JP2021178830A - Stable liquid pharmaceutical preparation containing teriparatide or salt thereof - Google Patents

Abstract

To provide a liquid pharmaceutical preparation that contains teriparatide or a salt thereof and is stable over a long time.SOLUTION: This liquid pharmaceutical preparation contains Component 1 and Component 2, and has a pH greater than 5.0 and less than or equal to 6.0: Component 1) teriparatide or a salt thereof; Component 2) a component that satisfies all of conditions 1)-3) below. Condition 1) being a pharmaceutical additive. Condition 2) being an organic acid or inorganic acid (acids a) or a salt of these, wherein none of the acids a have a pKa in the pH range 4.0-6.0 and at least one of the acids a has a pKa of less than 4.0. Condition 3) the molecular weight of the acids a being in the range 70-180. The liquid pharmaceutical preparation is stable over a long time, and is extremely useful in the pharmaceutical industry.SELECTED DRAWING: None

Description

The present invention relates to a liquid pharmaceutical preparation containing teriparatide or a salt thereof.

PTH (parathyroid hormone), along with calcitonin and vitamin D, is a hormone involved in the regulation of blood calcium concentration.

As for PTH peptide, which is a bioactive equivalent of natural PTH, PTH peptide-containing lyophilized preparations and PTH peptide-containing liquid preparations are also known (Patent Documents 1 and 2). Further, a method for improving the stability of a bioactive peptide containing PTH or the like by irradiation sterilization with radiation or the like is also known (Patent Document 3). Further, a teriparatide-containing liquid pharmaceutical composition having excellent stability is also known (Patent Document 4). A prefilled syringe formulation of teriparatide is also known (Patent Document 5). Alternatively, a pharmaceutical preparation containing a liquid pharmaceutical composition containing human PTH (1-34) (teriparatide) as an active ingredient and having excellent storage stability is also known (Patent Document 6).

On the other hand, sodium edetate, glycine, thioglycolic acid, cysteine hydrochloride, N-acetyl-L-cysteine (NAC), histidine L-hydrochloride, cysteine, methionine, sodium thiosulfate, sodium hydrogen sulfite, sodium pyrosulfate, hydrogen phosphate. Stabilizers of sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ascorbic acid, pyruvate, sodium pyruvate, vitamin E (ie, tocopherols such as α-tocopherol), derivatives of vitamin E (eg tocopherol acetate) It has also been reported that it is used as (Patent Documents 7 to 11).

Japanese Unexamined Patent Publication No. 5-306235 Japanese Unexamined Patent Publication No. 2004-010511 JP-A-2007-186466 International Publication No. 2019/059302 Japanese Unexamined Patent Publication No. 2018-188399 Japanese Unexamined Patent Publication No. 2019-156805 Japanese Patent Application Laid-Open No. 2003-192583 Japanese Patent Application Laid-Open No. 2003-212772 Special Table 2017-505331 Special Table 2016-503058 Gazette Japanese Unexamined Patent Publication No. 11-209288 Special Table 2001-525372A

Teriparatide® Subcutaneous Injection 56.5 μg Package Insert (Revised November 2019 (2nd Edition), Revised June 2019 (1st Edition)) Teriparatide (registered trademark) Subcutaneous injection 28.2 μg Autoinjector package insert (created in September 2019 (1st edition)) Forteo® Subcutaneous Injection Kit 600 μg Package Insert (Revised April 2019 (1st Edition)) Netsu Sokuktei 39 (2) 2012, The Japan Society of Calorimetry and Thermal Analysis 47 Takai et al., Peptide Chemistry 1979, (1980), pp.187-192 Merrifield, Advances In Enzymology, (1969), Vol.32, pp.221-296 Sung et al., Journal of Biological Chemistry, (1991), Vol.266, No.5, pp.2831-2835 Robinson et al., Proc. Natl. Acad. Sci. USA, (2001), Vol.98, No.8, pp.4367-4372 Journal of Biological Chemistry, (1991), Vol.266, No.33, pp.22549-22556 ARCHIVES OF BIOCHEMISTRY, (1972), Vol.150, pp.782-785 MOLECULAR PHARMACOLOGY, (2015), Vol.87, pp.766-775 Biotechnology, Vol. 95, No. 8, pp. 476-479 Endocrinology, (1969), vol.85, pp.801-810 Journal of the Crystallographic Society of Japan (1998), vol.40, pp.272-278 Biochemistry, (1993), vol.32, pp.6050-6057

One of the problems of the present invention is to provide a liquid pharmaceutical preparation containing teriparatide or a salt thereof and stable for a long period of time. In particular, it is an object of the present invention to provide a liquid pharmaceutical preparation containing teriparatide or a salt thereof whose stability is greatly improved at a pH of 4.0 or more and 6.0 or less. Further, a method for preserving the liquid pharmaceutical product, a method for producing the liquid pharmaceutical product, a method for stabilizing teriparatide or a salt thereof in the liquid pharmaceutical product, and a method for suppressing decomposition of teriparatide or a salt thereof in the liquid pharmaceutical product. It is also one of the subjects of the present invention to provide the above.

Since teriparatide or a salt thereof is a peptide, it has an isoelectric point (pI) thereof. Generally, it is known that the pI of teriparatide or a salt thereof is 8.3 to 8.4 (Patent Document 4). For a solution containing teriparatide or a salt thereof, teriparatide or its salt is positively charged as a whole when its pH is lower than pI, and teriparatide or its salt is negatively charged as a whole when its pH is higher than pI. ..

One of the factors affecting the stability of a peptide is electrostatic interaction (also referred to as electrostatic interaction) (Non-Patent Document 4). When the pH of a peptide-containing solution changes across the pI of the peptide, the overall charge state of teriparatide or its salt is reversed (positive → negative or negative → positive), resulting in stability of the peptide. It is thought that it may make a big change.

An organic acid or an inorganic acid or a salt thereof, the acid between pH 4.0-6.0 ("pH 4.0-6.0" means "pH 4.0 or more and 6.0 or less"). Organic acids or inorganic acids having no dissociation constant (pKa) or salts thereof do not have a significant change in their ionized state as a whole in the range of pH at least pH 4.0 to 6.0 in the solution. Similarly, in a solution containing teriparatide or a salt thereof that does not have pI in the same range, the pH does not change across pI even if the pH in the solution is changed between pH 4.0 and 6.0. Therefore, the charged state does not change significantly as a whole.

Under these circumstances, the present inventors include a specific acidic additive among organic acids or inorganic acids having no pKa between pH 4.0 to 6.0 or salts thereof, and teriparatide or a salt thereof. It was found that one index of the stability of teriparatide or a salt thereof is non-linearly improved with respect to an increase in pH in the pH range of 4.0 or more and 6.0 or less by adding to the liquid preparation. The present invention has been completed.

That is, the present invention includes the following.

[1] A liquid pharmaceutical product containing component 1 and component 2 and having a pH of more than 5.0 and 6.0 or less;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.
[2] A liquid pharmaceutical product containing component 1 and component 2 and having a pH of 4.0 or more and 6.0 or less;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 4) Condition 1) Pharmaceutical additive Condition 2) Organic acid (acid a) or its salt, acid a Of the pKa, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, which is an organic acid or a salt thereof Condition 3) Acid The molecular weight of a is in the range of 70 to 180. Condition 4) The acid a is a carboxylic acid having a cyclic group.
[3] A liquid pharmaceutical product containing component 1 and component 2 and having a pH of 4.0 or more and 6.0 or less;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 4) Condition 1) Pharmaceutical additive Condition 2) Inorganic acid (acid a) or its salt, acid a Of the pKa, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, which is an inorganic acid or a salt thereof Condition 3) Acid The molecular weight of a is in the range of 70 to 180. Condition 4) Acid a is an inorganic acid containing a sulfur atom.
[4] The liquid pharmaceutical preparation according to any one of [1] to [3], wherein teriparatide or a salt thereof is teriparatide acetate.
[5] The liquid pharmaceutical preparation according to any one of [1] to [4], wherein the content of teriparatide or a salt thereof per single dose is 28.2 μg in terms of teriparatide.
[6] The liquid pharmaceutical preparation according to any one of [1] to [5], wherein the mass ratio of component 1 to component 2 is 1:15 or more.
[7] The liquid pharmaceutical preparation according to [1], wherein the acid a is an organic acid or an inorganic acid in which the acid a is a carboxylic acid, or a salt thereof.
[8] Ingredient 2 is pyruvate, salicylic acid, thioglycolic acid, lactic acid, maleic acid, glycine, alanine, valine, leucine, isoleucine, serine, treonine, cysteine, methionine, aspartic acid, aspartic acid, glutamine, phenylalanine, proline, The liquid pharmaceutical preparation according to [1], which is an organic acid or an inorganic acid selected from the group consisting of sulfite, sulfuric acid, pyrosulfite, and phosphoric acid, or a salt thereof.
[9] The liquid pharmaceutical preparation according to [2], wherein the component 2 is an organic acid or a salt thereof selected from the group consisting of salicylic acid, phenylalanine, tyrosine, and tryptophan.
[10] The liquid pharmaceutical preparation according to [3], wherein the component 2 is an inorganic acid or a salt thereof selected from the group consisting of sulfurous acid, sulfuric acid, and pyrosulfurous acid.
[11] A method for preserving a liquid pharmaceutical product containing component 1 and having a pH of 4.0 or more and 6.0 or less, wherein the liquid pharmaceutical product contains component 2 satisfying all of the following conditions 1) to 3). A method for preserving a liquid pharmaceutical product, which comprises a step of preserving it in a liquid pharmaceutical product.
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.
[12] A method for stabilizing component 1 in a liquid pharmaceutical preparation containing component 1 and having a pH of 4.0 or more and 6.0 or less, and the component 2 satisfying all of the following conditions 1) to 3). A method for stabilizing component 1;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.
[13] A method for suppressing the decomposition of the component 1 in a liquid pharmaceutical preparation containing the component 1 and having a pH of 4.0 or more and 6.0 or less, satisfying all of the following conditions 1) to 3). A method for suppressing decomposition of component 1 including a step of incorporating component 2 into the liquid pharmaceutical product;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.
[14] A method for producing a liquid pharmaceutical product containing component 1 and having a pH of 4.0 or more and 6.0 or less, wherein the liquid pharmaceutical product contains component 2 satisfying all of the following conditions 1) to 3). A method for producing a liquid pharmaceutical product, which comprises a step of incorporating it into a liquid pharmaceutical product;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.

