KR101010547B1 - Pharmaceutical preparations containing arginine amides - Google Patents

Abstract

A solution containing a substance selected from the group consisting of arginine amides represented by the following general formula (I), an active ingredient thereof, and salts thereof as an active ingredient at a concentration of 1 mg / ml or more and about 10 mg / ml or less Is a solution containing at least water), the pharmaceutical formulation in the form of which the solution is filled in a container having a volume of at least about 1 ml and up to about 20 ml

[Formula I]

[R ¹ represents a (2R, 4R) -4-alkyl-2-carboxypiperidino group, R ² represents a phenyl group or a condensed polycyclic compound residue, and R ² is substituted with a lower alkyl group, a lower alkoxy group or a lower alkyl group The condensed polycyclic compound residue may be a condensed polycyclic compound residue including a benzene ring, and the benzene ring may be a sulfur atom of the sulfonyl group in the general formula (I). And another ring which may be a heterocyclic ring condenses on the benzene ring, and represents a residue having 7 to 14 carbon atoms in the ring of the polycyclic compound residue.

The pharmaceutical preparations and pharmaceutical compositions of the present invention have the advantages of high convenience and safety in the medical field, good storage stability, and simple production.

Arginineamides, agatrobans, pharmaceuticals

Description

Pharmaceutical preparations containing arginineamides {PHARMACEUTICAL PREPARATIONS CONTAINING ARGININE AMIDES}

The present invention relates to a pharmaceutical preparation comprising as an active ingredient a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof.

The following general formula (I):

[In the general formula (I), R ¹ represents a (2R, 4R) -4-alkyl-2-carboxypiperidino group, R ² represents a phenyl group or a condensed polycyclic compound residue defined below, and R ² May have one or more substituents selected from an amino group substituted with a lower alkyl group, a lower alkoxy group or a lower alkyl group. The condensed polycyclic compound residue is a condensed polycyclic compound residue including a benzene ring, the benzene ring being bonded to a sulfur atom of the sulfonyl group in the above general formula (I), and the benzene ring is condensed with another ring which may be a heterocycle. And a residue having a total carbon atom number of 7 to 14 constituting the ring of the polycyclic compound residue.] The substance selected from the group consisting of the arginine amides, salts and hydrates thereof has antithrombin activity. It is known as a compound (Unexamined-Japanese-Patent No. 56-15267, Unexamined-Japanese-Patent No. 55-33499, and 56-92213). Among them, agatroban ((2R, 4R) -1- [N ² -((RS) -3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl]- The generic name attached to 4-methyl-2-piperidine carboxylic acid and a hydrate is a pharmaceutical product sold under the trade name Novastan (registered trademark, Mitsubishi Well Pharma Co., Ltd.) and the like.

Arginine amides and agatroban represented by the general formula (1) are poorly soluble in water, and a commercially available formulation is currently prepared as a 20 ml ampoule. The liquid volume of 20 ml is larger than other general injections, and the ampoule itself is large. Therefore, a large space is required for storing and discarding the ampoule. In addition, the agatroban administered in the blood is rapidly lost, and in order to obtain a blood residence time necessary for treatment, it is necessary to continuously administer it in blood vessels. In the case of using, the solution contained in the ampoule needs to be sucked from the ampoule to the syringe once, and then mixed with the sap to prepare a dropper. At this time, since a large amount of ampoule of 20 ml takes one hand and time to suck the solution into the syringe in the ampoule, it is desired to provide a formulation having improved convenience.

Although various attempts have been made to prepare high concentration solutions of arginine amides and agatroban represented by the above general formula (1), they are prepared by adding an additive such as a surfactant, which is not highly safe as an injection ( Japanese Unexamined Patent Application Publication No. Hei 10-316595) or a preparation (Japanese Unexamined Patent Application Publication No. Hei 6-219948) that requires a complicated production process such as emulsification, is not suitable as an injection.

Moreover, the method of preparing a high concentration agatroban solution using the high concentration alcohols etc. which are represented by high concentration ethanol is also known (Unexamined-Japanese-Patent No. 1-31727). Injectable preparations commercially available in the United States are filled in 2.5 ml vials, in which 250 mg of agatroban is dissolved using a high concentration of ethanol. Since the use of a high concentration of ethanol may cause undesirable action due to ethanol such as vasodilation and inhibition of central action, it is preferable to use as little as possible the amount of ethanol when used as an additive.

Disclosure of Invention

As mentioned above, it is a subject of this invention to provide the pharmaceutical formulation which contains the said arginine amides as an active ingredient with high convenience in a medical field. Moreover, it is also a subject of this invention to provide the pharmaceutical formulation which is high in safety, excellent in storage stability, and easy to manufacture.

As a result of intensive studies, the present inventors found that a substance selected from the group consisting of arginine amides represented by the above general formula (I) as active ingredients, their salts and their hydrates has a concentration of 1 mg / ml or more and about 10 mg / ml or less. A pharmaceutical preparation in the form in which the solution is contained in a container having a volume of about 1 ml or more and about 20 ml or less, or an arginine amide represented by the general formula (I), which is an active ingredient, salts thereof, and A medicament consisting of a solution containing a substance selected from the group consisting of these hydrates at a concentration of about 1 mg / ml or more and about 10 mg / ml or less and having a viscosity of about 15 mPa · s or less at a shear rate of about 35.8 s ⁻¹ . By providing the composition, the inventors have found that the above problems are solved and have come to complete the present invention.

