable liquid preparation of the present invention include a method of weighing and mixing the compound of the present invention and a bicarbonate salt respectively and then dissolving in water, a method of dissolving a bicarbonate salt weighed in an aqueous solution containing the compound of the present invention , A method of dissolving the compound of the present invention which is weighed in an aqueous solution containing a hydrogencarbonate, and the like. There is also a method in which an aqueous solution containing the compound of the present invention and an aqueous solution containing a hydrogencarbonate salt are separately prepared, and these aqueous solutions are mixed and prepared. In the preparation methods other than these, any method may be used as long as it is a liquid formulation for injection containing two components of the compound of the present invention and the hydrogencarbonate.

As a method for preparing the injectable liquid preparation of the present invention, which further contains a pH adjuster in the compound of the present invention and a hydrogencarbonate salt, the compound of the present invention, the hydrogencarbonate salt and the pH adjuster are each weighed and mixed, A method of dissolving a bicarbonate salt and a pH adjuster weighed in an aqueous solution containing the compound of the present invention, a method of dissolving a pH adjuster weighed in an aqueous solution containing a compound of the present invention and a bicarbonate salt, A method of dissolving a bicarbonate salt weighed in an aqueous solution containing a compound and a pH adjuster, a method of dissolving a compound of the present invention and a pH adjuster which are weighed into an aqueous solution containing a bicarbonate salt, a method of dissolving the pH adjuster in an aqueous solution containing a bicarbonate salt and a pH adjusting agent A method of dissolving a compound of the present invention, a method of dissolving a compound of the present invention in which an aqueous solution containing a pH adjusting agent is weighed And a method of dissolving the compound and hydrogen carbonate. There is also a method of preparing an aqueous solution containing a compound of the present invention, an aqueous solution containing a hydrogencarbonate salt, and an aqueous solution containing a pH adjuster, respectively, and mixing these aqueous solutions. In the preparation methods other than these, any method may be employed as long as it is a liquid formulation for injection containing the three components of the compound of the present invention, the hydrogencarbonate and the pH adjuster.

As a method for preparing the injectable liquid preparation of the present invention further containing an inorganic salt in the compound of the present invention and a hydrogencarbonate salt, there may be mentioned, for example, the main use of the present invention wherein the compound of the present invention and a hydrogencarbonate salt further contain a pH- A method of preparing an aqueous solution using an inorganic salt in place of the pH adjusting agent in the same manner as the method of preparing the liquid preparation, and the like. In the preparation methods other than the above, any method may be used as long as it is a liquid formulation for injectable use containing the compound of the present invention, the hydrogencarbonate and the inorganic salt.

As a method for preparing the injectable liquid preparation of the present invention further containing an excipient in the compound of the present invention and a hydrogencarbonate salt, there may be mentioned, for example, a liquid preparation for injection of the present invention containing the compound of the present invention and a pH- There may be mentioned a method of preparing an agent using an excipient instead of the pH adjuster in the same manner as the method of preparing the agent. In the preparation methods other than the above, any method may be used as long as it is a liquid formulation for injectable use containing the three components of the compound of the present invention, the hydrogencarbonate and the excipient.

As a method for preparing the injectable liquid preparation of the present invention further containing a stabilizer in the compound of the present invention and the hydrogencarbonate, there may be mentioned, for example, And a method of preparing the same using a stabilizer instead of the pH adjuster in the same manner as the preparation of the preparation. In the preparation methods other than these, the liquid preparation for injection containing the three components of the compound of the present invention, the hydrogencarbonate and the stabilizer may be any operation.

In addition, as a method for preparing the injectable liquid preparation of the present invention, which further contains an anti-aging agent for the compound of the present invention and a hydrogencarbonate salt, there may be mentioned, for example, the main use of the present invention in which the compound of the present invention and a hydrogencarbonate salt further contain a pH- And a method of preparing a liquid formulation by using a wetting agent instead of the pH adjuster in the same manner as the preparation of the liquid formulation. In the preparation methods other than the above, any method may be used as long as it is a liquid formulation for injectable use containing the three components of the compound of the present invention, a hydrogencarbonate and an anhydrous agent.

Further, as a method for preparing the injectable liquid preparation containing the compound of the present invention and a buffer solution in addition to the hydrogencarbonate, there may be mentioned, for example, A method in which a buffer is used instead of the pH adjuster in the same manner as the preparation method of the preparation, and the like. In the preparation methods other than these, the liquid preparation for injectable use containing the three components of the compound of the present invention, the hydrogencarbonate and the buffer may be any operation.

