A liquid pharmaceutical composition containing teriparatide with excellent pharmacokinetics and / or safety.

Abstract

To provide a liquid pharmaceutical formulation of teriparatide or its salt that is superior in terms of pharmacokinetics. [Solution] A liquid pharmaceutical preparation for human subcutaneous administration, containing 28.2 μg of component 1 in terms of teriparatide as a single dose, wherein the concentration of component 1 is 80 to 240 μg / mL. • Ingredient 1) Teriparatide or its salt.

Description

[Technical Field]

[0001] The present invention relates to a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof. [Background technology]

[0002] PTH (parathyroid hormone), along with calcitonins and vitamin D, is a hormone involved in regulating blood calcium levels. Regarding PTH peptides, which are physiologically active equivalents of natural PTH, freeze-dried preparations containing PTH peptides and liquid preparations containing PTH peptides are also known. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 5-306235 [Patent Document 2] Japanese Patent Publication No. 2004-10511 [Patent Document 3] Japanese Patent Publication No. 2007-186466 [Patent Document 4] Special Publication No. 2001-525372 [Patent Document 5] International Publication No. 2006 / 22301 [Patent Document 6] International Publication No. 2012 / 169435 [Patent Document 7] Special Publication No. 2015-504087 [Patent Document 8] Japanese Patent Application Publication No. 63-57527 [Patent Document 9] Japanese Patent Application Publication No. 2-96533 [Patent Document 10] Special Publication No. 2004-513069 [Patent Document 11] Japanese Patent Publication No. 2005-213158 [Patent Document 12] International Publication No. 2011 / 139838 [Patent Document 13] Special Publication No. 2014-507484 [Non-patent literature]

[0004] [Non-Patent Document 1] Teribone (registered trademark) Subcutaneous Injection 56.5 μg Package Insert (Revised November 2015 (6th Edition, Revision of Precautions for Use, etc.)) [Non-Patent Document 2] Forteo® Subcutaneous Injection Kit 600μg Package Insert (Revised July 2014 (7th Edition)) [Non-Patent Document 3] Sung et al., Journal of Biological Chemistry, (1991), Vol.266, No.5, pp.2831-2835 [Non-Patent Document 4] Takei et al., Peptide Chemistry 1979, (1980), pp.187-192 [Non-Patent Document 5] Merrifield, Advances In Enzymology, (1969), Vol.32, pp.221-296 [Non-Patent Document 6] Kazuo Inokawa et al., Biometrics, (2015), 36, Special Issue, S3-S18 [Non-Patent Document 7] Mach et al., Therapeutic Delivery, (2011), Vol.2, No.6, pp.727-736 [Non-Patent Document 8] Kinnunen et al., Journal of Controlled Release, (2014), Vol.182, pp.22-32 [Non-Patent Document 9] "The Importance and Future Development of Pharmacokinetic Research in Pharmaceutical Development," Sumitomo Chemical II (26-34) [Non-Patent Document 10] Chen et al., Biochem. Biophys. Res. Commun., (1971), Vol.44, No.6, pp.1285-1291 [Non-Patent Document 11] Greenfield, Nature Protocols, (2006), Vol.1, No.6, pp.2876-2890 [Non-Patent Document 12] Lee et al., Biopolymers, (1989), Vol.28, pp.1115-1127 [Non-Patent Document 13] Strickland et al., Biochemistry, (1993), Vol.32, pp.6050-6057 [Non-Patent Document 14] Abstracts of the 118th Annual Meeting of the Pharmaceutical Society of Japan, 1998, 4, 34 [Non-Patent Document 15] Izutsu et al., Journal of Pharmaceutical Sciences, (2006), Vol.95, No.4, pp.781-789 [Non-Patent Document 16] Hirotsugu Hiramatsu (Graduate School of Pharmaceutical Sciences, Tohoku University), "Secondary Structure Analysis Method Using Infrared Absorption Spectroscopy," Protein Science Society Archives, 2009, 2, e054 [Non-Patent Document 17] Kenichi Izutsu et al., "Investigation of Secondary Structure in Aqueous Solutions and Freeze-Dried Solids for Non-Destructive Evaluation of Protein Pharmaceuticals," Abstracts of the 21st Near-Infrared Forum, 2005, p. 59 [Non-Patent Document 18] Armstrong et al., Proc. Natl. Acad. Sci. USA, (1993), Vol.90, pp.11337-11340 [Non-Patent Document 19] Chakrabartty et al., Biochemistry, (1993), Vol.32, No.21, pp.5560-5565 [Non-Patent Document 20] Wu et al., Proc. Natl. Acad. Sci. USA, (1979), Vol.76, No.8, pp.3656-3659 [Non-Patent Document 21] Aloj et al., Archives of Biochemistry and Biophysics, (1972), Vol.150, No.2, p.782-785 [Non-Patent Document 22] Salgin et al., International Journal of Electrochemical Science, (2012), Vol.7, pp.12404-12414 [Non-Patent Document 23] Yamamoto et al., Eur J Pharmacol.(2015), Vol.764, pp.457-462 [Non-Patent Document 24] Summary of application materials for Teribone (registered trademark) 56.5 μg for subcutaneous injection (http: / / www.pmda.go.jp / drugs / 2011 / P201100155 / index.html) [Non-Patent Document 25] Mitsuhiro Miyazawa, "Introduction to the Special Issue: Methods for Analyzing the Three-Dimensional Structure of Proteins," Sericulture and Insect Biotechnology, 2012, 81(2), pp. 105-106. [Non-Patent Document 26] The Pharmaceutical Society of Japan (ed.), Standard Pharmacy Series 7: The Science of Pharmaceutical Formulation, 1st Edition, 1st Printing, Published February 10, 2006, pp. 12-13. [Non-Patent Document 27] Noriko Kosakaya et al., "Factors Associated with the 5-Year Decrease in Lumbar Spine Bone Density in Japanese Women in Menopause," Journal of the Japanese Society of Nutrition and Food Science, 1999, Vol. 52, No. 5, pp. 307-313. [Non-Patent Document 28] Hitoshi Mizuno et al., "Evaluation of pH responsiveness of membrane-permeable peptides by amino acid sequence modification," Abstracts of the 48th Annual Conference of the College of Industrial Technology, Nihon University (2015-12-5), pp. 543-544. [Non-Patent Document 29] Tim J et al., Protein Science, (2007), Vol.16, pp.1193-1203 [Non-Patent Document 30] Leonid K., Drug Metab. Dispos., (2014), Vol.42, pp.1890-1905 [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a liquid pharmaceutical formulation for subcutaneous administration containing teriparatide or a salt thereof that exhibits good pharmacokinetics (e.g., high bioavailability) and / or high safety (e.g., reduced incidence of gastrointestinal side effects). [Means for solving the problem]

[0006] In one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the α-helix content in teriparatide or its salt is within a specific range (e.g., 13.0% or more).

[0007] In one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the number of amino acid residues forming an α-helix structure in teriparatide or its salt is within a specific range (e.g., 4.5 or more).

[0008] In one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the average residue molar ellipticity [θ] of the formulation is determined by circular dichroism (CD) spectral measurement (measurement wavelength 222 nm). 222 within a specific range (e.g., -6300 (deg.cm)) 2 It is less than or equal to / d mol).

[0009] These subcutaneous liquid pharmaceutical formulations offer excellent pharmacokinetics (e.g., high bioavailability).

[0010] Furthermore, in one embodiment of the subcutaneous liquid pharmaceutical preparation of the present invention, the amount of teriparatide or its salt administered per dose is a specific amount (e.g., 28.2 μg).

[0011] Alternatively, in one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the time to reach the peak plasma concentration (T) of teriparatide or its salt obtained by a single dose. max ) is within a specific range (e.g., less than 0.7 hours).

[0012] Alternatively, in one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the time elapsed after a single administration of the teriparatide or its salt in plasma is above a specific threshold (e.g., 250 pg / mL) is within a specific range (e.g., less than 1.0 hr).

[0013] These subcutaneous liquid pharmaceutical formulations offer excellent safety (e.g., reduced incidence of gastrointestinal side effects).

[0014] In other words, the present invention relates to the following inventions, etc. [1] A liquid pharmaceutical preparation for human subcutaneous administration, containing 28.2 μg of component 1 in teriparatide equivalent per dose, wherein the concentration of component 1 is 80 to 240 μg / mL. • Ingredient 1) Teriparatide or its salt. [2] A liquid pharmaceutical preparation for subcutaneous administration to humans as described in [1], wherein the concentration of component 1 is 100 to 200 μg / mL. [3] T100% of a single dose is calculated by a pharmacokinetic model-independent analysis (NCA (Non-Compartmental Analysis)). max A liquid pharmaceutical preparation for subcutaneous administration to humans according to [1] or [2] above, wherein the ratio is 0.5 to 0.7 (1 / hr). [4] A liquid pharmaceutical preparation for human subcutaneous administration according to [1] to [3] above, wherein the time elapsed after a single administration of component 1 is less than 2.1 hours, and the time elapsed after a single administration of component 1 is less than 1.0 hours. [5] A liquid pharmaceutical preparation for subcutaneous administration to postmenopausal women, as described in [1] to [4] above. [6] A liquid pharmaceutical preparation for human subcutaneous administration according to [1] to [5] above, wherein the number of amino acid residues forming an α-helix structure in component 1 is 4.5 or more and 5.5 or less. [7] The liquid pharmaceutical preparation described in [6] above, wherein the number of amino acid residues is the number of amino acid residues based on the α-helix content estimated using the following estimation formula 1 from the numerical value a of the average residue molar ellipticity obtained by circular dichroism (CD) spectral measurement satisfying the following measurement conditions 1 to 4; Measurement condition 1: The measurement wavelength is 222 nm; Measurement condition 2: The sample concentration (component 1 concentration) is 0.1 to 0.3 mg / mL; Measurement condition 3: The measurement temperature is 20°C; Measurement condition 4: Cell length is 1-2 mm; Estimation formula 1: α-helix content = -(value a + 2340) / 30300. [8] A liquid pharmaceutical preparation for subcutaneous administration to humans according to [1] to [7] above, wherein component 1 is teriparatide acetate. [9] The liquid pharmaceutical preparation for human subcutaneous administration described in [1] to [8] above, wherein the liquid pharmaceutical preparation for human subcutaneous administration is an aqueous pharmaceutical preparation for human subcutaneous administration (excluding reconstituted lyophilized preparations).

[10] The liquid pharmaceutical preparation for human subcutaneous administration according to [1] to [9] above, wherein the liquid pharmaceutical preparation for human subcutaneous administration is an aqueous pharmaceutical preparation for human subcutaneous administration, and the solvent is water for injection. [Effects of the Invention]

[0015] According to the present invention, a liquid pharmaceutical formulation containing teriparatide or a salt thereof is provided, which has excellent pharmacokinetics and / or safety. [Brief explanation of the drawing]