According to the present invention, a liquid pharmaceutical preparation containing teriparatide or a salt thereof and stable for a long period of time is provided. Separately from this, a method for preserving the liquid pharmaceutical product, a method for producing the liquid pharmaceutical product, a method for stabilizing teriparatide or a salt thereof in the liquid pharmaceutical product, or teriparatide or its salt in the liquid pharmaceutical product. A method of suppressing the decomposition of the salt is provided.

It is a figure which shows the relationship between the difference in the residual rate of teriparatide in the presence and absence of sodium salicylate, and pH. The horizontal axis (x) indicates pH, and the vertical axis (y) indicates the residual rate difference Δa (teriparatide residual rate (a2) in the presence of sodium salicylate in the presence of sodium salicylate-teriparatide residual rate (a1) in the absence of sodium salicylate). .. It is a figure which shows the relationship between the difference in the residual rate of teriparatide in the presence and absence of sodium thiosulfate, and pH. The horizontal axis (x) is pH, and the vertical axis (y) is the residual rate difference Δa (teriparatide residual rate (a2) in the presence of sodium thiosulfate in storage for 4 weeks-teriparatide residual rate (a1) in the absence of sodium thiosulfate). Is shown. It is a transcription of the mechanism of the deamidation reaction based on the conventional report described in Non-Patent Document 9. It is a transcription of the transition reaction to the succinimide intermediate in the mechanism of the deamidation reaction described in Non-Patent Document 9. This is an excerpt from the stoichiometric explanation of the transition reaction to a succinimide intermediate in the mechanism of the deamidation reaction described in Non-Patent Document 9.

Hereinafter, the present invention will be described in detail according to specific embodiments. However, the present invention is not bound by the following embodiments, and can be implemented in any embodiment as long as the gist of the present invention is not deviated.

(1) Liquid pharmaceutical product:
In one aspect of the present invention, the liquid pharmaceutical preparation is not particularly limited as long as it is a liquid pharmaceutical preparation containing teriparatide or a salt thereof (component 1) described later. Examples thereof include a preparation for oral administration (oral preparation) and a preparation for parenteral administration, but a preparation for parenteral administration is preferable. Examples of the parenteral preparation include a topical preparation such as an external preparation and a systemic preparation such as an injection, but a systemic preparation is preferable, and an injection is particularly preferable. Specific administration routes for systemic administration include intravenous administration, intramuscular administration, intradermal administration, subcutaneous administration, and the like, but subcutaneous administration is preferable. That is, in one aspect of the present invention, as the liquid pharmaceutical preparation, preferably, a liquid pharmaceutical preparation for subcutaneous administration or a liquid pharmaceutical preparation for injection can be exemplified, and most preferably a liquid pharmaceutical preparation for subcutaneous injection is exemplified.

In one aspect of the present invention, the "pharmaceutical" in a liquid pharmaceutical preparation means a drug used for the prevention / treatment / diagnosis of any disease for mammals (humans, monkeys, rats, etc.). As the liquid pharmaceutical preparation, a liquid pharmaceutical preparation for humans is preferably exemplified.

In one aspect of the present invention, the solvent used for the liquid pharmaceutical preparation is not particularly limited and may be an aqueous solvent or a non-aqueous solvent, but an aqueous solvent is preferable. That is, in one aspect of the present invention, the liquid pharmaceutical preparation is preferably an aqueous pharmaceutical preparation. In one embodiment of the present invention, when the liquid pharmaceutical preparation is a liquid pharmaceutical preparation for subcutaneous administration, a liquid pharmaceutical preparation for injection, or a liquid pharmaceutical preparation for injection for subcutaneous administration, the liquid pharmaceutical preparation is particularly an aqueous pharmaceutical preparation. It is preferable, and it can be prepared, for example, with water for injection or physiological saline. The aqueous solvent may contain various components such as a buffer as long as it does not deviate from the gist of the present invention.

(2) Teriparatide or its salt (ingredient 1):
In one embodiment of the present invention, human PTH (1-34) is the amino acid residue from the first to the 34th amino acid residue in the amino acid sequence of human PTH (1-84), which is a human parathyroid hormone, when viewed from the N-terminal side. It is a peptide represented by a partial amino acid sequence consisting of a group.

In one aspect of the invention, teriparatide means free human PTH (1-34). Teriparatide can also be in the form of salt.

In one aspect of the invention, the salt of teriparatide includes any salt formed by teriparatide and one or more volatile organic acids. Examples of the volatile organic acid include trifluoroacetic acid, formic acid, and acetic acid. The ratio of the free teriparatide and the volatile organic acid to form a salt is not particularly limited as long as the salt is formed. Of these, acetic acid is preferable as the volatile organic acid. That is, in one aspect of the present invention, teriparatide acetate can be preferably exemplified as the salt of teriparatide.

Since teriparatide or a salt thereof (component 1) is a peptide, it has an isoelectric point (pI) thereof. The measurement of pI can be carried out by a method known per se (for example, a method using HPLC or electrophoresis). Generally, it is known that the pI of teriparatide or a salt thereof (component 1) is 8.3 to 8.4 (Patent Document 4).

In one aspect of the present invention, the amount of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation is not particularly limited, but the following can be preferably exemplified. That is, the lower limit is preferably 10 μg or more, more preferably 20 μg or more, 25 μg or more, 27 μg or more, and further preferably 28 μg or more. The upper limit is preferably 100 μg or less, more preferably 90 μg or less, 80 μg or less, 70 μg or less, and further preferably 60 μg or less. Above all, as teriparatide, the content of component 1 is preferably 28.2 μg or 56.5 μg. When the teriparatide to be used is an acetate, an amount including the amount of acetic acid can be exemplified, and when the teriparatide pentaacetate is used, the content of component 1 as the teriparatide acetate is preferably 30.3 μg. Alternatively, the content of component 1 can be 60.6 μg as teriparatide acetate.

In one aspect of the present invention, the content of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation is not particularly limited, but the following can be preferably exemplified. That is, the lower limit is more preferably 25 μg or more, 27 μg or more, and more preferably 28 μg or more. Further, the upper limit is more preferably 80 μg or less, 70 μg or less, and more preferably 60 μg or less. Among them, the dose of component 1 per single dose is preferably 28.2 μg or 56.5 μg as teriparatide. When the teriparatide used is an acetate, the amount including the amount of acetic acid can be exemplified, and when the teriparatide pentaacetate is used, the content of the component 1 as the teriparatide acetate is 30.3 μg per administration. preferable. Alternatively, the content of teriparatide acetate per single dose of component 1 can be 60.6 μg.

In one aspect of the present invention, the concentration of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation is not particularly limited, but the following can be preferably exemplified. That is, the lower limit of teriparatide is preferably 50 μg / mL or more, more preferably 70 μg / mL or more, 80 μg / mL or more, and 100 μg / mL or more. The upper limit is preferably 500 μg / mL or less, more preferably 250 μg / mL or less, 200 μg / mL or less, 180 μg / mL or less, 160 μg / mL or less, and further preferably 150 μg / mL or less. Of these, 100 to 130 μg / mL is preferable, and 112 μg / mL can be most preferably exemplified.

In one aspect of the present invention, teriparatide or a salt thereof (component 1) contained in a liquid pharmaceutical preparation can be produced by a method known per se (for example, the methods described in Non-Patent Documents 5 to 7 and the like).

In one aspect of the present invention, when "teriparatide or a salt thereof (component 1)" is a teriparatide salt, the counter salt produced by the dissociation of the teriparatide salt in the liquid pharmaceutical preparation is regarded as a buffer agent according to the present invention. Not done. Further, the salt is not regarded as "organic acid or inorganic acid or a salt thereof (component 2)" according to the present invention.

(3) Organic acid or inorganic acid or a salt thereof (component 2):
The liquid pharmaceutical preparation according to the present invention has one characteristic in that it contains one or more organic acids or inorganic acids or salts thereof (component 2). In such a liquid pharmaceutical preparation, it is preferable that it can contribute to the stability of the component 1, and above all, it can contribute to the long-term storage stability of the component 1. In another embodiment, the component 2 may contribute to the suppression of the decomposition of the component 1. High storage stability means that when the liquid pharmaceutical product is stored under certain conditions, the content of the component 1 in the liquid pharmaceutical product is maintained, or the configuration of the present invention is not adopted (comparative example or control example). In comparison, it means that the content of component 1 is more maintained. In addition, suppression of decomposition means that when the liquid pharmaceutical product is stored under certain conditions, the content reduction of the component 1 due to the decomposition of the component 1 in the liquid pharmaceutical product is not substantially confirmed or the content is reduced. It means that it is reduced as compared with the case where the configuration of the present invention is not adopted (comparative example or control example).

One or more organic acids or inorganic acids or salts thereof (component 2) according to the present invention are components that satisfy all of the following conditions 1) to 3).