As a method for preparing the injectable liquid preparation of the present invention further containing a preservative in the compound of the present invention and a hydrogencarbonate salt, there may be mentioned, for example, A method in which a preservative is used instead of the pH adjuster in the same manner as the preparation method of the preparation, and the like. In the preparation methods other than the above, any method may be used as long as it is a liquid formulation for injection containing the three components of the compound of the present invention, the hydrogencarbonate and the preservative.

Examples of the method of preparing the solution for preparing the injectable freeze-dried preparation of the present invention include a method of appropriately combining and adjusting the method for preparing the injectable liquid preparation of the present invention, the method shown in the embodiment, And the like.

In the present invention, as a method for producing a freeze-dried preparation for main use according to the present invention, a solution for preparing a freeze-dried preparation for mainstream use of the present invention obtained by the above-mentioned method is used, .

Examples of the solvent used in dissolving the freeze-dried preparation for mainstream use of the present invention include dissolution liquids and the like. Examples of the dissolution solution include water (for example, purified water, distilled water for injection, sterile water, etc.), physiological saline, and glucose solution (for example, 5% glucose solution). The injection solution obtained by this method may be administered as it is, or it may be administered as an injection solution after diluting it with a suitable solution or the like. As the liquid, for example, there can be used an aqueous solution containing an aqueous solution (eg, an aqueous solution of sodium chloride, sodium chloride, sodium chloride, potassium chloride, sodium chloride, ) And acicular acid retention solution such as xylitol injection solution such as quartz inoculation solution 5% (Otsuka Seiyaku Kojo; standard pH 4.5 to 7.5; Kirit is a registered trademark of Otsuka Seiyaku Co., Ltd.) KN No. 1 (Otsuka Seiyaku Kojo; standard pH 4 to 7.5), and Sotta T 1 (Ajinomoto; manufactured by Takara Shuzo Co., Ltd.), such as concentrated glycerin and fructose injection, which is a standard pH 3-6; glycerol is a registered trademark of Chugai Seiyaku; KS No. 3 (Otsuka Seiyaku Kojo; specifications: pH 3.5 to 6.5; Sounder is a registered trademark of Ajinomoto) and Solmd 1 (Terumo; standard pH 4.5 to 7; Soldem is a registered trademark of Terumo) pH 4 to 7.5), KNMG 3 (Otsuka Seiyaku Kojo; standard pH 3.5 to 7; KNMG is a registered trademark of Otsuka Seiyaku Co., ), Sotta T3 (Aizinomoto; standard pH 3.5 to 6.5; Sotta is a registered trademark of Ajinomoto), Soldem 3A (Terumo; standard pH 5 to 6.5; Soldem is a registered trademark of Terumo) Aizuka Seiyakujo; Specified pH 4 to 5.2; Fijiazol is a registered trademark of Otsuka Seiyaku Co., Ltd.), Sotta T2 (Azinomoto; standard pH 3.5 to 6.5; registered trademark of Ajinomoto) Dextran 40 and glucose injection solutions such as dehydrated water and liquid dextrane injection solution (Otsuka Seiyaku Kojo; standard pH 3.5 to 6.5), and martos-10 (Otsuka Seiyaku Kojo; standard pH 4 to 6; Maltose, which is a registered trademark of Otsuka Seiyaku Co., Ltd., and the like.

In the present invention, the temperature for preparing the injectable liquid preparation of the present invention is about 0 캜 or more and about 35 캜 or less, more preferably 3 캜 or more and 35 캜 or less, still more preferably 3 캜 or more and 30 캜 or less Particularly preferably 5 占 폚 or more and 30 占 폚 or less, and particularly preferably 5 占 폚 or more and 27 占 폚 or less.

In the present invention, as the preservation of the injectable liquid preparation of the present invention, the liquid itself may be stored as an injection liquid, or the injection liquid may be added to various liquids and stored as a diluted liquid.

In the present invention, the injectable liquid preparation of the present invention maintains a clear solution state at room temperature of not less than about 15 ° C and not more than about 35 ° C, and at room temperature of not less than about 5 ° C and not more than about 15 ° C It is one.

In the present invention, the temperature for preserving the injectable liquid preparation of the present invention is about 0 캜 or more and about 35 캜 or less, more preferably 3 캜 or more and 35 캜 or less, still more preferably 3 캜 or more and 30 캜 or less Particularly preferably 5 占 폚 or more and 30 占 폚 or less, and particularly preferably 5 占 폚 or more and 27 占 폚 or less.

In the present invention, the injectable liquid preparation of the present invention can be used as a liquid preparation for injection of various kinds of liquids (for example, Sotta T3, Sotta T2, Sotta T1, KNMG 3, Fijiazol 3, Etc.), it is a formulation which retains the solution state which has been clarified even after a long period of time.