[0016] [Figure 1A] Figure 1A shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation A, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1B] Figure 1B shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation B, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1C] Figure 1C shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation C, prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1D] Figure 1D shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation D, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1E]Figure 1E shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation E, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1F] Figure 1F shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation F, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1G] Figure 1G shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation G, prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1H] Figure 1H shows the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulation H, which was prepared in "Preparation of Liquid Pharmaceutical Formulations for Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 1I]Figure 1I summarizes the measurement results obtained by performing circular dichroism (CD) spectral measurements on formulations A to H, prepared in "Preparation of Liquid Pharmaceutical Formulations Subject to Circular Dichroism (CD) Spectrum Measurement Test," using eight cumulative measurements at 20°C. The horizontal axis "Wavelength (nm)" represents the measurement wavelength (nm) (210-230 nm), and the vertical axis "[θ] / deg.cm2d mol-1" represents the average residue molar ellipticity [θ]. [Figure 2] Figure 2 summarizes the results obtained from circular dichroism (CD) spectral measurement tests and human pharmacokinetic studies (Example 3; Human Pharmacokinetic Study (2)) conducted on formulations A to H (a total of 8 formulations) prepared in "Preparation of Liquid Pharmaceutical Formulations Subject to Circular Dichroism (CD) Spectrum Measurement Tests." The results of the circular dichroism (CD) spectral measurement tests were defined as the measurement results of Measurement 2 of the same test (average residue molar ellipticity [θ] 222), and the results of the human pharmacokinetic studies were defined as the AUClastRatio, which is the ratio of each formulation to control formulation 2 in terms of AUClast (area under the plasma concentration-time curve up to the final observation time). [Figure 3] Figure 3 summarizes the results obtained from circular dichroism (CD) spectral measurement tests and human pharmacokinetic studies (Example 3; Human Pharmacokinetic Study (2)) conducted on formulations A to H (a total of 8 formulations) prepared in "Preparation of Liquid Pharmaceutical Formulations Subject to Circular Dichroism (CD) Spectrum Measurement Tests." The results of the circular dichroism (CD) spectral measurement tests were used as the measurement results for Measurement 2 of the same test (α-helix content ratio), and the results of the human pharmacokinetic studies were used as the AUClastRatio, which is the ratio of each formulation to control formulation 2 in terms of AUClast (area under the plasma concentration-time curve up to the final observation time). [Figure 4]Figure 4 summarizes the results obtained from circular dichroism (CD) spectral measurement tests and monkey pharmacokinetic studies (Example 2: Monkey Pharmacokinetic Study) for formulations A to H (a total of 8 formulations). The results of the circular dichroism (CD) spectral measurement tests were defined as the measurement result of Measurement 2 of the same test (average residue molar ellipticity [θ] 222), and the results of the monkey pharmacokinetic studies were defined as the AUClastRatio, which is the ratio of each formulation to control formulation 1 in terms of AUClast (area under the plasma concentration-time curve up to the final observation time). [Figure 5] Figure 5 summarizes the results obtained from circular dichroism (CD) spectral measurement tests and monkey pharmacokinetic studies (Example 2: Monkey Pharmacokinetic Study) for formulations A to H (a total of 8 formulations). The results of the circular dichroism (CD) spectral measurement tests were used as the measurement results for Measurement 2 of the same test (α-helix content ratio), and the results of the monkey pharmacokinetic studies were used as the AUClastRatio, which is the ratio of each formulation to control formulation 1 in terms of AUClast (area under the plasma concentration-time curve up to the final observation time). [Figure 6] Figure 6 shows the time course of plasma teriparatide acetate concentration obtained when formulations A, B, E, F, and H provided in the examples, and the 28.2 μg and 56.5 μg formulations provided in the reference example (reference example relating to an invention in which the Tmax of component 1 is within a specific range) were administered to humans. [Figure 7] Figure 7 is a schematic diagram of the pharmacokinetic model (1-compartment model) used in Examples 6 and 7. Here, Ka represents the absorption rate constant and Ke represents the elimination rate constant. [Modes for carrying out the invention]

[0017] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments and can be implemented in any form without departing from the spirit of the invention.

[0018] 1. Liquid pharmaceutical preparations for subcutaneous administration: In one aspect, the present invention provides a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the α-helix content of component 1 in the preparation is within a specific range.

[0019] In one aspect, the present invention provides a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the number of amino acid residues forming an α-helix structure in component 1 of the preparation is within a specific range.

[0020] In one embodiment, the present invention provides a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the average residue molar ellipticity [θ] of the preparation as determined by circular dichroism (CD) spectral measurement (measurement wavelength 222 nm) 222 -6300 (deg.cm) 2 The present invention provides a liquid pharmaceutical preparation for subcutaneous administration that is less than or equal to ( / d mol).

[0021] Furthermore, in another aspect of the present invention, there is a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the amount of teriparatide or a salt thereof administered per dose is a specific amount.

[0022] Furthermore, in another aspect, the present invention relates to a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the T of component 1 obtained by a single dose thereof max The present invention provides a liquid pharmaceutical preparation for subcutaneous administration in which the parameters are within a specific range.

[0023] Alternatively, in another aspect of the present invention, the present invention provides a liquid pharmaceutical preparation for subcutaneous administration containing teriparatide or a salt thereof as component 1, wherein the time elapsed in which the plasma concentration of teriparatide or a salt thereof is above a specific threshold after a single administration is within a specific range.

[0024] (1) Liquid pharmaceutical preparations: The liquid pharmaceutical preparation of the present invention is not particularly limited in form, as long as it is a liquid subcutaneous pharmaceutical preparation containing teriparatide or a salt thereof (component 1) as described below. Examples of the liquid pharmaceutical preparation of the present invention include subcutaneous injections and subcutaneous capsules. As long as the liquid pharmaceutical preparation of the present invention is for subcutaneous administration, its container, needle, packaging, etc., are not particularly limited. Here, "pharmaceutical preparation" means a drug used for the prevention / treatment / diagnosis of any disease in mammals (humans, monkeys, rats, etc.). As a pharmaceutical preparation, human pharmaceutical preparations are preferably given as examples. When the target of administration is a human, there are no particular limitations on their sex, age, presence or type of disease they have, but for example, they may be postmenopausal women.

[0025] The solvent used in the liquid pharmaceutical formulation of the present invention is not particularly limited and may be either an aqueous or non-aqueous solvent, but it is preferable that it contains an aqueous solvent, and the solvent may be substantially composed solely of an aqueous solvent. The present invention is preferably an aqueous pharmaceutical formulation. The liquid pharmaceutical formulation or solvent (such as an aqueous solvent) may contain various components such as inorganic salts, organic salts, buffers, and additives, without departing from the spirit of the present invention. For example, the liquid pharmaceutical formulation of the present invention can be prepared using water for injection or physiological saline solution.

[0026] Examples of the liquid pharmaceutical formulation of the present invention include, preferably, an aqueous pharmaceutical formulation for subcutaneous administration to humans, and most preferably, an aqueous pharmaceutical formulation for subcutaneous injection to humans. Here, when the liquid pharmaceutical formulation of the present invention is a formulation for subcutaneous administration, the site of subcutaneous administration is not particularly limited, but a site with few nerves and blood vessels, a lot of subcutaneous fat, and no bone is preferred. Preferred sites include the abdomen, upper arm, thigh, and buttocks, with the abdomen being preferred.

[0027] (2) Teriparatide or its salt (component 1): In the present invention, human PTH(1-34) is a peptide represented by a partial amino acid sequence consisting of the first to 34 amino acid residues viewed from the N-terminus of the amino acid sequence of human parathyroid hormone, human PTH(1-84).

[0028] In this invention, teriparatide refers to the free form of human PTH(1-34). Teriparatide may also be in the form of a salt.

[0029] In the present invention, examples of teriparatide salts include any salt formed by teriparatide and one or more volatile organic acids. Examples of volatile organic acids include trifluoroacetic acid, formic acid, and acetic acid. The ratio of free teriparatide to a volatile organic acid when forming a salt is not particularly limited as long as it forms a salt. Among these, acetic acid is preferred as the volatile organic acid. That is, teriparatide acetate is a preferred example of a teriparatide salt in the present invention.

[0030] Teriparatide or its salts are peptides and therefore possess an isoelectric point (pI). The pI can be measured using known methods (e.g., methods using HPLC or electrophoresis). Generally, the pI of teriparatide or its salts is known to be between 8.3 and 8.4.

[0031] Teriparatide or a salt thereof (component 1) can be produced by methods known to the present day (for example, methods described in Non-Patent Documents 3-5, etc.).

[0032] (3) Content, dosage, and concentration of teriparatide or its salt (component 1): The amount of teriparatide or its salt (component 1) contained in the liquid pharmaceutical formulation of the present invention is not particularly limited, but the following are preferred examples. Specifically, the amount of component 1 in the formulation is preferably 10 μg or more, more preferably 20 μg or more, 25 μg or more, 27 μg or more, and even more preferably 28 μg or more. Furthermore, the amount of component 1 in the formulation is preferably 100 μg or less, more preferably 50 μg or less, 40 μg or less, 35 μg or less, and even more preferably 30 μg or less. Among these, the content of component 1 is preferably 28.2 μg or 29.2 μg as teriparatide. If the teriparatide used is an acetate, the amount including the amount of acetate can also be given as an example. For example, in the case of teriparatide pentaacetate, the content of component 1 as teriparatide pentaacetate is preferably 30.3 μg or 31.3 μg.

[0033] The single dose of teriparatide or its salt (component 1) contained in the liquid pharmaceutical formulation of the present invention is not particularly limited, but the following are preferred examples. Specifically, the single dose of component 1 in the formulation is more preferably 25 μg or more, 27 μg or more, and more preferably 28 μg or more. Furthermore, the single dose of component 1 in the formulation is more preferably 35 μg or less, 30 μg or less, and more preferably 29 μg or less. Among these, the single dose of component 1 is preferably 28.2 μg as teriparatide. In particular, by setting the single dose of component 1 to be below the above upper limit, excellent safety associated with a single dose can preferably be obtained. Another example is a single dose of component 1 of 56.5 μg.

[0034] The concentration of teriparatide or its salt (component 1) contained in the liquid pharmaceutical formulation of the present invention is not particularly limited, but the following are preferably examples. Specifically, the concentration of component 1 in the formulation is preferably 50 μg / mL or more, more preferably 70 μg / mL or more, 80 μg / mL or more, 100 μg / mL or more, greater than 100 μg / mL, 110 μg / mL or more, and more preferably 120 μg / mL or more. Furthermore, the concentration of component 1 in the formulation is preferably 500 μg / mL or less, more preferably 250 μg / mL or less, less than 250 μg / mL, 240 μg / mL or less, 200 μg / mL or less, 180 μg / mL or less, and more preferably 160 μg / mL or less. Among these, 141 μg / mL is the most preferably exemplified. By setting the concentration of component 1 within the above range, preferably a high absorption rate of component 1 and excellent safety associated with a single dose of the formulation can be obtained. In this case, if component 1 is teriparatide salt, it is preferable to convert the concentration of component 1 to the concentration of its free form (teriparatide).

[0035] (4) α-helix content and number of α-helix-forming amino acid residues of teriparatide or its salt (component 1): In the present invention, the α-helix content of component 1 (teriparatide or its salt) means the ratio of the average number of amino acid residues that form an α-helix structure (the number of relevant residues) to the total number of amino acid residues (total number of residues: i.e., 34) contained in component 1 of the liquid pharmaceutical formulation of the present invention. The ratio may be expressed as a value obtained by dividing the number of relevant residues by the total number of residues (0 to 1), or it may be converted to a percentage (0 to 100 (%)). For example, an α-helix content of component 1 of 13% means that an average of approximately 4.42 (= 0.13 × 34) amino acid residues out of the 34 amino acid residues of component 1 form an α-helix structure.

[0036] Here, in component 1 contained in the liquid pharmaceutical formulation of the present invention, there may be many molecular species with respect to the α-helix structure formation site and its amount, and a dynamic equilibrium may exist among them, and many components 1 contained in the liquid pharmaceutical formulation of the present invention may exhibit substantially the same α-helix structure formation site and its amount. In any case, the α-helix content means the ratio of the number of amino acid residues in component 1 that form an α-helix structure to the total number of amino acid residues in component 1.

[0037] In the present invention, the α-helix content of component 1 contained in the liquid pharmaceutical formulation can be estimated, for example, by circular dichroism (CD) spectroscopy (see Non-Patent Documents 10-11, etc.). For example, using a liquid pharmaceutical formulation containing component 1 as a sample, the circular dichroism (CD) spectrum measurement value ([m deg]) at a measurement wavelength of 222 nm is obtained, and the measurement value is used to determine the average residue molar ellipticity ([deg.cm]). 2 It is preferable to convert this to [ / d mol] and use the resulting numerical value a of the average residue molar ellipticity to estimate the α-helix content of component 1 from the following formula.

number

[0038] The measurement conditions are not particularly limited; for example, measurements can be taken under the following conditions. 1) Measurement wavelength 222nm 2) Sample concentration (component 1 concentration): 0.1~0.3 mg / mL 3) Temperature 20℃ 4) Cell length 1-2 mm

[0039] The sample volume can be selected as appropriate, for example, about 0.5 mL. The apparatus for measuring the CD spectrum is not particularly limited, but for example, a circular dichroism meter (distributed by JASCO Corporation; J-720) can be used.

[0040] Furthermore, if liquid pharmaceutical preparations contain high concentrations of amino acids or other additives, the background noise may increase, making it difficult to measure the α-helix content using circular dichroism (CD) spectroscopy. In such cases, nuclear magnetic resonance (NMR) spectroscopy may be used instead of CD spectroscopy.

