Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to a liquid pharmaceutical preparation containing teriparatide or a salt thereof.
• PTH parathyroid hormone
• calcitonins and vitamin Ds is a hormone involved in regulating blood calcium levels.
• PTH peptides which are physiologically active equivalents of natural forms of PTH, PTH peptide-containing lyophilized preparations and PTH peptide-containing solutions are also known.
• An object of the present invention is to provide a liquid pharmaceutical preparation containing teriparatide or a salt thereof having good physical properties. More specifically, the subject of the present invention is 1) the liquid pharmaceutical preparation in which the formation of a deamidated form of teriparatide or a salt thereof is suppressed, 2) the formation of an aspartic acid isomer of a teriparatide or a salt thereof. The present invention is to provide the liquid pharmaceutical preparation in which 3) the long-term stable liquid pharmaceutical preparation, and 4) the liquid pharmaceutical preparation in which the formation of oxidized form of teriparatide or its salt is suppressed.
• the subject of the present invention is also 5) Test methods using teriparatide analogues, presence of teriparatide analogues as indicators, liquid pharmaceutical preparations containing high purity teriparatide or its salts in which the content of teriparatide analogues is reduced It is to provide.
• liquid pharmaceutical preparation of the present invention contains at least one inorganic salt and / or organic salt. Furthermore, one aspect of the liquid pharmaceutical preparation of the present invention is that its pH is in a predetermined range (eg, 3.0 to 5.0). In such liquid pharmaceutical preparations, the formation of a deamidated form of teriparatide or a salt thereof can be suppressed.
• liquid pharmaceutical preparation of the present invention contains at least one inorganic salt and / or organic salt.
• the pH is in a predetermined range (eg, 3.0 to 5.0). In such liquid pharmaceutical preparations, the formation of aspartate isomer of teriparatide or a salt thereof can be suppressed.
• liquid pharmaceutical preparation of the present invention is that its pH is in a predetermined range (eg, 4.0 to 5.0).
• a more specific embodiment is a preparation which is filled in a glass medical container, contains substantially no buffer, and has a pH in a predetermined range (eg, 4.0 to 5.0).
• the container is filled in a plastic medical container, substantially contains a buffer, further contains D-mannitol, and the pH thereof is within a predetermined range (eg, 4.0 to 5). 0).
• a specific additive eg, ⁇ -cyclodextrin
• Such liquid pharmaceutical formulations may be stable over time.
• One embodiment of the liquid pharmaceutical preparation of the present invention contains a predetermined amount of methionine (eg, teriparatide or a salt thereof and methionine in a mass ratio of 1: 0.5 to 1.0).
• methionine eg, teriparatide or a salt thereof and methionine in a mass ratio of 1: 0.5 to 1.0.
• formation of an oxidized form of teriparatide or a salt thereof eg, formation of oxidized teriparatide in which methionine residue at the eighth position from the N-terminus of teriparatide or a salt thereof is sulfoxidized
• One aspect of the liquid pharmaceutical preparation of the present invention contains mannitol.
• an oxidized form of teriparatide or a salt thereof eg, the formation of an oxidized form of a tryptophan residue at position 23 in teriparatide or a salt thereof
• the formation of an oxidized form of teriparatide or a salt thereof can be suppressed.
• One aspect of the present invention is the presence and / or presence of a specific teriparatide analog (eg, deamidated form, Asp isomerate), a high-quality liquid pharmaceutical preparation having a reduced content of the same analog, and the same analog It is a test
• a specific teriparatide analog eg, deamidated form, Asp isomerate
• a liquid pharmaceutical preparation comprising component 1 and component 2.
• Component 1) teriparatide or a salt thereof.
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1
• a salt of a species or more (however, component 2 is a component different from component 1).
• component 2 is a component different from component 1).
• the liquid pharmaceutical formulation as described in said [1] whose pH is less than 5.0.
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• a liquid pharmaceutical preparation which is substantially free (however, the pH is less than 5.0).
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• a liquid pharmaceutical preparation containing Component 1 and Component 2, which is a buffer (however, when Component 1 is a teriparatide salt, a salt detached from Component 1 does not correspond to the buffer here).
• a liquid pharmaceutical preparation which does not substantially contain (however, the pH is 5.0 or more).
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• Ingredient 4) D-mannitol.
• a liquid pharmaceutical formulation containing ingredient 1 and ingredient 5. Component 1) teriparatide or a salt thereof.
• Component 5) L-proline, betaine, ectoin, hydroxyectoin, L-arginine hydrochloride, L-histidine, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, One or more components selected from the group consisting of N-acetyl-arginine, L-lysine hydrochloride, and N-acetyl-DL-tryptophan.
• Component 5 is one or more components selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, N-acetyl-arginine, L-proline, L-arginine hydrochloride, and L-lysine hydrochloride.
• Component 2 is one or more salts selected from sodium chloride, calcium chloride, magnesium chloride, sodium bromide, sodium acetate, trisodium citrate and sodium carbonate according to the above [1] to [6]. Liquid pharmaceutical preparation. [15] The liquid pharmaceutical formulation as described in the above-mentioned [14], wherein component 2 is sodium chloride and / or trisodium citrate.
• Component 1) teriparatide or a salt thereof.