Condition 1) It is a pharmaceutical additive; Condition 2) It is an organic acid or an inorganic acid (acid a) or a salt thereof, and pKa is present in the range of pH 4.0 to 6.0 among the pKa of the acid a. It is an organic acid or an inorganic acid or a salt thereof, and the pKa of at least any one of the acids a is less than 4.0; condition 3) the molecular weight of the acid a is in the range of 70 to 180.

(3-1) Pharmaceutical Additives In the present invention, pharmaceutical additives are also referred to as pharmaceutical additives, which are ingredients other than the active ingredient (teriparatide or a salt thereof) contained in the pharmaceutical product, and the usefulness of the active ingredient and the pharmaceutical product. It is a component used for the purpose of enhancing, facilitating the formulation, stabilizing the quality, or improving the usability, and is a component easily recognized by those skilled in the art. Specifically, the pharmaceutical additives may be those described in the Pharmaceutical Additives Dictionary "Japan Pharmaceutical Additives Association, Yakuji Nippo Co., Ltd. (2016)", and are stabilizers, antioxidants, isotonic agents, etc. Examples thereof include pH adjusters, preservatives, soothing agents, solubilizers, solubilizing agents and the like.

(3-2) Organic Acid In the present invention, the organic acid is a general term for organic compounds having carbon as a main component and having acidic properties. Examples of the organic acid include carboxylic acid, sulfonic acid, and phenols, and carboxylic acid is preferable. The carboxylic acid is an organic acid having at least one carboxy group (-COOH) and can generally be represented as R-COOH (R is a monovalent functional group). An acid having two carboxy groups is sometimes called a dicarboxylic acid, and an acid having three carboxy groups is sometimes called a tricarboxylic acid.

In the present invention, the organic acid preferably has a cyclic group. Of these, a carboxylic acid having a cyclic group is preferable. Here, the cyclic group is a monovalent residue produced by removing one hydrogen atom on the ring-constituting atom constituting the cyclic compound. The cyclic compound is not particularly limited, but a saturated ring compound or an aromatic ring compound is exemplified, and an aromatic ring compound is preferable. The aromatic ring compound may be an aromatic carbocyclic compound or an aromatic heterocyclic compound. That is, the cyclic group may be aryl or heteroaryl. The cyclic compound may be a carbocyclic compound (a ring compound in which the element constituting the ring is carbon) or a heterocyclic compound (a ring in which the element constituting the ring contains both carbon and an element other than carbon). Formula compound). The cyclic compound is preferably a 5- to 7-membered ring, and most preferably a 6-membered ring. The cyclic group may be referred to as a cyclic compound group, or the cyclic compound group may be simply referred to as a cyclic group. For example, an aromatic compound group may simply be referred to as an aromatic ring group.

The cyclic compound may have any one or more hydrogen atoms of its ring-constituting atom substituted with a hydroxyl group, a halogen, an alkyl, and / or an alkenyl. The cyclic compound is not particularly limited, and examples thereof include benzene, thiophene, furan, pyrrole, pyridine, and pyrimidine, and benzene or thiophene is preferable. Specific examples of the cyclic compound group include cyclopentyl, cyclohexyl, hydroxycyclohexyl, cycloheptyl, phenyl, hydroxyphenyl, benzyl, styryl, 2-furyl, 3-thienyl, 4-pyridyl and the like.

Further, in the present invention, the organic acid may be an organic acid which is an amphoteric compound such as an amino acid. Here, the upper limit of the pI of the amino acid is not particularly limited, but 11 or less is exemplified, 10 or less is preferable, 9 or less is more preferable, 8 or less is further preferable, 7 or less is particularly preferable, and 6 or less is most preferable. Further, as another embodiment of the upper limit of the pI of the amino acid, 5 or less is exemplified, preferably less than 5, more preferably less than 4, still more preferably less than 4, and preferably 3 or less. Further, the lower limit of the pI of the amino acid is not particularly limited, but 2 or more is preferable, 3 or more is more preferable, and 4 or more is most preferable. Further, as another embodiment of the lower limit of the pI of the amino acid, more than 6 is exemplified, 7 or more is preferable, and 8 or more is more preferable. PI of 2 or more and less than 4, 2 or more and less than 5, or 6 or more and 11 or less is also exemplified as a preferable embodiment.

In the present invention, the organic acid is in the form of a salt, for example, an alkali metal such as lithium, sodium and potassium, an alkaline earth metal such as calcium and barium, other metals such as magnesium, aluminum, iron and zinc, methylamine and dimethylamine. , It may be in the form of a salt with aliphatic amines such as triethanol, aromatic amines such as aniline and fetishelamine, and heterocyclic amines such as pyrrolidine and piperidine.

In the present invention, the organic acid may be in the form of a solvate, for example, a hydrate, or may be anhydrous. Further, in the present invention, the organic acid can be used alone or in combination.

Organic acids or salts thereof include, for example, pyruvate, benzoic acid, sodium benzoate, ascorbic acid, edetic acid, gallic acid, salicylic acid, sodium salicylate, tartaric acid, thioglycolic acid, sodium thioglycolate, lactic acid, sodium lactate, lactic acid. Calcium, maleic acid, malic acid, sodium malate, L-aspartic acid, potassium L-aspartate, calcium L-aspartate, sodium L-aspartate, citric acid, other amino acids (eg, alanine, glycine, arginine, Metionine, lysine, leucine, cysteine, histidine) or salts thereof can be mentioned. Of these, salicylic acid and sodium salicylate are preferable.

(3-3) Inorganic acid In the present invention, the inorganic acid means an acid containing a non-metal atom other than a carbon atom such as a chlorine atom, a sulfur atom, a nitrogen atom and a phosphorus atom. Examples of the inorganic acid include phosphoric acid, pyrophosphate, perphosphate, sulfuric acid, sulfite, thiosulfate, pyrosulfite, nitrate, nitrite, hydrochloric acid, chloric acid, hypochloric acid, hydrogen peroxide, and hydrogen fluorinated. Examples include acid and persulfate. Among these, an inorganic acid containing a chlorine atom, a sulfur atom, and a phosphorus atom is particularly preferable, and an inorganic acid containing a sulfur atom is most preferable.

In the present invention, the inorganic acid is in the form of a salt, for example, an alkali metal such as lithium, sodium and potassium, an alkaline earth metal such as calcium and barium, other metals such as magnesium, aluminum, iron and zinc, methylamine and dimethylamine. , It may be in the form of a salt with aliphatic amines such as triethanol, aromatic amines such as aniline and fetishelamine, and heterocyclic amines such as pyrrolidine and piperidine.

In the present invention, the inorganic acid may be in the form of a solvate, for example, a hydrate. In addition, the inorganic acid can be used alone or in combination in the present invention.

As the inorganic acid or a salt thereof, for example, hydrochloric acid, sodium chloride, magnesium chloride, zinc chloride, ammonium chloride, calcium chloride, cetylpyridinium chloride, ferric chloride, sulfite, sodium sulfite, sodium hydrogen sulfite, sulfuric acid, sodium hydrogen sulfate, etc. Potassium sulfate, magnesium sulfate, zinc sulfate, potassium aluminum sulfate, oxyquinoline sulfate, thiosulfate, sodium thiosulfate, potassium thiosulfite, pyrosulfite, potassium pyrosulfite, sodium pyrosulfite, bicarbonate, phosphoric acid, sodium monohydrogen phosphate , Sodium dihydrogen phosphate, calcium hydrogen phosphate, potassium dihydrogen phosphate, pyrophosphate, tetrasodium pyrophosphate, sodium formaldehyde sulfiterate.

(3-4) pKa and molecular weight (A) Consideration on the mechanism of the stabilizing effect of the present invention (A-1) Mainly referred to as deamidation and / or aspartic acid residue isomerization (Asp isomerization) of teriparatide or a salt thereof. Consideration on the possibility of stabilizing effect of the present invention through the mechanism of decomposing inhibitory action

The organic acid, the inorganic acid or a salt thereof according to the present invention suppresses the decomposition of the teriparatide or a salt thereof coexisting with the liquid pharmaceutical product during storage of the liquid pharmaceutical product, and the suppression of the decomposition suppresses the increase in pH of the product. (In the present specification, "decomposition suppression is non-linear with respect to an increase in pH" means that the amount of change in the decomposition-suppressing effect with respect to a minute change in pH changes non-linearly with an increase in pH). The scientific mechanism for improvement is unknown. The inventor is not bound by this, but considers the possibility that the following mechanism is working. Here, the decomposition suppressing effect is, for example, the decomposition suppressing effect that can be indicated by the "difference index 1" in the examples and comparative examples of the present specification.

Further, the organic acid or the inorganic acid according to the present invention or a salt thereof suppresses the decomposition of the teriparatide or a salt thereof coexisting with the liquid pharmaceutical product at the time of storage of the liquid pharmaceutical product, and the degree of the decomposition suppression is the pH of the pharmaceutical product. The scientific mechanism that improves with increasing pH (stabilization enhancing effect with increasing pH) is unknown. The inventor is not obsessed with this, but also considers the possibility that the following mechanism is working in this regard as well. Here, the degree of suppression of decomposition is, for example, the degree that can be indicated by the "difference index 2 (%)" in the examples and comparative examples of the present specification.