In the present invention, a solution obtained by dissolving a lyophilized preparation for injection in a solution for dissolving a lyophilized preparation for injection may be prepared as an injectable solution, and the injection solution may be added to various kinds of liquids , And the diluted solution may be prepared as an injection solution.

In the present invention, the freeze-dried preparations for injection of the present invention can be used in a freeze-dried preparation having a room temperature of not less than about 15 ° C and not more than about 35 ° C, and even when the room temperature is not less than about 5 ° C and not more than about 15 ° C, Water, physiological saline, and glucose solution), and the clear solution state can be maintained.

In the present invention, the temperature of the preparation containing the injectable lyophilized preparation for injection of the present invention as an injection solution is about 0 캜 or more and about 35 캜 or less, more preferably 3 캜 or more and 35 캜 or less, still more preferably 3 캜 Or more and 30 DEG C or less, particularly preferably 5 DEG C or more and 30 DEG C or less, and particularly preferably 5 DEG C or more and 27 DEG C or less.

In the present invention, the freeze-dried preparation for injection of the present invention can be prepared by dissolving the preparation dissolved in a solution in various solutions (for example, SORTA T3, SORTA T2, SORTA T1, KNMG 3, 3, an ACTITY injection solution, and an empty 3G injection solution), the solution retained the clear solution state even after a long period of time.

In the present invention, the solution obtained by dissolving the lyophilized preparation for injection in a solution for dissolving the injectable preparation for freeze-dried preparation of the present invention in the form of an injection solution may be preserved as an injection solution, And the diluted solution may be stored as an injectable solution.

In the present invention, the injectable solution in which the freeze-dried preparation for injection of the present invention is dissolved in the solution or the solution in which the solution dissolved in the solution is further diluted with the aqueous solution is not more than about 15 ° C and not more than about 35 ° C at the room temperature, Even at a room temperature of about 5 ° C or more and about 15 ° C or less, the solution remains clear even after a long period of time without any problems.

In the present invention, the temperature for preserving the freeze-dried preparation for injection preparation of the present invention after preparation with an injection solution is about 0 캜 or more and about 35 캜 or less, more preferably 3 캜 or more and 35 캜 or less, still more preferably 3 Deg.] C to 30 deg. C, particularly preferably 5 deg. C or more and 30 deg. C or less, and particularly preferably 5 deg. C or more and 27 deg.

In the present invention, the low temperature means that the temperature is not less than 0 ° C and not more than 15 ° C. More preferably not less than 3 ° C and not more than 15 ° C, and particularly preferably not less than 5 ° C and not more than 15 ° C.

In the present invention, the long time in which the formulation of the present invention does not cause a change in formulation even if it is administered for a long period of time by mixing formulation with liquid indicates that it is from 3 hours to 72 hours. More preferably 6 hours to 72 hours, still more preferably 6 hours to 48 hours, particularly preferably 6 hours to 36 hours, and particularly preferably 6 hours to 24 hours.

In the present invention, as the injectable preparation containing the compound of the present invention and the hydrogencarbonate salt, the injectable preparation containing the three components of the compound of the present invention, the hydrogencarbonate and the pH adjusting agent is preferable, and the compound of the present invention, , a pH adjusting agent and an excipient are more preferable, and a injectable preparation containing 5 compounds of the compound of the present invention, a hydrogencarbonate, a pH adjuster, an excipient and an inorganic salt is particularly preferable.

In the present invention, injectable preparations containing the compound of the present invention, a hydrogencarbonate salt and sodium hydroxide are preferable, and the injectable preparation containing the compound of the present invention, hydrogencarbonate, sodium hydroxide and mannitol Particularly preferred are injectable preparations containing five components of the compound of the present invention, hydrogencarbonate, sodium hydroxide, mannitol and sodium chloride.

In the present invention, lyophilized preparations for injection containing sodium siburetate sodium salt or its hydrate, sodium hydrogen carbonate, mannitol and sodium chloride are particularly preferred, and the ratio of the content of each ingredient to the siberestat sodium salt or its hydrate It is preferable that 0.25 to 0.95 mol of sodium hydrogencarbonate, 4.3 to 7.3 mol of mannitol, and 0.27 to 0.9 mol of sodium chloride are contained per 1 mol of sodium carbonate.

The term " containing " as used herein means that the compound of the present invention and the hydrogencarbonate salt are used, but the term " containing " as used herein means, in addition to the compound of the present invention and the bicarbonate salt, It is used in the meaning that it may contain a component. This " contains " also includes a more limited meaning than what is basically made up of the compound of the present invention and the hydrogencarbonate. Herein, " basically consists of " is used to mean that the composition of the present invention, which is an essential ingredient, and the hydrogencarbonate are included as main components and may contain other minor components within a range not adversely affecting the action and effect of the present invention . The term " contains " means that the whole of the injectable preparation described in the present specification, for example, the injectable preparation containing the above three components, the injectable preparation containing the four ingredients, and the injectable preparation containing the five ingredients, etc. In any case, it is equally suitable.