[0041] However, generally speaking, when estimating the α-helix content of component 1 from circular dichroism (CD) spectrum measurement results, the estimated value of the α-helix content may differ depending on the estimation formula used. Furthermore, even when the same liquid pharmaceutical composition is targeted, the estimated value of the α-helix content obtained by NMR and the estimated value obtained by CD may differ. For example, depending on the estimation formula used when estimating the α-helix content by CD, the former may be higher than the latter.

[0042] Therefore, when using the NMR method, it is preferable to use a liquid pharmaceutical preparation whose α-helix content has been estimated by the CD spectrum measurement method as a control product, obtain the chemical shift of Cα obtained by NMR for the same control product, and perform numerical correction based on the difference in content obtained by the two measurement methods.

[0043] Other methods include ATR-FT IR (Fourier Transform Infrared Spectroscopy for Total Reflectance Measurement) and IR (Infrared Spectroscopy). The α-helix content of component 1 contained in a liquid pharmaceutical preparation can also be measured using methods such as optical methods (see Non-Patent Literature 16) and Raman spectroscopy. However, when applying these measurement methods, the test composition to be measured must be prepared to contain component 1 at a concentration of at least 1% (w / v).

[0044] When measuring the α-helix content of component 1 by NMR, it is preferable to appropriately adjust the concentration of component 1 in the liquid pharmaceutical preparation used for the test to a concentration suitable for measurement (Non-Patent Literature 25). For example, the concentration of component 1 in the liquid pharmaceutical preparation can be appropriately adjusted to 0.5 to 4 mM before performing the measurement by NMR.

[0045] The α-helix content of component 1 contained in the liquid pharmaceutical formulation of the present invention is not particularly limited, but is preferably 13% or more. More preferably, it is 13.5% or more, or 13.8% or more. By setting the α-helix content of component 1 contained in the liquid pharmaceutical formulation to be above the lower limit, a liquid pharmaceutical formulation exhibiting excellent pharmacokinetics can be obtained.

[0046] The α-helix content of component 1 contained in the liquid pharmaceutical formulation of the present invention should normally satisfy the above lower limit (13% or more, 13.5% or more, 13.8% or more, etc.), and the upper limit is not particularly limited, but preferably examples include 100% or less, 80% or less, 60% or less, 50% or less, 40% or less, 30% or less, 25% or less, 20% or less, 18% or less, 16% or less, or 15.8% or less.

[0047] The number of α-helix-forming amino acid residues in component 1 contained in the liquid pharmaceutical formulation of the present invention is not particularly limited, but can be selected from a range of 4 or more, and may be 4.2 or more, 4.4 or more, 4.42 or more, or 4.5 or more. Among these, 4.59 or more, 4.6 or more, 4.69 or more, or 4.7 or more can be more preferably exemplified. By setting the number of α-helix-forming amino acid residues in component 1 contained in the liquid pharmaceutical formulation to be equal to or greater than the above lower limit, a liquid pharmaceutical formulation for subcutaneous administration exhibiting good pharmacokinetics can be obtained.

[0048] The number of α-helix-forming amino acid residues in component 1 contained in the liquid pharmaceutical formulation of the present invention is usually sufficient to satisfy the above lower limit (4.2 or more, 4.5 or more, etc.), and the upper limit is not particularly limited, but may be, for example, 34 or less, 30 or less, 25 or less, 20 or less, 18 or less, 16 or less, 15 or less, 12 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6.8 or less, 6.5 or less, 6.1 or less, 5.5 or less, 5.44 or less, 5.4 or less, or 5.37 or less.

[0049] The upper limit of the mean residue molar ellipticity [θ] by circular dichroism (CD) spectrum measurement (measurement wavelength: 222 nm) shown by the liquid pharmaceutical preparation of the present invention is not particularly limited, but for example, it can be -6000 or less, -6100 or less, -6300 or less, -6400 or less, and among them, -6300 or less can be preferably exemplified. Similarly, the lower limit is not particularly limited either, but for example, -8000 or more, -7500 or more, -7300 or more, -7200 or more, or -7100 or more can be preferably exemplified. By setting the mean residue molar ellipticity [θ] by circular dichroism (CD) spectrum measurement (measurement wavelength: 222 nm) shown by the liquid pharmaceutical preparation to be not more than the above upper limit, a liquid pharmaceutical preparation for subcutaneous administration showing good pharmacokinetics can be obtained.

[0050] In the present invention, the means for adjusting or increasing the α-helix content rate or the number of α-helix-forming amino acid residues of Component 1 in the liquid pharmaceutical preparation is not particularly limited, but examples include not substantially containing a buffer in the liquid pharmaceutical preparation of the present invention, appropriately adding an ionic compound or an ionic substance (such as sodium chloride), adjusting the pH, etc. (refer to "(2) Preparation of the liquid pharmaceutical preparation used in the human pharmacokinetics test" in Example 1 described later, Examples 3 to 4 described later, Non-Patent Document 18, Non-Patent Document 20, etc.).

[0051] Alternatively, as a means for reducing the polarity of the liquid pharmaceutical preparation of the present invention, specifically, by adding various alcohols to the composition, the α-helix content rate or the number of α-helix-forming amino acid residues of Component 1 in the composition can be increased. Trifluoroethanol (TFE) is known as an alcohol with strong α-helix-forming ability (Non-Patent Document 19), but by adding isopropanol or ethanol, which are used as pharmaceutical additives, instead of TFE, to the liquid pharmaceutical preparation of the present invention, the α-helix content rate or the number of α-helix-forming amino acid residues of Component 1 in the composition can also be increased.

[0052] Also, calcium ions (Ca 2+By adding ) to the liquid pharmaceutical formulation of the present invention, the α-helix content and the number of α-helix-forming amino acid residues of component 1 in the composition can also be increased (Non-Patent Literature 20). The amount to be added is not particularly limited, but approximately 100 to 1000 times the concentration of component 1 is recommended. 2+ It is preferable to add [this ingredient].

[0053] Furthermore, Patent Document 5 discloses that adding sodium acetate buffer to a drug solution improved the bioavailability (BA) of the physiologically active peptide in the drug solution compared to when no buffer was added (Example 2). On the other hand, in the liquid pharmaceutical formulation of the present invention, good pharmacokinetics can be obtained even without substantially including a buffer (more specifically, an acetate buffer).

[0054] (5) Teriparatide or its salt (component 1) max : Time to reach the maximum plasma concentration of component 1 obtained when the liquid pharmaceutical formulation of the present invention is administered subcutaneously as a single dose (T max ;hr) is not particularly limited, but preferably the following are examples.

[0055] In other words, T is calculated by an analysis independent of the pharmacokinetic model (NCA (Non-Compartmental Analysis)). max Preferably, the T is 0.75 (hr) or less, and more preferably 0.7 (hr) or less, 0.65 (hr) or less, 0.625 (hr) or less, 0.6 (hr) or less, or 0.5 (hr) or less. In addition, the T calculated by pharmacokinetic model-independent analysis (NCA (Non Compartmental Analysis)) is also considered. max It is more preferable that the duration is 0.1 (hr) or more, 0.2 (hr) or more, 0.25 (hr) or more, 0.3 (hr) or more, 0.4 (hr) or more, or 0.5 (hr) or more. Among these, 0.5 to 0.7 (hr) and 0.5 to 0.625 (hr) are preferred. max By keeping the value within the aforementioned range, it is preferable to exhibit excellent safety associated with a single dose.

[0056] Alternatively, T can be calculated by analyzing a one-compartment (pharmacokinetic) model. max Preferably, it is 0.6 (hr) or less, more preferably 0.55 (hr) or less, or more preferably 0.5 (hr) or less. In addition, the T calculated by 1-compartment (pharmacokinetic) model analysis max It is more preferable that the T of component 1 is 0.1(hr) or more, 0.2(hr) or more, 0.25(hr) or more, 0.3(hr) or more, or 0.35(hr) or more. In particular, it is preferable that it is 0.3 to 0.6(hr) or 0.35 to 0.5(hr). max By keeping the value within the aforementioned range, it is preferable to exhibit excellent safety associated with a single dose.

[0057] The T of component 1 obtained when the liquid pharmaceutical formulation of the present invention is administered subcutaneously as a single dose. max The method for setting the range within the aforementioned range is not particularly limited.

[0058] T max The pharmacokinetics of a drug are characterized by its absorption, distribution, metabolism, and excretion (sometimes referred to as ADME, derived from the first letters of each term), and are generally defined by the drug's absorption rate constant (ka) and elimination rate constant (kel). Using a typical model, these can be calculated using the following equation.

number

[0059] In the embodiments of the present invention, when the liquid pharmaceutical formulation of the present invention is administered subcutaneously as a single dose, the T of component 1 obtained is present. max This refers to the T of component 1 obtained when a known component 1 formulation is administered subcutaneously as a single dose. max Considering that it showed a smaller value compared to kel, and that kel is considered to have less composition dependence on the formulation compared to ka, in the present invention, T of component 1 maxAs a method for bringing the value within the aforementioned range, a preferred example is one in which the ka of component 1 is increased (i.e., the absorption rate of component 1 is increased).

[0060] It can be considered that the ionization of component 1 contained in the liquid pharmaceutical formulation of the present invention may affect the absorption of component 1 when administered subcutaneously. Therefore, the T of component 1 max In order to keep it within the above range, component 1 contained in the liquid pharmaceutical preparation of the present invention can be a salt with one or more volatile organic acids, or the pH of the liquid pharmaceutical preparation of the present invention can be appropriately adjusted with reference to the examples described later. max In order to keep the range within the above-mentioned range, the additives of the liquid pharmaceutical formulation of the present invention can be appropriately selected with reference to the examples described later.

[0061] Also, the T of component 1 max In order to keep the concentration within the above range, it is preferable to appropriately adjust the concentration of component 1 contained in the liquid pharmaceutical preparation of the present invention within the above range, for example, to 80-240 μg / mL, 100-200 μg / mL, 109-190 μg / mL, or 120-160 μg / mL.

[0062] It is generally known that the molecular weight of a drug, excipients in the drug, anesthesia, heat, and pressure can affect the absorption rate and amount of drugs administered subcutaneously (Non-Patent Literature 30).

[0063] Furthermore, by increasing the concentration of component 1 contained in the liquid pharmaceutical preparation, the absorption rate constant (Ka) of component 1 obtained when the liquid pharmaceutical preparation is administered subcutaneously to the target patient becomes larger (Non-Patent Literature 26). As the Ka of component 1 increases, the T of component 1 max It can be shortened.

[0064] Furthermore, in the present invention, when the target of administration is a human, the T of component 1 max In order to keep this within the aforementioned range, the person to whom the liquid pharmaceutical formulation of the present invention is administered may be, for example, a postmenopausal woman.

[0065] The T of component 1 obtained when the liquid pharmaceutical formulation of the present invention is administered subcutaneously as a single dose. max This can be measured and confirmed by a method known to the public. The site of subcutaneous administration is not particularly limited, but areas with few nerves or blood vessels, plenty of subcutaneous fat, and no bone are preferred. Preferred such areas include the abdomen, upper arm, thigh, and buttocks, with the abdomen being the most preferred.

[0066] Component 1 T max When measuring, it is preferable to ensure a sufficient number of measurement points. For example, as in the various evaluation procedures in the examples described later, it is preferable to collect blood samples before administration, 5, 15, 30, and 45 minutes after administration, and 1, 1.5, 2, 3, 4, and 6 hours after administration, and measure the concentration of component 1 in the plasma.

[0067] (6) The time during which the concentration of teriparatide or its salt (component 1) is maintained above a specific threshold: The effects of a drug generally tend to increase as its blood concentration rises. For example, in the case of time-dependent antibiotics, Time above MIC (the time the blood concentration remains above the minimum inhibitory concentration (MIC)) is important in determining its action.

[0068] On the other hand, teriparatide is known to be involved in calcium homeostasis in the body, and high blood calcium levels are known to be one of the causes of nausea associated with teriparatide administration (Non-Patent Literature 23). Furthermore, repeated administration of teriparatide can maintain or enhance high blood calcium levels due to its physiological activity, and as a result, the risk of side effects such as hypercalcemia and hypercalciuria may be a concern.