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• the suppression of the deamidation reaction is the suppression of the formation of a deamidated form of component 1 in which the asparagine residue in component 1 located at the 16th position from the N-terminus of component 1 is changed to an isoaspartic acid residue [ 25].
• Component 2 is at least one salt selected from sodium chloride, calcium chloride, magnesium chloride, sodium bromide, sodium acetate, trisodium citrate and sodium carbonate (however, component 2 is a component different from component 1)
• Component 1) teriparatide or a salt thereof.
• Component 2) One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• Component 2 One or more salts selected from sodium salts, calcium salts and magnesium salts, and / or salts selected from hydrochloride, hydrobromide, acetate, citrate and carbonate 1 A salt of a species or more (however, component 2 is a component different from component 1).
• the suppression of the isomerization of aspartate residues is the suppression of the isomerization of aspartate residues of component 1 in which the aspartic acid residue located 30th from the N-terminus of component 1 is changed to an isoaspartic acid residue. The method according to [30] above.
• Component 2 is at least one salt selected from sodium chloride, calcium chloride, magnesium chloride, sodium bromide, sodium acetate, trisodium citrate and sodium carbonate (however, component 2 is a component different from component 1)
• Component 3 is not contained in the liquid pharmaceutical preparation, and the pH of the liquid pharmaceutical preparation is made to be more than 4.0 and not more than 5.0.
• a method comprising incorporating 1 and component 3 in a mass ratio of 1: 0.2 to 1.0, wherein the oxidized form of component 1 comprises a methionine residue at position 8 from the N-terminus of teriparatide
• a method which is a sulfoxidated teriparatide oxidized form or a salt thereof.
• Component 1) teriparatide or a salt thereof.
• Component 3) methionine.
• a method for suppressing the formation of an oxidized form of component 1 in a liquid pharmaceutical preparation containing component 1, comprising incorporating component 4 in the liquid pharmaceutical preparation, wherein the oxidized form of component 1 is N of component 1
• the salt to be released does not substantially correspond to the buffer here), and the method comprising bringing the pH of the liquid pharmaceutical preparation to more than 4.0 and not more than 5.0.
• Component 5 L-proline, betaine, ectoin, hydroxyectoin, L-arginine hydrochloride, L-histidine, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, One or more components selected from the group consisting of N-acetyl-arginine, L-lysine hydrochloride and N-acetyl-DL-tryptophan.
• Component 5 is one or more components selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, N-acetyl-arginine, L-proline, L-arginine hydrochloride, and L-lysine hydrochloride [37 ] The method as described in. [39] An analogue of ingredient 1 wherein the asparagine residue present 16th from the N-terminus of ingredient 1 is changed to an isoaspartic acid residue, the other residues being identical to the corresponding residues of teriparatide . Component 1) teriparatide or a salt thereof.
• Component 1) teriparatide or a salt thereof.
• liquid pharmaceutical preparation containing teriparatide or a salt thereof excellent in physical properties is provided.
• Liquid pharmaceutical preparations provides, in one aspect, a liquid pharmaceutical formulation comprising component 1) teriparatide or a salt thereof, and component 2) at least one or more inorganic salts and / or organic salts.
• the present invention provides, as one aspect, a liquid pharmaceutical preparation containing component 1) teriparatide or a salt thereof, and having a pH in a predetermined range (eg, 3.0 to 5.0).
• the liquid pharmaceutical preparation wherein the mass ratio of component 1 to component 2 is 1:20 or 20 or more.
• the present invention includes, in one aspect, component 1) teriparatide or a salt thereof, and contains a specific additive. More preferred specific embodiments of the present invention according to these embodiments are listed below.
• Component 1) A liquid pharmaceutical preparation containing teriparatide or a salt thereof and component 3) methionine, wherein component 1: component 3 is 1: 0.2 to 1.0.
• Component 1) Liquid pharmaceutical formulation containing teriparatide or a salt thereof, and component 4) D-mannitol.
• Component 1) Teriparatide or a salt thereof, and Component 5) L-proline, betaine, ectoin, hydroxyectoin, L-arginine hydrochloride, L-histidine, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin
• a liquid pharmaceutical preparation comprising one or more components selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, N-acetyl-arginine, L-lysine hydrochloride and N-acetyl-DL-tryptophan.
• Liquid pharmaceutical preparation The form of the liquid pharmaceutical preparation of the present invention is not particularly limited as long as it is a liquid pharmaceutical preparation containing teriparatide or a salt thereof (component 1) described later.
• Examples include preparations for oral administration (internal use drugs) or preparations for parenteral administration, but preparations for parenteral administration are preferred.
• preparations for parenteral administration include preparations for topical administration such as external preparations and preparations for systemic administration such as injections, but preparations for systemic administration are preferable, and injections are particularly preferable.
• specific administration routes for systemic administration include intravenous administration, intramuscular administration, intradermal administration, subcutaneous administration and the like, and subcutaneous administration is preferable. That is, as the liquid pharmaceutical preparation of the present invention, preferably a liquid pharmaceutical preparation for subcutaneous administration or a liquid pharmaceutical preparation for injection can be exemplified, and most preferably, a liquid pharmaceutical preparation for subcutaneous injection can be exemplified.