Here, the difference index 1 and the difference index 2 (%) will be briefly described.
The difference index 1 is Δa, and the following equation:
Δa = [Teriparatide residual rate after storage for a certain period in the presence of component 2 (a2)]-[Teriparatide residual rate after storage for a certain period in the absence of component 2 (a1)]
It is represented by.
The difference index 2 (%) is represented by "difference index 2 (%)" = Δa / (100-a1) × 100 (%).
The denominator "100-a1" means the amount of components other than teriparatide (teriparatide impurities) (strictly speaking, the ratio of teriparatide impurities) after storage for a certain period of time in the absence of component 2, and therefore the numerical value of the denominator is large. It means that it is unstable. Then, taking Examples 2 and 4 described later as an example, when the pH rises, the "100-a1" becomes larger (that is, the higher the pH, the more unstable). Then, the difference index 2 having the "100-a1" as the denominator has a smaller value "as unstable", that is, "as the pH rises", unless the component 2 has a special stabilizing and enhancing effect. The numerical value should be decreasing, and in Comparative Example 2, the difference index 2'decreases as the pH increases. On the other hand, when the component 2 is contained as in Examples 2 and 4, the difference index 2 becomes larger as the pH rises. In the present specification, this is referred to as "stabilization enhancing effect with an increase in pH". The teriparatide impurity may include a deamidated form of teriparatide (N16 → iso-D16, N16 → D16) or an Asp isomer (D30 → iso-D30) described in Patent Document 4.
In this specification, "(b1-b2) / b1 × 100 (%)" is further expressed as a difference index 2'(%). The difference index 2 (%) of "Δa / (100-a1) × 100 (%)" and the difference index 2'(%) of “(b1-b2) / b1 × 100 (%)” are strictly different. .. However, the former focuses on "Δ of deamidated impurities (which may contain deamidated substances (N16 → iso-D16, N16 → D16) or Asp isomers (D30 → iso-D30))", and the latter is ". Focusing on "Δ" of the total of teriparatide deamidated and Asp isomers, both deamidated (N16 → iso-D16, N16 → D16) or Asp isomers (D30 → iso-D30) It can be said that it is a similar evaluation index because it is common in that it focuses on the contained teriparatide impurities.

Conventionally, when a liquid pharmaceutical product containing teriparatide or a salt thereof is stored, multiple decomposition reactions such as deamidation, Asp isomerization, and oxidation are observed for teriparatide or a salt thereof, and stabilization is achieved by suppressing the decomposition. It has been reported that this is achieved (Patent Document 4).

In the same document, the deamidation / Asp isomerization of teriparatide or its salt is enhanced non-linearly or linearly depending on the increase in pH of the liquid pharmaceutical product containing teriparatide or its salt during storage. Has also been reported (Patent Document 4; Table 14-4).

On the other hand, in the same document, the oxidation of teriparatide or its salt (oxidation of the 8th or 18th methionine residue, etc.) is detected or presumed during storage of the liquid pharmaceutical preparation containing teriparatide or its salt, but the preparation. It is considered that the influence of the pH shown by is not shown on these oxidations (Patent Document 4; Tables 15 and 21).

When the organic acid or inorganic acid according to the present invention or a salt thereof is not contained in the liquid pharmaceutical product, the decomposition of the teriparatide or its salt contained in the pharmaceutical product tends to be non-linearly accelerated depending on the increase in pH. (Examples 1 to 4 of the present specification). In light of the above-mentioned disclosure of the same document, the organic acid or inorganic acid according to the present invention or a salt thereof is mainly deamidated and / or Asp isomers of teriparatide or a salt thereof at the time of storage of a liquid pharmaceutical preparation. It is presumed that there is a high possibility that a non-linear stabilizing effect (difference index 1) that depends on the increase in pH and a stabilization enhancing effect (difference index 2) that accompanies the increase in pH are exerted through the decomposing inhibitory effect of chemical acidation. Can be done.

According to the same document, deamide / Asp isomerization was observed for teriparatide or its salt during storage of liquid pharmaceutical preparations containing teriparatide or its salt, and sodium chloride, which is one of the inorganic acid salts, is excellent in its decomposition. However, in the same suppression, the non-linearity depending on the increase in pH is not recognized in the range exceeding pH 5 (Patent Document 4), and the liquid pharmaceutical preparation is prepared without sodium chloride for a certain period of time. Degree of suppression of decomposition by addition of sodium chloride per total increase in deamide form and Asp isomerization after storage (Comparative Example 2, b1 of the present specification) (sodium chloride in the total ratio of deamide form and Asp isomerization) The amount of change b1-b2) compared with the non-addition is not only not recognized as a non-linear increase depending on the increase in pH, but rather decreases depending on the increase in pH (Comparative Example 2 of the present specification, Difference index 2'). Therefore, the organic or inorganic acids or salts thereof according to the present invention are mainly referred to as deamidation and / or Asp isomerization of teriparatide or its salts by a mechanism that is at least partially different from the stabilizing mechanism of sodium chloride. It is considered that there is a possibility that a non-linear stabilizing effect (difference index 1) depending on the increase in pH and a stabilization enhancing effect (difference index 2) accompanying the increase in pH are exhibited through the decomposing action.

(A-2) Consideration on the transition stage to the succinimide intermediate (1)

Both deamidation and Asp isomerization go through succinimide intermediates (Non-Patent Document 9, Non-Patent Document 14). Here, the transition stage to the succinimide intermediate in deamidation will be considered as an example.

Non-Patent Document 9 reports the mechanism of deamidation in a peptide having a small size. Specifically, it is a mechanism based on the conventional report cited in Non-Patent Document 9, which is a reaction deamidated via a succinimide intermediate (scheme I path (a); transcribed in FIG. 3). ..

Further, Non-Patent Document 9 further considers the detailed mechanism of the transition to the succinimide intermediate (SCHEME II; transcribed in FIG. 4), and the transition to the succinimide intermediate (SCHEME I path (a)) is a deamidation reaction. The previous report, which is the rate-determining step of, is quoted (right column on page 22555). Therefore, without being bound by this, one theory is that the organic or inorganic acids or salts thereof according to the present invention are at least part of the stabilizing mechanism of sodium chloride at the transition stage to the succinimide intermediate. It is possible that different mechanisms are operating. Therefore, we will further consider the transition stage to the succinimide intermediate.

In Non-Patent Document 9, one of the conformers (SCHEME II; STRUCTUTE II) is succinimide in light of the fact that many small peptides have a series of rotatable conformers that convert to each other in aqueous solution. Discloses that it has the proper conformation to proceed to the intermediate (right column on page 22555).

And, in Non-Patent Document 9, since the conformational isomers (SCHEME II; STRUCTUTE II) having an appropriate conformation have high energies, (a series of various rotatable conformational isomers that are interconverted). It discloses that the rate of conversion to the conformer (from the body) is very small (ie, in SCHEME III (posted in FIG. 5), the "K" is very small) and the like (left column on page 22556).

According to the formula (2) above, the reaction rate catalyzed by the base is generally determined by determining the reaction temperature, the test peptide, the concentration of the test peptide, the type of the base, and the concentration of the base ([B]). It is also considered that the reaction rate will change depending on the concentration of the base ([B]).

On the other hand, when the organic acid or the inorganic acid according to the present invention or a salt thereof is not contained in the liquid pharmaceutical preparation, the decomposition of the teriparatide or its salt contained in the preparation tends to increase non-linearly depending on the increase in pH. (Examples 1 to 4 of the present specification), but the decomposition does not proceed depending on the hydroxide ion concentration (that is, in Examples 1 to 4 of the present specification, the pH is 4). When the pH is changed from 6 to 6, the hydroxide ion concentration becomes 100 times, but the decomposition rate does not increase to about 100 times according to the change).

In this regard, Non-Patent Document 9 _{touches on the difficulty of interpreting the fact that the phosphate ion concentration and kobs} are not linear, and one possibility is that the reaction rate-determining step is "base-free". It discloses that it has changed to the one (right column on page 22555).

Here, referring to the literature (Non-Patent Document 10) that reports the effect of an increase in pH on the structure of PTH, PTH in which more basic amino acids are present than acidic amino acids is static due to an increase in pH. It limits the electrical interaction, and that limitation allows for additional intramolecular interactions (right column on page 784), and the negative maximum of 222 nm in circular dichroism spectrum measurements increases with increasing pH. It can be understood that (that is, the content of α-helix is increasing).

It has also been reported that in the teriparatide molecule, helices are present at the 3rd to 12th and 17th to 26th positions from the N-terminal (Non-Patent Document 15). Since the asparagine residue is present at the 10th position from the N-terminal, it is considered that if the helix content in teriparatide increases, the ease of deamidation reaction of teriparatide may be affected.

Since teriparatide is human PTH (1-34) and similarly contains more basic amino acids than acidic amino acids, teriparatide or its salts cause structural changes such as secondary structure due to an increase in pH. As a result, for example, it is also possible to consider the possibility that the conversion rate (“K” in the equation (2) above) to a conformation isomer (SCHEME II; STRUCTUTE II) having an appropriate configuration is fluctuating. can.

The difference in the mechanism of stabilization of the organic acid or the inorganic acid or salts thereof and sodium chloride according to the present invention at the transition stage to the succinimide intermediate will depend on the difference in the base species, so to speak, as follows. Repeat the consideration as follows.

(A-3) Consideration on the transition stage to the succinimide intermediate (2)

The acid pHs of the two mineral and organic acid salts (sodium thiosulfate and sodium salicylate) disclosed in the examples herein are 0.6 and 1.6 and 2.81 and 13, respectively. Since it is .4, there is no significant change in the ionized state even if the pH of the environment in which they are placed rises from 4 to 6. That is, during this period, the thiosulfate ion is a substantially divalent anion and the salicylic acid is a substantially monovalent anion, and there is no significant change in the ionization state of both acids.

Further, since the pKa of the acid of the inorganic acid salt (sodium chloride) disclosed in the comparative example of the present specification is less than 1, even if the pH of the environment in which it is placed rises to about 4 to 5, it is in an ionized state. There is no big change in. That is, during this period, the chloride ion is generally maintained in a monovalent state.

