WO2004096229A1 - Medicinal composition in solution form - Google Patents

Abstract

A medicinal composition in a solution form which comprises (a) 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl]benzamide (compound (A)) or a physiologically acceptable salt thereof, (b) propylene glycol, and (c) water. The solution-form medicinal composition containing the compound (A) is useful as an injection or peroral drug. That is, the solution-form medicinal composition has a solubility and pH both in desired ranges and is highly stable.

Description

 Description Solution Pharmaceutical Composition Technical Field

 The present invention relates to a solution pharmaceutical composition containing a basic drug which is hardly soluble in water, specifically, 4-amino-3-5-chloro-2-N-ethoxy [N- [4- (4-benzole). 1.) A pharmaceutical composition in the form of a solution containing (121) morpholinyl] methyl] benzamide as an active ingredient and having improved solubility and stability. Background art

 (±) —4-amino-1-5-chloro-2-N-ethoxy [N-[[4- (4-funolenobenzyl)]-2-morpholinyl] methyl] benzamide (hereinafter referred to as mosapride) Serotonin 4 receptor agonist and has good gastrointestinal motility promoting action (US Pat. No. 4,870,074). In particular, the citrate dihydrate has already been commercialized for the purpose of improving gastrointestinal symptoms associated with chronic gastritis, and 2.5 mg or 5 mg (as mosapride as mosapride citrate) Tablets containing 1.72 mg or 3.444 mg) are commercially available. Mosapride (or its salts) is also useful as a treatment for reflux esophagitis, postgastrectomy syndrome, and other gastrointestinal symptoms. However, since mosapride and its salts are poorly soluble in water, no solution formulation containing mosapride or its salts has been found yet.

Usually, in order to dissolve a basic drug that is hardly soluble in water, such as mosapride, into an aqueous solution to form a solution formulation, an inorganic acid or an organic acid is added to enhance solubility or a surfactant. For example, a means such as adding In order to prepare or formulate mosapride into a solution at a concentration that is useful for use, it is necessary to take into account changes in the storage conditions of the solution, etc. Selection, acid selection, surfactant selection, etc.). The pH of the injection is preferably 2 or more from the viewpoint of irritation to the administration site. In addition, pharmaceutical formulations are not only soluble Higher stability is required. However, a highly stable solution preparation containing mosapride (or a salt thereof) that satisfies both such a dissolution angle and an appropriate pH has not been known. Disclosure of the invention

 The present invention provides a solution pharmaceutical composition containing mosapride, which is useful as an injection or an oral preparation, that is, a solution composition having both solubility and pH within a desired range and having high stability. Make it an issue.

 Until now, mosapride was soluble in pharmaceutically unacceptable organic solvents such as N, N-dimethylformamide-pyridine, but it was hardly soluble in water, so it was difficult to make pharmaceutically acceptable solution-form preparations. Was thought. The present inventors have conducted intensive studies in order to obtain a solution preparation of mosapride or a physiologically acceptable salt thereof, and studied various pharmaceutically acceptable solvents. Was unexpectedly found to dissolve very well. However, it was newly found that when mosapride was dissolved in propylene glycol, mosapride was unstable and decomposed in large quantities during storage. Therefore, as a result of further studies, the present inventor has found that if an aqueous solvent containing propylene glycol in a specific range and water in which mosapride is not soluble, mosapride is dissolved in a sufficient amount, and almost no decomposed product is obtained. It has been found that a solution formulation having both effects of not being produced can be obtained. The present inventors have further improved the solubility and stability of mosapride by further adjusting the pH to a specific range. (milliliters or less), it was found that injections or oral liquids could be produced, and the present invention was completed.

 That is, the present invention provides the following aspects of the invention.

 (1) (a) 4-amino-5-chloro-2-N-ethoxy_N _ [[4- (4-fluorobenzyl) _2-morpholinyl] methyl] benzamide (hereinafter referred to as compound A) or its physiological Acceptable salts,

 (b) About 1 O w_v% to about 92 wZ v. /. Propylene glycol and

(c) the amount of water required to complete the solution pharmaceutical composition A solution pharmaceutical composition comprising:

 (2) The solution pharmaceutical composition according to the above (1), wherein the pH is about 2 to about 5.5.

 (3) The solution pharmaceutical composition according to the above (1), wherein the component (b) is about 1 OwZv to about 75 w / v% propylene glycol.

(4) The compound (A) or a physiologically acceptable salt thereof according to the above (1), wherein the component (a) is a compound A or a physiologically acceptable salt thereof in an amount to give a concentration of about lmgZm 1 to about 12 _{mg /} m 1 in terms of compound A. A solution pharmaceutical composition as described.

 (5) The solution pharmaceutical composition according to the above (1), further comprising (d) an acidic substance.

(6) The acidic substance (d) according to (5), wherein the acidic substance (d) is at least one selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, lactic acid, acetic acid, tartaric acid, and citric acid. Solution pharmaceutical composition.

 (7) The solution pharmaceutical composition according to the above (1), wherein compound A is in a racemic form.

 (8) The solution pharmaceutical composition according to the above (1), wherein the physiologically acceptable salt of compound A is a citrate.

 (9) The solution pharmaceutical composition according to the above (1), wherein the component (a) is a citrate dihydrate of the compound A.

(10) Compound A or a physiologically acceptable salt thereof, in an amount of about 1111 _§ // 1111 to about 1 OmgZm 1 in terms of (&) compound,

 (b) about 2 OwZv% to about 75 w / v% propylene glycol,

 (c) the amount of water required to complete the solution pharmaceutical composition; and

 (d) at least one acidic substance selected from the group consisting of methanesulfonic acid, citric acid and hydrochloric acid,

The solution pharmaceutical composition according to the above (1), wherein the pH is about 2.5 to about 4.5.

 (11) (a) Compound A (racemic) citrate 'dihydrate in an amount to give a concentration of about 1.5 mg Zm 1 to about 5.5 mg / m 1 in terms of compound A,

(b) about 25 w / V% to about 55 w / V ⁰ /. Propylene glycol,

 (c) the amount of water required to complete the solution pharmaceutical composition; and

(d) at least one acidic substance selected from the group consisting of methanesulfonic acid, citric acid and hydrochloric acid, The solution pharmaceutical composition according to the above (1), wherein the pH is about 3 to about 4.

 (12) The solution pharmaceutical composition according to the above (1), which is in the form of an injection or an oral preparation.