• the “medicament” in the liquid pharmaceutical preparation means a drug used for the prevention / treatment / diagnosis of any disease to a mammal (human, monkey, rat, etc.).
• the solvent used for the liquid pharmaceutical preparation of the present invention is not particularly limited, and may be an aqueous solvent or a non-aqueous solvent, but is preferably an aqueous solvent. That is, the liquid pharmaceutical preparation of the present invention is preferably an aqueous pharmaceutical preparation.
• the liquid pharmaceutical preparation of the present invention is particularly an aqueous pharmaceutical preparation Is preferred, and may be prepared, for example, by water for injection or saline.
• the aqueous solvent may be selected from various components such as at least one or more of inorganic salts and / or organic salts (component 2), buffers, additives (components 3 to 6) described later without departing from the scope of the present invention. You may contain.
• human PTH (1-34) is composed of the first to 34th amino acid residues viewed from the N-terminal side in the amino acid sequence of human parathyroid hormone human PTH (1-84). It is a peptide shown by a partial amino acid sequence.
• teriparatide means free human PTH (1-34).
• Teriparatide can also be in the form of a salt.
• the teriparatide salt includes any salt formed by teriparatide and one or more volatile organic acids.
• volatile organic acids include trifluoroacetic acid, formic acid and acetic acid.
• the ratio of the free form teriparatide and the volatile organic acid to form a salt is not particularly limited as long as the salt is formed.
• acetic acid is preferable as the volatile organic acid. That is, as a salt of teriparatide in the present invention, teriparatide acetate can be preferably exemplified.
• teriparatide or a salt thereof is a peptide, it has its isoelectric point (pI).
• the measurement of pI can be performed by a method known per se (for example, a method using HPLC, electrophoresis or the like).
• the pI of teriparatide or a salt thereof (component 1) is known to be 8.3 to 8.4.
• the amount of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation of the present invention is not particularly limited, but the following can be preferably exemplified. That is, the lower limit is preferably 10 ⁇ g or more, and more preferably 20 ⁇ g or more, 25 ⁇ g or more, 27 ⁇ g or more, and further preferably 28 ⁇ g or more.
• the upper limit is preferably 100 ⁇ g or less, more preferably 50 ⁇ g or less, 40 ⁇ g or less, 35 ⁇ g or less, 30 ⁇ g or less, and further preferably 29 ⁇ g or less.
• the content of component 1 is preferably 28.2 ⁇ g or 29.2 ⁇ g.
• the content of component 1 can be 56.5 ⁇ g in terms of teriparatide.
• the teriparatide used is acetate
• the amount taking into account the amount of acetic acid can be exemplified, and in the case of teriparatide pentaacetate, the content of component 1 as teriparatide acetate is preferably 30.3 ⁇ g or 31.3 ⁇ g .
• the content of component 1 can be 60.6 ⁇ g as teriparatide acetate.
• the content per dose of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation of the present invention is not particularly limited, but the following can be preferably exemplified. That is, the lower limit is more preferably 25 ⁇ g or more, 27 ⁇ g or more, and further preferably 28 ⁇ g or more. The upper limit is more preferably 35 ⁇ g or less, 30 ⁇ g or less, and further preferably 29 ⁇ g or less. Among them, the dose per single dose of Component 1 is preferably 28.2 ⁇ g as teriparatide.
• the teriparatide used is acetate
• an amount considering the amount of acetic acid can be exemplified, and in the case of teriparatide pentaacetate, the content per ingredient of the component 1 is 30.3 ⁇ g as teriparatide acetate preferable.
• the concentration of teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation of the present invention is not particularly limited, but the following can be preferably exemplified. That is, as teriparatide, the lower limit is preferably 50 ⁇ g / mL or more, and more preferably 70 ⁇ g / mL or more, 100 ⁇ g / mL or more, 100 ⁇ g / mL or more, 110 ⁇ g / mL or more, and further preferably 120 ⁇ g / mL or more .
• the upper limit is preferably 500 ⁇ g / mL or less, more preferably 250 ⁇ g / mL or less, less than 250 ⁇ g / mL, 200 ⁇ g / mL or less, 180 ⁇ g / mL or less, and further preferably 160 ⁇ g / mL or less.
• 141 ⁇ g / mL can be most preferably exemplified.
• the teriparatide or a salt thereof (component 1) contained in the liquid pharmaceutical preparation of the present invention can be produced by a method known per se (for example, the methods described in Non-Patent Documents 3 to 5 and the like).
• teriparatide or a salt thereof (component 1) is a teriparatide salt
• a salt formed by dissociation of the teriparatide salt in the liquid pharmaceutical preparation of the present invention is not regarded as a buffer according to the present invention.
• the same salt is not considered as "the at least one or more inorganic salt and / or organic salt (component 2)" according to the present invention.
• the liquid pharmaceutical preparation of the present invention preferably contains at least one or more inorganic salts and / or organic salts. In such a liquid pharmaceutical preparation, preferably, both deamidation of component 1 and aspartic acid residue isomerization can be suppressed.
• the inorganic salt means a salt formed by binding an inorganic acid with a base.
• hydrochloride, hydrobromide and bisulfite can be exemplified.