In the present invention, the hydrogen carbonate ion derived from the hydrogencarbonate can be measured by a known analytical method. This analysis method is not particularly limited. Specific analytical methods include, for example, a neutralization titration method and an ion component measuring method (ion chromatograph method). When a sodium bicarbonate salt or a hydrate thereof is used as a injectable preparation and the carbonate ion is detected by any one of these analytical methods, the agent is included in the present invention.

In the present invention, cations (for example, sodium ion, potassium ion and the like) in the hydrogencarbonate can be measured by a known analytical method. This analysis method is not particularly limited. As a specific analysis method, for example, an ion component measurement method (ion chromatograph method) and the like are available.

In the present invention, when the inorganic salt to be used is sodium chloride, if desired, the chloride ion (Cl < ^- >) in sodium chloride can be measured by a known analytical method. This analysis method is not particularly limited. Specific analytical methods include, for example, titration with silver nitrate (for example, Fajans method, Mohr method, etc.), ion electrode method, ion component measurement method (ion chromatograph method), and gravimetric method. (For example, sodium ion, potassium ion, calcium ion, magnesium ion) and anions (for example, bromine ion (Br ^- ), sulfate ion (SO ₄ ^{2 -} ), etc.) ) Can be measured by known analytical methods. This analysis method is not particularly limited. Specific analytical methods include, for example, an ion component measurement method (ion chromatograph method), a gravimetric method, a spectrophotometric method, a gas chromatographic method, a radioactive analysis method, and an ion electrode method.

In the present invention, the injectable preparation of the present invention satisfies the characteristics (for example, stability, industrial productivity, safety, etc.) of a corresponding drug as a preparation made using the compound of the present invention.

[Example]

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Further, the scope of the present invention may be changed without departing from the scope of the present invention.

A method for producing a freeze-dried preparation for injection of the present invention is as follows.

≪ Example 1 >

Siberestat sodium salt tetrahydrate (4 g; 7.56 mmol), sodium hydrogencarbonate (400 mg; 4.76 mmol), and mannitol (8 g ) Was added 1N sodium hydroxide aqueous solution to adjust the pH to 7.7, and a clear solution was obtained. Next, sodium chloride (200 mg) was added to the bright solution to dissolve it. Finally, distilled water for injection was added so that the total amount became 200 mL. The total volume of 200 mL of the solution was aseptically filtered according to a conventional method and was filled into vials in 5 mL increments and lyophilized in accordance with a conventional method to obtain 100 mg of the lyophilized preparation for vaginal administration 40 vials ≪ / RTI >

≪ Example 2 >

(100 mg) of the compound of the present invention in a vial was obtained in the same manner as in <Example 1> except that sodium hydrogencarbonate (168 mg, 2.00 mmol) was used instead of sodium hydrogencarbonate (400 mg) A lyophilized preparation 40 vial was obtained.

&Lt; Example 3 >

(100 mg) of the compound of the present invention in a vial was obtained in the same manner as in <Example 1> except that sodium hydrogencarbonate (336 mg, 4.00 mmol) was used instead of sodium hydrogencarbonate A lyophilized preparation 40 vial was obtained.

<Example 4>

(100 mg) of the compound of the present invention in a vial was obtained in the same manner as in <Example 1>, except that sodium hydrogencarbonate (504 mg, 6.00 mmol) was used instead of sodium hydrogencarbonate A lyophilized preparation 40 vial was obtained.

&Lt; Example 5 >

(100 mg) of the compound of the present invention in a vial was obtained in the same manner as in <Example 1>, except that sodium hydrogencarbonate (672 mg, 8.00 mmol) was used instead of sodium hydrogencarbonate A lyophilized preparation 40 vial was obtained.

&Lt; Example 6 >

In the same manner as in Example 1, potassium hydrogen carbonate (400 mg, 4.00 mmol) was used instead of sodium hydrogencarbonate (400 mg), and 100 mg of the compound of the present invention A lyophilized preparation 40 vial was obtained.