That is, the following pharmaceutical formulation is provided by this invention.

(1) A solution containing a substance selected from the group consisting of arginine amides represented by the following general formula (I) as active ingredients, salts and hydrates thereof at a concentration of 1 mg / ml or more and about 10 mg / ml or less ( Provided that the solution is a solution containing at least water), wherein the solution is filled in a container having a volume of about 1 ml or more and about 20 ml or less:

[Formula (I)]

[In the general formula (I), R ¹ represents a (2R, 4R) -4-alkyl-2-carboxypiperidino group, R ² represents a phenyl group or a condensed polycyclic compound residue defined below, and R ² May have one or more substituents selected from an amino group substituted with a lower alkyl group, a lower alkoxy group or a lower alkyl group. The condensed polycyclic compound residue is a condensed polycyclic compound residue including a benzene ring, the benzene ring being bonded to a sulfur atom of the sulfonyl group in the above general formula (I), and the benzene ring is condensed with another ring which may be a heterocycle. And a residue having 7 to 14 carbon atoms in the ring of the polycyclic compound residue.

(2) R ¹ in General Formula (I) is a (2R, 4R) -4-methyl-2-carboxypiperidino group, and R ² is 3-methyl-1,2,3,4-tetrahydro-8- The pharmaceutical preparation according to the above (1), which is a quinolyl group.

(3) The pharmaceutical preparation according to the above (1), wherein the arginine amides are agatroban.

(4) The pharmaceutical preparation according to any one of (1) to (3), which is administered as an injection or used for preparation of a drop.

(5) The pharmaceutical preparation according to any one of (1) to (4), wherein a container has a capacity of about 10 ml or less.

(6) The pharmaceutical preparation according to any one of (1) to (4), wherein the container has a capacity of about 2 ml.

(7) The pharmaceutical preparation according to any one of (1) to (6), which comprises a solution containing about 5 mg / ml of a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof.

(8) The pharmaceutical preparation according to any one of (1) to (7), which contains a solution containing about 10 mg of a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof.

(9) The pharmaceutical formulation according to any one of (1) to (8), wherein the viscosity of the solution is about 15 mPa · s or less at a shear rate of about 35 · 8s ⁻¹ at 25 ° C.

(10) The pharmaceutical formulation according to any one of (1) to (8), wherein the viscosity of the solution is about 10 mPa · s or less at a shear rate of about 71 · 6s ⁻¹ at 25 ° C.

(11) The pharmaceutical formulation according to any one of (1) to (10), wherein the pH of the solution is about 4 to about 7.

(12) The pharmaceutical formulation according to any one of (1) to (10), wherein the pH of the solution is about 5 to about 7.

(13) The pharmaceutical preparation according to any one of (1) to (12), wherein formation of substances other than the active ingredient is substantially suppressed after heat sterilization.

(14) The pharmaceutical preparation according to any one of (1) to (12), wherein production of substances other than the active ingredient after storage at 40 ° C for 6 months after heat sterilization is suppressed to about 0.2% or less, respectively.

(15) The pharmaceutical preparation according to any one of (1) to (14), wherein the container is an ampoule.

(16) The pharmaceutical preparation according to any one of (1) to (15), wherein the solution contains a monohydric alcohol.

(17) The pharmaceutical preparation according to the above (16), wherein the monohydric alcohol is ethanol.

(18) The pharmaceutical formulation according to any of (16) or (17), wherein the content of monohydric alcohol in the solution is about 25% (w / v) or less.

(19) The pharmaceutical preparation according to the above (16), which contains about 20% (w / v) or less of ethanol in the solution.

(20) The pharmaceutical preparation according to any one of (1) to (19), wherein the solution contains a polyhydric alcohol.

(21) The pharmaceutical preparation according to the above (20), wherein the polyhydric alcohol is glycerin.

(22) The pharmaceutical preparation according to the above (20) or (21), wherein the content of the polyhydric alcohol in the solution is about 30% (w / v) or more.

(23) The pharmaceutical formulation according to any one of (20) or (21), wherein the content of the polyhydric alcohol in the solution is about 40% (w / v) or more.

(24) The pharmaceutical preparation according to any one of (1) to (23), which contains substantially no sugar in the solution.

(25) The pharmaceutical formulation according to any one of (1) to (23), wherein the solution contains a saccharide.

(26) The pharmaceutical preparation according to the above (25), wherein the saccharide is sorbitol.

(27) A compound selected from the group consisting of arginine amides represented by the following general formula (I), an active salt thereof, and hydrates thereof, which is an active ingredient, is contained at a concentration of 1 mg / ml or more and about 10 mg / ml or less, and contains a viscosity A pharmaceutical composition comprising a solution of less than or equal to about 15 mPa · s at a shear rate of about 35.8 s ⁻¹ at 25 ° C., wherein the solution is at least water containing solution:

[Formula (I)]

[In the general formula (I), R ¹ represents a (2R, 4R) -4-alkyl-2-carboxypiperidino group, R ² represents a phenyl group or a condensed polycyclic compound residue defined below, and R ² May have one or more substituents selected from an amino group substituted with a lower alkyl group, a lower alkoxy group or a lower alkyl group. The condensed polycyclic compound residue is a condensed polycyclic compound residue including a benzene ring, the benzene ring being bonded to a sulfur atom of the sulfonyl group in the above general formula (I), and the benzene ring is condensed with another ring which may be a heterocycle. And a residue having 7 to 14 carbon atoms in the ring of the polycyclic compound residue.