• sodium chloride, potassium chloride, ammonium chloride, calcium chloride, magnesium chloride, aluminum chloride, bromide Sodium and sodium bisulfite can be exemplified, and sodium chloride, calcium chloride, magnesium chloride and sodium bromide can be most preferably exemplified.
• the organic salt means a salt formed by combining an organic acid with a base.
• organic salts acetates, citrates and carbonates can be mentioned.
• sodium acetate, sodium citrate (monosodium citrate, disodium citrate and trisodium citrate), sodium carbonate can be preferably exemplified.
• sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt and aluminum salt can be preferably exemplified.
• the organic salt and the inorganic salt in the present invention may be anhydrous or may be hydrate.
• magnesium chloride is usually marketed as hexahydrate, and this can be used as it is as an inorganic salt in the present invention, or magnesium chloride anhydride obtained through dehydration treatment is used as an inorganic salt. You can also.
• magnesium chloride hydrate and “sodium acetate hydrate” mean “magnesium chloride hexahydrate” and “sodium acetate trihydrate”, respectively.
• At least one or more inorganic salts and / or organic salts are at least one or more inorganic salts, at least one or more inorganic salts and at least one or more organic salts, or at least one or more Means organic salt.
• One or more salts selected from sodium salts, calcium salts, and magnesium salts as at least one or more inorganic salts and / or organic salts, or hydrochlorides, hydrobromides, acetates, citrates And one or more salts selected from carbonates can be mentioned preferably, and sodium salt and / or citrate can be mentioned more preferably. More specifically, one or more salts selected from sodium chloride, calcium chloride, magnesium chloride, sodium bromide, sodium acetate, trisodium citrate and sodium carbonate can be mentioned more preferably.
• Non-Patent Document 8 the deamidation reaction of asparagine residues of small peptides is not affected by the ionic strength of the reaction solution (Abstract), and addition of sodium chloride to the reaction solution suppresses the deamidation reaction Not done (Table III) is disclosed. Moreover, in the literature to which Non-patent document 9 refers, it is also reported that the increase in ionic strength by sodium chloride addition accelerates the deamidation reaction (McKerrow and Robinson, 1971; Scotchler and Robinson, 1974; page 22553 left column) ).
• the addition of one or more inorganic salts and / or organic salts to the liquid pharmaceutical preparation suppresses the formation of the deamidated form of teriparatide or its salt (component 1) in the liquid pharmaceutical preparation. obtain. Further, in the present invention, by adding one or more inorganic salts and / or organic salts to a liquid pharmaceutical preparation, teriparatide or its salt (component 1) isomer isomer of an aspartic acid residue in the liquid pharmaceutical preparation. Production can be suppressed.
• the concentration is not particularly limited, but the lower limit is 250 ⁇ g / mL or more, 500 ⁇ g / mL or more, 1 mg / mL or more Alternatively, it is preferably 2 mg / mL or more, more preferably 3 mg / mL or more, and even more preferably 5.5 mg / mL or more.
• the upper limit is preferably 250 mg / mL or less, 100 mg / mL or less, or 25 mg / mL or less, and more preferably 11 mg / mL or less.
• the mass ratio of the teriparatide or its salt (component 1) (component 1: component 2) Is not particularly limited, but the lower limit is preferably 1: 5 or more, more preferably 1:10 or more, 1:15 or more, and even more preferably 1:20 or more. Most preferably, it is 35 or more.
• the upper limit is, for example, preferably 1: 500 or less, more preferably 1: 300 or less, and most preferably 1:80 or less.
• the “at least one or more inorganic salt and / or organic salt (component 2)” may be the same as or different from the components of the buffer described later.
• the buffer according to the present invention is not particularly limited as long as it can stabilize the pH of an aqueous solution and is generally used in the pharmaceutical field.
• Examples of the buffer according to the present invention include acetic acid, tartaric acid, lactic acid, citric acid, boric acid, phosphoric acid, carbonic acid and salts thereof. More specifically, acetic acid and sodium acetate, citric acid and trisodium citrate, sodium hydrogencarbonate and sodium carbonate, sodium dihydrogenphosphate and sodium dihydrogenphosphate can be exemplified.
• Such buffer may be included in the liquid pharmaceutical formulation of the present invention.
• a liquid pharmaceutical preparation substantially containing a buffer according to the present invention and further containing at least one inorganic salt and / or organic salt, teriparatide or a salt thereof in the preparation (component 1) Both the formation of the deamidated form of) and the formation of the aspartic acid residue isomerized form of component 1 can be suppressed.
• the liquid pharmaceutical preparation of the present invention may be a liquid pharmaceutical preparation substantially free of buffer, and among them, a liquid pharmaceutical preparation substantially free of acetate buffer is preferable.
• substantially does not contain the buffer, for example, when it is placed in a non-alkali glass container such as decomposition of teriparatide or its salt (component 1) and other additives, sulfur treatment, etc. Over time, such as alkaline elution, components of the drug solution and their reaction products, components dissolved in the drug solution from the container or container filled with drug solution, and various effects of the external environment during storage on the drug solution, etc. It means that the inclusion of a buffer whose pH fluctuation can not be suppressed is not regarded as inclusion.
• the buffer is not “substantially” contained in the liquid pharmaceutical preparation
• the case where a very small amount of buffer is contained in the liquid pharmaceutical preparation can be mentioned.