&Lt; Example 7 >

Siberestat sodium salt tetrahydrate (4 g; 7.56 mmol), sodium hydrogencarbonate (400 mg; 4.76 mmol), and mannitol (8 g ) Was added 1N sodium hydroxide aqueous solution to adjust the pH to 7.7, and a clear solution was obtained. Finally, distilled water for injection was added so that the total amount became 200 mL. The total volume of 200 mL of the solution was aseptically filtered according to a conventional method and was filled into vials in 5 mL increments and lyophilized in accordance with a conventional method to obtain 100 mg of the lyophilized preparation for vaginal administration 40 vials &Lt; / RTI &gt;

&Lt; Example 8 >

To a mixed solution of sibelestat sodium salt tetrahydrate (4 g; 7.56 mmol) and sodium bicarbonate (400 mg, 4.76 mmol) corresponding to the compound of the present invention, about 140 mL of distilled water for injection was added 1N Aqueous solution of sodium hydroxide was added to adjust the pH to 7.7 to obtain a clear solution. Next, sodium chloride (200 mg) was added to the bright solution to dissolve it. Finally, distilled water for injection was added so that the total amount became 200 mL. The total volume of 200 mL of the solution was aseptically filtered according to a conventional method and was filled into vials in 5 mL increments and lyophilized in accordance with a conventional method to obtain 100 mg of the lyophilized preparation for vaginal administration 40 vials &Lt; / RTI &gt;

&Lt; Example 9 >

To a mixed solution of sibelestat sodium salt tetrahydrate (4 g; 7.56 mmol) and sodium bicarbonate (400 mg, 4.76 mmol) corresponding to the compound of the present invention, about 140 mL of distilled water for injection was added 1N Aqueous solution of sodium hydroxide was added to adjust the pH to 7.7 to obtain a clear solution. Finally, distilled water for injection was added so that the total amount became 200 mL. The total volume of 200 mL of the solution was aseptically filtered according to a conventional method and was filled into vials in 5 mL increments and lyophilized in accordance with a conventional method to obtain 100 mg of the lyophilized preparation for vaginal administration 40 vials &Lt; / RTI &gt;

&Lt; Example 10 >

A lyophilized lyophilized preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained by using glucose (8 g) instead of mannitol (8 g) in the same manner as in <Example 1> .

&Lt; Example 11 >

A lyophilized lyophilized preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained by using lactose (8 g) instead of mannitol (8 g) in the same manner as in <Example 1> .

&Lt; Example 12 >

A lyophilized lyophilized preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained by using maltose (8 g) instead of mannitol (8 g) in the same manner as in <Example 1> .

&Lt; Example 13 >

A freeze-dried preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained in the same manner as in Example 1, except that glycerol (600 mg) was used instead of mannitol (8 g) .

&Lt; Example 14 >

Freeze dried preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained in the same manner as in Example 1 except that xylitol (2 g) was used instead of mannitol (8 g) &Lt; / RTI >

&Lt; Example 15 >

A lyophilized lyophilized preparation 40 vial containing 100 mg of the compound of the present invention in one vial was obtained by using sorbitol (8 g) instead of mannitol (8 g) in the same manner as in Example 1 .

&Lt; Example 16 >

Freeze dried preparation 40 vial containing 100 mg of the compound of the present invention in one vial was prepared in the same manner as in Example 1 except that dextran 40 (1.2 g) was used instead of mannitol (8 g) &Lt; / RTI >

&Lt; Comparative Example 1 &

Dried preparations obtained by the method described in the formulation examples 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 according to a conventional method and the solution was aseptically filtered according to a conventional method, , And lyophilized according to 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.

&Lt; Comparative Example 2 &

Dried preparation 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 (10 g) of the present invention was added. While the mixture was stirred 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 bright aqueous solution having a pH value of 7.65. Next, this aqueous solution was aseptically filtered according to a usual method, and filled into vials in 5 mL increments, followed by freeze-drying according to a conventional method to obtain 100 vials of the lyophilized preparation for injection use containing 100 mg of the compound of the present invention .

&Lt; Comparative Example 3 &

Dried preparations obtained by the method described in the section [0025] of Patent Document 3.

Mannitol (8 g) was dissolved in water (150 mL), and the compound (4 g) of the present invention was added and suspended. An aqueous sodium hydroxide solution (40 mg / mL; 5.6 mL) was added to the suspension while stirring with a stirrer, and a total amount of 200 mL was obtained with water to obtain a clarified aqueous solution. Next, this aqueous solution was aseptically filtered, packed into vials in an amount of 5 mL each, and lyophilized according to a conventional method to obtain 40 vials of lyophilized preparation for injection, containing 100 mg of the compound of the present invention .

&Lt; Comparative Example 4 &

Instead of sodium hydrogencarbonate, sodium acetate was generally used as a buffer which is generally used.

The same procedure as in Example 1 was repeated except that sodium acetate (1080 mg) (maximum performance capacity used as an additive of the injectable preparation so far) was used instead of sodium hydrogencarbonate (400 mg) Mg of the lyophilized preparation for injection 40 containing the compound of the present invention.