(13) (i) a drug-containing powder or granule containing Compound A or a physiologically acceptable salt thereof, and

 (ii) a drug solution containing propylene glycol and water,

A preparation for use consisting of

 (14) A commercial package containing the solution pharmaceutical composition according to (1) and a description of the composition, wherein the description and / or the package includes the composition for a specific disease. A commercial package stating that it should or should be used.

 (15) A commercial package containing the ready-to-use preparation described in (13) and a description of the preparation, wherein the preparation is used in the description and Z or the package for a specific disease. Or a commercial package stating that it should be used.

 (16) An effective amount of the solution pharmaceutical composition described in (1) above is administered to a patient for promoting gastrointestinal motility, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (GERD). Administering to the subject.

 (17) Use of the solution pharmaceutical composition according to (1) for promoting gastrointestinal motility, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (GERD).

 (18) A method for producing a solution pharmaceutical composition containing the compound A or a physiologically acceptable salt thereof,

 (i) a mixture comprising less water than is necessary to complete the solution pharmaceutical composition and propylene glycol in an amount that results in a concentration of about 1 OwZv% to about 92 w / v% in the final composition. Dissolving Compound A or a physiologically acceptable salt thereof in a solvent, and

 (ii) A production method comprising the step of adding water to the mixture obtained in step (i) to complete the composition.

(19) A method for producing a solution pharmaceutical composition containing the compound A or a physiologically acceptable salt thereof, (I ') to the final amount of up Ropi render recall of about 1 Ow / v% ~ about 92wZ _v% concentration in the composition, Compound A or a step of Ru physiologically dissolved acceptable salt, and

 (ϋ ′) a step of adding an amount of water necessary to complete the solution pharmaceutical composition to the liquid obtained in the step (i ′) to complete the composition,

A manufacturing method including:

 (20) The method according to any of (18) or (19) above, which comprises a step of adjusting the pH to about 2 to about 5.5 by adding an acidic substance and Z or an additive necessary for formulation as necessary. .

 (21) A solution pharmaceutical composition obtainable by the method according to any of (18) to (20).

 (22) A method for improving the solubility and stability of Compound A or a physiologically acceptable salt thereof in an aqueous solvent, wherein the amount of Compound A or a physiologically acceptable salt thereof is from about 1 OwZv% to about 92% in the final composition. An improved method comprising dissolving Compound A or a physiologically acceptable salt thereof in an aqueous solvent containing propylene dalicol in a concentration.

 (23) A solution pharmaceutical composition obtained by the method according to the above (22), wherein the solubility and stability of the compound A are improved. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the relationship between the solubility of compound A according to the present invention in water and pH.

 FIG. 2 shows the results of a stability test of the composition of the present invention (composition containing 1.7 lmg / m1 of compound A).

 FIG. 3 shows the results of a stability test of the composition of the present invention (composition containing 5.15 mg / ml of compound A). BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention is described in more detail below.

(a) jf dagger compound A or a physiologically acceptable salt thereof The compound A according to the present invention, that is, 4-amino-5-chloro-2-ethoxy-1-N — [[4- (4-fluorobenzyl) -2-morpholininole] methyl] benzamide has the following formula:

The compound has a good gastrointestinal motility promoting action as a selective serotonin 4 receptor agonist.

 The compound A according to the present invention may be a racemic form or one of the optically active forms, but a racemic form is preferred.

 Compound A may be in a free form or a physiologically acceptable salt thereof. The salt is preferably an acid addition salt. For example, addition salts of organic acids include formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, and the like. Examples of the addition salt include hydrochloride, sulfate, nitrate, phosphate and the like. Of these, citrate is particularly preferred. Further, Compound A or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. Preference is given to the hydrates of the citrates, especially to the hydrates of the citrates! /.

 Compound A or a physiologically acceptable salt thereof can be produced, for example, by the method described in US Pat. No. 4,870,074 or a method analogous thereto.

 The solution pharmaceutical composition of the present invention is obtained by converting Compound A or a physiologically acceptable salt thereof into Compound A in an amount of about 1 mg / m1 to about 12 mg / m1, preferably about 1 mg / m1. / m1 to about 10 mg Zml, more preferably about 1.5 mg / m1 to about 5.5 mg Zml.

According to the present invention, if the solvent (and pH) shown below is used, the solvent can be used to dissolve Compound A or a physiologically acceptable salt thereof in an amount larger than the desired concentration. Can be dissolved. Therefore, the above concentration of Compound A does not indicate a saturation concentration. The concentration is suitable for the conditions required for a solution pharmaceutical composition. The solvent in the composition of the present invention basically comprises the following propylene dalicol and water.

(b) propylene dalicol and (c) water

 The solvent according to the present invention is a mixed solvent of propylene glycol and water. As shown in the following examples, propylene dalicol dissolves Compound A, but when dissolved, produces a large amount of decomposed products during storage (Comparative Example 2). However, it was revealed that an aqueous solvent in which water in which Compound A was not dissolved (Comparative Example 1) was mixed with propylene dalicol was a solvent satisfying the solubility and stability of Compound A.

 Nevertheless, if the propylene glycol concentration remained high in the aqueous solvent, the solubility was maintained, but the storage stability was not satisfactory. That is, there are certain restrictions on the appropriate concentration range of propylene recall. Therefore, it is possible to significantly suppress the generation of decomposed products by adjusting ρ の of the solution composition to a certain extent on the acidic side within a range that does not cause irritation. Was. From these findings, an appropriate concentration range of propylene glycol was found. Specifically, the blending amount of propylene glycol is about

10 w / v% or more, usually about 1 OwZv% to about 92 ^%, preferably about 1

/. / o ~ Ί /. More preferably, from about 20 w / v% to about 75 wZv%, most preferably from about 25 w / v% to about 55 wZv%.

 Further, instead of part of the propylene glycol, another solvent such as ethanol, which does not adversely affect the effect of the propylene glycol, may be mixed and used. The mixing ratio is not particularly limited, but is about 1 OwZ v% or less based on the total amount of the solution composition.

In the composition, compound A, propylene glycol, and the remainder except for the oxidizing substances themselves and the additives themselves, which are added as necessary, are water, the amount of which is necessary to complete the solution pharmaceutical composition. It is. With respect to this amount of water, “the amount necessary to complete the solution pharmaceutical composition” means the total amount of water used in the process of preparing the desired solution pharmaceutical composition, and dissolves Compound A in propylene dalicol When propylene glycol is used as an aqueous solution at the time, the amount of water is used when adjusting the amount of water, when adding an acidic substance, the amount of water to be used as the aqueous solution, and finally when adjusting the total amount of the solution pharmaceutical composition. It is the total amount, such as the amount of residual water added.