• the amount may vary depending on the buffer to be selected, but for example, even if a buffer having a concentration of 1 mM or less, preferably 0.5 mM or less, more preferably 0.1 mM or less is contained in the liquid pharmaceutical preparation, Is considered "substantially" not included in the liquid pharmaceutical formulation.
• the buffer is considered to be “substantially” not included in the liquid pharmaceutical formulation is the lower end of the same range or value and in the embodiment of the liquid pharmaceutical formulation of the present invention in which the pH is a specific range or a specific value.
• the inclusion of at least a buffer having no buffer capacity can be mentioned.
• the buffer in an embodiment of the liquid pharmaceutical preparation of the present invention having a pH of 4 to 5, a buffer having at least a buffering capacity in a pH range of 3 to 6 or a pH of 4.6
• the buffer when the buffer contains at least a buffer having no buffering capacity in the pH range of 3.6 to 5.6, the buffer is used for the liquid pharmaceutical preparation of the present invention. It is considered “substantially” not included.
• the buffer is considered to be “substantially” not included in the liquid pharmaceutical formulation
• the buffer has a pKa ⁇ 1
• the liquid pharmaceutical preparation contains a buffer which is not included or overlapped in the same pH range or value.
• the pKa of the acetate buffer (which is actually the pKa of acetic acid) is 4.76
• this ⁇ 1 is 3.76 to 5.76
• the pH is less than 3.76 or more than 5.76.
• the acetate buffer is considered to be "substantially” not included in the liquid pharmaceutical formulation, even if the liquid pharmaceutical formulation exhibits an acetate buffer.
• phosphoric acid is a polybasic acid and has three types of pKa (2.12, 7.21, 12.32), H 3 PO 4 , NaH 2 PO 4 , NaH 2 PO 4
• H 3 PO 4 a polybasic acid and has three types of pKa (2.12, 7.21, 12.32)
• NaH 2 PO 4 NaH 2 PO 4
• Na 3 PO 4 Each combination of Na 2 HPO 4 , Na 2 HPO 4 and Na 3 PO 4 will have buffering action in the individual pH range, but if the combination is not specifically stated, the above three pKa's
• the phosphate buffer is contained in the liquid pharmaceutical preparation even if the liquid pharmaceutical preparation does not include or overlap the specified pH range of ⁇ 1 for any of the pKa. Are considered not to be included.
• the conjugate base eg, sodium acetate of a weak acid (eg, acetic acid) in the liquid pharmaceutical preparation of the present invention is contained, but when the weak acid (eg, acetic acid) is not contained in the preparation, the conjugate is used.
• the base is not considered a buffer according to the invention.
• the same conjugate base corresponds to the "at least one or more inorganic salt and / or organic salt (component 2)" according to the present invention described above, the "at least one or more inorganic salt” according to the present invention And / or an organic salt (component 2) ".
• Additives Components 3 to 6
• the liquid pharmaceutical preparation of the present invention can also contain various additives.
• additives include solubilizers, stabilizers, tonicity agents, pH adjusters, preservatives (preservatives) and the like.
• solubilizers examples include propylene glycol, dipropylene glycol, pentylene glycol, polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, popidone, polysorbate 80 and the like.
• Examples of the tonicity agent according to the present invention include D-mannitol, sorbitol, glucose, glycerin, propylene glycol, sodium chloride, potassium chloride and the like.
• pH adjusters examples include dilute hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine and the like.
• preservative examples include methyl paraooxybenzoate, ethyl paraooxybenzoate, propyl paraooxybenzoate, sodium benzoate, phenol, cresol, sorbic acid, benzyl alcohol and the like.
• the hydrochloride, N-acetyl-DL-tryptophan and the like can be exemplified.
• L-proline, L-arginine or a hydrochloride thereof, ⁇ -cyclodextrin, ⁇ -cyclodextrin, L-lysine or a hydrochloride thereof, mannitol and methionine can be preferably exemplified, and ⁇ -cyclodextrin and ⁇ - Most preferred are cyclodextrin, D-mannitol and L-methionine.
• the content of the stabilizer according to the present invention is not particularly limited, but the content is about 0.1 to 1000 times (mass ratio) of the content of teriparatide or its salt (component 1) contained in the liquid pharmaceutical preparation of the present invention. Is preferred.
• Methionine (component 3) The liquid pharmaceutical preparation of the present invention can contain methionine.
• methionine When methionine is added to the liquid pharmaceutical preparation of the present invention, it is preferably contained 0.1 times (mass ratio) or more of the content of teriparatide or a salt thereof (component 1), 0.3 times or more, 0. More preferably, it is contained 5 times or more, or 0.7 times or more.
• the upper limit of the amount of methionine added is not particularly limited as long as it is dissolved in the liquid pharmaceutical preparation of the present invention, but for example, it may preferably be 10.0 times or less or 5.0 times or less. Can be further preferably exemplified, and 1.0 times or less can be most preferably exemplified.
• the amount of methionine added to the liquid pharmaceutical preparation of the present invention can be preferably exemplified by about 0.5 to 1.0 times (mass ratio to teriparatide or salt).
• D-mannitol (component 4): D-mannitol can be contained in the liquid pharmaceutical preparation of the present invention.