&Lt; Comparative Example 5 &

Instead of sodium hydrogencarbonate, trisodium phosphate was generally used as a buffer which is generally used.

Was prepared in the same manner as in Example 1 except that trisodium phosphate (80 mg) (the maximum performance capacity used so far as an additive of the injectable preparation) was used instead of sodium hydrogencarbonate (400 mg) A lyophilized preparation for injection 40 containing 100 mg of the compound of the present invention was obtained.

&Lt; Comparative Example 6 >

Instead of sodium hydrogencarbonate, dipotassium hydrogen phosphate was generally used as a buffer which is generally used.

Was prepared in the same manner as in Example 1 except that dipotassium hydrogen phosphate (100 mg) (maximum performance capacity used as an additive of a preparation for injection so far) was used instead of sodium hydrogencarbonate (400 mg) To obtain 100 mg of a lyophilized preparation 40 vial containing the compound of the present invention.

&Lt; Comparative Example 7 &

Instead of sodium hydrogencarbonate, disodium hydrogenphosphate is generally used as a buffer commonly used.

Was obtained in the same manner as in <Example 1> except that disodium hydrogenphosphate (144 mg) (the maximum dissolving capacity in 200 mL of water (5 DEG C, left for 24 hours)) was used instead of sodium hydrogencarbonate (400 mg) Among the vials, 40 vials of lyophilized preparations for injections containing 100 mg of the compound of the present invention were obtained.

&Lt; Comparative Example 8 >

Instead of sodium hydrogencarbonate, citric acid monohydrate is generally used as a buffer which is generally used.

Was obtained in the same manner as in <Example 1> except that citric acid monohydrate (840 mg) (maximum dissolving capacity in 200 mL of water (5 DEG C, left for 24 hours)) was used instead of sodium hydrogencarbonate (400 mg) , 40 mg of a lyophilized preparation for injection use containing 100 mg of the compound of the present invention was obtained.

&Lt; Comparative Example 9 &

Instead of sodium bicarbonate, sodium citrate is generally used as a buffer which is generally used.

Was obtained in the same manner as in <Example 1> except that sodium citrate (588 mg) (the maximum dissolving capacity in 200 mL of water (5 DEG C, left for 24 hours)) was used instead of sodium hydrogencarbonate (400 mg) To obtain 100 mg of a lyophilized preparation 40 vial containing the compound of the present invention.

&Lt; Comparative Example 10 &

Instead of sodium hydrogencarbonate, trometamol was generally used as a buffer which is generally used.

Was obtained in the same manner as in <Example 1> except that trometamol (292 mg) (the maximum dissolving capacity in 200 ml of water (5 DEG C, left for 24 hours)) was used instead of sodium hydrogencarbonate (400 mg) , 40 mg of a lyophilized preparation for injection use containing 100 mg of the compound of the present invention was obtained.

&Lt; Comparative Example 11 &

Instead of sodium bicarbonate, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) was generally used as a buffer which is generally used.

In the same manner as in <Example 1>, instead of sodium bicarbonate (400 mg), HEPES (80 mg) (the maximum payout capacity used as an additive of the injectable preparation so far) Of the freeze-dried preparation 40 of the present invention containing the compound of the present invention.

The components per vial of the lyophilized preparation for injection use in Examples 1 to 16 and Comparative Examples 11 to 16 obtained by the above production method were shown in Tables 1 and 2 below .

The adjustment amount (pH 7.7) in Table 1 and the adjustment amount in pH 7.7 in Table 2 indicate the amount of the pH value of the solution before freeze-drying in each Experimental Example added so as to be 7.7. Herein, the compound of the present invention refers to a sodium salt of siberestat sodium tetrahydrate.

The process for preparing the injectable liquid preparation of the present invention can be produced as follows.

Siberestat sodium salt tetrahydrate and sodium hydrogencarbonate corresponding to the compound of the present invention are dissolved in distilled water for injection and subsequently adjusted to a pH of 7.7 with an aqueous solution of sodium hydroxide. Sterile filtration of the obtained solution, filling in a container (e.g., a vial and an ampoule), sealing the container with a stopper, and finally sterilizing. Alternatively, the lyophilized preparations for injection use of Examples 1 to 16 may be prepared by adding a dissolving solution such as water, physiological saline and / or glucose solution, and dissolving them clearly. The lyophilized preparations for use in Examples 1 to 16 were prepared by adding a solution such as water, physiological saline and / or glucose solution to clarify the solution, .