(28) The pharmaceutical composition according to the above (27), wherein the viscosity is about 10 mPa · s or less at a shear rate of about 71.6 s ⁻¹ at 25 ° C.

(29) R ¹ in General Formula (I) is a (2R, 4R) -4-methyl-2-carboxypiperidino group, and R ² is 3-methyl-1,2,3,4-tetrahydro-8- The pharmaceutical composition according to the above (27) or (28), which is a quinolyl group.

(30) The pharmaceutical composition according to any one of (27) to (29), wherein the arginine amides are agatroban.

(31) The pharmaceutical composition according to any one of (27) to (30), which is administered as an injection or used for the preparation of a drop.

(32) The pharmaceutical composition according to any one of (27) to (31), comprising a solution containing about 5 mg / ml of a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof.

(33) The pharmaceutical composition according to any one of (27) to (31), comprising a solution containing about 10 mg of a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof.

(34) The pharmaceutical composition according to any one of (27) to (33), wherein the pH of the solution is about 4 to about 7.

(35) The pharmaceutical composition according to any one of (27) to (33), wherein the pH of the solution is about 5 to about 7.

(36) The pharmaceutical composition according to any one of (27) to (35), wherein formation of substances other than active ingredients after heat sterilization is substantially suppressed.

(37) The pharmaceutical composition according to any one of (27) to (36), wherein production of substances other than the active ingredient after storage at 40 ° C. for 6 months after heat sterilization is suppressed to about 0.2% or less, respectively.

(38) The pharmaceutical composition according to any one of (27) to (37), wherein the solution contains a monohydric alcohol.

(39) The pharmaceutical composition according to the above (38), wherein the monohydric alcohol is ethanol.

(40) The pharmaceutical composition according to the above (38) or (39), wherein the monohydric alcohol in the solution is about 25% (w / v) or less.

(41) The pharmaceutical composition according to the above (40), which contains about 20% (w / v) or less of ethanol in the solution.

(42) The pharmaceutical composition according to any one of (27) to (41), wherein the solution contains a polyhydric alcohol.

(43) The pharmaceutical composition according to the above (42), wherein the polyhydric alcohol is glycerin.

(44) The pharmaceutical composition according to the above (42) or (43), wherein the polyhydric alcohol in the solution is about 30% (w / v) or more.

(45) The pharmaceutical composition according to the above (42) or (43), wherein the polyhydric alcohol in the solution is about 40% (w / v) or more.

(46) The pharmaceutical composition according to any one of (27) to (45), wherein the solution does not contain a saccharide.

(47) The pharmaceutical composition according to any one of (27) to (45), wherein the solution contains a saccharide.

(48) The pharmaceutical composition according to the above (47), wherein the saccharide is sorbitol.

(49) A pharmaceutical composition comprising as a active ingredient a solution containing about 1 mg / ml or more and about 10 mg / ml or less and having a viscosity of about 15 mPa · s or less at a shear rate of about 35.8 s ⁻¹ at 25 ° C.

(50) Production of substances other than the active ingredient after containing about 1 mg / ml or more of about 10 mg / ml or less of agatroban and after 6 months of storage at 40 ° C. after heat sterilization is about 0.2% or less, respectively. Pharmaceutical composition which consists of a suppressed solution.

(51) The production of substances other than the active ingredient after containing about 1 mg / ml or more and about 10 mg / ml or less of agatroban and after 6 months of storage at 40 ° C. is suppressed to about 0.2% or less, respectively. A pharmaceutical composition comprising a solution having a viscosity of about 10 mPa · s or less at a shear rate of about 71.6 s ⁻¹ at 25 ° C.

(52) Production of substances other than the active ingredient after containing about 5 mg / ml of agatroban and stored after heat sterilization at 40 ° C. for 6 months is suppressed to about 0.2% or less, respectively, and the viscosity of the solution A pharmaceutical composition consisting of a solution of about 10 mPa · s at 25 ° C. at a shear rate of about 71.6 s ⁻¹ .

(53) The pharmaceutical composition according to any one of (49) to (52), wherein the solution contains about 25% (w / v) or less of a monohydric alcohol and a polyhydric alcohol that is a dissolution aid, and has a pH of about A pharmaceutical composition comprising a solution of 4 to about 7 phosphorus.

(54) The pharmaceutical composition according to any one of (49) to (52), wherein about 10% (w / v) to about 25% (w / v) of monohydric alcohol and about 40% (w) in the solution / v) to a pharmaceutical composition comprising a polyhydric alcohol which is a dissolution aid of about 55% (w / v) and has a pH of about 4 to about 7.

(55) The pharmaceutical composition according to any one of (49) to (52), wherein the pharmaceutical composition comprises a solution having a pH of about 5 to about 7.

BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the relationship between the sorbitol concentration and a viscosity of Example 4.

2 is a diagram showing an HPLC chart of Example 5. FIG.

It is a figure which shows the relationship between pH of the pharmaceutical formulation of Example 6, and formation of an analogous substance.

To practice the invention  Best form for

The pharmaceutical preparation of the present invention is filled with a solution in a container having a volume of about 1 ml or more and about 20 ml or less, and the solution is an arginine amide represented by the general formula (1) as an active ingredient, salts thereof, and their hydrates. A solution containing a substance selected from the group consisting of at least about 1 mg / ml and about 10 mg / ml, and at least water.

