JP7372961B2 - Aqueous pharmaceutical composition containing vitamin D compound - Google Patents

Description

The present invention relates to an aqueous pharmaceutical composition containing a vitamin D compound as an active ingredient.

Preparations containing vitamin D compounds can be used to treat various symptoms associated with abnormal vitamin D metabolism associated with osteoporosis, chronic renal failure, hypoparathyroidism, rickets, osteomalacia, and secondary parathyroid glands under maintenance dialysis. It is sold as a treatment for hyperactivity disorder.

Intravenous dialysis preparations used for the treatment of secondary hyperparathyroidism include Rocaltrol ^{(registered trademark)} injection and Oxarol ^{(registered trademark) injection . (registered trademark)} Note, and all of its successors are currently in ampoule formulations. Additionally, Zemplar ^{(registered trademark)} Injection, which is sold overseas, is a vial preparation.

However, when applied to artificial dialysis lines, prefilled syringe preparations have been desired from the viewpoints of avoiding the risk of contamination during dispensing, dosage errors, and erroneous administration, speedy administration, and improving the labor productivity of medical workers.

On the other hand, injectable preparations containing vitamin D compounds have been studied in the following manner. Since vitamin D compounds are generally chemically unstable, many stabilization methods have been disclosed. Stabilization methods for aqueous solutions used as injections include adding nonionic surfactants for solubilization, as well as antioxidants such as ascorbic acid, or chelating agents to prevent discoloration and discoloration. A formulation that prevents this and is stable even in the presence of oxygen has been disclosed (Patent Document 1, Patent Document 2). Subsequently, in order to avoid discoloration of the water-soluble antioxidant such as ascorbic acid itself, a method was disclosed in which a lipophilic antioxidant was used to prevent oxidation due to exposure to air (Patent Document 3).

Subsequently, a study was conducted to supply the drug in plastic containers or containers with rubber stoppers, taking into consideration the convenience of drug use by medical personnel. When using an olefin polymer container, fat-soluble compounds may be adsorbed and the content of active ingredients may decrease. The solution is to use esters and sugar alcohols or glycerin (Patent Document 4), and the decomposition of the active ingredient that occurs when using a butyl material rubber stopper is avoided by using a halogenated butyl polymer stopper. A method (Patent Document 5) was reported and a vial formulation was developed.

Subsequently, a method for stabilizing an aqueous solution formulation using a prefilled syringe formulation was further disclosed (Patent Document 6, Patent Document 7). These products use a rubber member whose surface is treated with polytetrafluoroethylene (trade name: Teflon ^{(registered trademark)} ) to prevent the adsorption of vitamin D compounds onto the rubber stopper that occurs in containers that use halogenated butyl polymer stoppers. suppressed.

On top of that, in Patent Document 6, by using polyoxyethylene (20) sorbitan oleate or sodium edetate in addition to it, unknown impurities originating from the surface-treated member and specific vitamin D A prefilled syringe formulation that suppresses compound-derived impurities (9-hydroxy-isoform of maxacalcitol) has been disclosed.

Furthermore, Patent Document 7 discloses that solution discoloration due to peeling and salting out of silicone oil applied to the inner wall of a prefilled syringe container can be treated with sugar alcohols (D-mannitol, D-sorbitol), amino sugars (meglumine), or basic amino acids ( Disclosed is a method of suppressing this by adding substances such as L-arginine).

However, in formulations that use gaskets (sometimes called plunger stoppers) or caps, although adsorption of vitamin D compounds can be suppressed by surface treatment of the rubber members, new unknown impurities may be generated. There is. In general, the level of impurity content can often affect the toxicological profile of a composition, so either it does not produce any of the above impurities or it contains more such impurities than previously known. It is desirable to develop more stable solution compositions that produce less.

On the other hand, it is known that in pharmaceuticals containing ED-71, which is one of the vitamin D compounds, isomeric impurities such as tachysterol and trans isomers are generated as impurities derived from ED-71 (Patent Document 8) .

Isomers of vitamin D compounds are generally produced by photo-conversion, but it has also been reported that some vitamin D compounds are produced in the presence of iodine (Non-Patent Document 1).

Patent Document 8 discloses that specific isomers of ED-71, such as the tachysterol form and the trans form, are produced when a solution of ED-71 dissolved in MCT (medium chain fatty acid triglyceride) is stored in a soft capsule. The present invention relates to a method of suppressing the production of impurities by adding an antioxidant.

However, the above method is a technique for suppressing the formation of isomers of ED-71 in an oil solution such as medium-chain fatty acid triglyceride that is in contact with the soft capsule skin, and the vitamin D compound in the aqueous solution formulation that is in contact with the butyl rubber member. is not associated with the formation of isomeric impurities.

JP 05-238936 Tokuhei 8-18990 Special table 2006-502185 JP2001-261579 Special table 2009-525063 JP2015-034142 WO2015-119183 WO2005-074943

Journal of Pharmaceutical and Biomedical Analysis 40 (2006) 850-863

There is a need for a vitamin D compound-containing preparation sealed in a container including a rubber member, which is more stable and safe and in which the generation of impurities is suppressed.
An object of the present invention is to provide a vitamin D compound formulation using a container including a rubber member, which can suppress the production of impurities without losing the vitamin D compound as an active ingredient.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have discovered that the impurities in the preparation caused by contact with rubber members are isomers of vitamin D compounds, and furthermore, the production It was discovered that even if the surface is treated with a fluororesin such as polytetrafluoroethylene, the problem is caused by substances eluted from the rubber member (probably through the polytetrafluoroethylene coating). We have also discovered that the production of these isomeric impurities can be suppressed by adding one or more compounds selected from the group of compounds that have a specific partial structure and have radical scavenging activity to a vitamin D compound-containing preparation. Ta.

This application provides the following inventions.
[1] (A) Vitamin D compound; and (B) the following formula:

At least one compound having a structure represented by one or more of the following as a partial structure and having radical scavenging activity;
An aqueous pharmaceutical composition containing.
[2-1] (A) Vitamin D compound; and (B) the following formula:

[wherein X, Y are independently selected from formyl, -CHR ¹¹ OR ¹² , and -CHR ¹³ NR ¹⁴ R ¹⁵ ;
R ¹ , R ¹¹ and R ¹² are independently a hydrogen atom, C _1-6 alkyl, (C _1-20 alkyl) carbonyl, -P(O)(OH) ₂ and -P(O)(OH)( O ^- );
R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-20 alkyl)carbonyl]
A compound represented by or a salt thereof;

[wherein R ² is a hydrogen atom or C _1-6 alkyl;
R ³ , R ⁴ and R ⁵ are independently selected from a hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl)carbonyl]
A compound represented by or a salt thereof; and

[Wherein, R ⁶ is a hydrogen atom, -O ^- , C _1-6 alkyl, (C _1-20 alkyl) carbonyl, -P(O)(OH) ₂ and -P(O)(OH)(O ^- selected from );
R ⁷ is selected from -O ^- , -OH and C _1-6 alkoxy;
Q ^- is a counter anion or does not exist]
At least one compound selected from the compound represented by or a salt thereof;
The aqueous pharmaceutical composition according to [1], comprising:
[2-2] (A) Vitamin D compound; and (B) the following formula:

[wherein X is selected from formyl, -CHR ¹¹ OR ¹² and -CHR ¹³ NR ¹⁴ R ¹⁵ ;
Y is -CHR ¹¹¹ OR ¹²¹ ;
R ¹ is a hydrogen atom, C _1-6 alkyl or (C _1-20 alkyl)carbonyl;
R ¹¹ is a hydrogen atom or C _1-6 alkyl;
R ¹² is selected from a hydrogen atom, C _1-6 alkyl and (C _1-20 alkyl)carbonyl;
R ¹¹¹ is a hydrogen atom or C _1-6 alkyl;
R ¹²¹ is selected from a hydrogen atom, C _1-6 alkyl and (C _1-20 alkyl)carbonyl;
R ¹³ is a hydrogen atom or C _1-6 alkyl;
R ¹⁴ is a hydrogen atom or C _1-6 alkyl;
R ¹⁵ is a hydrogen atom or C _1-6 alkyl]
A compound represented by or a salt thereof;