&Lt; Test Example 1 >

Solubility test of injectable preparation at low temperature

5 mL or 10 mL of physiological saline was added to vials of various freeze-dried preparations obtained in Examples 1 to 16 and Comparative Examples 11 to 11 at room temperature (about 25 ° C) Saline solution or 5 mL of 5% glucose solution was added to dissolve the solution clearly. The clear solution was stored at 5 ° C (in a refrigerator) or at 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 Examples 4 to 11 were compared with Example 1, which is the injectable preparation of the present invention, (Example 16) had very good solubility at low temperatures (5 ° C and 15 ° C). Further, in the appearance confirmation, it was judged whether the solution obtained by the above method was the solution as it was, or a solution in which the solution was precipitated (for example, white turbid), a solution in which the solid was precipitated, and a solution in which the solid was precipitated.

In the following Table 3, the clarified experimental examples and comparative examples are indicated by marks &quot; &amp; cir & &quot; When the solubility test was not reviewed, it was marked with a -. The indication that the solution was gouged indicates that the state of the solution was completely transparent and clear in the visual examination of the solution by the naked eye. On the other hand, the fact that suspension, precipitation and precipitation means that a solid is precipitated in the solution when the appearance of the solution is visually observed, or the solid is precipitated.

&Lt; Test Example 2 &

Mixing test with low pH solution

(Example 1) to Example 16 and <Comparative Example 1> were compared with respect to the low pH sap of the Sorita T2 (Ajinomoto), KNMG 3 (Otsuka Seiyaku Kojo), and Fijiozole 3 (Otsuka Seiyaku Kojo) A combination test with various freeze-dried preparations for main use obtained in Examples 1 to 6 was carried out. Each lyophilized formulation for various injections was 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 and each of the solutions, 12.5 mL of Sotta T2, 16.7 mL of KNMG 3 and 12.5 mL of Fijiozole 3 were blended at room temperature (about 22 ° C to about 28 ° C). Each of the compounded solutions was stored at room temperature (about 22 ° C to about 28 ° C), and the appearance after 24 hours of mixing was confirmed. The appearance confirmation method is the same as in Test Example 1 above. In the following Table 4, the clarified experimental examples and comparative examples are indicated by marks &amp;bull;

The injectable preparations of Examples 1 to 16 and Comparative Example 1 were all clear solutions after 24 hours from immediately after mixing. On the other hand, the injection formulations of Comparative Examples 2 to 6 showed clouding, precipitation, precipitation, and the like in about 1 hour after mixing to about 5 hours after mixing.

As a result, as shown in the following Table 4, the injectable preparations of Examples 1 to 16 of the present invention were compared with those of Comparative Examples 2 to 6, It was found that it has very good solubility in the formulation.

As described above, from the results of Test Example 1 and Test Example 2, it can be seen that the injectable preparation of the present invention exhibits very good solubility in a dissolving solution at low temperature and / or exhibits very good solubility in combination with a low pH solution Could know.

From the above Table 3, the results of the dissolution test at the low temperature of the preparation of Comparative Example 3 are good, and the results of the test of the formulation of Comparative Example 1 with the low pH solution were good from Table 4, The preparations of Comparative Example 1 and Comparative Example 3 were all slightly unstable in the stability test (for example, the measurement of the pH value when the lyophilized preparation for injection was dissolved in the solution and the purity test). On the other hand, the present injectable preparations (Examples 1 to 16) were all stable in this stability test.

The injectable preparation according to the present invention can be prepared into an injectable solution ready for rapid treatment when an acute lung injury patient who is in a critical condition is urgently treated and can be administered to a patient at an early stage, And can be stored in the form of an injectable solution because it does not cause the disease.

Claims (30)