 In this specification, the term “amount required to complete the solution pharmaceutical composition” is simply “amount required to complete the composition”, “amount required to complete the composition” or “composition Amount to complete an object. "

 Thus, for example, when the solution pharmaceutical composition is an injection containing about 50 wZv% of propylene glycol and 5 mg / m1 of compound A, the water in the composition contains about 50 wZv%. It is.

 When other solvents such as ethanol are added to the mixture, these solvents are added instead of part of propylene glycol, so that the amount of water is hardly affected. The addition amount of the acidic substance for pH adjustment described below is small in view of the total composition amount.

((1 Xiao Xi substance

 In the solution pharmaceutical composition of the present invention, the addition of an acidic substance is not essential. That is, if the solution comprising Compound A or a physiologically acceptable salt thereof, propylene glycol and water has a pH of about 2 to about 5.5, the addition of an acidic substance is not necessary. If the pH deviates from the above range, the pH is adjusted to the above range by adding an acidic substance. The range is preferably from about 2.5 to about 5, more preferably from about 2.5 to about 4.5, and most preferably from about 3 to about 4. However, even if the pH is within the above range without adding an acidic substance, it is recommended to add an acidic substance to adjust the pH to a desired value. Such an acidic substance is not particularly limited as long as the pH of the solution pharmaceutical composition can be adjusted to the above range, and both an inorganic acid and an organic acid can be used. Specific examples include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid, and organic acids such as methanesulfonic acid, lactic acid, acetic acid, tartaric acid, and citric acid. Preferably, it is hydrochloric acid, phosphoric acid, citric acid, methanesulfonic acid, more preferably hydrochloric acid.

Method for producing solution pharmaceutical composition

 The method for producing the solution pharmaceutical composition of the present invention is not particularly limited, and can be produced according to a usual method, for example, the following method.

Dissolve Compound A or its physiologically acceptable salt in propylene dalicol When dissolving propylene glycol in an aqueous solution of propylene glycol obtained from a fixed amount of water smaller than that required to complete the pharmaceutical composition, the compound A or its physiologically acceptable After dissolving the salt, a method is employed in which a smaller amount of water is added than is necessary to complete the solution pharmaceutical composition.

 That is, Compound A or a physiologically acceptable salt thereof is added to a Zl solution obtained by adding a predetermined amount of propylene glycol to a certain amount of water and mixing, followed by stirring and dissolving. At this time, if compound A or a physiologically acceptable salt thereof is still cloudy in the mixture, the pH is adjusted to a desired pH by adding an appropriate amount of the above-mentioned acidic substance. Dissolve the physiologically acceptable salt. Even if Compound A or a physiologically acceptable salt thereof is dissolved before the addition of the acidic substance, the pH can be adjusted to an appropriate pH by adding the acidic substance as necessary. Coordination is encouraged. Thereafter, water is added to adjust the volume of the composition to prepare the solution pharmaceutical composition of the present invention. That is, in preparing the above composition, it is preferable to use a slightly smaller amount of water to be mixed with propylene glycol, and to adjust the volume to a certain volume by finally adding water.

 Alternatively, first add compound A or a physiologically acceptable salt thereof to propylene dalicol, stir and dissolve. In that case, you may heat as needed. Then add a certain amount of water and mix. The addition of the acidic substance is performed in the same manner as described above. Thereafter, the volume of the composition is adjusted by adding water to prepare the solution pharmaceutical composition of the present invention. In addition, an excess of an acidic substance is mixed into the above propylene glycol aqueous solution so as to be a more acidic solution than the desired pH, compound A or a physiologically acceptable salt thereof is dissolved, and then sodium hydroxide is added. The pH of the aqueous solution may be adjusted to a desired range with an appropriate basic substance.

Features and preferred embodiments of the present invention

One of the features of the present invention is the ability to dissolve compound A or a physiologically acceptable salt thereof. The compound has the advantage and disadvantage of accelerating the decomposition of compound A under storage conditions. By selecting as a solvent a mixture with water that does not substantially dissolve A or its physiologically acceptable salts, propylene glycol In other words, decomposition of compound A was suppressed while maintaining the solubility of the compound.

 Another feature of the present invention is that by maintaining the pH of the solution at about 2 to about 5.5, the decomposition of the compound A can be suppressed and at the same time, the appropriate concentration range of propylene glycol can be dramatically expanded. I did it.

 A further feature of the present invention is that the combination of propylene glycol and water does not dissolve Compound A or its physiologically acceptable salts in near-saturated conditions, but rather well below the saturating concentration. Since the dissolution is performed at a concentration, the precipitation of compound A, which would otherwise be caused by a change in storage conditions, is prevented, and the decomposition of compound A is significantly suppressed.

 Preferred embodiments of the present invention are the compositions described in the above items (2) to (12). Among them, more preferred embodiments are the compositions described in the above item (10), most preferably. An embodiment is the composition according to the above (11).

Application of the composition of the present invention to solution injection

 When the solution pharmaceutical composition of the present invention is used as an injection, for example, the obtained composition is sterilized by filter sterilization, high-pressure steam sterilization or the like according to a known method. In addition, the above-mentioned solution pharmaceutical composition may contain, if necessary, suitable additives such as isotonic agents such as sodium chloride, pudose sugar and sorbitol, and preservatives such as sodium benzoate and methyl paraoxybenzoate. It may be. It is preferable that these additions U are added before adding the acidic substance.

 The injection of the present invention can be used not only as an intravenous injection but also as an intramuscular injection and an intraperitoneal injection, but is not limited thereto. In addition, the obtained injection can be used by mixing it with an infusion.

Application of the composition of the present invention to an oral preparation

Oral solution

When the solution pharmaceutical composition of the present invention is used as an oral liquid preparation, the composition may contain the following various additives as necessary. For example, sugars such as glucose, sorbitol, mannitol, xylitol, sweeteners such as saccharin sodium, aspartame, thaumatin, neotame and sour agents such as citric acid, tartaric acid, lactic acid, and umami components such as L-glutamic acid or a salt thereof. Compound A suffers An appropriate amount may be contained for the purpose of suppressing taste. In addition, if necessary, the yarn composition may be: Laminobenzoic acid may contain a suitable amount of a methyl ester, an ethyl ester, a propyl ester, a butyl ester or the like as a preservative. The timing and amount of addition can be determined according to the production of ordinary oral liquid preparations.