• the content of D-mannitol is not particularly limited, but it is preferable that the D-mannitol content is about 10 to 1000 times (mass ratio) the content of teriparatide or a salt thereof (component 1).
• the liquid pharmaceutical preparation of the present invention includes L-proline, betaine, ectoin, hydroxyectoin, L-arginine or its hydrochloride, L-histidine or its hydrochloride, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin , One or more components (component 5) selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, L-lysine or a hydrochloride thereof, N-acetyl-DL-tryptophan, and N-acetyl-arginine You can Component 5 includes one or more selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, N-acetyl-arginine, L-lysine or a hydrochloride thereof, L-proline, and L-arginine or a hydrochloride thereof It is preferable that it is
• component 5 When component 5 is to be contained in a liquid pharmaceutical preparation, it is preferable that the liquid pharmaceutical preparation contains a buffer, for example, it is preferable that an acetic acid buffer is contained.
• a buffer for example, it is preferable that an acetic acid buffer is contained.
• the pH of the liquid pharmaceutical preparation is not particularly limited, and may be in a suitable range described later.
• the pH of the liquid pharmaceutical preparation in the present invention is not particularly limited.
• the pH of the liquid pharmaceutical preparation of the present invention may preferably be as follows. That is, it can be neutral or acidic (pH is 8.0 or less), and the lower limit is, for example, 3.0 or more, 3.6 or more, 3.8 or more, 4.0 or more, 4.0 or more, 4 It is preferable to set it as 1 or more, 4.2 or more, or 4.4 or more.
• the upper limit may be, for example, 7.0 or less, less than 7.0, 6.0 or less, 5.0 or less, less than 5.0, 4.9 or less, 4.8 or less, or 4.6 or less preferable.
• PTH and PTH fragments are used as an aqueous solution agent, their storage stability is poor, and so conventionally used as a freeze-dried preparation, or using a specific stabilizer or preservative such as polyol or m-cresol. It has been practiced to use an aqueous solution.
• a buffer to the preparation to reduce pH fluctuation when it is made into a liquid pharmaceutical preparation (non- See Patent Document 2 and Patent Document 4 etc.).
• the buffer in a liquid pharmaceutical preparation containing teriparatide or a salt thereof (component 1), is substantially contained in the preparation by specifying the pH range within the above-mentioned suitable range. It can be made into the liquid pharmaceutical preparation which shows long-term stability, without making it contain. In addition, it becomes possible to improve stability further if a specific container is used as a container with which the liquid pharmaceutical preparation of this invention is filled so that it may mention later.
• the pH of the liquid pharmaceutical preparation of the present invention can be adjusted by a method known per se, for example, using a buffer and a pH adjuster.
• liquid pharmaceutical preparation of the present invention can be produced by various production methods known per se.
• the various components described above constituting the liquid pharmaceutical preparation of the present invention may be appropriately selected, mixed with an appropriate solvent and dissolved.
• the liquid pharmaceutical preparation of the present invention is produced as a liquid pharmaceutical preparation for subcutaneous administration, a liquid pharmaceutical preparation for injection, or a liquid pharmaceutical preparation for injection for subcutaneous administration, it is preferable to use an aqueous liquid pharmaceutical preparation.
• an aqueous liquid pharmaceutical preparation it is preferable that the preparation be sterilized before administration.
• the aseptic process is adopted as the aseptic process, each weighed raw material is dissolved in water for injection and the like, and the solution can be filter-sterilized to produce a liquid pharmaceutical preparation.
• Water for injection is generally understood as sterile purified water adapted to the pyrogen (endotoxin) test, and water for injection manufactured by the distillation method may also be referred to as distilled water for injection.
• the liquid pharmaceutical preparation for injection is further filled and sealed in a container that has been subjected to washing and sterilization treatment, and after inspection, packaging, etc., an injection prepared by filling the liquid pharmaceutical preparation for injection can be produced.
• a container for example, an ampoule, a vial, a prefilled syringe, a bag and the like can be exemplified.
• the material of the container is not particularly limited, and glass and plastic can be mentioned. From the viewpoint of strength, ease of handling, safety, etc., plastic can be preferably exemplified as the material of the container.
• the liquid pharmaceutical preparation of the present invention may include an aspect of a liquid pharmaceutical preparation reconstituted from a lyophilised preparation. Also, the liquid pharmaceutical preparation of the present invention may not be a liquid pharmaceutical preparation that is reconstituted from a lyophilised preparation. Conventionally, it is known that a lyophilized preparation containing teriparatide or a salt thereof is dissolved in physiological saline or the like at the time of use to make a liquid pharmaceutical preparation, but the liquid pharmaceutical preparation of the present invention is such a lyophilized preparation Or a preparation (pre-liquidized preparation) which does not undergo such a lyophilized preparation.
• Deamidation means a reaction in which the amide in the organic compound of interest is removed nonenzymatically. Although some proteins and peptides (hereinafter sometimes referred to as proteins etc.) contain asparagine residues and glutamine residues, all residues have an amide in the side chain, and this amide is The reaction to be removed is also included in the deamidation (Non-patent Document 6). Degradation of proteins and the like in pharmaceutical preparations such as proteins and the subsequent reduction in activity can present important challenges in the pharmaceutical industry.