[0069] In the present invention, one embodiment is a liquid pharmaceutical preparation in which the time elapsed after a single subcutaneous administration of teriparatide or its salt to a specific threshold is within a specific range, and two embodiments of the specific threshold can be exemplified.

[0070] If one is designated as a specific threshold a and the other as a specific threshold b, then both specific thresholds a and b are not particularly limited, but specific threshold a is preferably 50 (pg / mL) or higher, and can be 60 (pg / mL) or higher, or 80 (pg / mL) or higher. The upper limit of specific threshold a is preferably 200 (pg / mL) or lower, 150 (pg / mL) or lower, or 120 (pg / mL) or lower. A preferred example of specific threshold a is 100 (pg / mL). By keeping the time elapsed in which the plasma component 1 concentration is 100 (pg / mL) or higher above specific threshold a within a specific range, the increase in blood calcium concentration associated with a single administration is preferably suppressed. Suppression of the increase in blood calcium concentration can contribute to reducing the frequency of gastrointestinal side effects and / or the risk of developing hypercalcemia / urinary tract disease.

[0071] Here, the specific range of elapsed time is not particularly limited, but it can be within 3 hours, and preferably less than 2.5 hours, less than 2.1 hours, less than 2.0 hours, less than 1.73 hours, less than 1.7 hours, less than 1.5 hours, and even less than 1.0 hour. The lower limit is also not particularly limited, but it can be 0.5 hours or more, 0.7 hours or more, and even more than 0.8 hours. Among these, it is even more preferable that it be less than 2.1 hours, 0.7 to 2.1 hours, less than 1.7 hours, or 0.7 to 1.7 hours.

[0072] As mentioned above, the specific threshold b is not particularly limited, but it is preferably 100 (pg / mL) or higher, can be 150 (pg / mL) or higher, or 200 (pg / mL) or higher, and preferably has an upper limit of 500 (pg / mL) or lower, 400 (pg / mL) or lower, or 300 (pg / mL) or lower. A preferred example of the specific threshold b is 250 (pg / mL). By having the elapsed time during which the plasma component 1 concentration is 1 or higher than the specific threshold b fall within a specific range, it is possible to preferably demonstrate excellent safety associated with a single dose (particularly safety in which the frequency of gastrointestinal side effects is suppressed).

[0073] The aforementioned elapsed time is not particularly limited, but can be less than 1.4 hours, preferably less than 1.3 hours, less than 1.2 hours, less than 1.1 hours, less than 1.0 hours, and more preferably less than 0.9 hours, less than 0.8 hours, or less than 0.7 hours. The lower limit is also not particularly limited, but can be 0.0 hours or more, and more preferably 0.1 hours or more. Among these, less than 0.8 hours and 0.1 hours or more are more preferable.

[0074] When administering the liquid pharmaceutical formulation of the present invention as a single subcutaneous dose, it is generally considered that increasing or decreasing the dose of component 1 per dose tends to increase or decrease the plasma concentration of component 1. Therefore, since the elapsed time during which the plasma concentration of component 1 is above a specific threshold is within a specific range, it is preferable to appropriately adjust the dose of component 1 per dose within the aforementioned range, and it is most preferable to use 28.2 μg of teriparatide.

[0075] It can be considered that the ionization of component 1 contained in the liquid pharmaceutical formulation of the present invention may affect the absorption of component 1 when administered subcutaneously. Therefore, in order to adjust the time elapsed in which the plasma concentration of component 1 is above a specific threshold, component 1 contained in the liquid pharmaceutical formulation of the present invention may be a salt of teriparatide with one or more volatile organic acids, or the pH of the liquid pharmaceutical formulation of the present invention may be appropriately adjusted with reference to the examples described later. Furthermore, for a similar purpose, additives to the liquid pharmaceutical formulation of the present invention may be appropriately selected with reference to the examples described later.

[0076] Furthermore, in order to define the elapsed time as the time elapsed from the point in time when component 1 reaches the specified threshold to the point in time when it falls below that threshold, it is preferable to appropriately adjust the concentration of component 1 contained in the liquid pharmaceutical preparation of the present invention within the above range, for example, it can be 80-240 μg / mL, 100-200 μg / mL, 109-190 μg / mL, or 120-160 μg / mL.

[0077] In the case where there are two specific thresholds for component 1 (specific thresholds a and b, where b > a), the T of component 1 maxBy making it smaller, the elapsed time (elapsed time a) from the point in time when a specific threshold a is reached to the point in time when it falls below that value may become shorter, but excessive T max Reducing the value may increase the elapsed time (elapsed time b) from the point in time when a specific threshold b is reached to the point in time when it falls below that value. Therefore, in such cases, it is preferable to shorten both elapsed time a and elapsed time b in a balanced manner to optimize the safety of a single dose. More specifically, for example, the concentration of component 1 contained in the liquid pharmaceutical preparation of the present invention may be set to the aforementioned concentration range, or the T of component 1 may be set. max It is desirable to set the above time range.

[0078] By increasing the concentration of component 1 contained in a liquid pharmaceutical preparation, the absorption rate constant (Ka) of component 1 obtained when the liquid pharmaceutical preparation is administered subcutaneously to the target patient becomes larger (Non-Patent Literature 26). As the Ka of component 1 increases, the T of component 1 max The time interval is shortened, and as a result, the slope of the elimination phase of the concentration of component 1 in plasma may become larger (i.e., the flip-flop phenomenon is resolved, so the slope of the elimination phase may approach the elimination rate constant). max By shortening the time interval and increasing the slope of the elimination phase of the concentration of component 1 in the plasma, the elapsed time from the point in time when component 1 reaches the specified threshold to the point in time when it falls below that threshold can be shortened.

[0079] In the present invention, when the target of administration is a human, the human to whom the liquid pharmaceutical formulation of the present invention is administered is preferably female, 45 years of age or older (preferably 50 years of age or older), and weighs 42 to 62 kg (preferably 45 to 60 kg).

[0080] Furthermore, in the present invention, when the target of administration is a human, the human to whom the liquid pharmaceutical preparation of the present invention is administered may be, for example, a postmenopausal woman, in order to adjust the elapsed time during which the plasma component 1 concentration is above a specific threshold (Non-Patent Literature 27).

[0081] Alternatively, in the present invention, if the target of administration is a human, the dosage of the liquid pharmaceutical preparation of the present invention can be appropriately adjusted by a physician or other professional according to the body weight of the person to whom it is administered.

[0082] The plasma component 1 concentration obtained when the liquid pharmaceutical formulation of the present invention is administered subcutaneously as a single dose can be measured and confirmed by a method known to the present invention (see Figure 6). The site of subcutaneous administration is not particularly limited, but a site with few nerves and blood vessels, a lot of subcutaneous fat, and no bone is preferred. Preferred sites include the abdomen, upper arm, thigh, and buttocks, with the abdomen being the most preferred.

[0083] When measuring the concentration of component 1 in plasma, it is preferable to ensure a sufficient number of measurement points. For example, as in the various evaluation procedures in the examples described later, it is preferable to collect blood samples before administration, 5, 15, 30, and 45 minutes after administration, and 1, 1.5, 2, 3, 4, and 6 hours after administration, and measure the concentration of component 1 in plasma.

[0084] (7) pH, additives, buffers: The pH of the liquid pharmaceutical formulation in the present invention is not particularly limited, but the following are preferred examples. That is, the pH of the liquid pharmaceutical formulation is preferably 3.5 or higher, 4.0 or higher, greater than 4.0, 4.2 or higher, or 4.4 or higher. The pH of the liquid pharmaceutical formulation is preferably 6.0 or lower, 5.5 or lower, 5.0 or lower, less than 5.0, 4.9 or lower, or 4.8 or lower. Among these, it is preferable to have a pH of 5.0 or lower, more preferably 4.0 or higher and 5.0 or lower, 4.0 or higher and less than 5.0, 4.2 or higher and less than 5.0, and most preferably 4.4 or higher and 4.9 or lower. By setting the pH of the formulation within the above range, excellent stability (e.g., suppression of the formation of deamide and cleaved products (31-34) of component 1) and / or pharmacokinetics can be efficiently obtained.

[0085] Furthermore, the liquid pharmaceutical formulation of the present invention may contain various additives. Examples of additives include solubilizers, stabilizers, isotonic agents, pH adjusters, and preservatives. Examples of additives include sodium chloride, D-mannitol, sucrose, and L-methionine. Examples of pH adjusters include hydrochloric acid and sodium hydroxide.

[0086] Furthermore, the liquid pharmaceutical formulation of the present invention may contain buffering agents commonly used in the pharmaceutical field. Alternatively, the formulation of the present invention may be a liquid pharmaceutical formulation that substantially does not contain buffering agents, and in particular, a liquid pharmaceutical formulation that substantially does not contain an acetate buffering agent preferably allows for efficient acquisition of excellent pharmacokinetics.

[0087] When the liquid pharmaceutical formulation of the present invention contains at least one inorganic salt and / or organic salt, its concentration is not particularly limited, but is preferably 2 mg / mL or higher, more preferably 3 mg / mL or higher, and most preferably 5.5 mg / mL or higher. On the other hand, it is preferably 25 mg / mL or lower, and most preferably 11 mg / mL or lower.

[0088] When the liquid pharmaceutical formulation of the present invention contains at least one inorganic salt and / or organic salt, the mass ratio of the inorganic salt to teriparatide or its salt (mass ratio of component 1 to component 2) is not particularly limited, but the lower limit is preferably 1:5 or higher, more preferably 1:10 or higher, or more preferably 1:15 or higher, even more preferably 1:20 or higher, and most preferably 1:35 or higher. On the other hand, the upper limit is preferably 1:500 or lower, more preferably 1:300 or lower, and most preferably 1:80 or lower.

[0089] The pH of the liquid pharmaceutical formulation of the present invention can be adjusted by methods known to the present day, for example, by using a buffer or a pH adjuster.

[0090] Furthermore, as one embodiment of the liquid pharmaceutical formulation of the present invention, a liquid pharmaceutical formulation can be exemplified that contains 28.2 μg or 56.5 μg of teriparatide acetate in terms of teriparatide as a single dose, excluding lyophilized formulations that also contain sodium chloride and refined sucrose. Furthermore, as one embodiment of the liquid pharmaceutical formulation of the present invention, a liquid pharmaceutical formulation can be exemplified that contains glacial acetic acid, sodium acetate (which may be anhydrous), and D-mannitol, and has a pH of 3.8 to 4.5 (for example, a pH of 4.1), excluding liquid pharmaceutical formulations. Alternatively, as one embodiment of the liquid pharmaceutical formulation of the present invention, a liquid pharmaceutical formulation can be exemplified that contains 28.2 μg or 56.5 μg of teriparatide acetate in terms of teriparatide as a single dose, excluding lyophilized formulations. Furthermore, as one embodiment of the liquid pharmaceutical formulation of the present invention, examples include liquid pharmaceutical formulations excluding lyophilized formulations containing component 1 and monosaccharides (e.g., mannitol, glucose, sorbitol, inositol). Alternatively, as one embodiment of the liquid pharmaceutical formulation of the invention, examples include liquid pharmaceutical formulations excluding liquid pharmaceutical formulations containing component 1 and xylitol.

[0091] (8) Freeze drying: The liquid pharmaceutical formulation of the present invention may include a form of liquid pharmaceutical formulation reconstituted from a lyophilized formulation, or it may not be a liquid pharmaceutical formulation reconstituted from a lyophilized formulation. Conventionally, it is known that a lyophilized formulation containing teriparatide or a salt thereof is prepared as a liquid pharmaceutical formulation by dissolving (redissolving) it in physiological saline solution or the like at the time of use. However, the liquid pharmaceutical formulation of the present invention may be a redissolved product of such a lyophilized formulation (a product prepared at the time of use), or it may be a formulation that does not go through a lyophilized formulation (a formulation that has been pre-liquidated). The present invention makes it possible to provide a formulation with good pharmacokinetics even without going through a lyophilized formulation.

[0092] (9) Pharmacokinetics: In one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the α-helix content of teriparatide or its salt (component 1) is within a specific range (for example, 13.0% or more). Furthermore, in one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the number of α-helix-forming amino acid residues in component 1 is within a specific range (for example, 4.5 or more). Such a subcutaneous liquid pharmaceutical formulation provides excellent pharmacokinetics.