Oral semi-solid preparation

 By adding the solution pharmaceutical composition of the present invention to a suitable carrier, or by holding or filling in a container, an oral preparation having a semisolid or solid appearance can be prepared. For example, a gelling agent such as gelatin, agar, xanthan gum, guar gum, and dielan gum is added as an additive to the above-mentioned solution pharmaceutical composition, and the mixture is heated to form a uniform liquid containing compound A, which is then treated in a unit dose. For example, a jelly-like oral preparation (semi-solid preparation) can be obtained by dividing the mixture so as to contain it and then cooling, or cooling and hardening and then dividing. If necessary, the oral preparations may contain the following additives, sugars such as sucrose, glucose, sorbitol, xylitol tonole, saccharin sodium, ashalletame, thaumatin, neotame, etc. An agent may be contained as a flavoring component. Further, in order to enhance palatability, menthol, strawberry flavor, peach flavor, yogurt flavor, and the like may be contained. In addition, preservatives such as methyl paraoxybenzoate (methylparaben), ethyl ethyl paraoxybenzoate, and propyl paraoxybenzoate can also be contained. The timing and amount of addition can be determined in accordance with the production of ordinary oral semi-solid preparations. The gel-like preparation can be formed into tablets or capsules by increasing the gel strength by appropriately adjusting the concentration of the gelling agent.

Preparations for use

 The solution pharmaceutical composition of the present invention may be prepared as a ready-to-use preparation prepared immediately before use. That is, the present invention provides a ready-to-use preparation comprising a drug-containing powder or granule and a drug solution.

 (i) Drug-containing powder or granule

The drug-containing powder or granule contains Compound A or a physiologically acceptable salt thereof, and contains various additives used in the above solution injection or oral solution. Fill in a suitable container.

(ii) Drug solution

 The drug solution contains propylene glycol and water. Further, if necessary, the composition may further contain an acidic substance, and may contain various additives used for the above solution injection or oral solution. The kind of the acidic substance is as described above, and the concentration of each may be blended so as to be the concentration in the solution or the pharmaceutical composition when mixed with the drug-containing powdery or granular material.

 When actually used as a solution injection or an oral preparation, etc., the required amount of the above-mentioned drug solution is added to the drug-containing powdery or granular substance, and the compound A is sufficiently mixed and dissolved to thereby provide the compound of the present invention. Solution compositions can be prepared and used.

Example

 Hereinafter, the present invention will be described in more detail based on Examples, Comparative Examples, and Test Examples, but is not limited thereto.

 In the following Examples and the like, the racemic form of compound A is defined as compound A-a, and the citrate dihydrate of compound A-a is defined as compound A-b.

 The test performed in Test Example 2 below, that is, the stability test under the conditions of “storage at 60 ° C. for one month” was performed to show that the composition of the present invention was extremely stable. This is a stability test under severe conditions. Accelerated stability test, usually performed to estimate the storage stability of a drug at room temperature, from "40 ° C, 6 months storage" Is also a severe test.

 In order to evaluate stability in a very short period of time, stability tests may be performed even under harsher conditions of storage at 80 ° C for 1 week. That is, the stable regeneration test performed in Comparative Example 2 and Test Example 1 is a very severe test (stability test under much severer condition) as compared with the severe test (super 1-5 test).

Comparative Example 1 (Compound A—a solubility in water)

 Using Compound Ab, the solubility of Compound A_a in water (20 ° C.) was examined. Figure 1 shows the results.

As shown in Fig. 1, the solubility of compound A-a in water is as low as 0.0013 mg / m1 at pH 6.1 and 0.3 emg / m1 at H3.5. Was something. Comparative Example 2 (Solubility and Stability of Compound A-a in Propylene Dalicol)

 (1) (Compound A—a composition containing 1.7 lmgZml)

 50 g of propylene glycol was placed in a glass beaker, and 132 mg of Compound A-b was added thereto with stirring, and dissolved by stirring. In the resulting mixture, compound Ab was completely dissolved. This solution was filtered through a Durapore PVDF membrane filter (Mirex — GV, 0.22μπι, manufactured by Nippon Millipore) set in a glass syringe, filled into 2 ml 1 colorless ampules in 2 ml portions, and sealed with a gas burner for sealing. After the occlusion, it was sterilized (121 ° C, 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho). This ampule was subjected to a stability test (ultra-severe test) under the condition of “storage at 80 ° C for one week”. That is, after storage at 80 ° C. for one week, the total amount of related substances before and after storage of the solution was measured by a high-speed solution mouth chromatography (area percentage). The term “total amount of related substances” means the total amount of decomposition products of compound A_a and by-products contaminating compound A-a, that is, intermediates and impurities generated during production of compound A-a.

 As a result, although the total amount of related substances before storage was 0.60%, the amount of related substances after one week increased remarkably to 39.8%.

 (2) (Compound A—a 5.15 mg / m1 containing composition)

 In the same manner as in the above (1), put 50 g of propylene glycol into a glass beaker, add 397 mg of compound A-b thereto while stirring, dissolve by stirring, and dissolve the obtained ampoule. Stability test (super-severe test) under the condition of “storage at 80 ° C for one week”.

 As a result, the total amount of related substances before storage was 1.86. /. Nevertheless, the total amount of related substances after one week increased remarkably to 50.3%.

Example 1 (Compounds containing A_a 1.71 mg Zm1 and 5.15 mg Zm1) (1) Preparation of solution composition containing compound A—a 1.7 lmg / ml

In a glass beaker, less than the amount of propylene glycol (hereinafter sometimes referred to as PG) in an amount such that each concentration is 30, 50, 70 (w / V)% in the solution composition and the composition is completed Of water, and while stirring the solution, add 132 mg of Compound A-b and, if necessary, an appropriate amount of 0.1 ImolZ liter of monohydrochloric acid. H2. The solution was adjusted to a solution of 1 to 4.8, and the remaining water was added to produce 5 Om1 of a colorless and transparent solution pharmaceutical composition.

 Each of the obtained solutions was filtered through a Durapore PVDF membrane filter (Mirex-1 GV, 0.22 μΐΆ, manufactured by Nippon Millipore) set in a glass syringe, and filled into 2 ml 1 colorless samples in 2 ml increments. After closing with a closing gas burner, the mixture was sterilized (121 ° C, 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho) to produce an injection of Compound A-a.