[wherein R ² is a hydrogen atom or C _1-6 alkyl;
R ³ is selected from a hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl)carbonyl;
R ⁴ is a hydrogen atom;
R ⁵ is a hydrogen atom]
A compound represented by or a salt thereof; and

[wherein R ⁶ is selected from a hydrogen atom, C _1-6 alkyl and (C _1-20 alkyl)carbonyl;
R ⁷ is -O ^- or C _1-6 alkoxy;
Q ^- is a counter anion or does not exist]
At least one compound selected from the compound represented by or a salt thereof;
The aqueous pharmaceutical composition according to [1] or [2-1], comprising:
[2-3] (A) Vitamin D compound; and (B) the following formula:

[wherein X is selected from formyl, -CHR ¹¹ OR ¹² and -CHR ¹³ NR ¹⁴ R ¹⁵ ;
Y is -CHR ¹¹¹ OR ¹²¹ ;
R ¹ is a hydrogen atom or (C _1-20 alkyl) carbonyl;
R ¹¹ is a hydrogen atom;
R ¹² is a hydrogen atom or (C _1-20 alkyl) carbonyl;
R ¹¹¹ is a hydrogen atom;
R ¹²¹ is a hydrogen atom or (C _1-20 alkyl) carbonyl;
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or C _1-3 alkyl;
R ¹⁵ is a hydrogen atom or C _1-3 alkyl]
A compound represented by or a salt thereof;

[wherein R ² is a hydrogen atom or C _1-3 alkyl;
R ³ is selected from a hydrogen atom, C _1-3 alkyl and (C _1-3 alkyl)carbonyl;
R ⁴ is a hydrogen atom;
R ⁵ is a hydrogen atom]
A compound represented by or a salt thereof; and

[wherein R ⁶ is a hydrogen atom or (C _1-20 alkyl) carbonyl;
R ⁷ is -O ^- or C _1-3 alkoxy;
Q ^- is a counter anion or does not exist]
At least one compound selected from the compound represented by or a salt thereof;
The aqueous pharmaceutical composition according to [1], [2-1] or [2-2], comprising:
[3] (A) a vitamin D compound, and (B) at least one compound selected from the following:
(b-1) Pyridoxine, pyridoxamine, pyridoxal, mono-, di-, and triesters thereof with fatty acids or phosphoric acids having 14 to 20 carbon atoms, and salts thereof;
(b-2) tryptophan and derivatives thereof in which the amino group is converted to a fatty acid amide having 1 to 4 carbon atoms, and salts thereof; and (b-3) carnitine and its combination with a fatty acid having 1 to 20 carbon atoms; The aqueous pharmaceutical composition according to [1] or [2], which contains an ester and a salt thereof.
[4-1] The compound (B) is pyridoxine, pyridoxine dipalmitate, pyridoxine tripalmitate, pyridoxine dicaprylate, pyridoxine phosphate, pyridoxamine, pyridoxal, pyridoxal monophosphate, N-acetyl-L-tryptophan, The composition according to [3], which is selected from N-acetyl-DL-tryptophan, L-carnitine, palmitoyl-DL-carnitine, acetylcarnitine, and salts thereof.
[4-2] The composition according to [3] or [4-1], wherein the compound (B) is used as a hydrate.
[4-3] The compound (B) is pyridoxine hydrochloride, pyridoxine dipalmitate, pyridoxine tripalmitate, pyridoxine dicaprylate, pyridoxine phosphate, pyridoxamine dihydrochloride, pyridoxamine dihydrochloride monohydrate, pyridoxal Hydrochloride, pyridoxal phosphate hydrate, N-acetyl-L-tryptophan, N-acetyl-DL-tryptophan, N-acetyl-L-tryptophan sodium, L-carnitine, palmitoyl-DL-
The composition according to [3], [4-1] or [4-2], which is selected from carnitine and acetylcarnitine.
[4-4] The compound of [3], [4-1] to [4-3], wherein the compound (B) is selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan, and L-carnitine. The composition according to any one of the above.
[4-5] The composition according to [3], wherein the compound (B) is N-acetyl-L-tryptophan.
[5-1] The composition according to any one of [1] to [4], wherein the vitamin D compound is calcitriol or maxacalcitol.
[5-2] The composition according to any one of [1] to [4], wherein the vitamin D compound is calcitriol.
[5-3] The composition according to any one of [1] to [4], wherein the vitamin D compound is maxacalcitol.
[6-1] (A) Maxacalcitol or calcitriol; (B) Pyridoxine hydrochloride, pyridoxine dipalmitate, pyridoxamine dihydrochloride, pyridoxamine dihydrochloride monohydrate, pyridoxal hydrochloride, pyridoxal phosphate ester At least one compound selected from hydrate, N-acetyl-L-tryptophan, N-acetyl-DL-tryptophan, N-acetyl-L-tryptophan sodium, L-carnitine, and acetylcarnitine; and (C) an interface An aqueous pharmaceutical composition containing an active agent.
[6-2] (A) Maxacalcitol or calcitriol; (B) Pyridoxine hydrochloride, pyridoxamine dihydrochloride, pyridoxamine dihydrochloride monohydrate, pyridoxal hydrochloride, N-acetyl-L-tryptophan, N - at least one compound selected from acetyl-DL-tryptophan, sodium acetyltryptophan, L-carnitine, and acetylcarnitine; and (C) a surfactant.
[7-1] The composition according to any one of [1] to [6], which contains the compound (B) in an amount of 0.001 to 10 mg per 1 mL of the aqueous pharmaceutical composition.
[7-2] The compound of (B) is contained in an amount of 0.01 to 5 mg per 1 mL of the aqueous pharmaceutical composition, [1]
The composition according to any one of [6].
[7-3] The composition according to any one of [1] to [6], which contains the compound (B) in an amount of 0.01 to 3 mg per mL of the aqueous pharmaceutical composition.
[7-4] The composition according to any one of [1] to [6], which contains the compound (B) in an amount of 0.1 to 10 mM per mL of the aqueous pharmaceutical composition.
[7-5] The composition according to any one of [1] to [6], which contains the compound (B) in an amount of 1 to 10 mM per mL of the aqueous pharmaceutical composition.
[8] The composition according to any one of [1] to [7], wherein the aqueous pharmaceutical composition is enclosed in a container containing a rubber member.
[9] The composition according to [8], wherein the rubber member is used for a cap and/or a gasket of a container.
[10-1] From [1], the composition further contains an antioxidant selected from dl-α-tocopherol, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid or a salt thereof. 9].
[10-2] The above antioxidant is contained in an amount of 0.001 to 10 mg per mL of the aqueous pharmaceutical composition, [10-
1] The composition described above.
[10-3] The composition according to [10-1], which contains the antioxidant in an amount of 0.001 to 1 mg per mL of the aqueous pharmaceutical composition.
[10-4] The composition according to [10-1], which contains the antioxidant in an amount of 0.01 to 10 mM per mL of the aqueous pharmaceutical composition.
[10-5] The antioxidant is contained in an amount of 0.01 to 1 mM per mL of the aqueous pharmaceutical composition, [10-1
] The composition described.
[10-6] The composition according to any one of [10-1] to [10-5], wherein the antioxidant is ascorbic acid or a salt thereof.
[11-1] The composition according to any one of [1] to [10], which has a pH of about 7.0 to 8.5.
[11-2] The composition according to any one of [1] to [10], which has a pH of about 7.5 to 8.5.
[11-3] The composition according to any one of [1] to [10], which has a pH of about 7.8 to 8.2.
[11-4] The composition according to any one of [1] to [10], which has a pH of about 7.0 to 7.7.
[12] The product according to any one of [1] to [11], which has a profile of a vitamin D compound residual rate of 93% or more and an isomer impurity production rate of 1% or less after storage for one week under light-shielded conditions at 60°C. Composition of.
[13-1] Vitamin D compound and
The formula below:

A step of mixing at least one compound having a structure represented by one or more of the following as a partial structure and having radical scavenging activity, and a step of enclosing the obtained mixture in a container containing a rubber member. A method for producing an aqueous pharmaceutical preparation containing a vitamin D compound sealed in the container.
[13-2] Vitamin D compound and
The formula below:

At least one compound having a structure represented by one or more of A method for producing an aqueous pharmaceutical formulation containing a vitamin D compound.
[13-3] In one embodiment of the above production method, the vitamin D compound is calcitriol or maxacalcitol.
[13-4] In one embodiment of the above production method, the vitamin D compound is maxacalcitol.
[13-5] In one embodiment of the above production method, the vitamin D compound is calcitriol.
[13-6] In one embodiment of the above production method, at least one compound having radical scavenging activity is
(b-1) Pyridoxine, pyridoxamine, pyridoxal, mono-, di-, and triesters thereof with fatty acids or phosphoric acids having 14 to 20 carbon atoms, and salts thereof;
(b-2) tryptophan and derivatives thereof in which the amino group is converted to a fatty acid amide having 1 to 4 carbon atoms, and salts thereof; and (b-3) carnitine and its combination with a fatty acid having 1 to 20 carbon atoms; selected from esters, salts thereof, or hydrates thereof.
[13-7] In one embodiment of the above production method, at least one compound having radical scavenging activity is selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, and L-carnitine.
[13-8] In one embodiment of the above production method, the compound having radical scavenging activity is N-acetyl-L-tryptophan.
[13-9] In one embodiment of the above production method, the compound having radical scavenging activity is added at 0.001 to 10 mg, 0.01 to 5 mg, 0.01 to 3 mg, 0.1 to 10 mM, or 1 to 10 mM per mL of the preparation.
[13-10] In one embodiment of the above production method, the step of adding an antioxidant selected from dl-α-tocopherol, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid or a salt thereof to the preparation. Including further.
[13-11] In one embodiment of the above manufacturing method, the antioxidant is added in an amount of 0.001 to 1 ml per mL of the preparation.
10 mg, 0.001-1 mg, 0.01-10 mM or 0.01-1 mM is added.
[13-12] In one embodiment of the above production method, ascorbic acid or a salt thereof may be further added to the preparation.
[13-13] The above production method may include a step of adjusting the pH of the formulation to 7.5 to 8.5.
[13-14] The above production method may include a step of adjusting the pH of the formulation to 7.8 to 8.2.
[13-15] In one aspect of the above manufacturing method, the rubber member is a polytetrafluoroethylene surface-treated rubber member.
[13-16] In one embodiment of the above manufacturing method, the rubber member or the rubber member surface-treated with polytetrafluoroethylene resin is used for the cap and/or gasket of the container.
[14-1] The following formula for the vitamin D compound-containing pharmaceutical composition:

A method for suppressing the production of isomeric impurities of a vitamin D compound in the pharmaceutical composition, the method comprising adding at least one compound having a structure represented by one or more of the above as a partial structure and having radical scavenging activity. , where the pharmaceutical composition is enclosed in a container containing a rubber member.
[14-2] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the vitamin D compound is calcitriol or maxacalcitol.
[14-3] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the vitamin D compound is maxacalcitol.
[14-4] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the vitamin D compound is calcitriol.
[14-5] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the additive comprises:
(b-1) Pyridoxine, pyridoxamine, pyridoxal, mono-, di-, and triesters thereof with fatty acids or phosphoric acids having 14 to 20 carbon atoms, and salts thereof;
(b-2) tryptophan and derivatives thereof in which the amino group is converted to a fatty acid amide having 1 to 4 carbon atoms, and salts thereof; and (b-3) carnitine and its combination with a fatty acid having 1 to 20 carbon atoms; One or more selected from esters, salts thereof, or hydrates thereof.
[14-6] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the additive is one of pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, and L-carnitine. or more selected.
[14-7] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the additive is N-acetyl-L-tryptophan.
[14-8] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the at least one compound is 0.001 to 10 mg, 0.01 to 5 mg, or 0.01 to 3 mg per mL of the preparation.
, 0.1-10mM, or 1-10mM.
[14-9] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the vitamin D compound is selected from dl-α-tocopherol, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, or a salt thereof. The method further includes adding an antioxidant to the composition.
[14-10] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, the antioxidant is 0.001 to 10 mg, 0.001 to 1 mg, 0.01 to 10 mM, or 0.01 mg per mL of the preparation. ~1 mM added.
[14-11] In one embodiment of the method for suppressing the production of isomeric impurities of the vitamin D compound, ascorbic acid or a salt thereof may be further added to the preparation.
[14-12] The method for suppressing the production of isomeric impurities of the vitamin D compound may include the step of adjusting the pH of the preparation to 7.5 to 8.5.
[14-13] The method for suppressing the production of isomeric impurities of the vitamin D compound may include the step of adjusting the pH of the preparation to 7.8 to 8.2.
[14-14] In one aspect of the method for suppressing the production of isomeric impurities of the vitamin D compound, the rubber member is a polytetrafluoroethylene surface-treated rubber member. [14-15] In one aspect of the method for suppressing the production of isomeric impurities of the vitamin D compound, the rubber member or the rubber member whose surface has been treated with a polytetrafluoroethylene resin is used as a cap and/or a gasket of a container. used in
[15] The following formula for stabilizing a vitamin D compound-containing pharmaceutical composition sealed in a container containing a rubber member:

Use of at least one compound having a structure represented by one or more of the following as a partial structure and having radical scavenging activity.
[16] An aqueous pharmaceutical composition containing (a) maxacalcitol or calcitriol; (b) N-acetyltryptophan or pyridoxine; and (c) polysorbate 80 or polysorbate 20.
[17] The aqueous pharmaceutical composition according to any one of [1] to [5], further comprising (C) a surfactant; and (D) an isotonizing agent.
[18] An aqueous pharmaceutical composition for treating secondary hyperparathyroidism, comprising: (a) maxacalcitol or calcitriol; (b) N-acetyltryptophan or pyridoxine; and (c) polysorbate 80 or polysorbate 20.
The said composition containing.
[19] The aqueous pharmaceutical composition according to [18], wherein (a) is maxacalcitol.
[20] The aqueous pharmaceutical composition according to [18], wherein (a) is calcitriol.
[21] The aqueous pharmaceutical composition according to any one of [18] to [20], wherein (b) is N-acetyltryptophan.
[22] The aqueous pharmaceutical composition according to any one of [18] to [20], wherein (b) is pyridoxine.
[23] The aqueous pharmaceutical composition according to any one of [18] to [22], which contains the above (a) in an amount of 0.1 to 100 μg, 0.1 to 50 μg, or 0.2 to 20 μg per mL of the composition.
[24] The aqueous pharmaceutical composition according to any one of [18] to [22], containing 0.001 to 10 mg, 0.01 to 5 mg, 0.01 to 3 mg, 0.1 to 10 mM, or 1 to 10 mM of the above (b) per mL of the composition. thing.
[25] A prefilled syringe preparation in which the above aqueous pharmaceutical composition or preparation is enclosed in a syringe having a rubber cap and/or gasket.
[26] The above aqueous pharmaceutical composition or preparation may be substantially free of sodium edetate.
[27] Pharmaceutical preparations containing vitamin D compounds,
(b-1) Pyridoxine, pyridoxamine, pyridoxal, mono-, di-, and triesters thereof with fatty acids or phosphoric acids having 14 to 20 carbon atoms, and salts thereof;
(b-2) tryptophan and derivatives thereof in which the amino group is converted to a fatty acid amide having 1 to 4 carbon atoms, and salts thereof; and (b-3) carnitine and its combination with a fatty acid having 1 to 20 carbon atoms; Adding at least one additive selected from the group consisting of esters, salts thereof, or hydrates of any of them; filling a preparation containing the additive into a container containing a butyl rubber member; and a method for suppressing the formation of isomeric impurities of a vitamin D compound in a formulation in a container, the method comprising storing the formulation in a state filled in the container.
[28] The method of [27], wherein the vitamin D compound residual rate in the preparation is 93% or more after storage for one week under 60°C light-shielded conditions.
[29] The method of [27] or [28], wherein the production rate of isomer impurities in the preparation is 1% or less after storage at 60°C under light-shielded conditions for one week.
[30] The isomeric impurities of the vitamin D compound are analogues I, II, IV, and V, which are structural isomers of maxacalcitol obtained by performing reverse-phase HPLC measurement under the conditions described in the examples. , or structural isomers of vitamin D compounds corresponding to analogs thereof (excluding previtamin D forms).