In General Formula (I), R ¹ represents a (2R, 4R) -4-alkyl-2-carboxypiperidino group. Here, alkyl means C1-C5 lower alkyl groups, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, for example.

R ² represents a phenyl group or a condensed polycyclic compound residue as defined below.

A condensed polycyclic compound residue is a condensed polycyclic compound residue containing a benzene ring, the benzene ring couple | bonds with the sulfur atom of the sulfonyl group in the said General formula (I), and the other ring which may be a heterocyclic ring condenses to this benzene ring, The total number of carbon atoms constituting the ring of the polycyclic compound residue is 7-14.

More preferably the condensed polycyclic compound residue is a bicyclic compound residue or a tricyclic compound residue. The bicyclic compound residue is preferably a group in which a 5- or 6-membered ring is condensed to the benzene ring, and the 5- or 6-membered ring may be a heterocyclic ring. The tricyclic compound residue is preferably a group in which a 5- or 6-membered ring is condensed with another 5- or 6-membered ring, and the 5- or 6-membered ring may be a heterocyclic ring. The heteroatom constituting the heterocycle is, for example, an oxygen atom, a nitrogen atom, or a sulfur atom.

R ² may be substituted with one or more groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and an amino group substituted with a lower alkyl group. As the lower alkyl group, for example, a C1 to C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group or tert-butyl group, lower alkoxy group, for example, methoxy group, ethoxy group, pro Examples of the amino group substituted with a C1 to C5 alkoxy group such as an alkoxy group, an isopropoxy group or a butoxy group and a lower alkyl group include an alkylamino group or a dialkylamino group substituted with a lower alkyl group as described above. .

Specific examples of the condensed polycyclic compound residue represented by R ² include anthryl group, phenanthryl group, benzofuranyl group, dibenzothienyl group, phenoxatinyl group, quinolyl group, carbazolyl group, acridinyl group, and phenazinyl. Groups, phenothiazinyl groups, phenoxazinyl groups, benzimidazolyl groups, fluorenyl groups, 2,3-dihydrobenzofuranyl groups, thioxanthenyl groups, naphthyl groups, tetrahydronaphthyl groups, isoquinolyl groups, A tetrahydroquinolyl group, a tetrahydroisoquinolyl group, etc. are mentioned. In the said general formula (I), although the benzene ring of the said polycyclic compound residue and the sulfur atom of the sulfonyl group in general formula (I) bond, the binding position on a benzene ring is not specifically limited.

The following compounds are mentioned as a specific compound contained in arginine amides.

(2R, 4R) -1- [N ^2- (3-isopropoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid;

(2R, 4R) -1- [N ^2- (3,5-dimethyl-4-propoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid;

(2R, 4R) -1- [N ² - (5,6,7,8- tetrahydro-naphthalene-2-sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid;

(2R, 4R) -1- [N ^2- (5-dimethylamino-1-naphthalenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid;

(2R, 4R) -1- [N ^2- (3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidine Carboxylic acid;

(2R, 4R) -1- [N ² - (2- dibenzothiophene-sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid;

(2R, 4R) -1- [N ^2- (2,4-dimethoxy-3-butoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid;

(2R, 4R) -1- [N ^2- (3,5-dimethyl-4-propoxybenzenesulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid;

(2R, 4R) -1- [N ^2- (3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidine Carboxylic acid;

(2R, 4R) -1- [N ² - (2- carbamic jolsul sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid;

(2R, 4R) -1- [N ² - (2- fluorene-sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid;

(2R, 4R) -1- [N ² - (2- page noksa tea Insular sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid;

(2R, 4R) -1- [N ² - (2- anthracene sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid; And

(2R, 4R) -1- [N ² - (7- methyl-2-naphthalene-sulfonyl) -L- see carbonyl] -4-methyl-2-piperidine carboxylic acid.

Among the above-mentioned, the agatroban mentioned above as a especially preferable thing is mentioned.

Isomers, such as optical isomers and diastereomers, exist in the said arginine amides, Any of these may be used as arginine amides, and the mixture of arbitrary isomers may be used.

The arginine amides can be easily produced according to the method described in JP-A-56-15267, JP-A-55-33499, JP-A-10-101649 and the like.

In addition, the arginine amides of the present invention can form addition salts with various inorganic or organic acids or inorganic bases or organic bases according to the method described in JP-A-56-15267.

It is preferable to use the pharmaceutical formulation of this invention as an injection. When using as an injection, it can also be diluted and used at the time of use. In addition, the drop preparation may be prepared when necessary using the pharmaceutical preparation of the present invention. For example, a drop preparation may be prepared by adding the pharmaceutical preparation of the present invention in sap. Alternatively, it may be used in addition to the dialysate at the time of dialysis.

The container used for the filling of the pharmaceutical preparation of the present invention may be a container having a capacity of about 1 ml or more and about 20 ml or less, and the shape and material are not particularly limited. Glass ampoules, glass or plastic vials, polymer bags and the like, which are commonly used for filling pharmaceutical preparations, can be appropriately used. In view of convenience in the medical field, about 10 ml or less is preferable and about 2 ml is most preferable as a container capacity. The pharmaceutical preparation of the present invention contains alginineamides represented by the general formula (I) as active ingredients at a concentration of about 1 mg / ml or more and about 10 mg / ml, but preferably a concentration of about 5 mg / ml. to be. The weight of the arginine amides contained in the container is preferably about 10 mg. As a container, a glass ampoule is preferable.