• Proteins etc. differ in their primary to quaternary structures. And, it is also known that the deamidation reaction depends on the primary to quaternary structures of individual proteins to be targeted (Non-patent Document 6).
• Non-Patent Document 8 the deamidation reaction of asparagine residues of small peptides is not affected by the ionic strength of the reaction solution (Abstract), and addition of sodium chloride to the reaction solution does not suppress the deamidation reaction (Table III) is disclosed. Further, in the literature to which Non-Patent Document 8 refers, it is also reported that the increase in ionic strength by the addition of sodium chloride accelerates the deamidation reaction (McKerrow and Robinson, 1971; Scotchler and Robinson, 1974; page 22553, left column) ).
• the deamidation reaction of teriparatide acetate in the liquid pharmaceutical preparation is significantly suppressed by adding one or more inorganic salts such as sodium chloride and / or an organic salt (component 2) to the liquid pharmaceutical preparation. It can be done.
• Deamidation of teriparatide or a salt thereof includes any biochemical deamidation reaction exhibited by teriparatide or a salt thereof.
• deamidation refers to an amide functional group in the side chain of at least one residue of asparagine residues at positions 10, 16, and 33 and glutamine residue at position 29 in the amino acid sequence of teriparatide or a salt thereof. Can be the reaction to be removed.
• teriparatide there are lysine, serine and phenylalanine as amino acid residues at the C-terminal side of asparagine residues.
• the deamidation in the side chain of an asparagine residue is caused by the reaction of the nitrogen in the peptide bond formed with the asparagine residue and the adjacent residue, and the amide in the side chain of the asparagine residue via a succinimide intermediate. It means a reaction that changes to an aspartic acid residue or an isoaspartic acid residue.
• Deamidation in the side chain of glutamine residues is also similar to deamidation in the side chain of asparagine residues.
• the deamidation reaction in which the 16th asparagine residue from the N terminus of the component 1 changes to an aspartate residue, the 16th asparagine residue from the N terminus of the component 1 is an isoasparginate residue The deamidation reaction which changes into can be preferably illustrated.
• Deamidation suppression of teriparatide or a salt thereof can be detected and quantified using known techniques by, for example, LC / MS / MS (liquid chromatography / tandem mass spectrometry).
• the mass ratio of Component 1 to Component 2 suitable for suppressing the deamidation of Component 1 is not particularly limited, but as described above, the lower limit is preferably, for example, 1: 5 or more, 1:10 or more, 1: More preferably, it is 15 or more, more preferably 1:20 or more, and most preferably 1:35 or more.
• the upper limit is, for example, preferably 1: 500 or less, more preferably 1: 300 or less, and most preferably 1:80 or less.
• component 2 can be added to the liquid pharmaceutical preparation for the purpose of suppressing deamidation of component 1, it is also preferable to optimize the pH of the liquid pharmaceutical preparation.
• the above-mentioned suitable pH range can be exemplified as a suitable pH for suppressing the deamidation of Component 1. It is further preferred to add component 2 to the liquid pharmaceutical formulation and to optimize the pH.
• the pH is preferably 4.6 or less, more preferably 4.4 or less, or 4.1 or less.
• the lower limit is not particularly limited, but is preferably 3.0 or more, and more preferably 3.4 or 3.6 or more.
• the pH is preferably 4.6 or less, more preferably 4.4 or less, or 4.1 or less.
• the lower limit is not particularly limited, but is preferably 3.0 or more, and more preferably 3.4 or 3.6 or more.
• a buffer may or may not be substantially contained in the liquid pharmaceutical preparation for the purpose of suppressing deamidation of Component 1.
• the component 2 when the component 2 is added to the liquid pharmaceutical preparation, it is preferable to further contain a buffer.
• the pH of the liquid pharmaceutical preparation is less than 5.0, it is preferable to add the component 2 to the liquid pharmaceutical preparation and to substantially contain a buffer.
• the pH of the liquid pharmaceutical preparation may be less than 5.0, and while the component 2 is added to the liquid pharmaceutical preparation, the liquid pharmaceutical preparation may be substantially free of a buffer.
• the specificity of the reaction attributed to component 2 eg, suppressing the influence on the isomerization reaction in which the 30th aspartic acid residue from the N terminus of component 1 is changed to an isoaspartic acid residue
• the liquid pharmaceutical preparation may be substantially free of a buffer.
• the specificity of the reaction attributed to Component 2 can be improved.
• the specificity of the reaction for example, the specificity such as suppressing the deamidation reaction of the component 1 can be mentioned while suppressing the influence of the component 1 on the isomerization reaction.
• the specificity which suppresses the deamidation reaction in which the 16th asparagine residue from the N-terminus of is converted to isoasparginate can also be preferably exemplified.
• the method is particularly advantageous for storing the liquid pharmaceutical preparation according to the invention, in particular for the purpose of maintaining its quality when stored at room temperature or under refrigeration, for a period of three months or more. And so on.
• Isomerization of the aspartic acid residue of teriparatide or a salt thereof is a reaction in which the 30th aspartic acid residue from the N-terminus is changed to an isoaspartic acid residue in the amino acid sequence of teriparatide or a salt thereof be able to.
• the structural change from an aspartic acid residue to an isoaspartic acid residue can be understood by those skilled in the art (such as non-patent document 8), and the reaction can be detected and quantified using known techniques.