In an aqueous pharmaceutical composition containing a vitamin D compound as an active ingredient, the production of one or more isomeric impurities can be suppressed at the same time without loss of the vitamin D compound.

This is a representative example of HPLC measurement results showing isomers of vitamin D compounds.

The present disclosure will be described in more detail below.
1. vitamin D compound
Vitamin D compounds used in this disclosure include active vitamin _D3 and its derivatives. Examples include, but are not limited to, active vitamin D ₃ such as calcitriol (1,25(OH) ₂ D ₃ ), active vitamin D ₃ derivatives such as maxacalcitol, and preferably maxacalcitol. Examples include sacalcitol. Here, calcitriol is (5Z,7E)-9,10-seco-5,7,10(19)-cholestatriene-1α,3β,25-triol [(5Z,7E)-9,10- seco-5,7,10(19)-cholestatriene-1α,3β,25-triol], and maxacalcitol is -(3-hydroxy-3-methylbutyloxy)-9, 10-secopregna-5, 7, 10(19)-triene-1, 3-diol [(+)-(5Z, 7E)-(1S, 3R , 20S)-20-(3-Hydroxy-3-methylbutyloxy)-9, 10-secopregna-5, 7, 10(19)-triene-1, 3-diol]. In addition, active vitamin D ₃ and its derivatives each include pharmaceutically acceptable salts (alkali metal salts, alkaline earth metal salts, etc.), and hydrates or solvates (alcohol solvates, etc.). is included. In many cases, active vitamin D ₃ and its derivatives are known substances and can be obtained by purchasing commercially available products or by producing them by known methods. For example, calcitriol and the like can be purchased from Nippon Micro Bio Pharma Co., Ltd. and the like. Furthermore, maxacalcitol can be obtained, for example, according to the method described in Organic Process Research & Development, 2005, Vol. 9, pp. 278-287.

In one non-limiting embodiment, the content of vitamin D compound in the aqueous pharmaceutical composition of the present disclosure is, for example, 0.1-100 μg, 0.1-50 μg, 0.1-30 μg, 0.2-20 μg, 0.3-10 μg per mL of composition. It may be selected from 20 μg, 0.5 to 50 μg, 0.5 to 10 μg, 1.0 to 20 μg, etc.

2. Compound with radical scavenging activity The present disclosure provides a new useful additive for pharmaceutical formulations containing vitamin D compounds as an active ingredient (hereinafter referred to as "the additive of the present invention"). ). Specifically, the present inventors discovered that water-soluble compounds such as (1) pyridine derivatives such as pyridoxine, (2) indole derivatives, and (3) carnitine derivatives are combined with the vitamin D compound itself in a vitamin D compound aqueous solution preparation. It has been found that the present invention exhibits an effect of suppressing the formation of isomeric impurities in vitamin D compounds due to eluate derived from contact with the rubber member of a drug container without causing any reaction. Without being bound by theory, the present inventors hypothesize that the radical scavenging activity resulting from the characteristic structures of these water-soluble compounds is responsible for the above-mentioned effects.

In one aspect of the present invention, the additive of the present invention is selected from a group of compounds having a specific partial structure and having radical scavenging activity. Such specific substructures are selected from structures represented by formula (ia) or (ib), (ii) or (iii) below.

The additive of the present invention can have one or more of these structures as a partial structure in its molecule. A compound having a structure represented by one or more of formulas (ia), (ib), (ii), or (iii) as a partial structure refers to a compound in which these partial structures are substituted with various substituents. It also includes compounds in which other structures are bonded.

Furthermore, these compounds may be in the form of pharmaceutically acceptable salts or esters. A compound having an amino group may be in the form of an amide. Salt forms include the above compounds and inorganic or organic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, tartaric acid, glycolic acid, fumaric acid, succinic acid, palmitic acid, trifluoroacetic acid, citric acid, maleic acid). acids, phosphonic acids, sulfonic acids, methanesulfonic acids, sulfamic acids, caprylic acids, etc.), or basic salts (e.g. alkali metal salts such as sodium or potassium salts, e.g. calcium or magnesium salts). alkaline earth metal salts, such as ammonium salts, or, for example, methylamine, dimethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, morpholine, N-methylpiperidine, N-ethylpiperidine, di salts with organic bases such as benzylamine, tris-(2-hydroxyethyl)amine, or basic amino acids). Further examples include salts of pyridine derivatives, indole derivatives, and carnitine derivatives with other acids or bases commonly used in the technical field to which they belong.

Pharmaceutically acceptable esters of the additives of the present invention can be formed at any hydroxyl or carboxy group within the molecule. For example, phosphoric acid ester, carbonic acid alkyl ester, carbamic acid ester, α-acyloxyalkyl ether (e.g., acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, etc.), C _1-6 alkoxymethyl ester (e.g., methoxymethyl), C _{1 -6} alkanoyloxymethyl ester (e.g. pivaloyloxymethyl, phthalidyl ester), C _3-8 cycloalkoxycarbonyloxy C _1-6 alkyl ester (e.g. 1-cyclohexylcarbonyloxyethyl), 1,3-dioxolene-2 -onylmethyl ester (for example, 5-methyl-1,3-dioxolene-2-onylmethyl), C _1-6 alkoxycarbonyloxyethyl ester (for example, 1-methoxycarbonyloxyethyl), and the like.

Specific examples of the additives of the present invention include pyridoxine, pyridoxamine, pyridoxal, tryptophan, carnitine, or any salt, ester, or amide thereof, or any solvate (hydrate or other) thereof. ). Regarding the partial structures of these additives, it is known that partial structure (i) is important for the generation of radicals similar to pyridoxine (J. Phys. Chem. B, Vol. 113, No. 29 , 2009). In addition, the partial structure (ii) was identified because N-acetyltryptophan is known as a radical scavenger, and L-cysteine, which is also known as a radical scavenger, had no effect ( WO2010/038771). Furthermore, the partial structure (iii) is the structure of carnitine itself, and exhibits radical scavenging activity (Ilhami Gulcin. Life Sciences, 78, 803-811, 2006.).

Radical scavenging activity can be measured as follows. For example, the absorption of radical-releasing 1,1-diphenyl-2-picrylhydrazyl (DPPH) at 517 nm can be measured by adding a test compound and observing the decrease in absorption. In addition, the value of the ethanol solution of (R)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), which is a strong radical scavenger, was 100%. can be used as a control. The calculation formula is as follows.

Radical scavenging activity (%) = (ΔDPPH -ΔSample) / (ΔDPPH -ΔTrolox)× 100
In the above calculation, when the radical scavenging activity is 10% or more, it is effective when used as an additive in the present invention, but it is preferably 20% or more, more preferably 40% or more, and 70% or more. More preferred.

In another embodiment, the additive of the present invention may be selected from compounds represented by the following general formulas (iv) to (vi) or salts thereof.