Therefore, it is considered difficult to reduce the difference in the stabilization mechanism of the organic acid or the inorganic acid or a salt thereof and sodium chloride according to the present invention to the difference in the electrostatic interaction.

On the other hand, salicylic acid has a benzene ring, and hydrochloric acid and thiosulfuric acid do not have an aromatic ring like the benzene ring. Therefore, it is also considered difficult to reduce the difference in the stabilization mechanism of the organic acid or the inorganic acid or a salt thereof and sodium chloride according to the present invention to the difference in the hydrophobic interaction.

Further, since salicylic acid is an organic acid, thiosulfate is an inorganic acid, and hydrochloric acid is an inorganic acid, it is considered difficult to explain the above-mentioned difference between organic acid and inorganic acid.

By the way, the molecular weights of thiosulfate and salicylic acid are about 110 and about 140, respectively, and the molecular weight of hydrochloric acid is about 40. In terms of molecular weight, thiosulfate and salicylic acid and hydrochloric acid are distinctly different.

Non-Patent Document 9 discloses the possibility that the "molecular size" of the base species is involved in the deamidation reaction. That is, an intermediate (SCHEME) in which a base approaches and interacts with a hydrogen molecule that binds to nitrogen in the backbone of an asparagine residue to a conformational isomer (SCHEME II; STRUCTUTE II) having an appropriate configuration. II; STRUCTUTE III), the base is "bulky" because the side chain that binds to the carbon atom of the residue next to the C-terminal side of the asparagine residue can be a barrier. It discloses that it is not preferable.

In Non-Patent Document 11, the kinase has an N-terminal domain mainly composed of β-sheet and a C-terminal domain composed of α-helix, and they are bound at a hinge region, and "low molecular weight". Many kinase inhibitors have been reported to target the same hinge region (page 766, right column).

Thus, considering that the molecular weight of a molecular species that interacts with a protein or peptide is important, in the present invention, even if the pH rises from 4 to 6, the ionized state does not change significantly. By being an acid or an inorganic acid or a salt thereof and the molecular weight of the acid is within a certain range, for example, in the transition step to the succinimide intermediate in deamidation, the specific effect of the present invention is exhibited. It is rational as one theory to think that it will be obtained.

(B) pKa

One of the characteristics of the organic acid or the inorganic acid (acid a) or a salt thereof according to the present invention is that none of the pKas indicated by the acid a is present in the pH range of 4.0 to 6.0. Due to these characteristics, the acid a becomes an acid in which the ionization state does not change significantly in an environment of pH 4.0 to 6.0.

pKa is one of the indexes for quantitatively expressing the strength of acid, and is also called the acid dissociation constant. It is a numerical value in water at 25 ° C., and is a numerical value in water at 25 ° C. It can be calculated by the method described in 343 (edited by the Chemical Society of Japan, Maruzen Publishing Co., Ltd.). For pKa, a numerical value known in the literature (for example, Science Chronological Table 2013 (desk version), Maruzen Publishing Co., Ltd.) can also be used. For example, the pKa of salicylic acid is 2.81, 13.4, and the pKa of thiosulfate is 0.6, 1.6.

The acid a preferably has at least one of its pKa of less than 4.0, more preferably less than 3. In addition, if the conjugate base of acid a (eg, when acid a is H ₂ SO ₃ (sulfurous acid), the conjugate base is _{H SO 3} ⁻ ), the basicity of the conjugate base may be increased to facilitate the transition to the succinimide intermediate. From the viewpoint that it can be considered that there is, at least one of the pKa is preferably 0 or more, and more preferably 1 or more.

Also, none of the pKa indicated by acid a is present in the pH range of 6.0-7.0, and / or none of the pKa indicated by acid a is present in the range 3.0-4.0. preferable. Due to such characteristics, the acid a can further suppress the change of ionization state in the environment of pH 4.0 to 6.0.

(C) Molecular Weight The organic acid or the inorganic acid (acid a) or a salt thereof according to the present invention is characterized in that the molecular weight of the acid a is within a predetermined range. Due to such characteristics, it is considered that the acid a can exert a non-linear stabilizing effect (difference index 1) depending on the increase in pH and a stabilization enhancing effect (difference index 2) accompanying the increase in pH.

The molecular weight of the acid a can be exemplified to be 180 or less, preferably 170 or less, more preferably 150 or 160 or less, and most preferably 140 or less. The molecular weight of the acid a can be exemplified to be 70 or more, preferably 80 or more, more preferably 90 or 100 or more, and most preferably 110 or more. Thiosulfuric acid has a molecular weight of about 114 and salicylic acid has a molecular weight of about 138.

(D) Preferable Example An organic acid in which none of the pKas is present in the pH range of 4.0 to 6.0, and at least one of the pKas is less than 4.0, and the molecular weight thereof. The following acids can be exemplified as organic acids having a value in the range of 70 to 180.

Further, none of the pKa is an inorganic acid that does not exist in the pH range of 4.0 to 6.0, and at least one of the pKa is an inorganic acid having a pKa of less than 4.0, and the molecular weight thereof is 70 to 180. The following acids can be exemplified as the inorganic acids in the range of.

The pH of the acids of the two types of inorganic acid salts and organic acid salts (sodium thiosulfate and sodium salicylate) disclosed in the examples of the present specification is 0.6, 1.6 and 2.81, respectively. And 13.4, so even if the pH of the environment in which they are placed rises from 4 to 6, there is no significant change in the ionized state. That is, during this period, the thiosulfate ion is a substantially divalent anion and the salicylic acid is a substantially monovalent anion, and there is no significant change in the ionization state of both acids.

Further, since the pKa of the acid of the inorganic acid salt (sodium chloride) disclosed in the comparative example of the present specification is less than 1, even if the pH of the environment in which it is placed rises to about 4 to 5, it is in an ionized state. There is no big change in. That is, during this period, the chloride ion is generally maintained in a monovalent state.

The concentration of the organic acid or the inorganic acid or a salt thereof contained in the liquid pharmaceutical preparation according to the present invention is not particularly limited, but the lower limit is 250 μg / mL or more, 500 μg / mL or more, and 1 mg / mL or more. It is preferable, and more preferably 2 mg / mL or more. On the other hand, the upper limit is preferably 250 mg / mL or less, 100 mg / mL or less, or 25 mg / mL or less, and more preferably 11 mg / mL or less.

In one embodiment of the present invention, when the liquid pharmaceutical preparation contains one or more organic acids or inorganic acids or salts thereof, the mass ratio to the teriparatide or its salt (component 1) (component 1: mass ratio of component 2). ) Is not particularly limited, but the lower limit is preferably, for example, 1: 5 or more, more preferably 1: 8 or more, 1:10 or more, and 1:15 or more, and above all, 1:20 or more. Is the most preferable. On the other hand, the upper limit is, for example, preferably 1: 500 or less, preferably 1: 300 or less, preferably 1: 200 or less, more preferably 1: 100 or less, and 1:80. Most preferably:

In one aspect of the present invention, the "organic acid or inorganic acid or a salt thereof (component 2)" may be the same component as the component of the buffer described later, or may be a different component.

The organic acids or inorganic acids or salts thereof (component 2) in Examples 2 and 4 of the present specification and the contrasting components in Comparative Examples 1 to 3 of the present specification are summarized below.

(4) Buffer:
The liquid pharmaceutical preparation according to the present invention may or may not contain a buffer. Here, the buffer is not particularly limited as long as it can stabilize the pH of the liquid pharmaceutical preparation and is generally used in the pharmaceutical field. The action of keeping the pH constant in this way is called a buffering action, and the scale showing the action is called a buffering ability (Non-Patent Document 12).

When the liquid pharmaceutical product according to the present invention contains a buffering agent, a buffering agent or the like showing an effective buffering range at the pH or a pH in the immediate vicinity thereof can be appropriately selected according to the pH of the liquid pharmaceutical product described later. For example, when adjusting the pH of the liquid pharmaceutical preparation according to the present invention to the range of 4 to 5, an acetate buffer having an effective buffer range of 3.80 to 5.80 can be preferably used.

Further, for example, a wide-area buffer that exhibits a substantially uniform buffering capacity at a wide pH can be prepared by mixing buffer solutions that show pKa different from each other, and such a wide-area buffer may be used.

The liquid pharmaceutical preparation according to the present invention may be a liquid pharmaceutical preparation substantially free of a buffer. In particular, when the pH of the liquid pharmaceutical product according to the present invention is in the range of 4.0 to 6.0, the component 1 tends to be stable as compared with other pH ranges. Therefore, the liquid according to the present invention is found. It is also possible that the pharmaceutical product is substantially free of the buffer.

As the liquid pharmaceutical preparation containing substantially no buffer, a liquid pharmaceutical preparation containing substantially no acetate buffer is preferable. A person skilled in the art can easily understand "substantially" by, for example, referring to a previously reported report (Patent Document 4).

That is, the fact that the buffer is not "substantially" contained here means that, for example, it is placed in a glass container that does not have alkali countermeasures such as decomposition of teriparatide or a salt thereof (component 1) and other additives, and sulfer treatment. Over time due to the components of the drug solution and its reactants, such as the alkali elution of the time, the components eluted into the drug solution from the container or container filled with the drug solution, and the various effects of the external environment during storage on the drug solution. It means that the content of a buffer that cannot suppress the specific pH fluctuation is not regarded as the content.