 (2) Preparation of solution composition containing compound A-a 5.15 mg / m1

 In the same manner as in the above (1), the amount of propylene dalicol and the amount of the composition to be completed to be 50, 70, and 90 (w / v)% in the solution composition in the glass beaker. A small amount of water is mixed, and while stirring the solution, 97 mg of compound A-b3 and, if necessary, an appropriate amount of 0.1 mol-hydrochloric acid are added to adjust the solution to pH 2.5-4.9, and the remaining water is added. Was added to produce 50 ml of a colorless and transparent solution pharmaceutical composition.

 Fill each 2 m1 colorless ampoule while filtering each solution obtained using a Durapore PVDF membrane filter (Mirex-1 GV, 0.22 / zm, manufactured by Nippon Millipore) set in a glass syringe. After closing with a sealing gas burner, the mixture was sterilized (121 ° C, 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho) to produce an injection solution of Compound A-a.

Test example 1

 Each of the injection solutions obtained in Example 1 was subjected to a stability test (ultra-severe test) under the conditions of “storage at 80 ° C. for one week”. That is, after storing at 80 ° C for one week, the total amount of related substances before and after storage of each solution was measured by a high-speed solution-mouth-Matdarafu method (area percentage).

 The total amount of related substances (%) after one week is shown in FIG. 2 (Example 1 (1)) and FIG. 3 (Example 1 (2)). As a result, the composition of the present invention was found to be stable.

Example 2 (Compound A—a Injection containing 1.62 mg / m1)

 Add 4 Oml of water for injection to a glass beaker, and add 50 g of propylene glycol.

-Stirred for 5 minutes with Ra (Toyo Kagaku Sangyo) to mix evenly. Next The compound A-b25Omg was added to the mixture and dissolved by stirring for 15 minutes. Four different pH solutions (see Table 1 below) were prepared by adding 0.1 mol / l monohydrochloric acid to this solution. Water for injection was added to each of these solutions to make the total amount 10 Om1. Each of the obtained solutions was filtered through a Durapore PVDF membrane filter (Mirex-1 GV, 0.22μπι, manufactured by Nippon Millipore) set in a glass syringe, and filled into 2 ml colorless ampoules in 2 ml increments. Then, the mixture was sterilized (121 ° C, 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho) to produce an injection (see Table 1 below).

Test example 2 (60 ° C, 1 month stability test)

 Each of the injection solutions (2- 2 to 2-④) obtained in Example 2 was subjected to a stability test (severe test) under the conditions of “60. C, stored for 1 month”. That is, after each injection was stored at 60 ° C. for one month, the total amount of related substances before and after storage of each solution was measured by high-speed solution chromatography (area percentage). In addition, the “solution state” was evaluated by the Foreign Insoluble Matter Test for Injections. The results are shown in Table 1.

 Table 1 Stability of the injection of the present invention (60 ° C, 1 month)

 As a result of the above test, all injections were found to be stable in a severe test at 60 ° C for 1 month.

Example 3 (Compound A-a 1.62 mg / m1 containing composition)

To a smaller amount of water than the amount required to complete the composition, propylene dalicol is finally added so as to have the respective concentrations shown in Table 2, and compound A--b 5. Omg and, if necessary, methanesulfonic acid aqueous solution were added to adjust the pH, and then water was added to produce 2 ml of a colorless and transparent liquid pharmaceutical composition. Obtained Table 2 shows the H of each composition.

 Table 2: 1.6 SmgZml Compound A—a-containing composition

Example 4 (Compound A_a 3.25 mg / m1 containing composition)

 To a smaller amount of water than the amount required to complete the composition, propylene dalicol is finally added so as to have the respective concentrations shown in Table 3, and compound A--b 10. After adjusting the pH by adding Omg and an aqueous methanesulfonic acid solution, water was added to produce 2 ml of a colorless and transparent solution pharmaceutical composition. Table 3 shows the pH of each composition obtained.

 Table 3: 3.2 SmgZml Compound A—a-containing composition

Example 5 (Compound A-a 4.87 mg / m 1-containing composition)

 To 0.8 ml of water was added 1 g of propylene glycol, and while stirring, 5.0 mg of compound A-b and an aqueous solution of methanesulfonic acid were added to adjust the pH, and then water was added. Thus, 2 ml of a colorless and transparent solution pharmaceutical composition was produced. Table 4 shows the pH of the obtained composition.

Table 4: Injection containing 4.87 mg / m1 Compound A-a

Example 6 (Compound A-a 10.3 mg / m1 containing composition)

5 g of propylene glycol and compound A-b159 mg were added to a glass beaker, and the mixture was stirred and melted at about 60 ° C for 3 minutes using a magnetic stirrer (Toyo Kagaku Sangyo). Water for injection was added to this solution to make the total amount 1 Om1. Got The pH of the composition was about 4.2.

Example 7 (Injection containing 1.72 mg of compound A—a)

 According to the formulation (production amount) shown in Formulation Example 1 (Table 5), an injection of Compound Aa was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 120OM type, manufactured by Fine) and mixed uniformly. Next, 13.225 g of compound A_b was dissolved in the mixture by stirring for 15 minutes. The solution was adjusted to l3.5 with lmol / l monohydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered through a Durapore PVDF membrane filter (MCGL 10S, 0.22 im, manufactured by S Millipore). This filtrate is filled into 2m1 colorless ampules in 2ml increments using an ampoule filling and sealing machine (Noduginoya Machine, Model H-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Works) (121 ° C, 20 Min) to give an injection.