[0093] When liquid pharmaceutical formulations are administered to mammals such as humans and monkeys, the extent to which they reach the systemic circulation and exert their effects is a crucial issue. Generally, when liquid pharmaceutical formulations are administered intravenously, the drug in the formulation is almost completely utilized by the body. However, when administered non-intravenously (oral, rectal, transdermal, subcutaneous, etc.), not all of it reaches the circulation. AUC (area under the plasma concentration-time curve) is often used as an indicator to measure the amount that reaches the systemic circulation. In addition, the ratio of the AUC obtained by non-intravenous administration to the AUC obtained by intravenous administration is sometimes used as the (absolute) bioavailability (%) to evaluate the bioavailability of a drug. Improving pharmacokinetic parameters such as AUC and bioavailability when administered non-intravenously is important for enhancing the therapeutic effect and safety of the drug.

[0094] The pharmacokinetics of liquid pharmaceutical formulations can be evaluated using various pharmacokinetic parameters as indicators. Examples of pharmacokinetic parameters include the time to reach peak plasma concentration (T). max ), maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC), and bioavailability (%) are preferred examples. AUC is not particularly limited, but for example, inf (Area under the plasma concentration-time curve up to infinity), AUC last Examples include the area under the plasma concentration-time curve (AUCτ) obtained during one dosing interval in repeated administration (AUCτ from time zero to dosing interval time τ).

[0095] While the administration site is not particularly limited when evaluating pharmacokinetic parameters, areas with few nerves or blood vessels, abundant subcutaneous fat, and no bone are preferred. Preferred such sites include the abdomen, upper arm, thigh, and buttocks, with the abdomen being the most preferred.

[0096] The method for calculating pharmacokinetic parameters is not particularly limited, and they can be calculated using either pharmacokinetic model-independent analysis or pharmacokinetic model-dependent analysis (e.g., 1-compartment model) (Non-Patent Literature 6). However, it is preferable that they be calculated using a pharmacokinetic model-independent analysis, i.e., NCA (Non-Compartmental Analysis). Examples of AUC calculation methods in NCA include the linear trapezoidal rule and the log linear trapezoidal rule. For example, the time to reach peak plasma concentration (T max For absorption phases up to T, the linear trapezoidal method is used. max In subsequent phases of disappearance, the AUC can also be calculated using the log-linear trapezoidal method.

[0097] When calculating pharmacokinetic parameters, it is preferable to ensure a sufficient number of measurement points. For example, as shown in the various evaluation procedures in the examples described later, blood samples can be collected before administration, 5, 15, 30, and 45 minutes after administration, and 1, 1.5, 2, 3, 4, and 6 hours after administration, to measure the concentration of teriparatide or salt in the plasma.

[0098] To calculate the pharmacokinetic parameters of liquid pharmaceutical formulations, it is preferable to ensure a sufficient number of samples. Each pharmacokinetic parameter may be the mean value obtained by adding the values ​​shown by each case and dividing by the number of samples, or it may be the median value obtained by ranking the values ​​shown by each case. To obtain the pharmacokinetic parameters of multiple types of liquid pharmaceutical formulations, between-group comparative studies and crossover studies can be used. Teriparatide is relatively easy to wash out, and because it allows for a compact sample size, it is preferable to apply crossover studies to obtain the pharmacokinetic parameters of multiple types of liquid pharmaceutical formulations.

[0099] As an indicator of pharmacokinetics, the absolute bioavailability (%) of component 1 can be calculated, for example, using the following formula.

number

[0100] AUC inf Due to measurement errors, etc., an absolute bioavailability (%) exceeding the theoretical upper limit of 100% may be obtained. The absolute bioavailability (%) of component 1 is not particularly limited, but preferably includes the following examples. That is, it is preferable to have a bioavailability of 70% or more, 80% or more, 90% or more, 95% or more, 100% or more, or 110% or more. Furthermore, it is preferable to have an upper limit of 180% or less, 160% or less, or 150% or less. Among these, it is preferable to have a bioavailability of 90% or more and 160% or less, and most preferably 100% or more and 150% or less.

[0101] Component 1 C max While not particularly limited, the following are preferred examples. Specifically, it is preferable that the values ​​are 230 (pg / mL) or higher, 240 (pg / mL) or higher, or 250 (pg / mL) or higher. Furthermore, as upper limits, for example, it is preferable that the values ​​are 380 (pg / mL) or lower, 360 (pg / mL) or lower, or 350 (pg / mL) or lower. Among these, 250 to 350 (pg / mL) is preferred.

[0102] AUC of component 1 last While not particularly limited, the following are preferred examples. Specifically, it is preferable that the values ​​are 350 (hr·pg / mL) or higher, 360 (hr·pg / mL) or higher, 370 (hr·pg / mL) or higher, 380 (hr·pg / mL) or higher, and 390 (hr·pg / mL) or higher. Furthermore, as upper limits, for example, it is preferable that the values ​​are 600 (hr·pg / mL) or lower, 580 (hr·pg / mL) or lower, 570 (hr·pg / mL) or lower, 550 (hr·pg / mL) or lower, and 530 (hr·pg / mL) or lower. Among these, it is preferable that the values ​​be between 350 and 550 (hr·pg / mL).

[0103] AUC of component 1 inf While not particularly limited, the following are preferred examples. Specifically, it is preferable that the values ​​are 380 (hr·pg / mL) or higher, 390 (hr·pg / mL) or higher, 400 (hr·pg / mL) or higher, and 420 (hr·pg / mL) or higher. Furthermore, as upper limits, for example, it is preferable that the values ​​are 650 (hr·pg / mL) or lower, 600 (hr·pg / mL) or lower, 590 (hr·pg / mL) or lower, 580 (hr·pg / mL) or lower, and 560 (hr·pg / mL) or lower. Among these, it is preferable that the values ​​be between 400 and 600 (hr·pg / mL).

[0104] Absolute bioavailability (%) of component 1, T max , C max AUC last、 AUC inf It is preferable that at least 1 of the range be set to the above range.

[0105] However, the mechanism by which these groundbreaking results were achieved remains unknown.

[0106] In terms of pharmacokinetics, for example, subcutaneous antibody preparations used in clinical practice generally have only 50-60% bioavailability. While it has been reported that the factors potentially inducing this low bioavailability include the charge and hydrophobicity of the proteins in the preparation, the additive components, the dosage, and the depth of administration, as well as the adsorption of positively charged antibodies to subcutaneous tissue (Non-Patent Literature 7), no indication or suggestion has been made regarding the influence of the secondary structure of the antibodies in the preparation on bioavailability. Another report indicates that when a lyophilized teriparatide acetate preparation (with purified sucrose and sodium chloride as additives) is dissolved in physiological saline (pH 5.0-7.0), the peak blood concentration is reached in approximately 35-50 minutes, and the AUC is high. inf It has also been disclosed that the absolute bioavailability calculated from is nearly 100% (see the "[Pharmacokinetics] 2. Bioavailability" section in Non-Patent Literature 1), but no indication has been given of the effect of the secondary structure of teriparatide acetate in the drug solution on bioavailability.

[0107] On the other hand, regarding aspects of the secondary structure of teriparatide, for example, it has been reported that in aqueous solution, teriparatide is mainly flexible and elongated, with the exception of a non-random substructure at positions 20-24 from the N-terminus (Arg-Val-Glu-Trp-Leu), and that the secondary structure is hardly observed by two-dimensional NMR measurement (Non-Patent Literature 12). However, this document does not suggest any influence of the secondary structure of teriparatide on its pharmacokinetics such as absorption, metabolism, and excretion.

[0108] Thus, it is difficult to consider the effect of the secondary structure of teriparatide on its pharmacokinetics based solely on conventional reports. Under these circumstances, the inventors will now discuss the mechanism by which they were able to obtain the groundbreaking results described above.

[0109] The skin plays a crucial role in maintaining homeostasis by separating the internal and external environments of the body. To fulfill this role, it possesses various functions and a complex structure to achieve them. When the skin is observed in cross-section, it can be seen that it has a roughly three-layered structure: the epidermis, dermis, and subcutaneous tissue. The subcutaneous tissue is mainly composed of adipose tissue and is responsible for storing triglycerides, providing insulation, and acting as a cushion against external forces.

[0110] Since the composition of a pharmaceutical preparation administered subcutaneously differs from the structure of the subcutaneous tissue to which it is administered, it has been suggested that various stresses may affect the stability, solubility, and function of the drug after it has been administered subcutaneously and before it reaches the blood vessels and lymphatic vessels (Non-Patent Literature 8). As described in Non-Patent Literature 8, examples of stress include: 1) steric impairment, electrostatic interactions, and specific interactions in the extracellular matrix (Table 4); 2) the effect of pH changes before and after administration on the protective effect of additives contained in each pharmaceutical preparation on the drug (pp. 27-28); 3) aggregation of the drug and adsorption to subcutaneous tissue due to rapid movement of additives after administration (Figure 5D); 4) the effect of pH changes before and after administration on the stability of the drug (p. 29); 5) the effect of temperature changes near the drug before and after administration on the absorption of the drug (p. 29); and 6) the effect of changes in interstitial fluid hydrostatic pressure or colloid osmotic pressure due to administration on the stability of the drug (pp. 29-30).

[0111] While the inventors are not bound by this, one theory is that the α-helix content in teriparatide or its salts is involved in at least one of the above-mentioned stresses.

[0112] The involvement here is not particularly limited, as long as it is a mechanism by which teriparatide or its salts administered subcutaneously exhibit superior pharmacokinetics. For example, one possible approach is to consider a mechanism in which the α-helix or the amount thereof in teriparatide or its salts increases its bioavailability (%) by 1) improving vascular endothelial permeability.

[0113] Vascular endothelial cells are cells that make up the innermost layer of blood vessels that circulate throughout the body, and they play important roles in the adhesion of inflammatory cells to blood vessels, vascular permeability, and regulation of the coagulation and fibrinolytic systems. On the other hand, it is known that their α-helix plays a significant role in the membrane permeability of peptides (Non-Patent Literature 28).

[0114] Therefore, one possible theory is that when teriparatide or its salt administered subcutaneously contains a certain amount of α-helices, the membrane permeability of the peptide to vascular endothelial cells increases compared to cases where α-helices are not present, leading to increased transfer into the bloodstream and, consequently, a higher bioavailability (%).

[0115] Furthermore, one possible approach is to suggest that teriparatide or its salts may increase their bioavailability (%) by directly or indirectly suppressing various impairments and interactions in the extracellular matrix, such as the α-helix or its quantity.

[0116] The extracellular matrix is ​​a supramolecular structure located outside the cell, playing a skeletal role, providing a scaffold for cell adhesion, and participating in signal transduction. The extracellular matrix is ​​composed of structural proteins (such as collagen) and proteoglycans. Proteoglycans are complexes in which glycosaminoglycans (sometimes referred to as GAGs) are covalently bonded to a core protein; examples of GAGs include chondroitin sulfate, hyaluronic acid, and heparin. Collagen and GAGs are also known to potentially trigger specific interactions with subcutaneously administered drugs (Non-Patent Literature 8).

[0117] On the other hand, it is known that the parathyroid hormone PTH(1-84) induces an α-helix through interaction with heparin and various polyanionic substances (Non-Patent Literature 29). Based on the idea that the interaction between GAGs and various proteins regulates various biological phenomena in disease stages, and that heparin, when interacting with heparin-binding proteins, prioritizes the protein with its native structure, a model has been proposed in which PTH(1-84) undergoes structural changes such as an α-helix through interaction with GAGs, and that PTH(1-84) that has undergone such structural changes binds to the receptor (Non-Patent Literature 29).

[0118] Therefore, one possible theory is that when alpha-helices are present in teriparatide or its salts administered subcutaneously, the interaction with GAGs is attenuated compared to cases where they are not present, resulting in a mechanism that increases bioavailability (%). The mechanism by which alpha-helices affect the interaction between teriparatide or its salts and GAGs is not particularly limited, but it could be considered, for example, as a change in the polarity-nonpolarity balance in teriparatide or its salts.

[0119] Previous reports have indicated that teriparatide is primarily flexible and elongated in aqueous solutions (Non-Patent Document 12), leading the inventors to consider that there is a high probability that there is no significant difference in tertiary structure.