The pharmaceutical preparation of the present invention is aspirated into a syringe, for example, when a solution is aspirated from a pharmaceutical preparation filled with an ampoule into a syringe, and then the solution is mixed with a sap to prepare a drop. It is preferable to include the solution which is easy to do. Such pharmaceutical formulations preferably have a viscosity of the solution of about 15 mPa · s or less at a shear rate of about 35.8 s ⁻¹ at 25 ° C., particularly preferably a viscosity of the solution at a shear rate of about 71.6 s ⁻¹ at 25 ° C. It is 10 mPa * s or less. Viscosity can be measured using a rotational viscometer (type B) at 25 degreeC, as shown in the Example mentioned later.

The solution contained in the pharmaceutical composition of the present invention contains at least water, but does not exclude the presence of other solvents. The solution preferably contains at least 30% (w / v) of water. More preferably, it is a solution containing 35%-55% (w / v) of water.

The composition of the solution which melt | dissolved arginine amides in the density | concentration of about 1 mg / ml or more and about 10 mg / ml or less is not specifically limited, Various compositions are possible. As an example of a preferable prescription, the prescription which added monohydric alcohol for the dissolution of arginine amides is mentioned. As the monohydric alcohol, any pharmaceutically acceptable compound such as methanol or ethanol can be used, but in the present invention, ethanol is preferably used. In the case of using ethanol, the concentration in the solution is preferably about 25% (w / v) or less, preferably 20% (w / v) or less, in consideration of the central inhibitory effect due to ethanol. More preferably, they are 10%-25% (w / v), More preferably, they are 10%-20% (w / v), Most preferably, they are 15%-20% (w / v).

When the amount of monohydric alcohol is reduced in consideration of safety, polyhydric alcohol can be added as a dissolution aid. In this specification, although polyhydric alcohol means bivalent or more alcohol, it uses as a concept which does not contain a saccharide. As the polyhydric alcohol, any pharmaceutically acceptable one can be used. However, in the present invention, dihydric or trivalent polyhydric alcohols are preferable, and glycerin is particularly preferable. Although content of polyhydric alcohol is not specifically limited, About 30% (w / v)-about 60% (w / v), More preferably, about 40% (w / v)-about 55% (w / v) Can be used in the range of.

Although sugar can also be used for the pharmaceutical formulation or pharmaceutical composition of this invention, For example, sugars, such as glucose and fructose, or sugar alcohols, such as xylitol and sorbitol, are mentioned. Of these, sorbitol is preferable. However, the use of sugars may increase the viscosity of the solution, and it is generally not preferable to add a large amount of sugars. Therefore, the pharmaceutical formulation of the present invention preferably does not contain a large amount of sugars, and the content of sugars is, for example, about 30% (w / v) or less, preferably 25% (w / v) or less. . Moreover, it is also preferable that it does not contain a saccharide substantially.

The pharmaceutical formulation of the present invention can be prepared by dissolving arginine amides in a solution containing the monohydric alcohols and the like. A polyhydric alcohol and / or a saccharide can be added to a solution as needed. When dissolving, the order and conditions are not particularly limited, but first, arginine amides are dissolved in a monohydric alcohol or a mixture of a monohydric alcohol and a polyhydric alcohol and / or a sugar, followed by addition of water to prepare a mixture. It is preferable.

The pharmaceutical formulation of the present invention is a stable formulation wherein the production of substances other than the active ingredient is substantially suppressed after heat sterilization. More preferably, when stored at 40 ° C. for 6 months after heat sterilization, the amount of production of substances (individual decomposition products) other than the active ingredient is suppressed to about 0.2% or less. Whether or not it is a pharmaceutical formulation in which production other than the active ingredient is substantially suppressed can be easily confirmed by analyzing the solution after heat sterilization by HPLC, as described in Examples later. Although heat sterilization is not specifically limited as long as it can ensure the safety as a medicine, Usually, the thing which has the effect of the same grade as 121 degreeC, 20-minute heat sterilization can be used. Substances (individual decomposition products) other than the active ingredient of the present invention include decomposition products derived from the active ingredient and other unknown compounds. For example, when the active ingredient is agatroban, the following main degradation products (degradant i) and other unknown compounds are included as substances other than the active ingredient.

As an example of the stable pharmaceutical formulation which the production | generation of substances other than an active ingredient was substantially suppressed after heat sterilization, the pharmaceutical formulation which prepared the said solution containing arginine amides, and adjusted the pH of a solution before heat sterilization is mentioned. The pH of the solution is preferably about 4 to about 7, more preferably about 5 to about 7. Adjustment of pH can be performed using a conventional pH adjuster. For example, pH adjusting agents such as hydrochloric acid or sodium hydroxide can be used.

As described above, a solution containing alginylamides is prepared, the pH is adjusted as necessary, and then dispensed into a container such as a cleaned ampoule, melted, and further heat sterilization. The pharmaceutical preparation of this invention can be prepared by this.

The pharmaceutical composition provided by the present invention contains at least about 1 mg / ml, and also about 10 mg of a substance selected from the group consisting of the above-mentioned arginine amides represented by the general formula (I) as active ingredients, their salts and their hydrates. / Ml, and a pharmaceutical composition comprising a solution having a viscosity of about 15 mPa · s or less at a shear rate of about 35.8 s ⁻¹ at 25 ° C. The pharmaceutical composition is preferably filled in a container having a capacity of about 1 mg / ml or more and about 20 mg / ml or less, but the capacity of the container is not limited to the above.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. The agatroban used in the following example is manufactured according to the method of Unexamined-Japanese-Patent No. 10-101649. In addition, all the viscosity shown below was measured on condition of the following.