A injectable preparation containing 0.25 to 0.95 mol of the hydrogencarbonate salt per 1 mol of sivelestat sodium salt or its hydrate, and siberestat sodium salt or its hydrate. The preparation according to claim 1, wherein the hydrogencarbonate is sodium hydrogencarbonate, potassium hydrogencarbonate or both. The preparation according to claim 2, wherein the hydrogencarbonate is sodium hydrogencarbonate. The formulation according to any one of claims 1 to 3, further comprising a pH adjuster. The formulation according to claim 4, containing an excipient or an inorganic salt or both. The preparation according to claim 4, wherein the pH adjuster is sodium hydroxide. The preparation according to claim 5, wherein the excipient is mannitol. The preparation according to claim 5, wherein the inorganic salt is sodium chloride. The formulation according to any one of claims 1 to 3, which is a freeze-dried preparation for injection. 10. The preparation according to claim 9, which is soluble at a temperature of 0 DEG C or higher and 15 DEG C or lower relative to the dissolution liquid. 11. The preparation according to claim 10, wherein the preparation is soluble at 5 DEG C or more and 15 DEG C or less with respect to the dissolution liquid. 11. The preparation according to claim 10, wherein the solution is water, physiological saline or glucose solution or a combination thereof. The formulation according to any one of claims 1 to 3, wherein the preparation is a liquid formulation for injection. 14. The preparation according to claim 13, which is a solution in which the lyophilized preparation for injection is dissolved in a solution. 14. The preparation according to claim 13, wherein the solution in which the lyophilized preparation for injection is dissolved in a solution is diluted in a solution having a pH of 7 or less. The method according to claim 15, wherein the solution having a pH of 7 or less is at least one selected from the group consisting of Solita T3 (Sotta®), Sotta T2 (Sotta®), Sotta T1 (Sotta®), KNMG (Actin) (registered trademark) or Veen 3G injectable solution (VIN is registered trademark), 3 (KNMG is registered trademark), Physiosol 3 (registered trademark of Fijiazol), Actit (registered trademark) Or a combination thereof. 14. The preparation according to claim 13, which is a solution for preparing a freeze-dried preparation for injection. 18. The preparation according to claim 17, wherein the solvent of the solution for preparing the injectable lyophilized preparation is water. 4.3 to 7.3 moles of mannitol relative to 1 mole of sodium bicarbonate or its hydrate, 0.25 to 0.95 mole of sodium bicarbonate, 1 mole of sibelestat sodium salt or its hydrate per mole of sibelestat sodium salt or its hydrate, and A freeze-dried preparation for free-use for injection containing 0.27 to 0.9 mol of sodium chloride per 1 mol of siberestat sodium salt or a hydrate thereof. 4.3 to 7.3 moles of mannitol relative to 1 mole of sodium bicarbonate or its hydrate, 0.25 to 0.95 mole of sodium bicarbonate, 1 mole of sibelestat sodium salt or its hydrate per mole of sibelestat sodium salt or its hydrate, and A liquid preparation for injectable use containing 0.27 to 0.9 moles of sodium chloride per 1 mole of sibelestat sodium salt or its hydrate. 21. The injectable liquid preparation according to claim 20, wherein the pH value is 7.5 to 8.5. 4.3 to 7.3 moles of mannitol relative to 1 mole of sodium bicarbonate or its hydrate, 0.25 to 0.95 mole of sodium bicarbonate, 1 mole of sibelestat sodium salt or its hydrate per mole of sibelestat sodium salt or its hydrate, and A liquid preparation for injection use containing 0.27 to 0.9 mol of sodium chloride per 1 mol of siberestat sodium salt or a hydrate thereof and having a pH value adjusted by sodium hydroxide. 23. The injectable liquid preparation according to claim 22, having a pH value of 7.5 to 8.5. A freeze-dried preparation for injectable use prepared by freeze-drying the injectable liquid preparation according to claim 22 or claim 23. The freeze-dried preparation of claim 24, wherein the pH value of the solution in which the lyophilized preparation for injection is dissolved in the solution is from 7.5 to 8.5. 4.3 to 7.3 moles of mannitol relative to 1 mole of sodium bicarbonate or its hydrate, 0.25 to 0.95 mole of sodium bicarbonate, 1 mole of sibelestat sodium salt or its hydrate per mole of sibelestat sodium salt or its hydrate, and A lyophilized preparation for injectable use containing 0.27 to 0.9 mol of sodium chloride per mol of siberestat sodium salt or a hydrate thereof, wherein the pH value of the solution obtained by dissolving the lyophilized preparation for use in the present invention in a solution is adjusted to 7.5 to 8.5 &Lt; / RTI &gt; 1. A freeze-dried preparation for injectable use containing a siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt, which contains 0.25 to 0.95 mol of the hydrogencarbonate per 1 mol of the sodium salt of siberestat or a hydrate thereof, Wherein the liquid formulation is capable of maintaining a clear solution state at 0 캜 or higher and 15 캜 or lower. 1. A liquid preparation for injectable administration containing a siberestat sodium salt or a hydrate thereof and a hydrogencarbonate salt, the liquid suspension containing 0.25 to 0.95 mol of a hydrogencarbonate per 1 mol of siberestat sodium salt or a hydrate thereof, In which the liquid formulation after blending can maintain a clear solution state. A freeze-dried preparation for injectable use containing a siberestart sodium salt or a hydrate thereof, which is capable of maintaining a clear solution state at a temperature of 0 ° C to 15 ° C after mixing with a dissolution liquid, In a solution of 0.25 to 0.95 mol of the hydrogencarbonate per 1 mol of the siberestat sodium salt or hydrate thereof. In order to prepare a formulation capable of maintaining a clear solution state after mixing with a liquid having a pH of 7 or less as a liquid preparation for injection containing a siberestart sodium salt or a hydrate thereof, a solution for preparing a freeze- Wherein a 0.25 to 0.95 molar amount of hydrogencarbonate is used per 1 mol of the sodium salt of siberestat or its hydrate.