 Table 5 Formulation Example 1 (pH3.5)

Example 8 (Compound A—a Injection containing 1.72 mg / ml)

According to the formulation (production amount) shown in Formulation Example 2 (Table 6), an injection of Compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 1200M, manufactured by Fine), and mixed uniformly. Next, 13.225 g of compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 2.5 with 1 mol liter of monohydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 / m, manufactured by Nippon Millipore). This filtrate was filled into 2 ml 1 colorless ampules using an ampoule filling and sealing machine (Haginoya Machine, Model H-01) in 2 ml portions. After sealing, the solution was sterilized with a high-pressure steam sterilizer (SANKIDA MFG.) (121 ° C, 20 ° C). Min) to give an injection. Table 6 Formulation Example 2 (pH2.5)

Example 9 (injection containing compound A-a 3.43 mg / m1)

 According to the formulation (production amount) shown in Formulation Example 3 (Table 7), an injection of Compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 120OM, manufactured by Fine) to mix uniformly. Next, 26.45 g of compound A-b was added, and the mixture was stirred for 15 minutes. 1 mol / L monohydrochloric acid was gradually added to this cloudy liquid to dissolve it, and the pH was finally adjusted to 3.0. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 / m, manufactured by Millipore Japan). This filtrate was filled into a 2 m1 colorless sample in ampoules (Haginoya Machine, Model H-01) at 2 m1 each, sealed, and then sterilized by a high-pressure steam sterilizer (Sanukita Seisakusho) at 121 ° C. 20 minutes) to give an injection.

 Table 7 Formulation Example 3 (pH3.0)

Example 10 (Compound A—a Injection containing 5.15 mg / ml)

According to the formulation (production amount) shown in Formulation Example 4 (Table 8), an injection of Compound Aa was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 1200M, manufactured by Fine), and mixed uniformly. Next, 39.675 g of compound A-b was added and dissolved by stirring for 15 minutes. Lraol / liter monohydrochloric acid was gradually added to this turbid solution to dissolve it, and the pH was finally adjusted to pH 2.5. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. Use this solution with a Durapore P VDF membrane filter (MCGL 10 S, 0. 22 μπι, manufactured by Nippon Millipore). This filtrate was filled into a 2 m1 colorless amplifier with an ampoule filling and sealing machine (Haginoya Machine, Model Η-01), 2 m1 each, and after sealing, sterilized with a high-pressure steam sterilizer (Sankida Works) (121 °). C, 20 minutes) to give an injection.

 Table 8 Formulation Example 4 (pH 2.5)

Example 11 (Injection containing 1.72 mg / ml of compound A-a)

 According to the formulation (production amount) shown in Formulation Example 5 (Table 9), an injection of the compound A-1a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred with a stirrer (FBL 120OM type, manufactured by FINE) for 5 minutes and mixed uniformly. Next, 13.225 g of compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 3.5 with 1 mol Z liter-hydrochloric acid. Then, an appropriate amount of water was added to bring the total volume to 5 liters. This solution was filtered through a Durapore PVDF membrane filter (MCGL 10S, 0.22 / im, manufactured by Nippon Millipore). This filtrate is filled in a 1 Om 1 colorless ampoule in 10 ml increments with an ampoule filling and sealing machine (Haginoya Machine, Model H-01), roasted, and sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) (121 ° C) , 20 minutes) to give injection IJ.

 Table 9 Formulation Example 5 (pH 3.5)

Example 12 (Compound A -a 1.72 mg / m1 containing injection)

According to the formulation (production amount) shown in Formulation Example 6 (Table 10), an injection of Compound Aa was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred with a stirrer (FBL 120OM type, manufactured by Fine) for 5 minutes and mixed uniformly. Next, add 13.225 g of Compound A-b and stir for 15 minutes W- This solution was adjusted to pH 3.5 with 0.5 mol / liter methanesulfonic acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. The liquid to Deyura pore PVDF membrane filter (MCGL 10 _S, 0.22 μιη Ν Nippon Millipore Ltd. §) and filtered through a. This filtrate was filled in 2 m1 colorless ampules in 2 m1 increments using an ampoule filling and sealing machine (Haginoya Machine, Model Η-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Works) (121 ° C). , 20 minutes) to give an injection.

 Table 10 Formulation Example 6 (pH3.5)

Example 13 (Injection containing compound A_a 1.72 mg gm1) (no acidic substance added) According to the formulation (production amount) shown in Formulation Example 7 (Table 11), an injection of compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 1200 MM, manufactured by Fine) to mix uniformly. Next, 13.225 g of compound A-b was added and stirred for 15 minutes. The H of the resulting solution was 4.5. Thereafter, an appropriate amount of water for injection was added to make the total amount 5 liters. This solution was filtered through a Durapore PVDF membrane filter (MCGL 10S, 0.22 / m, manufactured by Nippon Millipore). This filtrate was filled into a 2 m1 colorless ampule in 2 m1 increments using an ampoule filling and sealing machine (Nogiginoya Machine, Model H-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) (121 °). C, 20 minutes) to give an injection.

 Table 11 Formulation Example 7 (pH 4.5)

Example 14 (Compound A -a 1.72 mg / m1 containing injection)

Compound A—a injection was prepared according to the formula (production volume) shown in Formulation Example 8 (Table 12). did. That is, 2 liters of water for injection was placed in a stainless steel container, and 1.5 kg of propylene glycol was added. The mixture was stirred for 5 minutes with a stirrer (FBL 120OM, manufactured by Fine), and mixed uniformly. Next, 13.225 g of the compound A-b was added and stirred for 15 minutes. This solution was adjusted to pH 2.5 with 1 mol / liter hydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total amount 5 liters. This solution was filtered through a Durapore PVD F membrane filter (MCGL 10S, 0.22 / zm, manufactured by Nippon Millipore). This filtrate is filled into 2m1 colorless ampules in 2ml increments using an ampoule filling and sealing machine (Haginoya Machine, Model H-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) at 121 ° C for 20 minutes. ) To give an injection.

 (Table 12 Formulation example 8 (t) H2.5)

Example 15 (Compound A-a 3.43 mg / m1 containing injection)

According to the formulation (production amount) shown in Formulation Example 9 (Table 13), an injection of Compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 1.5 kg of propylene dariko was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 120OM, manufactured by Fine), and mixed uniformly. Next, 26.45 g of compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 2.0 with 1 mol Z 1 monohydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 / m, manufactured by Nippon Millipore). This filtrate was filled into 2ml 1 colorless ampules by 2ml each with an ampoule filling and sealing machine (Nogiginoya Machine, Model H-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) (121 ° (: , 20 minutes) to give an injection. Table 13 Formulation Example 9 (pH 2.0)

Example 16 (Compound A -a 1.72 mg ng no m1 containing injection)

According to the formulation (production amount) shown in Formulation Example 10 (Table 14), an injection of Compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene dalicol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 1200M manufactured by Fine), and mixed uniformly. Next, 13.225 g of the compound Ab was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 4.0 with 1 mol / liter hydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 μm _s, manufactured by Nippon Millipore). This filtrate was filled into 2 ml colorless samples by ampoule filling and sealing machine (Haginoya Machine, Model H_01) in 2 ml increments, sealed, and then sterilized (121 ° C for 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho). Injectable.