Measuring instrument: Type B viscometer (manufacturer: Tokimek, publisher: Toki Industry Co., Ltd.)

Measuring temperature: 25 ℃

Revolutions: 60rpm (based on the instruction manual, not less than 10mPa · s is measured at 30rpm, shear rate ^{60rpm: 71.58s -1, 30rpm: 35.79s} -1)

Example 1

As shown in Table 1, 10.0 g of ethanol (99.5%), sorbitol 20.0 g, glycerin 30.0 g, and agatroban 500 mg were weighed into a 100 ml volumetric flask, and water for injection was added to make 100 ml. It was. The volumetric flask was immersed in a 25 degreeC water tank, and the clear solution was obtained by ultrasonic irradiation. Similarly, about 2-4 shown in Table 1, each component of ethanol, sorbitol, and concentrated glycerin is weighed so that it may become the density | concentration shown in a table | surface, the water for injection is added, and the pharmaceutical composition containing 5 mg / mL of agatroban is prepared. It was. As a result, all the pharmaceutical compositions obtained in 1-4 were colorless, transparent, and clarified at 25 degreeC room temperature.

Similarly, about the prescription shown in Table 2 and Table 3, the pharmaceutical composition containing 5 mg / ml of agatroban was similarly prepared (in Tables 2 and 3, agatroban concentration is represented by mg / ml, Ethanol, concentrated glycerin concentration is expressed in% (w / v)).

In addition, Table 2 and Table 3 show the viscosity of each formulation and the stability when it preserve | saved for 24 hours at 4 degreeC.

Pharmaceutical compositions containing agatroban at a concentration of about 5 mg / ml were obtained, and these pharmaceutical compositions had a viscosity that was easily aspirated by a syringe, and the stability was also good.

Similarly, the prescription shown in Table 4 was similarly prepared and the pharmaceutical composition containing 5 mg / ml of agatroban was prepared (in Table 4, agatroban concentration is represented by mg / ml, and ethanol and concentrated glycerin concentration). Is represented by% (w / v)).

In addition, Table 4 shows the viscosity of each formulation.

Pharmaceutical compositions containing agatroban at a concentration of about 5 mg / ml were obtained, and these pharmaceutical compositions had a viscosity that was easily aspirated by a syringe.

Medicinal composition One 2 3 4 Agatrovan 5 mg / ml 5 5 5 ethanol 10 w / v% 40 10 15 Sorbitan 20 w / v% 30 - - Dark glycerin 30 w / v% - 55 45 When prepared under room temperature Dissolution Dissolution Dissolution Dissolution Stability at 4 ℃ Good Good Good Good

Medicinal composition 5 6 7 8 Agatrovan 5 5 5 5 ethanol 10 15 20 25 Dark glycerin 50 50 50 50 When prepared under room temperature Dissolution Dissolution Dissolution Dissolution Stability at 4 ℃ Good Good Good Good Viscosity (25 ℃) 6.0 7.1 7.9 9.0

Medicinal composition 9 10 11 12 13 14 Agatrovan 5 5 5 5 5 5 ethanol 20 25 30 15 20 30 Dark glycerin 45 45 45 40 40 40 When prepared under room temperature Dissolution Dissolution Dissolution Dissolution Dissolution Dissolution Stability at 4 ℃ Good Good Good Good Good Good Viscosity (25 ℃) 6.7 7.4 7.9 5.0 5.6 6.6

Medicinal composition 14-1 14-2 14-3 Agatrovan 5 5 5 ethanol 12 15 17 Dark glycerin 50 45 40 Viscosity (25 ℃) 6.5 6.3 5.5

Example 2

10 ml of the dissolution liquid of the composition shown below was added previously to the conical flask with a stopper which weighed about 200 mg of agatroban. Thereafter, the mixture was immediately stirred using a stirrer in a constant temperature of 2 ° C. After 24 hours, 1 ml of the suspension was collected and filtered through a 0.45 µm membrane filter to obtain a sample for HPLC.

The temperature of the thermostat was reset to 25 ° C., and further stirring was continued. After 24 hours, 1 ml of the suspension was collected and filtered through a 0.45 µm membrane filter to obtain a sample for HPLC.

About each dissolution liquid, the viscosity and the solubility in 2 degreeC and 25 degreeC were measured, and the result is shown in following Table 5 (in table, solubility was shown as mg / mL and prescription concentration was shown by w / v%). The obtained pharmaceutical composition had the viscosity which is easy to aspirate by a syringe. In addition, it can be seen that as the amount of ethanol increases, the solubility of agatroban increases.

Medicinal composition 15 16 17 18 19 Melt composition
(w / v%)
ethanol 8 % 10% 8 % 10% 6.5% glycerin 50% 50% 29.5% 29.5% 29.5% Sorbitol - - 20% 20% 30% Viscosity (25 ° C, cp) 5.48 5.81 6.10 6.65 9.40 Solubility
(Mg / ml) 2 ℃ 5.21 6.71 3.46 4.99 2.67 25 ℃ 6.22 8.12 3.86 5.42 3.93

Example 3

In the same manner as in Example 2, a solution of the following composition was prepared, and the viscosity was measured. The results are shown in Table 6 (in the table, the solubility was in mg / ml and the prescribed concentration was expressed in w / v%).