[0120] Furthermore, no clear relationship was found between the zeta potential and pharmacokinetics of teriparatide in aqueous solution. Based on these findings, the inventors believe that the relationship between the α-helix content and the number of α-helix-forming amino acid residues of teriparatide in aqueous solution and its pharmacokinetics has become clearer.

[0121] In teriparatide, the amino acid residues forming the α-helix may be any of the 1st to 34th positions at the N-terminus, and are not particularly limited; for example, they may be positions 3 to 12, 17 to 26, etc. These amino acid residues appear to readily form helix structures. Therefore, in the formulation of the present invention, at least one of these amino acid residues may form an α-helix.

[0122] In particular, of these amino acid residues (3-12, 17-26), an average of 4 or more (for example, 4.2 or more, 4.4 or more, 4.42 or more, 4.5 or more, 4.59 or more, 4.6 or more, 4.69 or more, or 4.7 or more) may form an α-helix. Also, of these amino acid residues (3-12, 17-26), an average of 20 or fewer (for example, 18 or fewer, 16 or fewer, 15 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6.8 or fewer, 6.5 or fewer, 6.1 or fewer, 5.5 or fewer, 5.44 or fewer, 5.4 or fewer, or 5.37 or fewer) may form an α-helix.

[0123] Furthermore, among the amino acid residues, at least one amino acid residue selected from the 13th (lysine residue), 14th (histidine residue), and 27th (lysine residue) from the N-terminus may form an α-helix. Since all of these residues are basic amino acid residues, it is presumed that they are positively charged when administered to subcutaneous tissue.

[0124] These amino acid residues appear to be relatively strongly affected by any of the aforementioned stresses, and by forming α-helices around these amino acid residues, efficient and favorable pharmacokinetics can be obtained.

[0125] (10) Safety: In one embodiment of the liquid pharmaceutical formulation of the present invention, the single dose of teriparatide or its salt is a specific amount (e.g., 28.2 μg). Alternatively, in one embodiment of the liquid pharmaceutical formulation of the present invention, the time (T) to reach the peak plasma concentration of teriparatide or its salt obtained by a single dose. max The duration of time elapsed is within a specific range (e.g., less than 0.7 hours). Alternatively, in one embodiment of the subcutaneous liquid pharmaceutical formulation of the present invention, the time elapsed during which the plasma concentration of teriparatide or its salt obtained by a single dose is above a specific threshold (e.g., 100 pg / mL or 250 pg / mL) is within a specific range (e.g., less than 2.1 hours or less than 1.0 hour). Excellent safety can be obtained with these subcutaneous liquid pharmaceutical formulations.

[0126] Here, safety encompasses both adverse events, which are all undesirable medical occurrences, and side effects, where a causal relationship between the adverse event and the drug cannot be ruled out.

[0127] Serious adverse events include death and disability, but safety in this invention is not limited to these and includes all risks that may affect the evaluation of the efficacy (benefit) of the drug.

[0128] The types and degrees of safety are not particularly limited, and include, for example, disorders or undesirable symptoms occurring in the skin and skin appendages, muscles and skeleton, central and peripheral nerves, autonomic nerves, vision, smell, psychiatry, gastrointestinal tract, liver and bile ducts, metabolic and nutritional disorders, endocrine system, cardiovascular system, respiratory system, blood cells and platelets, urinary system, reproductive system, and the entire body, without limiting their severity or frequency. Preferably, gastrointestinal side effects and the risk of hypotension can be given as examples, and among these, the frequency of nausea, vomiting, and vomiting can be given as the most preferred example.

[0129] Pharmaceuticals, such as those used to treat lifestyle-related diseases, are often used repeatedly and continuously over long periods, and continuing treatment is crucial for achieving good results. However, repeated administration of a drug can increase trough levels, potentially intensifying side effects. Treatment discontinuation due to such increased side effects can negatively impact the effectiveness of the treatment.

[0130] Alternatively, a transient increase in the blood concentration of a drug may occur with each administration, leading to frequent or severe side effects. In such cases, the undesirable outcome of treatment discontinuation may result.

[0131] Thus, it is desirable that safety be considered both each time a drug is administered and over the period of continuous use. In other words, it is preferable that a drug possesses safety in terms of both single-dose administration and repeated, continuous administration.

[0132] The liquid pharmaceutical formulation of the present invention preferably exhibits improved safety associated with a single dose compared to conventional pharmaceutical formulations containing teriparatide. Examples of improved safety associated with a single dose, though not limited to these, preferably include a reduction in the frequency of gastrointestinal side effects and / or the risk of hypotension associated with a single dose.

[0133] (11) Properties etc.: The liquid pharmaceutical formulation of the present invention is preferably colorless and clear, at least during its manufacture, and its osmotic pressure ratio to physiological saline can be about 1 (e.g., 1.0 to 1.4).

[0134] 2. Manufacturing method for liquid pharmaceutical preparations: The liquid pharmaceutical formulation of the present invention can be manufactured by various known manufacturing methods. Typically, the various components constituting the liquid pharmaceutical formulation of the present invention can be appropriately selected and mixed and dissolved in a suitable solvent.

[0135] When manufacturing the subcutaneous liquid pharmaceutical preparation of the present invention, it is preferable to use an aqueous liquid pharmaceutical preparation. In the case of an aqueous liquid pharmaceutical preparation, it is preferable that it be sterilized before administration. When an aseptic technique is used as the sterilization treatment, the liquid pharmaceutical preparation can be manufactured by dissolving each weighed raw material in water for injection or the like, and then filtering and sterilizing the dissolved solution. Water for injection is generally understood as sterile purified water that has passed the pyrogenic substance (endotoxin) test, and water for injection produced by distillation is sometimes referred to as distilled water for injection.

[0136] This liquid pharmaceutical preparation for injection can be further filled and sealed into washed and sterilized containers, and after inspection and packaging, an injectable drug can be manufactured by filling the liquid pharmaceutical preparation for injection. Examples of containers include ampoules, vials, pre-filled syringes, and bags. The material of the container is not particularly limited, but glass and plastic can be used. From the viewpoint of strength, ease of handling, and safety, plastic can be preferably used as the material of the container.

[0137] 3. Methods to improve pharmacokinetic parameters: In one aspect, the present invention provides a method for improving the pharmacokinetic parameters of a liquid pharmaceutical preparation containing component 1 when the preparation is administered subcutaneously, the method comprising adjusting (increasing, for example) the α-helix content of component 1 and / or the number of α-helix-forming amino acid residues in component 1.

[0138] This method can be implemented, for example, by sequentially carrying out the following steps. Step 1) Prepare a liquid pharmaceutical preparation containing component 1 such that the α-helix content of component 1 is within the specified range (e.g., 13.0% or more) and / or the number of α-helix-forming amino acid residues in component 1 is within the specified range (e.g., 4.5 or more). Step 2) The liquid pharmaceutical preparation is administered subcutaneously to a human, and blood samples are collected from the human before administration and at multiple time points after administration. Step 3) Measure the concentration of component 1 in the blood sample at each time point. Step 4) Calculate a numerical value A of a certain pharmacokinetic parameter a from the concentration of component 1 at each time point. Step 5) When a liquid pharmaceutical preparation containing component 1, in which the α-helix content and / or the number of α-helix-forming amino acid residues in component 1 are outside the specified range, is administered subcutaneously to a human, the numerical value B of the pharmacokinetic parameter a obtained is compared with numerical value A, and it is determined whether numerical value A is better than numerical value B.

[0139] When the pharmacokinetic parameter is the absolute bioavailability (%) of component 1, an increase in this value signifies an improvement in the pharmacokinetic parameter. The pharmacokinetic parameter is the AUC of component 1. last or AUC inf If this is the case, an increase in that value means an improvement in the pharmacokinetic parameter.

[0140] Furthermore, in one embodiment, the present invention provides a method for improving the pharmacokinetic parameters of component 1 when a liquid pharmaceutical preparation containing teriparatide or a salt thereof is administered subcutaneously, characterized by implementing at least one of the following: 1) setting the single dose of component 1 to the aforementioned specific amount (e.g., 28.2 μg), 2) setting the concentration of component 1 within a specific range (e.g., 120-160 μg / mL), 3) making component 1 a salt of one or more volatile organic acids, 4) adjusting the pH of the liquid pharmaceutical preparation, and 5) appropriately including additives in the preparation. Here, the improvement of the pharmacokinetic parameters is the T of component 1. max This can be confirmed by measuring whether the value falls within the aforementioned range (e.g., 0.2 to 0.7 hours).

[0141] 4. How to manage quality: In one aspect, the present invention provides a method for controlling the quality of a liquid pharmaceutical preparation for subcutaneous administration containing component 1, comprising measuring the α-helix content of component 1 and / or the number of α-helix-forming amino acid residues in component 1 in the liquid pharmaceutical preparation, comparing the obtained measured values ​​of the α-helix content and / or the number of α-helix-forming amino acid residues in component 1 with a predetermined reference value, and determining that the quality of the liquid pharmaceutical preparation is maintained if the measured values ​​are equal to or greater than the reference value.

[0142] Here, the predetermined standard value is the lower limit of the specific range of α-helix content of component 1 (e.g., 13.0% or more).

[0143] Furthermore, the value to be compared with the reference value may be the number of α-helix structure-forming residues, in which case the predetermined reference value shall be the lower limit of the α-helix structure-forming residue range in component 1 (e.g., 4.5 or more).

[0144] Alternatively, the value to be compared to the reference value can be the average residue molar ellipticity [θ] obtained by circular dichroism (CD) spectroscopy (measurement wavelength 222 nm), in which case the predetermined reference value is the upper limit of the range of the average residue molar ellipticity [θ] obtained by circular dichroism spectroscopy (e.g., -6300 or less).

[0145] Here, the quality of a liquid pharmaceutical formulation refers to, for example, the pharmacokinetic parameters obtained when the liquid pharmaceutical formulation is administered subcutaneously as a single dose. These pharmacokinetic parameters include the absolute bioavailability (%) and AUC of component 1. last AUC inf Examples of such cases are preferable. [Examples]

[0146] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples and can be implemented in any form without departing from the spirit of the invention.

[0147] In addition, in the following examples, the term "formulation" may be used as a term equivalent to the "liquid pharmaceutical preparation" of the present invention.

[0148] Example 1 (Preparation of liquid pharmaceutical formulation): (1) Preparation of liquid pharmaceutical formulations used in pharmacokinetic studies in monkeys: Formulations A to H were prepared according to Tables 1 to 2 below. These formulations are, in terms of their composition, almost identical to formulations A to H described later in "(2) Preparation of liquid pharmaceutical formulations used in human pharmacokinetic studies".

[0149] Prescriptions A to D were prepared according to Table 1 below. The specific preparation method for each formulation is as follows: First, the additive solutions listed in the "Additives" column of the table were mixed and diluted to approximately 46 mL with sterile water for injection. Then, 2.5 mL of teriparatide acetate solution (2820 μg / mL as teriparatide) was added to the mixture to prepare approximately 48.5 mL of drug solution a. Here, sterile water for injection was used as the solvent for each additive solution and the teriparatide acetate solution. Furthermore, hydrochloric acid was added to drug solution a to adjust the pH to the pH listed in the "pH" column of the table, and a total volume of 50 mL of formulation was prepared using sterile water for injection.

[0150] After sterilizing each formulation by filtration, 1.5 mL of each formulation was filled into plastic vials to produce plastic vials containing each formulation, which were then used in pharmacokinetic studies in monkeys.

[0151] The composition of each formulation is as indicated in the "Final Content" column of the table. [Table 1]

[0152] Furthermore, prescriptions E to H were prepared according to Table 2 below. The specific preparation method for each formulation is as follows: First, each additive listed in the "Additives" column of the table was mixed with sterile water for injection to a total volume of 3000 mL. Then, teriparatide acetate (282 mg as teriparatide) was added to 1600 mL of this mixture and dissolved to prepare drug solution a. Furthermore, diluted hydrochloric acid was added to drug solution a to adjust the pH to the pH listed in the "pH" column of the table, and then the total volume was reduced to 2000 mL with sterile water for injection to prepare the formulation.

[0153] After sterilizing each formulation by filtration, 1.5 mL of each formulation was filled into plastic vials to produce plastic vials containing each formulation, which were then used in pharmacokinetic studies in monkeys.