 Table 14 Formulation Example 10 (pH 4.0)

Example 17 (Compound A-a 1.72 mg / m1-containing injection)

According to the formulation (production amount) shown in Formulation Example 11 (Table 15), an injection of Compound A-a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.0 kg of propylene dalicol was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 1200M, manufactured by Fine), and mixed uniformly. Next, 13.225 g of compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 3.0 with 1 mol Z liter-hydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered through a Durapore PVD membrane filter (MCGL 10S, 0.22 im, manufactured by Nippon Millipore). Was. This filtrate was filled into 2 ml colorless samples by ampoule filling and sealing machine (Haginoya Machine, Model H-01), 2 ml each, and after sealing, sterilized by high-pressure steam sterilizer (Sankida Seisakusho) (121 ° C for 20 minutes) And used as an injection.

 Table 15 Formulation Example 11 (pH3.0)

Example 18 (Compound A -a containing 1.72 mg / ml ¾lt agent)

 According to the formulation (production amount) shown in Formulation Example 12 (Table 16), an injection of Compound A-a was produced. That is, 2 liters of water for injection were placed in a stainless steel container, and 1.0 kg of propylene glycol was added thereto, followed by stirring with a stirrer (FBL 120OM type, manufactured by Fine) for 5 minutes, and uniformly mixed. Next, 13.225 g of Compound Ab was dissolved in the mixture by stirring for 15 minutes. This solution was adjusted to pH 2.5 with 1 mol Z 1 monohydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total amount 5 liters. This solution was filtered through a Durapore PVDF filter (MCGL 10S, 0.22 μπι, manufactured by Nippon Millipore). This filtrate was filled into a 2 ml colorless sample in 2 ml portions using an ampoule filling and sealing machine (Haginoya Machine, Model Η-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) at 121 ° C Min) to give an injection.

 Table 16 Formulation Example 12 (pH2.5)

Example 19 (prepared preparation before use)

According to the formulation (production amount) shown in Formulation Example 13 (Table 17), a solution for injection of compound A-a and a drug-containing powder or granule were produced. That is, 2 liters of water for injection was put into a stainless steel container, and 2.5 kg of propylene glycol was stirred for 5 minutes with a Kamen ぇ stirrer (FBL 1200 MM manufactured by Fine), and then 1 mol, liter-hydrochloric acid 9.5 m 1 was added and stirred, and mixed uniformly. Thereafter, an appropriate amount of water for injection was added to make the total amount 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 μτΆ, manufactured by Nippon Millipore). This filtrate was filled in 2 m1 colorless ampules in 2 m1 units in an ampoule filling and sealing machine (Haginoya Machinery, Η_01 type), sealed, and then sterilized in a high-pressure steam sterilizer (Sanukita Seisakusho) (121 ° C, 20 ° C). After that, a solution for injection was prepared (Formulation Example 13-1). In addition, this filtrate is filled into a 20 ml colorless ampule in 20 ml increments using an ampoule filling and sealing machine (Haginoya Machine, Model H-01), sealed, and then sterilized with a high-pressure steam sterilizer (Sankida Seisakusho) at 121 ° C for 20 minutes. ) And a solution for injection was prepared (Formulation Example 13-2).

 The drug-containing powders or granules having the composition of Formulation Examples 13-3 and 13-4 were prepared using powder of compound A-b (sterilized product) in an isolator validated for aseptic filling operation. Was weighed according to the prescription example. They were filled into glass vials and plugged with petit rubber stoppers.

 To use the above-prepared preparation for injection as an injection, compound A-a is prepared by injecting a solution weighed out in a glass syringe into a pail of a powdery or granular substance containing a drug and dissolving it. Solution.

 Table 17 Formulation Example 13

 Example 20 (oral solution)

According to the formulation (production volume) shown in Formulation Example 14 (Table 18), an oral solution of Compound Aa was produced. That is, 1.5 liters of purified water was placed in a stainless steel container, 500 g of sorbitol paste, 5 g of citrate, and 5 g of sodium L-glutamate were added, and the mixture was stirred and dissolved for 15 minutes with a stirrer (FBL 1200M type, manufactured by Fine). In addition, 2.5 kg of nonglycorone was added, stirred for 5 minutes, and mixed uniformly. Next, 13.225 g of compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 3.5 with 1 mol / liter hydrochloric acid. Thereafter, an appropriate amount of purified water was added to bring the total volume to 5 liters. This solution was filtered with a Durapore PVDF membrane filter (MCGL 10S, 0.22 m, manufactured by Nippon Millipore). The filtrate was filled into a 100 ml glass bottle to prepare an oral liquid preparation (syrup). For this preparation, for example, 2 ml, which is the efficacious amount, is weighed into a measuring force and taken in divided doses.

 Table 18 Formulation Example 14 (pH3.5)

Example 21 (Compound A—a 1.72 mg / m1 containing injection)

According to the formulation (production amount) shown in Formulation Example 15 (Table 19), an injection of Compound A_a was produced. That is, 2 liters of water for injection was placed in a stainless steel container, 2.5 kg of propylene d'Arylonole was added, and the mixture was stirred for 5 minutes with a stirrer (FBL 120OM, manufactured by Fine), and mixed uniformly. Next, 13.225 g of the compound A-b was added and dissolved by stirring for 15 minutes. This solution was adjusted to pH 3.5 with 1 mol / liter hydrochloric acid. Thereafter, an appropriate amount of water for injection was added to make the total volume 5 liters. This solution was filtered through a Durapore PVD membrane filter (MCGL 10S, 0.22 / zm, manufactured by Nippon Millipore). Fill the vial (Hirasawa Seisakusho) with 20 ml 1 colorless vial by 10 ml each, then stopper with a rubber stopper (V5-F8, Daikyo Rubber Co., Ltd.), cover the flip-off cap, and wind the machine. After tightening with a (fan machine), it was sterilized (121 ° C, 20 minutes) with a high-pressure steam sterilizer (Sankida Seisakusho) to produce an injection. Table 19 Prescription example 15 (pH 3.5)

Example 22 (semi-solid preparation)

 According to the formulation (production amount) shown in Formulation Example 16 (Table 20), a semi-solid (jelly) preparation of compound A-a was produced. That is, 1 liter of purified water was placed in a stainless steel container, 2.5 g of methyl paraben was added, and the mixture was heated and dissolved at 90 ° C. with stirring for 10 minutes, and then cooled to room temperature. Next, 500 g of D-sorbitol and 5 g of citrate were added and dissolved by stirring for 10 minutes. Next, 2.5 kg of propylene glycol was added, and the mixture was stirred for 5 minutes and uniformly mixed. Next, 15.87 g of the compound A_b was dissolved by stirring for 15 minutes. 500 g of gelatin was added to this solution, and the mixture was heated to 80 ° C. with stirring to dissolve. Then, the mixture was cooled to about 50 ° C, and an appropriate amount of purified water was added to make the total volume 5 liters.