Medicinal composition 20 21 22 ethanol 0 0 0 glycerin 45 55 45 Sorbitol - - 15 Solubility (2 ℃) 1.47 1.90 1.50 Viscosity (25 ℃)
mPas 3.54 5.00 6.75

Example 4

In the same manner as in Example 1, a pharmaceutical composition of the prescription shown in Table 7 was prepared (in the table, ethanol and glycerin concentrations are expressed as% (w / v)), and sorbitol concentrations in each composition were 0 to 40% ( The viscosity at the time of adding (% by weight) was measured. The concentration of agatroban is 5 mg / ml. The results are shown in FIG. From the results in FIG. 1, the viscosity of the solution was found to be greatly affected by the concentration of sorbitol.

Medicinal composition 23 24 25 26 27 ethanol 5 5 5 7 10 glycerin 20 30 35 35 30

Example 5

450 g of glycerin was added to a 1 L beaker, and the mixture was stirred, and 150 g of ethanol was added thereto and mixed under stirring. 5 g of agatroban was added to this mixture, and it heated and dissolved as needed. 380 g of distilled water for injection was added to the solution and mixed under stirring. 0.024 mol / L hydrochloric acid was added to the obtained solution, pH was adjusted to about 6, distilled water for injection was added, and the total amount was 1L. This solution is heat sterilized (121 degreeC, 20 minutes), and the result of having investigated the production | generation of substances other than the active ingredient immediately after that by HPLC is shown in FIG. 2, it can be seen that the pharmaceutical composition of the present invention is substantially suppressed the production of substances other than agatroban even after heat sterilization.

HPLC measurement was performed on condition of the following.

Sample preparation:

2 ml of the sample is accurately weighed, and the mobile phase (A) is added to make exactly 20 ml to obtain a sample solution.

Exam conditions:

Detector: ultraviolet absorbance photometer (wavelength: 254 nm)

Column: Nucleosil 0DS 5 μm, 4.6 I.D. × 250 cm (Chemco)

Column temperature: 45 ° C

Mobile phase: 0.25% acetic acid Buffer (pH5): Methanol = 55:45, v / v (0.25% acetic acid Buffer: 2.5 ml acetic acid was added to make 1000 ml to pH5 with ammonia reagent)

Flow rate: 1 ml / min

Injection volume: 10 μL

Apparatus using HPLC: pump LC-10 AD, injector SIL-10A, thermostat CTO-10A, detector SPD-10A (all from Shimadzu Corporation)

Example 6

450 g of glycerin was added to a 1 L beaker and stirred, and 150 g of ethanol was added and mixed under stirring. 5 g of agatroban was added to this mixture, and it heated and dissolved as needed. 380 g of distilled water for injection was added to the solution and mixed under stirring. To the obtained solution, 0.024 mol / L hydrochloric acid or 0.025 mol / L sodium hydroxide was added, the pH was adjusted to about 4, 4.5, 5, 5.5, 6, 6.7, or 7.5, and distilled water for injection was added to make the total amount 1 L. It was set as. The obtained solution was heat-sterilized (121 degreeC, 20 minutes), and production | generation of the substance other than an active ingredient was investigated by HPLC (same conditions as Example 5). The results are shown in FIG. The results of Fig. 3 show that the production of substances other than the active ingredient is suppressed at pH 4 to pH 7, preferably pH 5 to pH 7.

Example 7

About 25 mg or 100 mg of agatroban was weighed and added to a stoppered Erlenmeyer flask. 5 ml of the dissolution liquid of the composition shown in Table 8 previously prepared was added to it. The pH of each solution was adjusted using hydrochloric acid or sodium hydroxide. Thereafter, the mixture was immediately stirred using a stirrer in a constant temperature of 5 ° C. After 24 hours, 1 ml of the suspension was collected and filtered through a 0.45 µm membrane filter to obtain a sample for HPLC. Table 8 shows the solubility in each solution.

As described above, dissolution of at least 5 mg / ml of agatroban was confirmed in all of the solutions containing 15% and 20% of ethanol (99.5) and also containing 40, 45 and 50% of concentrated glycerin.

Example 8

To a prescription containing 10 mg of agatroban, 300 mg of ethanol (99.5) and 900 mg of concentrated glycerin in 1 ampoule (2 ml), hydrochloric acid or sodium hydroxide is added, and then water for injection is added to make 2 ml, pH5 An injection solution of .0 to 6.8 was prepared. These injection solutions were stored for 6 months at 40 ° C./75% RH after heat sterilization (121 ° C., 20 minutes), and the stability of agatroban in various pH injection solutions was examined. The production of substances other than the active ingredient was measured by the following method. The examination results are shown in Table 9.

How to measure

4 ml of this product is weighed, and a mobile phase is added to make 10 ml to obtain a sample solution. 5 ml of this solution is accurately weighed, and the mobile phase is added to make 50 ml exactly. 5 ml of this solution is accurately weighed, and a mobile phase is added to make exactly 100 ml to obtain a standard solution. About 50 microliters of sample solutions and a standard solution, a test is performed by the liquid chromatograph method on condition of the following. Each peak area of each liquid is measured by an automatic integration method, and the ratio of the individual peak areas of the sample solution to 200 times the peak area of the agatroban of the standard solution is determined.

Exam conditions

Detector: ultraviolet absorbance photometer (wavelength: 259nm)

Column: A stainless steel tube having an internal diameter of 4.6 mm and a length of 25 cm was filled with 5 µm octadecylsilylated silica gel for liquid chromatography.