[0154] The composition of each formulation is as indicated in the "Final Content" column of the table. [Table 2]

[0155] (2) Preparation of liquid pharmaceutical formulations used in human pharmacokinetic studies: Formulas A to H were prepared according to Table 3 below.

[0156] The specific preparation methods for each prescription are as follows: First, each additive listed in the "Additives" column of the table (however, L-methionine is a pre-dissolved L-methionine solution) was mixed with sterile water for injection, and teriparatide acetate (1425.6 mg as teriparatide) was added to prepare 9.5 kg of drug solution a. Then, diluted hydrochloric acid was added to drug solution a to adjust the pH to the pH listed in the "pH" column of the table, and then 10.10 kg of the prescription was prepared using sterile water for injection.

[0157] After sterilizing each formulation by filtration, ampoules containing 2 mL of each formulation were prepared (formulation formulations) and subjected to human pharmacokinetic studies. Each formulation formulation had a formulation volume of 0.2 mL and contained a formulation with a single dose equivalent to 28.2 μg of teriparatide acetate.

[0158] The composition of each formulation is as indicated in the "Final Content" column of the table. [Table 3]

[0159] (3) Preparation of control liquid pharmaceutical formulation: (3-1) Preparation of control formulation 1: A commercially available lyophilized teriparatide preparation ("Teribone Subcutaneous Injection 56.5 μg," manufactured by Asahi Kasei Pharma Co., Ltd.; Non-Patent Literature 1) was dissolved in 0.45 mL of Japanese Pharmacopoeia physiological saline solution. 0.2 mL of this solution was taken using a syringe to prepare Control Formula 1, and the syringe filled with Control Formula 1 was used as the Control Formula 1 preparation. Control Formula 1 has a volume of 0.2 mL, a teriparatide acetate concentration of 141 μg / mL (in teriparatide equivalent), and contains 28.2 μg of teriparatide acetate per dose (in teriparatide equivalent).

[0160] (3-2) Preparation of control formula 2: A control formulation 2 was prepared by adding 1.0 mL of Japanese Pharmacopoeia physiological saline solution to a commercially available lyophilized teriparatide preparation ("Teribone Subcutaneous Injection 56.5 μg," manufactured by Asahi Kasei Pharma Co., Ltd.; Non-Patent Literature 1) and dissolving it. A syringe filled with control formulation 2 was used as the control formulation 2 preparation. Control formulation 2 has a volume of 0.89 mL, a teriparatide acetate concentration of 63.5 μg / mL in teriparatide equivalent, and contains 56.5 μg of teriparatide acetate per dose in teriparatide equivalent.

[0161] (3-3) Preparation of control formulation 3: Control formulation 3 was prepared according to Table 4 below. The specific preparation methods for each formulation are as follows: First, each additive listed in the "Additives" column of the table was mixed with sterile water for injection to prepare 3000 g of solution a. Teriparatide acetate (352.5 mg as teriparatide) was dissolved in 2480 g of solution a, and the total volume was made 2500 mL using solution a to prepare control formulation 3.

[0162] After filter-sterilizing control formulation 3, it was filled into 0.2 mL portions into plastic syringes, and the syringes filled with control formulation 3 were used as the control formulation 3 preparation. Control formulation 3 has a volume of 0.2 mL, a teriparatide acetate concentration of 141 μg / mL in teriparatide equivalent, and contains 28.2 μg of teriparatide equivalent per dose.

[0163] [Table 4]

[0164] (4) Preparation of liquid pharmaceutical preparations subjected to circular dichroism (CD) spectral measurement tests: Formulations A to H were prepared according to Table 5 below. These formulations are substantially identical in composition to formulations A to H described in "(2) Preparation of liquid pharmaceutical formulations used in human pharmacokinetic studies" above.

[0165] The specific preparation methods for each formulation are as follows: First, each additive listed in the "Additives" column of the table was mixed with sterile water for injection to prepare a total volume of 3000 mL of solution a. Teriparatide acetate (282 mg as teriparatide) was dissolved in 1600 mL of solution a to prepare drug solution a. Then, diluted hydrochloric acid was added to drug solution a to adjust the pH to the pH listed in the "pH" column of the table, and a total volume of 2000 mL of formulation was prepared using sterile water for injection.

[0166] After sterilizing each formulation by filtration, 2 mL of each formulation was filled into 2 mL ampoules to produce ampoules containing each formulation (formulation ampoule formulations), which were then subjected to stability testing of the filling containers. In addition, after sterilizing each formulation by filtration, 0.2 mL of each formulation was filled into plastic syringes to produce plastic syringe formulations containing each formulation (formulation syringe formulations), which were then subjected to stability testing of the filling containers.

[0167] The composition of each formulation is as indicated in the "Final Content" column of the table. [Table 5]

[0168] (5) Preparation of liquid pharmaceutical formulations subjected to stability testing: Formulations A, B, E, F, and H were prepared according to Table 6 below.

[0169] The specific preparation methods for each formulation are as follows. First, each additive described in the "Additive" column in the table was mixed with water for injection to prepare a 3000 mL solution a. Teriparatide acetate (282 mg as teriparatide) was dissolved in 1600 mL of solution a to prepare a drug solution a. Then, after adjusting the pH to the value described in the "pH" column in the table by adding diluted hydrochloric acid to the drug solution a, a 2000 mL formulation was prepared using the above solution a.

[0170] After subjecting each formulation to filtration sterilization, 2 mL of each was filled into 2 mL ampoules to produce ampoules filled with each formulation (formulation ampoule preparations), which were subjected to stability tests. Also, after subjecting each formulation to filtration sterilization, 0.2 mL of each was filled into plastic syringes to produce plastic syringes filled with each formulation (formulation syringe preparations), which were subjected to stability tests.

[0171] The composition of each formulation is as described in the "Final Content" column in the table.

Table 6

[0172] Example 2 (Pharmacokinetic study in monkeys): (1) Test method: Using Formulations A to H prepared in the above Example 1 "(1) Preparation of Liquid Pharmaceutical Preparations for Monkey Pharmacokinetic Tests", Control Prescription 1 prepared in the above Example 1 "(3) Preparation of Control Liquid Pharmaceutical Preparations", and Control Prescription 3, monkey pharmacokinetic tests were each carried out.

[0173] Female cynomolgus monkeys aged 4 to 6 years were subcutaneously administered with Formulations A to H, Control Formulation 1, and Control Preparation 3, and blood samples were collected from the femoral vein at 5, 15, 30, 60, 120, and 180 minutes after administration. The PK test was conducted in two tests (Test 1 and Test 2). Each test was performed in a crossover design, and an appropriate washout period was set between each period. Six animals were used in each test. Plasma was collected from the blood obtained by these blood samplings by centrifugation, and the concentration of teriparatide in the plasma was measured by ELISA method (High Sensitivity Human PTH(1-34) ELISA kit, Immutopics Inc.). Based on the teriparatide concentration in the plasma obtained by the measurement, the area under the plasma concentration-time curve (AUC) was calculated.

[0174] (2) Test results: The test results are shown in Tables 7 and 8 below. [Table 7]

[0175] [Table 8]

[0176] As shown in Tables 7 and 8 above, it was shown that the AUCs when Formulations A, B, E, F, and H were subcutaneously administered were increased compared to the AUC when Control Formulation 3 was administered. Also, it was shown that the AUC when Formulation B was administered was increased compared to Control Formulation 1. From the above results, it was confirmed that in cynomolgus monkeys, Formulations A, B, E, F, and H showed better pharmacokinetics compared to Control Formulation 3.

[0177] Example 3 (Human pharmacokinetic study): (1) Test (1) Method: Using the Control Formulation 2 and 3 preparations prepared in the above Example 1 "(3) Preparation of Control Liquid Pharmaceutical Preparation", Human Pharmacokinetics Test (1) was conducted.

[0178] Specifically, a pharmacokinetic study was conducted in 12 healthy postmenopausal women under open-label conditions. Control formulation 3 was administered subcutaneously as a single dose to the abdomen, thigh, or upper arm, and the pharmacokinetic parameters when administered to the abdomen were compared with those when control formulation 2 was administered subcutaneously to the upper arm.

[0179] Plasma teriparatide acetate concentrations were measured in blood samples collected before administration, and at 5, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, and 6 hours after administration. The pharmacokinetic parameter AUC was calculated from the plasma teriparatide acetate concentration using an independent method according to the following formula. last AUC inf and C max This was calculated for each subject.

[0180] AUC last = Area under the plasma concentration-time curve up to the final observation time using the linear trapezoidal rule. (AUC in human pharmacokinetic study (2)) last (The same definition) AUC inf = Area under the plasma concentration-time curve up to infinity using the linear trapezoidal rule (AUC in human pharmacokinetic study (2)) inf (The same definition) C max = maximum plasma concentration (Human pharmacokinetic study, Test (2) C max (The same definition)

[0181] Calculated AUC last AUC inf and C max The ratio of control formulation 3 to control formulation 2 and its 95% confidence interval were calculated using the following method: logarithmically transformed AUC. last AUC inf and C maxRegarding this, subjects (within the order group) were regarded as variable effects, and the order group and formulations (control formulations 2 to 3) were regarded as fixed effects, and analysis was performed using the analysis of variance method with a mixed effect model. The estimated differences and 95% confidence intervals of the formulations were exponentially transformed and shown in the form of the ratio and confidence interval of each formulation.

[0182] In addition, as safety evaluation items, adverse events, clinical examinations (blood test, biochemical test, urine test, immunological test), vital signs (axillary body temperature, systolic / diastolic blood pressure, pulse rate), 12-lead electrocardiogram, and body weight were set, and safety evaluation by administration of control formulations 2 and 3 was performed.

[0183] Twelve subjects were randomly assigned to 4 groups of 3 cases each, and the test was carried out according to the following schedule in Table 9 over 4 periods.

[0184]

Table 9

[0185] (2) Test (1) Results: The test results are shown in Tables 10 and 11 below. C when control formulation 3 was administered subcutaneously max was about 1 / 2 of that when control formulation 2 was administered subcutaneously, and AUC last and AUC inf were about 1 / 4 (Table 11).

[0186]

Table 10

[0187]

Table 11

[0188] (3) Examination (2) Method: Human pharmacokinetic studies (2) were conducted using formulations A to H prepared in Example 1 "(2) Preparation of liquid pharmaceutical formulations used in human pharmacokinetic studies" and control formulation 2 prepared in Example 1 "(3) Preparation of control liquid pharmaceutical formulations".

[0189] The subjects were 24 healthy postmenopausal women. The study was conducted in an open-label manner, comparing the pharmacokinetic parameters obtained from a single subcutaneous administration of prescriptions A-H into the abdomen with the pharmacokinetic parameters obtained from a control prescription 2 subcutaneously administered into the upper arm.

[0190] This study was conducted in two cohorts: Cohort 1 consisted of groups I, II, III, and IV, and Cohort 2 consisted of groups V, VI, VII, and VIII. In each cohort, 12 subjects were randomly assigned to one of four groups of three. Subjects were administered prescriptions A-H and control prescription 2 according to the dosing schedule shown in Table 12 below.

[0191] In Table 12, "-" indicates that none of the prescriptions A-H or control prescription 2 were administered. Each prescription was administered once per period, and the number of days in each period was appropriately set in accordance with the purpose of this study.

[0192] [Table 12]

[0193] Plasma teriparatide acetate concentrations were measured using blood samples collected before administration, and at 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, and 6 hours after administration. The pharmacokinetic parameter AUC was derived from the plasma teriparatide acetate concentration using an independent model. last AUC inf and C max This was calculated for each subject.

[0194] Calculated AUC last AUC inf and C maxThe ratios of prescriptions A to H to control prescription 2 and their 95% confidence intervals were calculated using the following method. First, the calculated AUC last AUC inf and C max We logarithmically transform the result, and then logarithmically transform the AUC. last AUC inf and C max The analysis was performed using a mixed-effects model with analysis of variance, where the subjects (within the ordinal group) were treated as a random effect, and the ordinal group and prescriptions as fixed effects. The estimated differences and 95% confidence intervals for each prescription were exponentially transformed and presented in the form of ratios and confidence intervals for each prescription.