 Table 20 Prescription examples 16

産業上の利用可能性

Industrial applicability

The solution pharmaceutical composition of the present invention contains Compound A or a physiologically acceptable salt thereof at a high concentration, and is useful as an injection or an oral preparation. In addition, the solution pharmaceutical composition of the present invention has high stability and can be stored for a long time. Furthermore, since Compound A has high solubility in the above-mentioned drug solution, the composition of the present invention can be in the form of a ready-to-use preparation prepared immediately before use. In addition, the solution pharmaceutical composition of the present invention can be used for injection or oral preparation. It can be manufactured with conventional equipment without any special conditions and equipment required for manufacture. In addition, when the solution pharmaceutical composition of the present invention is used as an injection, it has the effect of low irritation.

Claims

The scope of the claims 1. (a) 4-Amino-5-chloro-2-ethoxy-1-N-[[4- (4-phenolic benzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as Compound A) or its physiological A salt acceptable to (b) from about 10 w / v _^0/0 propylene glycol and about 92 w / V% and (c) the amount of water required to complete the solution pharmaceutical composition, A solution pharmaceutical composition comprising:  2. The solution pharmaceutical composition according to claim 1, wherein the pH is from about 2 to about 5.5. 3. Component (b) is about 1 OwZv ⁰ /. 2. The solution pharmaceutical composition of claim 1, wherein the composition is from about 75% w / v propylene glycol.  4. The solution according to claim 1, wherein the component (a) is Compound A or a physiologically acceptable salt thereof in an amount to give a concentration of about lmgZml to about 12mg / ml in terms of Compound A. Pharmaceutical composition.  5. The solution pharmaceutical composition according to claim 1, further comprising (d) an acidic substance. 6. The solution medicine according to claim 5, wherein the acidic substance (d) is at least one selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, lactic acid, acetic acid, tartaric acid, and citric acid. Composition.  7. The solution pharmaceutical composition according to claim 1, wherein compound A is in a racemic form.  8. The solution pharmaceutical composition according to claim 1, wherein the physiologically acceptable salt of compound A is citrate.  9. The solution pharmaceutical composition according to claim 1, wherein the component (a) is a citrate dihydrate of the compound A.  10. (&) Compound A or a physiologically acceptable salt thereof in an amount to give a concentration of about 1111 §71111 to about 1 Omg / m1 in terms of Compound 8, (b) about 20 w / V% to about 75 w / V ⁰ /. Propylene glycol,  (c) the amount of water required to complete the solution pharmaceutical composition; and (d) at least one acidic substance selected from the group consisting of methanesulfonic acid, citric acid and hydrochloric acid, The solution pharmaceutical composition of claim 1, wherein: H is from about 2.5 to about 4.5. 1 1. (a) the concentration to become the amount of the compound to about 1.5m in terms of A _{g / /} m 1~ about 5.5 mg / m 1, Kuen salt dihydrate of Compound A (racemate) ,  (b) from about 25 w / V% to about 55 w / V% propylene glycol,  (c) the amount of water required to complete the solution pharmaceutical composition; and  (d) at least one acidic substance selected from the group consisting of methanesulfonic acid, citric acid and hydrochloric acid, The solution pharmaceutical composition of claim 1, wherein: H is from about 3 to about 4.  12. The solution pharmaceutical composition according to claim 1, which is in the form of an injection or an oral preparation.  13. (i) Drug-containing powder or granule containing Compound A or a physiologically acceptable salt thereof, and  (ii) a drug solution containing propylene dalicol and water, A preparation for use consisting of  14. A commercial package comprising the solution pharmaceutical composition of claim 1 and a description of the composition, wherein the description is included in the description or in the package for a particular disease. A commercial package stating that it should or should be used.  15. A commercial package containing the ready-to-use preparation according to claim 13 and a description of the preparation, wherein the description and / or the package or the package use the preparation for a specific disease. A commercial package stating that you should.  16. An effective amount of the solution pharmaceutical composition according to claim 1 is administered to a patient for promoting gastrointestinal motility, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (GERD). A method comprising:  17. Use of the solution pharmaceutical composition according to claim 1 for promoting gastrointestinal motility, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (GERD).  18. A method for producing a solution pharmaceutical composition comprising Compound A or a physiologically acceptable salt thereof, comprising: (i) the final combination of water with less than the amount required to complete the solution pharmaceutical composition; Dissolving Compound A or a physiologically acceptable salt thereof in a mixed solvent containing propylene glycol in an amount of about 1 OwZvO / o to about 92 w / v% in the composition; and  (ii) a step of adding water to the mixture obtained in step (i) to complete the composition.  19. A method for producing a solution pharmaceutical composition containing Compound A or a physiologically acceptable salt thereof,  (i ') dissolving Compound A or a physiologically acceptable salt thereof in propylene glycol at a final concentration of about 10 V% to about 92 wZ V% in the composition , and  (ii ′) a step of adding an amount of water necessary for completing the solution pharmaceutical composition to the liquid obtained in step (i ′) to complete the composition, A manufacturing method including:  20. The method according to any one of claims 18 or 19, comprising the step of adjusting the pH to about 2 to about 5.5 by adding an acidic substance and / or an additive necessary for formulation as necessary.  21. A solution pharmaceutical composition obtainable by the method according to any of claims 18-20.  22. A method for improving the solubility and stability of Compound A or a physiologically acceptable salt thereof in an aqueous solvent, comprising from about 10 wZ V% to about 92 w / v% in the final composition. An improved method comprising dissolving Compound A or a physiologically acceptable salt thereof in an aqueous solvent containing propylene glycol in an amount to give a concentration of  23. A solution pharmaceutical composition having improved solubility and stability of compound A, obtainable by the method of claim 22.