[wherein X, Y are independently selected from formyl, -CHR ¹¹ OR ¹² , and -CHR ¹³ NR ¹⁴ R ¹⁵ ;
R ¹ , R ¹¹ and R ¹² are independently selected from a hydrogen atom, C _1-6 alkyl, (C _1-20 alkyl)carbonyl, and -P(O)(OH) ₂ ;
R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-20 alkyl)carbonyl]
A compound represented by or a salt thereof;

[wherein R ² is a hydrogen atom or C _1-6 alkyl;
R ³ , R ⁴ and R ⁵ are independently selected from a hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl)carbonyl]
A compound represented by or a salt thereof; and

[Wherein, R ⁶ is a hydrogen atom, -O ^- , C _1-6 alkyl, (C _1-20 alkyl) carbonyl, -P(O)(OH) ₂ and -P(O)(OH)(O ^- selected from );
R ⁷ is selected from -O ^- , -OH and C _1-6 alkoxy;
Q ^- is a counter anion or does not exist]
A compound represented by or a salt thereof.

As used herein, "C _1-6 alkyl" means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl , i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl, for example, C _1-4 alkyl and C _1-3 alkyl. Further, in this specification, "C _1-6 alkyl" means methyl, ethyl, n-propyl, i-propyl and cyclopropyl.

In the present specification, "(C _1-20 alkyl)carbonyl" refers to an alkylcarbonyl group [( (C _1-20 alkyl)CO- group], and includes, for example, (C _1-6 alkyl) carbonyl groups such as acetyl and propionyl (where C _1-6 alkyl group is as defined above), as well as carbon It may be an alkylcarbonyl group derived from a medium-chain fatty acid having 5 to 12 carbon atoms, or an alkylcarbonyl group derived from a long-chain fatty acid having 12 or more carbon atoms (for example, a palmitoyl group).

In the present specification, "C _1-6 alkoxy" means an alkyloxy group [-O-(C _1-6 alkyl)] having an alkyl group having 1 to 6 carbon atoms as previously defined as the alkyl moiety, such as , methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1- Includes ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. Examples include C _1-4 alkoxy and C _1-3 alkoxy.

In the present specification, "(C _1-6 alkyl)carbonyl" means an alkylcarbonyl group having the previously defined C _1-6 alkyl group as the alkyl moiety, such as methylcarbonyl (acetyl), ethylcarbonyl, tert- In addition to butylcarbonyl, (C _1-3 alkyl)carbonyl and the like are included.

In this specification, "-O ^- " means an oxygen atom having a monovalent negative charge, and this may form a zwitterion within the molecule or may have a separate counter ion.
In this specification, Q ⁻ means a counter anion, and is not particularly limited as long as it is a counter anion used as an additive for pharmaceuticals. It may be a high anion that forms a salt with multiple cations, or may be absent if a zwitterion is formed within the molecule.

Specific examples of the additives of the present invention include at least one compound selected from:
(1) Pyridoxine, pyridoxamine, pyridoxal, and their mono-, di-, and triesters with fatty acids or phosphoric acids having 14 to 20 carbon atoms, and salts thereof;
(2) Tryptophan, derivatives thereof in which the amino group is converted to a fatty acid amide having 1 to 4 carbon atoms, and salts thereof; and (3) carnitine and its ester with a fatty acid having 1 to 20 carbon atoms, and the like. salt.

Other specific examples of additives of the invention are pyridoxine, pyridoxine dipalmitate, pyridoxine tripalmitate, pyridoxine dicaprylate, pyridoxine phosphate, pyridoxamine, pyridoxal, pyridoxal monophosphate, N-acetyl-L-tryptophan , N-acetyl-DL-tryptophan, L-carnitine, palmitoyl-DL-carnitine and acetylcarnitine, and salts thereof.

The above compounds can be used as hydrates.
Some chemical structures are illustrated.
Pyridoxine dipalmitate (CAS 635-38-1)

Pyridoxine tripalmitate (CAS 4372-46-7)

Pyridoxine phosphate (C ₈ H ₁₂ NO ₆ P, 3 isomers)

Regarding N-acetyltryptophan, what is acetylated is the N in the amino group bonded to the alpha carbon of the amino acid, not the N in the side chain indole ring. For reference, N-acetyl-L-
Shows the chemical structure of tryptophan (CAS 1218-34-4).

In one non-limiting embodiment, specific examples of the additive of the present invention include (1) pyridoxine hydrochloride, (2) pyridoxine palmitate (di, tri), (3) pyridoxine dicaprylate, (4) pyridoxamine. dihydrochloride, (5) pyridoxamine dihydrochloride monohydrate, (6) pyridoxal hydrochloride, (7) pyridoxal phosphate hydrate, (8) N-acetyl-L-tryptophan, (9) N- Examples include acetyl-DL-tryptophan, (10) sodium acetyltryptophan, (11) L-carnitine, and (12) acetylcarnitine.

In yet another non-limiting embodiment, specific examples of the additives of the invention include pyridoxine hydrochloride, pyridoxine palmitate, pyridoxamine dihydrochloride, pyridoxamine dihydrochloride monohydrate, pyridoxal hydrochloride, pyridoxal Examples include phosphate ester hydrate, N-acetyl-L-tryptophan, N-acetyl-DL-tryptophan, sodium acetyltorptophan, L-carnitine, acetylcarnitine, and the like.

In yet another non-limiting embodiment, specific examples of additives of the invention include pyridoxine hydrochloride, pyridoxine dipalmitate, pyridoxine tripalmitate, pyridoxine dicaprylate, pyridoxine phosphate, pyridoxamine dihydrochloride, pyridoxamine Dihydrochloride monohydrate, pyridoxal hydrochloride, pyridoxal phosphate hydrate, N-acetyl-L-tryptophan, N-acetyl-DL-tryptophan, N-acetyl-L-tryptophan sodium, L-carnitine, palmitoyl Examples include -DL-carnitine and acetylcarnitine.

The amount of the additive of the present invention to be used is not particularly limited, but examples include 0.001 to 10 mg, 0.01 to 5 mg, or 0.01 to 3 mg per mL of the aqueous pharmaceutical composition. Further, the molar concentration in the aqueous pharmaceutical composition includes 0.01-100mM, 0.1-50mM, 0.1-30mM, 0.1-10mM, 1-10mM, etc. Alternatively, the amount of the additive of the present invention to be used for the vitamin D compound is, for example, 0.0001 to 20 mg, 0.001 to 10 mg, 0.001 to 6 mg, etc. per 1 μg of the vitamin D compound.

The additives of the present invention can be used alone or in combination of two or more. For example, the effects can be further enhanced by using the above-mentioned compounds alone or in combination, and in some cases by combining them with other conventionally used compounds having radical scavenging ability, and by adjusting the blending amount as appropriate.

3. Solvents and Solubilizing Agents The pharmaceutical compositions of the present disclosure include an aqueous solvent as a solvent for the vitamin D compound. Examples of the aqueous solvent of the present disclosure include commonly used water for injection, sterile saline for injection, and the like. The amount of water in the compositions of the present disclosure is usually at least about 50 to about 99% w/w.

Furthermore, vitamin D compounds generally have low solubility in water. Therefore, the aqueous pharmaceutical composition of the present invention preferably uses a surfactant and, if desired, a solubilizing agent in addition to the aqueous solvent.

As the surfactant, those used in general liquid preparations for injection can be used, and examples thereof include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil derivatives, sorbitan fatty acid Examples include esters, glycerin fatty acid esters, propylene glycol fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene alkyl ethers, sucrose fatty acid esters, etc., preferably polyoxyethylene hydrogenated castor oil derivatives, polyoxy Examples include ethylene sorbitan fatty acid esters. Polyoxyethylene hydrogenated castor oil derivatives are not particularly limited, and examples include polyoxyethylene hydrogenated castor oil 60 (HCO-60). Polyoxyethylene sorbitan fatty acid esters are not particularly limited, but include, for example, polyoxyethylene (20) sorbitan oleate (polysorbate 80), polyoxyethylene sorbitan monolaurate (20E.O.; polysorbate 20), etc. can be mentioned. The amount of surfactant to be used is not particularly limited, but examples include 0.01 to 5 mg, 0.05 to 2 mg, 0.1 to 10 mg, 0.1 to 3 mg, etc. per 1 mL of the pharmaceutical composition. Alternatively, examples thereof include 0.001 to 0.5% by weight, 0.005 to 0.2% by weight, 0.01 to 0.3% by weight, 0.05 to 1% by weight, etc., based on the weight of the entire pharmaceutical composition.
Examples of the solubilizing agent include alcohols such as ethanol, polyhydric alcohols such as polyethylene glycol, and the like. These solubilizing agents can be used alone or in combination of two or more, but preferably absolute ethanol is used. The content of the solubilizing agent in the aqueous pharmaceutical composition of the present invention is not particularly limited, but for example, 0.01 to 100 μL/mL, 0.05 to 50 μL/mL, 0.2 to 10 μL/mL, 0.5 ~5 μL/mL, etc.