[0195] Furthermore, AUC obtained from a separate human pharmacokinetic study using teriparatide acetate formulations different from those of formulations A-H. inf (11.4 ng·min / mL) (Non-patent Literature 24; 2.7.1.2.2 Bioavailability), and the AUC calculated for formulations A to H and control formulation 3 as described above. inf Using this method, the absolute bioavailability (%) of teriparatide in plasma was estimated according to the following formula.

number

[0196] The aforementioned pharmacokinetic study is a clinical pharmacology study in which a teriparatide acetate preparation containing 14.1 μg of teriparatide is administered intravenously for 3 minutes to 5 healthy men in their 30s and 5 healthy men in their 60s.

[0197] Furthermore, adverse events were observed in subjects who received prescriptions A-H (12 cases per prescription) and subjects who received control prescription 2 (24 cases in total). The adverse event rate (%) was calculated by dividing the number of subjects who experienced each adverse event by the number of subjects who received the prescription and multiplying by 100. In addition, elevated serum calcium levels were observed in subjects who received prescriptions A-H and control prescription 2. The elevation of serum calcium levels was defined as the difference (mean value) between the serum calcium level 6 hours after administration and the serum calcium level before administration.

[0198] T max was also calculated as the average value of the time when the teriparatide acetate concentration in the plasma of each subject reached the maximum.

[0199] (4) Test (2) Results: (4-1) Exam: The test results are shown in Tables 13 - 19 below. For the formulations where the upper limit of the 95% confidence interval of the ratio to Control Formulation 2 exceeded 0.5, for AUC last they were Formulations A, B, E, F, and H, for AUC inf they were Formulations A, E, F, and H, and for C max they were all of Formulations A - H. No order effect was observed between Formulations A - H and Control Formulation 2 (Table 14).

[0200]

Table 13

[0201]

Table 14

[0202]

Table 15

[0203] From the above results, from the perspective of pharmacokinetics, it was found that Formulations A, B, E, F, and H were preferable.

[0204]

Table 16

[0205]

Table 17

[0206]

Table 18

[0207] In subjects administered prescriptions A-H, adverse events such as headache, abdominal distension, diarrhea, nausea, vomiting, and injection site erythema were observed, but no other adverse events were observed. Of these adverse events, headache, nausea, vomiting, and injection site erythema were recognized as side effects. The incidence rates of vomiting, nausea, and injection site erythema are shown in Table 18 above.

[0208] [Table 19]

[0209] Based on the above results, in terms of safety associated with single-dose administration (especially gastrointestinal side effects), T max Liquid teriparatide acetate formulations with a small threshold or a short time interval during which the plasma teriparatide acetate concentration is above the threshold can generally be considered superior.

[0210] Example 4 (Circular Dichroism (CD) Spectrum Measurement Test): (1) Test method: Using a circular dichroism dispersometer (distributed by JASCO Corporation; J-720), formulations A to H prepared in Example 1 "(4) Preparation of liquid pharmaceutical formulations used for circular dichroism (CD) spectrum measurement test" and control formulations 1 and 3 prepared in Example 1 "(3) Preparation of control liquid pharmaceutical formulations" were each placed in a 1 mm cell, and circular dichroism (CD) spectra were measured by 8 accumulations at 20°C. A placebo solution of each formulation was used as a blank solution.

[0211] The test was conducted in two parts. Measurement 1 involved measuring the circular dichroism spectrum of control formulations 1, 3, B, and D (a total of 4 formulations), while Measurement 2 involved measuring formulations A through H (a total of 8 formulations).

[0212] (2) Test results: The test results are shown in Tables 20-22 below. [Table 20]

[0213]

Table 21

[0214]

Table 22

[0215] Here, in the table, the “average residue molar ellipticity [θ]” is a value obtained by converting the measured value ([m deg]) at a measurement wavelength of 222 nm to the residue molar ellipticity ([deg·cm 2 / d mol]), and the “α-helix content ratio” is the α-helix content ratio estimated based on the average residue molar ellipticity [θ] using the following formula.

Equation

[0216] The average residue molar ellipticities [θ] of Formulations A to H in the measurement results of Measurement 2 (measurement wavelength 190 to 260 nm) are shown in FIGS. 1A to H, respectively. Further, the average residue molar ellipticities [θ] of Formulations A to H in the measurement results of Measurement 2 (the 210 to 230 nm portion of the measurement wavelength) are shown in FIG. 1I. Also, in the measurement results of Measurement 2, the relationship between the average residue molar ellipticity [θ] 222 and AUC last Ratio (the ratio of each formulation to the control formulation 2 with respect to AUC last ) is shown in FIG. 2, and the relationship between the α-helix content ratio and AUC last Ratio is shown in FIG. 3, respectively.

[0217] The formulations A to H prepared in the aforementioned "Preparation of Liquid Pharmaceutical Formulations Used in Human Pharmacokinetic Studies" are almost identical to the formulations A to H prepared in the aforementioned "Preparation of Liquid Pharmaceutical Formulations Used in Monkey Pharmacokinetic Studies." Therefore, assuming that the results of the monkey pharmacokinetic studies would hardly change even if the former formulations A to H were replaced with the latter formulations A to H, the α-helix content and average residue molar ellipticity [θ] of teriparatide or its salt contained in the liquid pharmaceutical composition of the present invention are determined. 222 The relationship between the composition and the pharmacokinetic parameters of teriparatide or its salts when administered subcutaneously to monkeys was investigated. The results are shown in Figures 4-5.

[0218] As is clear from comparing these results with those of Example 3, a clear correlation was found between pharmacokinetics and the α-helix content and the number of α-helix-forming amino acid residues. Specifically, the formulations that showed good pharmacokinetics in Example 3 (Formulations A, B, E, F, and H) all showed larger values ​​in α-helix content and the number of α-helix-forming amino acid residues compared to the other formulations (Formulations C, D, G, and control formulation 3). The inventors believe that by utilizing the present invention, it is possible to obtain a liquid pharmaceutical composition for human subcutaneous administration containing teriparatide or a salt thereof that exhibits exceptionally remarkable pharmacokinetics, more efficiently, economically, and safely than ever before.

[0219] Example 5 (Stability Test): (1) Test method: Stability tests were conducted using ampoule formulations A, B, E, F, and H prepared in the aforementioned "liquid pharmaceutical formulations subjected to stability testing," as well as syringe formulations A, B, E, F, and H prepared in the aforementioned "liquid pharmaceutical formulations subjected to stability testing."

[0220] Specifically, each formulation was stored in a stability tester at 25°C / 60%RH, then sampled after three months, and its stability was measured by high-performance liquid chromatography.

[0221] (2) Test results: The test results are shown in Tables 23 and 24 below. In the table, "Content relative to initial level" refers to the percentage of teriparatide remaining at 3 months, with the initial teriparatide level set to 100. In the table, "Total amount of related substances" refers to the percentage of the total amount of related substances present at 3 months, with the total amount of teriparatide and related substances present at 3 months set to 100.

[0222] [Table 23]

[0223] [Table 24]

[0224] Example 6 (Simulation test 1 on pharmacokinetics): We assumed two formulations: one containing a theoretical component 1, with an absorption rate constant Ka of 0.48 (1 / hr) obtained when administered subcutaneously to humans as a single dose (formulation a); and another containing a different theoretical component 1, with an absorption rate constant Ka of 2 (1 / hr) obtained when administered subcutaneously to humans as a single dose (formulation b). We then used a simulation method utilizing a publicly known pharmacokinetic model to confirm the effect of changes in absorption rate on the plasma concentration profile of component 1. The pharmacokinetic model used was Phenix WinNonlin 7.0 software (Certara: formerly Pharsight Corporation), which includes a 1-component analysis of primary absorption and primary elimination processes. A compartment model was used. A schematic overview of the 1-compartment model used in this example and Example 7 is shown in Figure 7. The clearance and distribution volume of formulation a and formulation b were set to appropriate identical values, and the amount of component 1 contained in formulation a and formulation b was set to 28.2 μg in both cases. A summary of the simulation results is shown in Table 25 below.

[0225] In the 1-compartment model, the following equation (A) applies.

number

[0226] [Table 25]

[0227] Example 7 (Simulation test 2 on pharmacokinetics): (1) Test (1) Method: Based on the results obtained from human pharmacokinetic studies of each formulation No. 1 to 12 listed in Table 26 below, V / F, Ka, and CL / F were calculated using a 1-compartment model similar to that in Example 6, and the relationship between the concentration of component 1 in the formulation and the calculated Ka was examined. Specifically, the concentration of component 1 in the formulation (X) and the calculated Ka (Y) were subjected to simple regression analysis, and the slope, intercept, and coefficient of determination were calculated. Here, Ka represents the absorption rate constant, V / F represents the volume of distribution, and CL / F represents the clearance, and the 1-compartment model is equivalent to the model based on equation (A) described above.

[0228] [Table 26]

[0229] (2) Test (1) Results: The Ka values ​​for each formulation, calculated using a one-compartment model, are shown in Table 27 below. Simple regression analysis using these Ka values ​​revealed a high correlation between the concentration of component 1 in the formulation (X) and Ka (Y), as shown by the following equation.

number

[0230] [Table 27]

[0231] (3) Examination (2) Method: Furthermore, the Ka and Kel values ​​for each formulation (however, those with a concentration of component 1 exceeding 100 μg / mL and high bioavailability, Nos. 4-8 and 10-12) obtained using a 1-compartment model are substituted into the following formula to obtain the theoretical T for each formulation. max The result was calculated.

number

[0232] (4) Test (2) Results: The calculated results are summarized in Table 28 below. As a result, the Ka range for each formulation was 0.84 to 1.22. Note that the T values ​​for formulations No. 4 to 8 obtained by a method other than the model were also calculated. max (Test results of Example 3 (2) Table 16: Formulations A, B, E, F, and H) max ) and the theoretical T of formulations No. 4-8 listed in the table below max Since no significant discrepancies were observed, the pharmacokinetic parameters (V / F, Ka, and CL / F) for each formulation calculated using the 1-compartment model are considered to be reasonable estimates.

[0233] [Table 28]

[0234] Furthermore, when the maximum and minimum Ka values ​​(0.84 (1 / hr) and 1.22 (1 / hr)) from the table above were input into the simple regression analysis formula, the concentration of component 1 in the formulation was 109-190 (μg / mL). The T values ​​of formulations No. 10-12 obtained as median values ​​by a non-model method were also obtained. max This is shown in Table 29 below.

[0235] [Table 29]

[0236] Reference example (T of component 1) max Examples of inventions within a specific range: A double-blind clinical trial was conducted in 30 healthy postmenopausal women to compare the pharmacokinetics, bone metabolism markers, and safety of a single subcutaneous administration of teriparatide 28.2 μg or 56.5 μg with placebo.

[0237] The teriparatide 28.2 (or 56.5) μg preparation is an injectable preparation obtained by dissolving a lyophilized preparation containing teriparatide acetate in 1 mL of Japanese Pharmacopoeia physiological saline solution immediately before use. Specifically, the teriparatide 28.2 μg preparation has a volume of 1.0 mL and contains 28.2 μg of teriparatide acetate per dose, while the teriparatide 56.5 μg preparation has a volume of 1.0 mL and contains 28.2 μg of teriparatide acetate per dose, in terms of teriparatide.

[0238] The incidence rate of adverse events (%) was calculated by dividing the number of people who experienced each adverse event by the number of people who received the drug and multiplying by 100. Furthermore, an increase in serum calcium levels was observed in subjects who received the teriparatide 28.2 (or 56.5) μg formulation. The increase in serum calcium levels was defined as the difference (mean value) between the serum calcium level 6 hours after administration and the serum calcium level before administration.

[0239] T max This was calculated as the average time at which the plasma teriparatide acetate concentration was highest for each patient.

[0240] The test results are shown in Tables 30-33 below. [Table 30]

[0241] [Table 31]

[0242] [Table 32]

[0243] [Table 33] [Industrial applicability]

[0244] The liquid pharmaceutical formulation of the present invention is superior in terms of pharmacokinetics. The method for improving pharmacokinetic parameters of the present invention is also a groundbreaking method for controlling the active ingredient. Therefore, the present invention is extremely useful in the pharmaceutical industry.

Claims

[Claim 1] An aqueous pharmaceutical preparation for human subcutaneous administration, wherein the concentration of component 1 is 100 to 200 μg / mL, and the preparation contains L-methionine. • Ingredient 1) Teriparatide or a salt thereof.

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