Column temperature: constant temperature around 45 ° C

Mobile phase: pH was adjusted to 5.0 by adding ammonia reagent to dilute acetic acid (100) (1 → 400). 450 ml of methanol is added to 550 ml of this liquid.

Flow rate: It adjusts so that the retention time of the peak eluting first among two peaks of an agatroban may be about 50 minutes.

Area measurement range: From the peak of the solvent, the range of about 1.4 times the holding time of the peak eluting first of the two peaks of the agatroban.

It was confirmed that in the range of pH 5.0-6.8, the degradation product i was 0.10 to 0.14%, other flexible substance (other unknown substance) was less than 0.10%, and the agatroban ampoule preparation of this invention was stable in this pH range.

Example 9

450 g of glycerin was added to a 1 L beaker, and the mixture was stirred, and 150 g of ethanol was added thereto and mixed under stirring. 5 g of agatroban was added to this mixture, and it heated and dissolved as needed. 380 g of distilled water for injection was added to this solution, and the mixture was mixed under stirring. To the obtained solution, 0.024 mol / L hydrochloric acid or 0.025 mol / L sodium hydroxide was added to adjust the pH to about 6, and distilled water for injection was added to make the total amount 1L. 2 mL of this solution was dispensed into 1 ampoule to obtain an ampoule formulation. The agatroban ampoule preparation in that case is the following composition.

Formulation purpose Ingredient Name Compounding amount Active ingredient
Dissolution aids
Dissolution aids
pH regulator
pH regulator
solvent Agatrovan
Ethanol anhydride
Dark glycerin
Hydrochloric acid
Sodium hydroxide
Water for injection 10mg
300mg
900mg
Suitable amount
Suitable amount
Suitable amount system 2 ml

Comparative example

The pharmaceutical composition shown as a "comparative composition" in following Table 11, the pharmaceutical composition of Example 6 of Unexamined-Japanese-Patent No. 1-31727 (it shows as a "known composition" in a table) similarly to the said Example 1, and A formulation commercially available in the United States as agatroban (represented as "American commercial formulation" in the table: a mixed solution of 40.0 g of ethanol, 30.0 g of sorbitol, and 20.0 g of distilled water for injection is heated to 50 ° C, and agatroban 10.0 g was added to dissolve, and the viscosity of the formulation obtained by adding 100 ml of water for injection was measured. The results are shown in Table 11. The viscosity at 25 degreeC of a US commercial formulation is 13.8 mPa * s, and this American commercial formulation measured at 30 rpm. In addition, the viscosity measurement in the sample of the viscosity of 20 mPa * s or more was implemented at 15 rpm.

In Table 11, "operability from a syringe" is operability when a solution is drawn into a 10 ml syringe when 21G (gauge) is used as an injection needle (force of finger required and load applied to a finger or palm). Indicates. When using 22G or 23G thinner needles than 21G, since operability falls further, it is preferable that the viscosity of a pharmaceutical composition is 10 mPa * s or less, and is as low as possible.

As shown in Table 11, operability of the well-known composition and the US commercial formulation were both reduced. Moreover, in the high viscosity solution of 20 mPa * s or more, there exists a possibility that a problem may arise in the dispensing process into ampoules, etc. at the time of manufacture, etc. (The filling of an accurate capacity becomes difficult.).

According to the present invention, there is provided a novel pharmaceutical preparation and a pharmaceutical composition comprising, as an active ingredient, a substance selected from the group consisting of the above arginine amides, salts and hydrates thereof. The pharmaceutical preparations and pharmaceutical compositions of the present invention have the advantages of high convenience and safety in the medical field, good storage stability, and simple production.

Claims (55)

Contain 1 mg / mL to 10 mg / mL of agatroban and contain up to 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in solution A pharmaceutical composition comprising a solution containing a phosphorus polyhydric alcohol. 5 mg / ml of agatroban and 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in the solution. Pharmaceutical composition which consists of a solution to make. Contain 1 mg / ml to 10 mg / ml of agatroban and contain up to 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in solution A pharmaceutical composition comprising a phosphorus polyhydric alcohol and composed of a solution in which the production of substances other than the active ingredient after storage and sterilization at 40 ° C. for 6 months is suppressed to 0.2% or less, respectively. 5 mg / ml of agatroban and 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in the solution. The pharmaceutical composition which consists of a solution which suppressed production | generation of substances other than an active ingredient after each heat sterilization and preserve | saved at 40 degreeC for 6 months, respectively 0.2% or less. Contain 1 mg / ml to 10 mg / ml of agatroban and contain up to 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in solution A pharmaceutical composition comprising a phosphorus polyhydric alcohol and composed of a solution having a viscosity of 10 mPa · s or less at a shear rate of 71.6 s ⁻¹ at 25 ° C. 5 mg / ml of agatroban and 25% (w / v) monohydric alcohol and 40% (w / v) to 55% (w / v) dissolution aid in the solution. The pharmaceutical composition which consists of a solution whose viscosity is 10 mPa * s or less at the shear rate of 71.6s- ¹ at 25 degreeC. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition whose content of saccharides in a solution is 25% (w / v) or less. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition wherein the solution is substantially free of sugars. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition which consists of a solution whose pH is 4-7. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition which consists of a solution whose pH is 5-7. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition whose monohydric alcohol is ethanol. 7. The method according to any one of claims 1 to 6, Pharmaceutical composition whose polyhydric alcohol is glycerin. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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