4. Route of Administration For the pharmaceutical compositions of the present disclosure, the intended route of administration is suitably parenteral, ie, by injection into the animal or human body. Said routes include intravenous, intramuscular and subcutaneous administration, with intravenous administration being particularly suitable for the compositions of the present disclosure for use in connection with, for example, secondary hyperparathyroidism. .

However, wherever relevant, the compositions of the present disclosure may be suitable for use by other routes of administration, such as oral, topical or nasal routes. In such cases, the person skilled in the art can make any necessary adjustments with respect to the concentration of active ingredient and other ingredients contained in the composition.

Compositions of the present disclosure are typically provided as aqueous solutions. However, in certain cases, for example in connection with administering the compositions by topical or oral routes, the compositions of the present disclosure include liquid compositions that may be provided in the form of solutions or gels.

5. Other Ingredients The aqueous pharmaceutical composition of the present disclosure may contain other active ingredients and/or other additives in addition to the vitamin D compound and the additive having radical scavenging activity.

When the aqueous pharmaceutical composition of the present disclosure is used as an injection, other additives that can be used include those used in general liquid preparations for injection, such as antioxidants, pH adjusters, and Tonicity agents are preferably used.

Examples of antioxidants include water-soluble antioxidants and fat-soluble antioxidants. Examples of water-soluble antioxidants include ascorbic acid or its metal salts, sodium sulfite, sodium pyrosulfite, etc.; examples of fat-soluble antioxidants include tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, Examples include propyl gallate, nordihydroguaiaretic acid, benzotriazole, and 2-mercaptobenzimidazole. In one non-limiting embodiment, examples include tocopherol, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, preferably tocopherol, dibutylated hydroxytoluene, ascorbic acid. The amount of the antioxidant used is not particularly limited, but examples include 0.001 to 10 mg, 0.002 to 5 mg, 0.005 to 0.1 mg, 0.01 to 0.05 mg, or 0.01 to 10 mM, and 0.01 to 1 mM per mL of the aqueous pharmaceutical composition.

The pH of the aqueous pharmaceutical composition of the present disclosure is 5.0 to 9.5, preferably 7.0 to 8.5 to ensure safety for the human body, solubilization and stability of the vitamin D compound in the liquid. It is preferable from the viewpoint of performance etc. Furthermore, depending on the type of vitamin D compound, the pH of the aqueous pharmaceutical composition of the present disclosure may be adjusted as appropriate to 7.5 to 8.5, 7.8 to 8.2, 7.0 to 7.7, etc. can. To adjust the pH of the vitamin D compound-containing solution to the above range, any compound that can be used as a pharmaceutical additive can be used, such as citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, propionic acid, and adipine. organic acids such as gluconic acid, succinic acid, maleic acid, malic acid; inorganic acids such as carbonic acid, boric acid, phosphoric acid, sulfuric acid, hydrochloric acid; potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, carbonic acid pH adjustment can be performed using an alkaline compound such as sodium hydrogen. When adjusting the pH to 7.5 to 8.5, typically a combination of disodium hydrogen phosphate and potassium dihydrogen phosphate or sodium dihydrogen phosphate can be used as a pH adjusting agent.

Examples of the tonicity agent include salts such as sodium chloride, sugars such as glucose, and the like. In an aqueous solution formulation, the tonicity agent may be added in an amount that provides the same osmotic pressure as body fluids or physiological saline.

In addition to the above ingredients, the above aqueous solution formulation contains other ingredients such as soothing agents (benzyl alcohol, lidocaine, procaine, etc.) and preservatives (paraoxybenzoic acid, chlorobutanol, benzalkonium chloride, thimerosal, etc.). It may be included.

The aqueous pharmaceutical composition of the present invention can optionally contain a pharmaceutically acceptable carrier or excipient.

6. Pharmaceutical Container The aqueous pharmaceutical composition of the present disclosure is preferably filled into a container. The shape of the container is not particularly limited, but includes, for example, a vial, syringe, bag, bottle, etc., and preferably a syringe. Although the form of this syringe is not particularly limited, for example, it may be a prefilled syringe filled with a liquid preparation. The material of the container is not particularly limited, and examples thereof include glass containers and plastic containers. Such containers may have a cap and/or a gasket.

Examples of the cap and/or gasket include thermoplastic elastomer, butyl rubber, halogenated butyl rubber, butadiene rubber, isoprene rubber, and the like. Common materials are rubbers such as butyl rubber, chlorinated butyl rubber, butadiene rubber, isoprene rubber, etc.

The term "container containing a rubber member" in the present disclosure refers to the container described above with a rubber member attached thereto. One specific embodiment thereof is a container in which a rubber member is used for a cap and/or a gasket (plunger stopper).

Further, although not particularly limited, the cap and/or gasket may be surface-treated with a fluororesin. The fluororesin used for surface treatment is not particularly limited, but includes, for example, Teflon ^{(registered trademark)} , and more specifically, polytetrafluoroethylene (PTFE), tetrafluoroethylene/peroxide, etc. Fluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), tetrafluoroethylene/ethylene copolymer (ETFE), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene ( PCTFE), chlorotrifluoroethylene/ethylene copolymer (ECTFE), etc., and polytetrafluoroethylene (PTFE), tetrafluoroethylene/ethylene copolymer (ETFE), etc. The benefits of the present disclosure are significant when the aqueous pharmaceutical composition of the present disclosure is filled into a container and can come into direct contact with the cap and/or gasket.

7. Preparation of vitamin D compound-containing solution The method for preparing the aqueous pharmaceutical composition of the present disclosure is not particularly limited, and any method that does not cause decomposition or alteration of the vitamin D compound and other components contained in the liquid may be used. It may be prepared by any method. As a typical example, the following method can be mentioned.

First, a vitamin D compound is dissolved in a surfactant while heating if necessary. Alternatively, the vitamin D compound may be dissolved in a small amount of ethanol, and the solution may be added to the surfactant solution and stirred. At this time, it is preferable to carry out the process under an inert gas atmosphere.

Next, the above-mentioned surfactant solution of the vitamin D compound is added to distilled water for injection, and at the same time, the additive of the present invention and desired antioxidants, tonicity agents, preservatives, buffers, etc. are added, and inert Stir and dissolve under gas atmosphere.

Next, the obtained solution is further adjusted to the desired volume with distilled water for injection, this solution is filtered or sterile-filtered under an inert gas atmosphere, and the desired amount is filled into a sterile/dry container. The aqueous pharmaceutical composition of the present disclosure is obtained by heat sterilization. Note that, if necessary, the solution may be adjusted to a desired pH before or after adjusting the desired volume with distilled water for injection. Further, it is preferable that the distilled water for injection used be previously subjected to deaeration, nitrogen bubbling, boiling treatment, etc. to reduce the amount of dissolved oxygen.