As an example in which the buffer agent is considered to be "substantially" not contained in the liquid pharmaceutical product, there may be a case where a trace amount of the buffer agent is contained in the liquid pharmaceutical product. The amount may vary depending on the buffer selected, but even if the liquid pharmaceutical formulation contains a buffer having a concentration of, for example, 1 mM or less, preferably 0.5 mM or less, more preferably 0.1 mM or less. Is considered to be "substantially" not included in the liquid pharmaceutical product.

As another example in which the buffer is considered to be "substantially" not contained in the liquid pharmaceutical product, in the embodiment of the liquid pharmaceutical product of the present invention in which the pH is in a specific range, ± 1 from the lower limit and the upper limit of the same range, respectively. In the range of, at least the content of a buffering agent having no buffering ability can be mentioned. For example, in the embodiment of the liquid pharmaceutical preparation of the present invention having a pH of 4 to 6, when a buffer having at least no buffering ability is contained in the pH range of 3 to 7, the liquid pharmaceutical preparation of the present invention is contained. Is considered to be "substantially" free of buffer.

As another example in which the buffer agent is considered to be "substantially" not included in the liquid pharmaceutical product, in the embodiment of the liquid pharmaceutical product of the present invention in which the pH is in a specific range, the pKa ± 1 of the buffer is in the same pH range. Examples thereof include the case where a buffering agent that is not contained in or does not overlap with the liquid pharmaceutical product is contained in the liquid pharmaceutical product. For example, since the pKa of the acetic acid buffer (actually, the pKa of acetic acid) is 4.76, this ± 1 is 3.76 to 5.76, and the pH of the liquid pharmaceutical preparation is more than 5.76. The acetate buffer is considered to be "substantially" absent from the liquid pharmaceutical formulation, even if it contains the acetate buffer.

When the acid component of the buffer added to the liquid pharmaceutical preparation according to the present invention corresponds to the "organic acid or inorganic acid (component 2)" according to the present invention, the buffer is also treated as component 2.

(5) pH:
In one aspect of the present invention, the pH of the liquid pharmaceutical product is not particularly limited, but the pH of the liquid pharmaceutical product can preferably be exemplified as follows. That is, it can be neutral or acidic (pH is 8.0 or less), and the lower limit is, for example, 3.6 or more, 3.8 or more, 4.0 or more, 4.1 or more, 4.2 or more, 4 4.4 or higher, 4.5 or higher, 4.6 or higher, 4.7 or higher, 4.8 or higher, 4.9 or higher, 5.0 or higher, 5.1 or higher, 5.2 or higher, 5.3 or higher, 5 It is preferably 0.4 or more, or 5.5 or more. The upper limit is preferably 7.0 or less, 6.5 or less, 6.4 or less, 6.3 or less, 6.2 or less, 6.1 or less, or 6.0 or less. Above all, it is preferably 6.0 or more, and further, 4.0 or more and 6.5 or less, 4.0 or more and 6.0 or less, 4.5 or more and 6.0 or less, 5.0 or more and 5.0 or more. It is preferably 6.0 or less, or 5.5 or more and 6.0 or less. Here, an embodiment in which "greater than or equal to" related to the lower limit of each pH is set to "excess" and "less than or equal to" related to the upper limit of each pH is set to "less than" is also disclosed. The most preferable pHs include "more than 5.0 and 6.0 or less" and "more than 4.0 and 6.0 or less".

When PTH or a PTH fragment (such as teriparatide) is used as an aqueous solution, its storage stability is poor. Therefore, conventionally, a freeze-dried preparation or a specific stabilizer or preservative such as polyol or m-cresol is used. It has been practiced to use the existing aqueous solution. In addition, since peptides and proteins are generally unstable in an aqueous solution, when making a liquid pharmaceutical preparation, it was common to add a buffer to the preparation to reduce pH fluctuation (non-). See Patent Document 3, Patent Document 12, etc.).

On the other hand, according to a preferred embodiment of the present invention, in a liquid pharmaceutical preparation containing teriparatide or a salt thereof (component 1), by specifying the pH range within the above-mentioned suitable range, a buffering agent can be substantially added to the preparation. It is possible to prepare a liquid pharmaceutical preparation showing long-term stability without containing it. As will be described later, if a specific container is used as a container for filling the liquid pharmaceutical product of the present invention, the stability can be further improved.

The pH of the liquid pharmaceutical preparation of the present invention can be adjusted by a method known per se, for example, using a buffer or a pH adjuster.

(6) Other Ingredients The liquid pharmaceutical preparation according to the present invention contains other ingredients different from those of Ingredient 1 and Ingredient 2, such as stabilizers, antioxidants, tonicity agents, preservatives, soothing agents, and solubilizers. , Dissolution aid, etc. can be appropriately contained.

(7) Method for producing liquid pharmaceutical product In one aspect of the present invention, the method for producing a liquid pharmaceutical product containing component 1 and having a pH of 4.0 or more and 6.0 or less, the following conditions 1) to 3 ) Provided is a method for producing a liquid pharmaceutical product, which comprises a step of incorporating a component 2 satisfying all of the same into the liquid pharmaceutical product.

Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.

Here, the component 1 may be any embodiment disclosed in the above-mentioned "(2) teriparatide or a salt thereof (component 1)", and the component 2 may be the above-mentioned "(3) organic acid or inorganic acid". Alternatively, it may be an embodiment of any one or two or more kinds of components 2 disclosed in "Salts thereof (Component 2)", and the pH of the liquid pharmaceutical preparation as a product is disclosed in "(5) pH". It may be in any embodiment.

The compounding ratio (mass ratio) of the component 1 and the component 2 is not particularly limited, but the lower limit is preferably, for example, 1: 5 or more, and is preferably 1: 8 or more, 1:10 or more, and 1:15 or more. It is more preferable, and most preferably 1:20 or more. On the other hand, the upper limit is, for example, preferably 1: 500 or less, preferably 1: 300 or less, preferably 1: 200 or less, preferably 1: 100 or less, and 1: 80 or less. Is most preferable.

The liquid pharmaceutical preparation of the present invention can be produced by various production methods known per se. Usually, the above-mentioned various components constituting the liquid pharmaceutical preparation of the present invention may be appropriately selected and mixed with an appropriate solvent to dissolve them. During production, other components different from those of component 1 and component 2, such as stabilizers, antioxidants, tonicity agents, preservatives, soothing agents, solubilizers, lysis aids, etc., are appropriately formulated. Can be added.

When the liquid pharmaceutical product according to the present invention is produced as a liquid pharmaceutical product for injection, it is preferably an aqueous liquid pharmaceutical product. In the case of an aqueous liquid pharmaceutical product, it is preferably aseptically treated before administration. When an aseptic technique is adopted as the aseptic treatment, a liquid pharmaceutical preparation can be produced by dissolving each of the weighed raw materials in water for injection or the like and filtering and sterilizing the solution. Water for injection is generally understood as sterile purified water suitable for the exothermic substance (endotoxin) test, and water for injection produced by a distillation method is sometimes referred to as distilled water for injection.

This liquid pharmaceutical product for injection can be further filled and sealed in a container that has been washed and sterilized, and subjected to inspection, packaging, and the like to produce an injection product filled with the liquid pharmaceutical product for injection. Here, examples of the container include ampoules, vials, prefilled syringes, bags, and the like. The material of the container is not particularly limited, and examples thereof include glass and plastic. From the viewpoint of strength, ease of handling, safety and the like, plastic can be preferably exemplified as the material of the container.

(8) Freeze-drying:
The liquid pharmaceutical preparation according to the present invention may include an embodiment of a liquid pharmaceutical preparation reconstituted from a lyophilized preparation. Further, the liquid pharmaceutical preparation of the present invention does not have to be a liquid pharmaceutical preparation reconstituted from a freeze-dried preparation. Conventionally, it has been known that a lyophilized preparation containing teriparatide or a salt thereof is dissolved in physiological saline or the like at the time of use to obtain a liquid pharmaceutical preparation. It may be a redissolved product (preliminary product) of a freeze-dried preparation, or a preparation (preliminarily liquefied) that does not undergo such a freeze-dried preparation.

(9) Stabilization method:
In one aspect of the present invention, the liquid pharmaceutical preparation containing the component 1 can stabilize the component 1 by adding the component 2. As the component 2, one or two or more kinds can be appropriately selected from the above-mentioned organic acid or inorganic acid or salts thereof.

Here, the stabilization of the component 1 is a state such as decomposition of the component 1 (for example, oxidation, deamidation, cleavage, Asp isomerization), denaturation of the component 1, inactivation of the component 1, and precipitation of the component 1. Comprehensively includes suppression / deterrence of the condition enhancement. However, as described above, the organic acid or the inorganic acid or a salt thereof according to the present invention mainly undergoes the deamidation of component 1 and / or the inhibitory action of decomposition such as Asp isomerization during storage of the liquid pharmaceutical preparation. Since it is highly possible that the non-linear stabilizing effect (difference index 1) depending on the increase in pH and the stabilizing enhancement effect (difference index 2) accompanying the increase in pH are exhibited, it can be inferred that the component 1 has a non-linear stabilizing effect. As stabilization, suppression of decomposition of component 1 is preferable, and suppression of deamidation and / or Asp isomerization of component 1 can be more preferably exemplified.

Specifically, in one embodiment of the present invention, it is a method for stabilizing component 1 in a liquid pharmaceutical preparation containing the component 1 and having a pH of 4.0 or more and 6.0 or less, and the following conditions 1). ~ 3) It is possible to present a method for stabilizing the component 1, which comprises a step of incorporating the component 2 satisfying all of the components into the same liquid pharmaceutical preparation.

Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.

Here, the component 1 may be any embodiment disclosed in the above-mentioned "(2) teriparatide or a salt thereof (component 1)", and the component 2 may be the above-mentioned "(3) organic acid or inorganic acid". Alternatively, it may be any one or two or more kinds of component 2 disclosed in "Salts thereof (Component 2)", and the pH of the liquid pharmaceutical preparation may be any aspect disclosed in "(5) pH". It may be there.