8. Usage form The usage form of the aqueous pharmaceutical composition of the present disclosure is not particularly limited, but for example, the aqueous pharmaceutical composition of the present disclosure may be used as it is, the aqueous pharmaceutical composition of the present disclosure may be used after being diluted, or the aqueous pharmaceutical composition of the present disclosure may be used after being diluted. A lyophilized product of the disclosed aqueous pharmaceutical composition may be redissolved (ie, reconstituted) in water or the like and used. The aqueous pharmaceutical composition of the present disclosure is preferably used as an injectable preparation for use in therapy, for example. Diseases to be treated are not particularly limited, but include, for example, secondary hyperparathyroidism. When administering the aqueous pharmaceutical composition of the present disclosure to a patient, the vitamin D compound may be administered in an amount of 0.1 to 30 μg or 0.5 to 20 μg per dose.

9. Isomeric Impurities of Vitamin D Compounds The additives of the present invention inhibit the formation of one or more isomeric impurities in the aqueous pharmaceutical compositions of the present disclosure without loss of vitamin D compounds. be able to.

It is preferable that the vitamin D compound residual rate in the preparation is 93% or more after storage for one week under 60° C. light-shielded conditions. Furthermore, it is preferable that the production rate of isomer impurities in the preparation is 1% or less after storage for one week under light-shielded conditions at 60°C.

Specific examples of isomeric impurities in vitamin D compounds include structural isomers (analogs) of maxacalcitol found by performing reversed-phase HPLC measurements under the conditions described in the examples, or structural isomers of maxacalcitol. It is a structural isomer of another vitamin D compound corresponding to the body (excluding previtamin D form).

In one embodiment, a representative example of an isomeric impurity of maxacalcitol is Analog IV. In another embodiment, representative examples of isomeric impurities of maxacalcitol are analogs II and IV. In yet another embodiment, representative examples of isomeric impurities of maxacalcitol are Analogs I, II, IV and V.

The present disclosure will be described in more detail below based on Examples, but the present disclosure is not limited to these Examples.
Measurement of maxacalcitol residual rate
In each Example, reverse phase HPLC measurements were performed under the following conditions, and the maxacalcitol concentrations before and after storage were calculated. The ratio (residual rate: %) to the content of maxacalcitol contained in the preparation immediately after filling was determined.

Reversed phase HPLC
Liquid chromatography device: Waters “e2695”
Mobile phase: 25mmol/L phosphate buffer/MeCN/THF mixture (65:35:5)
Flow rate: 0.7 mL/min
Detection wavelength: 265 nm
Column used: Kinetex 2.6μm C18 100A (phenomenex)
Column temperature: 25°C
Sample temperature: 10°C

Identification of unknown impurities The isomers of vitamin D compounds were designated as "Analogs I, II, III, IV, and V", and RRT (Relative Retention Time) was calculated from these HPLC measurement results. (Table 1, Figure 1).

From the acquired MS spectra (all data not disclosed), it is thought that both are structural isomers with the same molecular weight as the main peak, maxacalcitol (C ₂₆ H ₄₂ O ₄ ) (Table 1-2) .

Analog II is a 9-hydroxy isomer, which is a known impurity (Patent Document 6), and analog III
is the previtamin D form. It is known that vitamin D undergoes a reversible isomerization reaction depending on temperature and time in solution, and forms an equilibrium mixture with previtamin D.

Measurement of isomeric impurity production rate
Proportion of analogue I (%) =A_{Class I} /A_total× 100
Proportion of analogue II (%) =A_{Class II} /A_total× 100
Proportion of analogue III (%) =A_{Class III} /A_total× 100
Proportion of analog IV (%) =A_{Class IV} /A_total× 100
Proportion of analog V (%) =A_{Class V} /A_total× 100

A_Maxa: Peak area value (Maxacalcitol)
A_{Class I} : Peak area value (Analog I)
A_{Class II} : Peak area value (analog II) / 1.1
A_{Class III} : Peak area value (analog III) / 0.5
A_{Class IV} : Peak area value (analog IV)
A_{Class V} : Peak area value (analog V)
A_Others: Peak area value (other)
A_total:A_Maxa +A_{Class I} + A_{Class II} + A_{Class III}+A_{Class IV}+A_{Class V} +A_Others

Example 1: Effect of eluate from rubber stopper on maxacalcitol residual rate and isomeric impurity production rate (1)
57.6 g of disodium hydrogen phosphate dodecahydrate, 1.32 g of potassium dihydrogen phosphate, and 15 g of sodium chloride were each weighed out and put into a graduated cylinder. 2700 mL of distilled water for injection was added to this graduated cylinder and stirred to dissolve the raw materials. After that, add distilled water for injection to make the total volume 3000.
The liquid volume was adjusted to mL, and stirring was performed again to obtain a placebo solution. 0.25 g of polysorbate 20 (manufactured by SEPPIC) was weighed and poured into a new measuring cylinder. 2500 mL of the previously prepared placebo solution was put into this graduated cylinder and stirred to prepare a homogeneous 0.1 mg/mL polysorbate 20-containing placebo solution. Add 100 mL of this placebo solution and 100 chlorinated butyl rubber plunger stoppers (D21-7H: Daikyo Seiko Co., Ltd.) whose top surface is laminated with polytetrafluoroethylene (PTFE) to a glass container, and heat at 60°C. A rubber stopper extract was obtained by storing it in a constant temperature bath for one week under light-shielded conditions.

This extract (Rubber stopper extract ratio: 100%) was diluted 5 times (Rubber stopper extract ratio: 20%) and 10 times (Rubber stopper extract ratio: 20%) using a placebo solution containing 0.1 mg/mL polysorbate 20. : 10%), 20-fold dilution (rubber plug extract ratio: 5%), and 100-fold dilution (rubber plug extract ratio: 1%) to prepare five types of solutions with different rubber plug extract ratios. After adjusting the pH of these solutions, maxacalcitol was added at a final content of 2.5 g/mL to obtain drug solutions (formulations 1-1 to 1-5) shown in Table 2. 1 mL of each of these drug solutions was filled into brown vials.

The five formulations described above were stored for one week in a 60°C constant temperature bath under light-shielded conditions. The maxacalcitol concentration was measured by reverse phase HPLC before the start of storage and after 1 week of storage, and the main peak residual rate (%) after 1 week of storage compared to before the start of storage was calculated. A peak for analog IV was observed in all five drug solutions. This was presumed to be a product resulting from mixing the rubber stopper extract and the maxacalcitol drug solution. The results are shown in Table 3 below.

In formulation 1-1, which had the highest rubber stopper extract concentration, a significant decrease in the main peak residual rate and an increase in the amount of analog IV were observed. On the other hand, as the concentration of rubber stopper extract contained in the solution decreased (100% → 20% → 10% → 5% → 1%), it was confirmed that the main peak residual rate increased and the amount of analog IV produced decreased. Ta.
These results revealed that the eluate from the rubber stopper affected the stability of the vitamin D compound.

Example 2: Effect of adding various radical scavengers to the drug solution in a prefilled syringe containing a rubber member Disodium hydrogen phosphate dodecahydrate 38.4 g, potassium dihydrogen phosphate 0.88 g, sodium chloride 10 g and 0.2 g of polysorbate 20 (manufactured by SEPPIC) were each weighed out and put into a measuring cylinder. 1600 mL of distilled water for injection was added to this graduated cylinder and stirred to dissolve. Thereafter, the liquid volume was adjusted with distilled water for injection so that the total volume was 2000 mL, and the mixture was stirred again. After taking 40 mL of this solution, a specified amount of each radical scavenger was added, and the pH was adjusted to 7.80-8.20 using 1 M sodium hydroxide. Thereafter, maxacalcitol was added to give a final content of 2.5 g/mL to obtain drug solutions (prescriptions 2-2 to 2-7) having the formulations shown in Table 4.

A glass barrel (Hypak SCF 1 mL: BD) with a butyl rubber tip cap (West) is filled with 1 mL of each of the above formulations, and then the top is laminated with polytetrafluoroethylene (PTFE) and made of chlorinated butyl rubber. Jar stopper (D21-7H: Daikyo Seiko Co., Ltd.)
A prefilled syringe preparation was obtained.

The formulations 2-1 to 2-7 were stored for one week in a 60°C constant temperature bath under light-shielded conditions with the chip cap facing upward. The maxacalcitol concentration was measured by reverse phase HPLC before the start of storage and after 1 week of storage, and the main peak residual rate (%) after 1 week of storage compared to before the start of storage was calculated. The results are shown in Table 5 below.

In formulation 2-1, in which a prefilled syringe was filled with a commercially available formulation of Oxarol ^{(registered trademark)} injection (does not contain a radical scavenger), a peak of analog IV was observed. This was presumed to be a product resulting from the reaction between active vitamin D ₃ and the rubber stopper that came into contact with the liquid when the prefilled syringe was filled, or the eluate from the rubber stopper into the drug solution.

However, by adding an appropriate amount of pyridoxine hydrochloride (formulation 2-2), N-acetyl-DL-tryptophan (formulation 2-3) or L-carnitine (formulation 2-4), the content of maxacalcitol can be reduced. It has become clear that it is possible to reduce the amount of analog IV while maintaining the same level.

On the other hand, addition of Trolox (formulation 2-5) suppressed the production of analog IV, but a significant decrease in maxacalcitol content was observed. Therefore, it cannot be said that simply high radical scavenging activity alone contributes to the stabilization of vitamin D compounds.

In addition, DL-aspartic acid (Formulation 2-6) and N-acetyl-L-cysteine (Formulation 2-7), which are the same amino acids as N-acetyl-DL-tryptophan (Formulation 2-3), which have been shown to be effective, In addition, a decrease in the maxacalcitol content and an increase in the amount of analog IV were observed.

It is widely known that the reactivity of amino acids largely depends on their own side chains. From these results, it was considered that the effect of N-acetyl-DL-tryptophan shown in Formulation 2-3 was due to the contribution of the indole ring within the molecule.

Furthermore, from a comparison of the residual rate of maxacalcitol and the amount of analog IV, the rubber stopper extraction ratio 5% (×20) solution (Formulation 1-4, Example 1) is equivalent to Formulation 2-1 filled in a prefilled syringe. It was thought that the drug solution contained a large amount of eluate from the rubber stopper. Therefore, this rubber stopper extraction ratio was set as the evaluation system from now on.

Example 3: Effects of various additives 76.8 g of disodium hydrogen phosphate dodecahydrate, 1.76 g of potassium dihydrogen phosphate, and 20 g of sodium chloride were each weighed and put into a measuring cylinder. 3800 mL of distilled water for injection was added to this graduated cylinder and stirred to dissolve the raw materials. Thereafter, the liquid volume was adjusted with distilled water for injection so that the total volume was 4000 mL, and stirring was performed again to obtain a placebo solution. 5.0 g of polysorbate 80 (manufactured by SEPPIC) was weighed and poured into a new graduated cylinder. 2500 mL of the previously prepared placebo solution was placed in the graduated cylinder and stirred to prepare a homogeneous 2 mg/mL polysorbate 80-containing placebo solution. Add 100 mL of this placebo solution and 100 chlorinated butyl rubber plunger stoppers (D21-7H: Daikyo Seiko Co., Ltd.) whose top surface is laminated with polytetrafluoroethylene (PTFE) to a glass container, and heat at 60°C. A rubber stopper extract was obtained by storing it in a constant temperature bath for one week under light-shielded conditions.

This extract was diluted 20 times (rubber stopper extract ratio: 5%) using a placebo solution containing 2 mg/mL polysorbate 80. By adding specified amounts of additives to these solutions, adjusting the pH, and then adding maxacalcitol to a final content of 2.5 g/mL, drug solutions of Formulation 3-1 to Formulation 3-4 shown in Table 6 can be obtained. I got it. 1 mL of each of these drug solutions was filled into brown vials.

The above four formulations (formulations 3-1 to 3-4) were stored for one week in a 60°C constant temperature bath under light-shielded conditions. The maxacalcitol concentration was measured by reverse phase HPLC before the start of storage and after 1 week of storage,
The residual rate (%) of maxacalcitol after one week of storage was calculated compared to before the start of storage. The results are shown in Table 7 below.

It has become clear that by adding an appropriate amount of N-acetyl-DL-tryptophan (Formulation 3-2) or pyridoxine hydrochloride (Formulation 3-3), the analog IV content can be reduced to 0.15% or less.
It was also shown that the addition of N-acetyl-DL-tryptophan can also suppress the production of 9-hydroxyisomer (analog II).

On the other hand, when we investigated sodium edetate (Patent Document 6), which has been reported to have a stabilizing effect on active vitamin _D3 (formulation 3-1), the amount of analog IV was reduced to a level below the detection limit. On the other hand, a decrease in the residual rate of maxacalcitol was observed. It was also revealed that the addition of sodium edetate also increased the amount of 9-hydroxyisomer (analog II), a known impurity, produced.

Therefore, in order to suppress the effect of eluate from the rubber stopper on active vitamin _D3 , it is most effective to add a radical scavenger such as pyridoxine hydrochloride or N-acetyl-DL-tryptophan. it is conceivable that.

Claims (12)

maxacalcitol, a surfactant, a solubilizing agent, at least one compound having radical scavenging activity, a pharmaceutically acceptable carrier, and an aqueous solvent. A method for producing a toll-containing aqueous pharmaceutical formulation, comprising:
The production method, wherein the at least one compound having radical scavenging activity is selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, N-acetyl-L-tryptophan or a salt thereof, and L-carnitine . mixing maxacalcitol, a surfactant, a solubilizing agent, at least one compound having radical scavenging activity, a pharmaceutically acceptable carrier, and an aqueous solvent;
A method for producing an aqueous pharmaceutical formulation containing maxacalcitol enclosed in a container containing a rubber member, the method comprising the step of encapsulating the obtained mixture in a container containing a rubber member,
The production method, wherein the at least one compound having radical scavenging activity is selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, N-acetyl-L-tryptophan or a salt thereof, and L-carnitine . The manufacturing method according to claim 1 or 2, further comprising the step of adjusting the pH of the formulation to 7.5 to 8.5. A method for suppressing the production of isomeric impurities of maxacalcitol in an aqueous pharmaceutical preparation containing maxacalcitol, the method comprising adding a radical scavenger to the preparation, the method comprising:
The method, wherein the radical scavenger is selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, N-acetyl-L-tryptophan, and L-carnitine . Adding at least one radical scavenger selected from pyridoxine hydrochloride, N-acetyl-DL-tryptophan or a salt thereof, N-acetyl-L-tryptophan, and L-carnitine to an aqueous pharmaceutical formulation containing maxacalcitol. thing,
maxacalcitol in the formulation in the container, comprising: filling the formulation containing the at least one radical scavenger into a container containing a butyl rubber member; and storing the formulation in the container. A method for suppressing the formation of isomeric impurities. The method according to claim 5 , wherein the residual rate of maxacalcitol in the preparation is 93% or more after storage for one week under light-shielded conditions at 60°C. The method according to claim 5 or 6 , wherein the production rate of maxacalcitol isomer impurities in the preparation is 1% or less after storage for one week under light-shielded conditions at 60°C. 8. The isomer impurities are analogues I, II, IV, and V, which are structural isomers of maxacalcitol obtained by performing reversed-phase HPLC measurement under the conditions described in the examples. Method. The method according to any one of claims 1 to 8 , wherein the formulation contains 0.1 to 50 μg of maxacalcitol per mL of the formulation. 10. The method according to claim 9 , wherein the at least one compound having radical scavenging activity or radical scavenger is added in an amount of 0.01 to 5 mg or 0.1 to 10 mM per mL of the preparation. The method according to any one of claims 1 to 10 , wherein the aqueous pharmaceutical formulation containing maxacalcitol is a prefilled syringe formulation enclosed in a syringe having a rubber cap and/or gasket. 12. The method according to claim 11 , wherein the maxacalcitol-containing aqueous pharmaceutical preparation is a therapeutic agent for secondary hyperparathyroidism.

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