Further, the liquid pharmaceutical preparation containing the component 1 can also contain the above-mentioned "(4) buffer". Further, the liquid pharmaceutical preparation containing the component 1 may also contain the above-mentioned "(6) other component" in the component 1.

The decomposition of component 1 can be detected and quantified using, for example, a well-known technique by LC / MS / MS (liquid chromatography / tandem mass spectrometry) (Patent Document 4). The denaturation or inactivation of component 1 can be measured by, for example, a method for measuring the activity of component 1 (Non-Patent Document 13). The precipitate of component 1 can be detected, for example, as a white turbidity that can be observed from the appearance of the liquid pharmaceutical preparation according to the present invention.

Stabilization is performed, for example, when the liquid pharmaceutical product is stored under certain conditions, the content or activity of the component 1 in the liquid pharmaceutical product is maintained, or the configuration of the present invention is not adopted (comparative example or control). It can be confirmed by maintaining the content or activity of the component 1 more than the example).

(10) Decomposition suppression method:
In one aspect of the present invention, the liquid pharmaceutical preparation containing the component 1 can suppress the decomposition of the component 1 by adding the component 2. As the component 2, one or two or more kinds can be appropriately selected from the above-mentioned organic acid or inorganic acid or salts thereof.

Here, the suppression of decomposition of the component 1 comprehensively includes suppression / suppression of states such as oxidation, deamidation, cleavage, and Asp isomerization, or enhancement of the states. However, as described above, the organic acid or the inorganic acid or a salt thereof according to the present invention mainly undergoes the deamidation of component 1 and / or the inhibitory action of decomposition such as Asp isomerization during storage of the liquid pharmaceutical preparation. Since it is highly possible that the non-linear stabilizing effect (difference index 1) depending on the increase in pH and the stabilizing enhancement effect (difference index 2) accompanying the increase in pH are exhibited, it can be inferred that the component 1 has a non-linear stabilizing effect. As the decomposition suppression, the suppression of deamidation and / or Asp isomerization of the component 1 can be preferably exemplified.

Specifically, in one embodiment of the present invention, the component 1 is contained and the pH is 4.0 or more. A method for suppressing the decomposition of the component 1 in a liquid pharmaceutical product having 6.0 or less, which comprises a step of incorporating the component 2 satisfying all of the following conditions 1) to 3) into the liquid pharmaceutical product. It is possible to present a method for suppressing the decomposition of.

Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.

Here, the component 1 may be any embodiment disclosed in the above-mentioned "(2) teriparatide or a salt thereof (component 1)", and the component 2 may be the above-mentioned "(3) organic acid or inorganic acid". Alternatively, it may be any one or two or more kinds of component 2 disclosed in "Salts thereof (Component 2)", and the pH of the liquid pharmaceutical preparation may be any aspect disclosed in "(5) pH". It may be there.

Further, the liquid pharmaceutical preparation containing the component 1 can also contain the above-mentioned "(4) buffer". Further, the liquid pharmaceutical preparation containing the component 1 may also contain the above-mentioned "(6) other component" in the component 1.

The decomposition of component 1 can be detected and quantified using, for example, a well-known technique by LC / MS / MS (liquid chromatography / tandem mass spectrometry) (Patent Document 4).

As for the suppression of decomposition, when the liquid pharmaceutical product is stored under certain conditions, the content reduction of the component 1 due to the decomposition of the component 1 in the liquid pharmaceutical product is not substantially confirmed, or the content reduction is the present invention. It is exemplified that the configuration is reduced as compared with the case where the configuration of is not adopted (comparative example or control example).

(11) Storage method:
As one aspect of the present invention, a method for preserving a liquid pharmaceutical product containing the component 1 and having a pH of 4.0 or more and 6.0 or less, wherein the component 2 satisfying all of the following conditions 1) to 3). It is possible to present a storage method of a liquid pharmaceutical product, which comprises a step of containing and storing the liquid pharmaceutical product in the same liquid pharmaceutical product;
Ingredient 1) Teriparatide or its salt Ingredient 2) Ingredients satisfying all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. , Of the pKa of the acid a, pKa does not exist in the range of pH 4.0 to 6.0, and the pKa of at least any one of the acids a is less than 4.0, an organic acid or an inorganic acid or them. Condition 3) The molecular weight of acid a is in the range of 70 to 180.

Here, the component 1 may be any embodiment disclosed in the above-mentioned "(2) teriparatide or a salt thereof (component 1)", and the component 2 may be the above-mentioned "(3) organic acid or inorganic acid". Alternatively, it may be any one or two or more kinds of component 2 disclosed in "Salts thereof (Component 2)", and the pH of the liquid pharmaceutical preparation may be any aspect disclosed in "(5) pH". It may be there.

Further, the liquid pharmaceutical preparation containing the component 1 can also contain the above-mentioned "(4) buffer". Further, the liquid pharmaceutical preparation containing the component 1 may also contain the above-mentioned "(6) other component" in the component 1.

According to the storage method of the present invention, an inhibitory effect on decomposition of component 1 that occurs during storage of a liquid pharmaceutical preparation, such as oxidation, deamidation, cleavage, and Asp isomerization, can be obtained. As the suppression of the decomposition of the component 1, the suppression of the deamidation and / or the Asp isomerization of the component 1 can be preferably exemplified.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not bound by the following examples, and can be carried out in any form as long as the gist of the present invention is not deviated.

In addition, in the following examples, "prescription" and "prescription preparation" may be described as the wording corresponding to the "liquid pharmaceutical preparation" of the present invention.

Example 1 (Manufacturing of liquid pharmaceutical product)
(1) Production of Liquid Pharmaceutical Formulation for Stability Test by Addition of Sodium Salicylate Formulations 101-107 and control formulations 101-104 were prepared according to Table 4 below.

The specific preparation method for each prescription is as follows. First, the active ingredient and each additive described in the "Amount added at the time of manufacture" column in the table were dissolved in about 25 mL of water for injection. Further, in order to adjust to the pH described in the "pH" column in the table, 0.01N hydrochloric acid is used when adjusting to pH 4.0 or pH 5.0, and 0.01N is used when adjusting to pH 6.0. The pH was adjusted with sodium hydroxide. Then, the weight was corrected with water for injection so that the total amount was 40 g. The weight-corrected chemical solution was filtered using a 0.22 μm filtration filter, and then filled in a plastic syringe in an amount of about 0.5 mL each. The notation of the teriparatide concentration of the final content is the notation of the teriparatide acetate concentration in terms of teriparatide.

The composition of each formulation is as described in the "Final Content" column in Table 4.

（２）チオ硫酸ナトリウム添加による安定性試験に供した液状医薬製剤の製造
下記表５にしたがって処方１００１〜１００３、対照処方１００１〜１００３を調製した。

(2) Production of Liquid Pharmaceutical Formulation for Stability Test by Addition of Sodium Thiosulfate Formulations 1001-1003 and control formulations 1001-1003 were prepared according to Table 5 below.

The specific preparation method for each prescription is as follows. First, the active ingredient and each additive described in the "Amount added at the time of manufacture" column in the table were dissolved in about 25 mL of water for injection. Further, in order to adjust to the pH described in the "pH" column in the table, 0.01N hydrochloric acid is used when adjusting to pH 4.0 or pH 5.0, and 0.01N is used when adjusting to pH 6.0. The pH was adjusted with sodium hydroxide. Then, the weight was corrected with water for injection so that the total amount was 40 g. The weight-corrected chemical solution was filtered using a 0.22 μm filtration filter, and then filled in a plastic syringe in an amount of about 0.5 mL each. The notation of the teriparatide concentration of the final content is the notation of the teriparatide acetate concentration in terms of teriparatide.

The composition of each formulation is as described in the "Final Content" column in Table 5.

Example 2 (Confirmation of stabilizing effect of liquid pharmaceutical product by addition of sodium salicylate)
Stability tests were performed using formulations 101-104 and control formulations 101-104 prepared in Example 1 (1).

Specifically, after storing each pharmaceutical product in a stability tester at 40 ° C./75% RH, sampling was performed at the 2nd and 4th weeks, and the stability was measured by high performance liquid chromatography.

The conditions for high performance liquid chromatography are as follows.

(1) Detector: Ultraviolet absorptiometer (measurement wavelength: 214 nm)
(2) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 150 mm is filled with 3.5 μm octadecylsilylated silica gel for liquid chromatography (Zorbax 300SB-C18 manufactured by Agilent Technologies, or an equivalent product).
(3) Column temperature: Constant temperature around 40 ° C. (4) Mobile phase Mobile phase A: Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, add phosphoric acid to adjust the pH to 2.3, and then add water. Make 1000 mL. Add 100 mL of acetonitrile to 900 mL of this solution.
Mobile phase B: Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, add phosphoric acid to adjust the pH to 2.3, and then add water to make 1000 mL. Add 500 mL of acetonitrile to 500 mL of this solution.
(5) Liquid transfer of mobile phase The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 6 below.

（６）流量：毎分１．０ｍＬ
（７）検出時間：試料溶液注入後４５分間。ただし溶媒ピークの後ろからとする。

(6) Flow rate: 1.0 mL / min
(7) Detection time: 45 minutes after injection of the sample solution. However, it is from behind the solvent peak.

The test results are shown in Table 7 below.
The numerical value in the table shows the ratio (%) of the amount of teriparatide remaining in the 2nd week or the 4th week when the amount of teriparatide before storage is 100.

Table 7 shows that the formulation with sodium salicylate is more stable at any pH than the control formulation without sodium salicylate. In particular, it is shown that the stabilizing effect of the addition of sodium salicylate is remarkable in a high pH range.

For example, Table 8 shows the relationship between the difference (Δa) in the residual ratio (%) of teriparatide between the presence and absence of sodium salicylate and the pH after storage of the liquid pharmaceutical product at 40 ° C./75% RH.

As an index for measuring the long-term storage stability of the liquid pharmaceutical product, the difference in the residual ratio of teriparatide after storage of the liquid pharmaceutical product for 4 weeks (difference index 1: Δa in Table 8 (= teriparatide in the presence of sodium salicylate during storage for 4 weeks)). When the residual rate (a2) -teriparatide residual rate in the absence of sodium salicylate (a1)) was confirmed, it was found that there was no linearity between pH and Δa. In addition, teriparatide in the absence of sodium salicylate was found. Ratio of Δa to the content (100-a1) of impurities (components other than teriparatide: may contain deamides (N16 → iso-D16, N16 → D16) or Asp isomers (D30 → iso-D30)) ( The difference index 2) increased with increasing pH.

Therefore, when a second-order regression was performed on pH and Δa, a very high correlation could be observed (Fig. 1). In FIG. 1, a rapid increase in Δa was observed when the pH exceeded 4.0, and the increase in Δa became more remarkable when the pH was 5 or higher.

The quadratic regression was performed by using the "polynomial approximation (degree 2)" function in "formatting the approximate curve" of Microsoft Excel.

Example 3 (Dose-dependent confirmation of stabilizing effect by addition of sodium salicylate)
Stability tests were performed using formulations 104-107 and control formulations 104 prepared in Example 1 (1).

Specifically, after storing each pharmaceutical product in a stability tester at 40 ° C./75% RH, sampling is performed at the 2nd and 4th weeks, and the product is stabilized by high performance liquid chromatography in the same manner as in Example 2. Sex was measured.

The test results are shown in Table 9 below.
The numerical value in the table shows the ratio (%) of the amount of teriparatide remaining in the 2nd week or the 4th week when the amount of teriparatide before storage is 100.

Table 9 shows that the addition of 1 mg / mL sodium salicylate to the aqueous preparation containing teriparatide sufficiently stabilizes the liquid preparation, and even if the amount of sodium salicylate added is increased, the stabilizing effect hardly changes. Shown.

Example 4 (Confirmation of stabilizing effect of liquid pharmaceutical product by addition of sodium thiosulfate)
Stability tests were performed using formulations 1001-1003 and control formulations 1001-1003 prepared in Example 1 (2).

Specifically, after storing each pharmaceutical product in a stability tester at 40 ° C./75% RH, sampling is performed at the 2nd and 4th weeks, and the product is stabilized by high performance liquid chromatography in the same manner as in Example 2. Sex was measured.

(3) Test result:
The test results are shown in Table 10 below.
The numerical value in the table shows the ratio (%) of the amount of teriparatide remaining in the 2nd week or the 4th week when the amount of teriparatide before storage is 100.

Table 10 shows that the formulation with sodium thiosulfate is more stable at any pH than the control formulation without sodium thiosulfate. Moreover, it is shown that the stabilizing effect by the addition of sodium thiosulfate is remarkable especially in a high pH range.

For example, Table 11 shows the relationship between the difference (Δa) in the residual ratio (%) of teriparatide between the presence and absence of sodium thiosulfate and the pH after storage of the liquid pharmaceutical product at 40 ° C./75% RH. ..

As an index for measuring the long-term storage stability of the liquid pharmaceutical product, the difference in the residual ratio of teriparatide after storage of the liquid pharmaceutical product for 4 weeks (difference index 1: Δa in Table 11 (= sodium thiosulfate in the presence of sodium thiosulfate in storage for 4 weeks)) When the teriparatide residual rate (a2) -teriparatide residual rate (a1) in the absence of sodium thiosulfate was confirmed, it was found that there was no linearity between pH and Δa, and sodium thiosulfate was absent. Δa with respect to the content (100-a1) of teriparatide impurities (components other than teriparatide: may contain deamides (N16 → iso-D16, N16 → D16) or Asp isomers (D30 → iso-D30)). (Difference index 2) increased with increasing pH.

Therefore, when a second-order regression was performed on pH and Δa, a very high correlation could be observed (Fig. 2). In FIG. 2, Δa turned to increase when the pH was 4.5 or higher, and the increase in Δa became more remarkable when the pH was 5 or higher.

The quadratic regression was performed by using the "polynomial approximation (degree 2)" function in "formatting the approximate curve" of Microsoft Excel.

Comparative Example 1 (Confirmation of stabilizing effect of liquid pharmaceutical product by adding m-cresol)
(1) Preparation of prescription Comparative prescriptions 1 and 2 were prepared according to Table 12 below. 50 mg of D-mannitol was dissolved in 800 mL of water for injection, and water for injection was added to the solution and mass-up to 1000 mL to prepare a solution. A solution for dissolving the drug substance was prepared by collecting 180 mL of the solution, adjusting the pH to 4.0 or 5.0 with 0.01N hydrochloric acid, adding the solution and measuring up to 200 mL. A drug solution was prepared by adding teriparatide acetate to the final concentration shown in Table 12 with respect to 150 mL of the drug substance dissolving solution. The chemical solution was aseptically filtered, filled and sealed in an ampoule to prepare Comparative Formulations 1 and 2. The notation of the teriparatide concentration of the final content is the notation of the teriparatide acetate concentration in terms of teriparatide.

Comparative formulations 3-4 were prepared according to Table 12 below. A lysate (1) was prepared by dissolving 50 mg of D-mannitol in 800 mL of water for injection and mass-up to 1000 mL by adding water for injection. The solution (2) was prepared by collecting 400 mL of the solution (1), adding 1.30 mL (d = 1.04 g / ml) of m-cresol, and mass-up to 450 mL with the solution (1). .. 180 mL of the solution (2) was collected, the pH was adjusted to 4.0 or 5.0 with 0.01N hydrochloric acid, and the solution was scalpel-up to 200 mL using the solution (2) to prepare a drug substance dissolution solution. A drug solution was prepared by adding teriparatide acetate to the final concentration shown in Table 12 with respect to 150 mL of the drug substance dissolving solution. The chemical solution was aseptically filtered, filled and sealed in an ampoule to prepare Comparative Formulations 3 to 4. The notation of the teriparatide concentration of the final content is the notation of the teriparatide acetate concentration in terms of teriparatide.

The composition of each formulation is as described in the "Final Content" column in Table 12.

(2) Test method A stability test was carried out using the prepared comparative formulations 1 to 4. Specifically, after storing each pharmaceutical product in a stability tester at 40 ° C./75% RH, sampling is performed at the 2nd and 4th weeks, and the product is stabilized by high performance liquid chromatography in the same manner as in Example 2. Sex was measured.

(3) Test results The test results are shown in Table 13 below. The numerical value in the column of "40 ° C. 4W (a1)" or "40 ° C. 4W (a2)" in the table is the ratio of the amount of teriparatide remaining in the 4th week when the amount of teriparatide before storage is 100 (%). ) Is shown.

Comparative Example 2 (Confirmation of stabilizing effect of liquid pharmaceutical product by adding sodium chloride)
(1) Preparation of formulation The comparative formulations 5 to 10 shown in Table 14 were prepared according to the method described in Example 1 of Patent Document 4.

(2) Test method A stability test was carried out using the comparative formulations 5 to 10 shown in Table 14 according to the method described in Example 2 of Patent Document 4.

(3) Test results The test results are shown in Table 15 below. “25 ° C. 3M (b1)” or “25 ° C. 3M (b2)” in the table starts from the total ratio (%) of the deamidated and Asp isomers of teriparatide that were present after 3 months. The value (%) obtained by subtracting the total ratio (%) of the deamidated form and the Asp isomerized form of the existing teriparatide is shown.

Comparative Example 3 (Confirmation of stabilizing effect of liquid pharmaceutical product by adding ascorbic acid)

Comparative formulation 11 containing ascorbic acid was prepared according to conventional methods. A stability test was performed using the prepared comparative formulation 11. Specifically, after storing the formulation in a stability tester at 40 ° C./75% RH, sampling was performed at the 2nd and 4th weeks, and stability was obtained by high performance liquid chromatography in the same manner as in Example 2. It was measured. When the amount of teriparatide before storage was 100, the percentages of the amount of teriparatide remaining at the 2nd and 4th weeks were 12.0 (%) and 8.7 (%), respectively.

The liquid pharmaceutical preparation of the present invention is a long-term stable liquid pharmaceutical preparation and is extremely useful in the pharmaceutical industry.

Claims (2)

A method for suppressing the decomposition of a component 1 during storage of a liquid pharmaceutical preparation containing the component 1, which comprises adding the component 2 at the time of preparation of the same preparation;
Ingredient 1) Teriparatide acetate component 2) Ingredients that satisfy all of the following conditions 1) to 3) Condition 1) Pharmaceutical additive Condition 2) Organic acid or inorganic acid (acid a) or a salt thereof. Of the pKa of the acid a, no pKa is present in the pH range of 4.0 to 6.0, and at least any one of the acids a has a pKa of less than 4.0, which is an organic acid or an inorganic acid or a salt thereof. However, the organic acid is an organic acid having a cyclic group and one carboxy group, and the inorganic acid is an inorganic acid containing a sulfur atom. Condition 3) The molecular weight of the acid a is in the range of 70 to 180. The decomposition suppressing method according to claim 1, wherein the pH of the liquid pharmaceutical product exceeds 4.0 and is 5.0 or less at the time of preparation of the liquid pharmaceutical product.

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