• the mass ratio of Component 1 to Component 2 suitable for suppressing isomerization of the aspartic acid residue of Component 1 (hereinafter referred to as the ratio of (Component 1) :( Component 2) as appropriate, is not particularly limited, As described above, the lower limit is, for example, preferably 1: 5 or more, more preferably 1:10 or more, 1:15 or more, and even more preferably 1:20 or more, and more preferably 1:35 or more. It is most preferable that On the other hand, the upper limit is, for example, preferably 1: 500 or less, more preferably 1: 300 or less, and most preferably 1:80 or less. When the component 2 of 1:20 or more is contained in the liquid pharmaceutical preparation, the isomerization reaction of the aspartic acid residue of the component 1 can be significantly suppressed.
• component 2 can be added to the liquid pharmaceutical preparation for the purpose of suppressing isomerization of the aspartic acid residue of component 1, it is also preferable to optimize the pH of the liquid pharmaceutical preparation.
• the above-mentioned suitable pH range can be exemplified as a suitable pH for suppressing the isomerization of the aspartic acid residue of Component 1. It is further preferred to add component 2 to the liquid pharmaceutical formulation and to optimize the pH.
• the pH is preferably 4.6 or less, more preferably 4.4 or less, or 4.1 or less.
• the lower limit is not particularly limited, but is preferably 3.0 or more, and more preferably 3.4 or 3.6 or more.
• the isomerization of aspartic acid residues can be significantly suppressed even without the addition of Component 2 to the liquid pharmaceutical preparation.
• a buffer may or may not be substantially contained in the liquid pharmaceutical preparation for the purpose of suppressing isomerization of the aspartic acid residue of Component 1.
• the component 2 when the component 2 is added to the liquid pharmaceutical preparation, it is preferable to further contain a buffer.
• the pH of the liquid pharmaceutical preparation is less than 5.0
• the purpose is to suppress the isomerization reaction in which the 30th aspartic acid residue from the N-terminus of Component 1 is changed to an isoaspartic acid residue
• the pH is less than 5.0
• the method is particularly advantageous for storing the liquid pharmaceutical preparation according to the invention, in particular for the purpose of maintaining its quality when stored at room temperature or under refrigeration, for a period of three months or more. And so on.
• PTH is an aqueous solution agent
• its storage stability is poor, and it is important to avoid this problem (Patent Document 2).
• Patent Document 2 the degradation of proteins and the like in pharmaceutical preparations such as proteins and the subsequent reduction in activity can present important challenges in the pharmaceutical industry.
• analogues of Component 1 generated or increased in the process of storing the liquid pharmaceutical preparation.
• analogues of Component 1 such as deamidated form of Component 1, cleaved form of Component 1, isomeric form of aspartic acid residue of Component 1, oxidized form of Component 1 etc. It is preferable to suppress the occurrence or increase of Therefore, for the purpose of enhancing the storage stability of the liquid pharmaceutical preparation of the present invention, it is preferable to take measures such as addition of at least one of the components 2 to 5, pH optimization, and storage temperature / humidity control.
• the pH can be neutral or acidic (pH is 8.0 or less), and the lower limit is, for example, 3.0 or more, 3.6 or more, 3.8 or more, 4.0 or more, or 4. More than 0, 4.1 or more, 4.2 or more, or 4.4 or more is preferable.
• the upper limit may be, for example, 7.0 or less, less than 7.0, 6.0 or less, 5.0 or less, less than 5.0, 4.9 or less, 4.8 or less, or 4.6 or less preferable. As a suitable range, it can be 3.0 or more and 5.0 or less, or 4.0 or more and 5.0 or less, for example.
• the container for storing the liquid pharmaceutical preparation during storage is not particularly limited, but glass medical containers (glass ampoules, glass vials, glass syringes, etc.) and plastic medical containers (plastic ampoules, plastic vials, plastic Preferably, it is filled in a syringe or the like) and stored.
• a buffer may or may not be substantially contained in the liquid pharmaceutical preparation.
• the buffer is not substantially contained in the liquid pharmaceutical preparation.
• the buffer be substantially contained in the liquid pharmaceutical preparation.
• the pH of the liquid pharmaceutical preparation of the present invention at the start of storage is preferably 4.0 or more and 5.0 or less.
• the liquid pharmaceutical preparation of the present invention For the purpose of enhancing the storage stability of the liquid pharmaceutical preparation of the present invention, it is preferable to add at least one of the components 2-5 to the preparation, and at least component 5 is contained in the liquid pharmaceutical preparation of the present invention. Is preferred.
• the pH at the start of storage of the liquid pharmaceutical preparation of the present invention is not particularly limited, but for example, preferably 4.0 or more and 5.2 or less.
• component 5 is contained in the liquid pharmaceutical preparation of the present invention, it is preferable to substantially contain the buffer of the liquid pharmaceutical preparation of the present invention, and more preferable to substantially contain the acetate buffer.
• the addition amount of the component 5 is not particularly limited, but the weight ratio of the component 1: component 5 is preferably 1: 1 to 2,000.
• Component 1 content and Component 1 related substance total amount can be mentioned, and Component 1 content after storage for a certain period of time (e.g.
• the storage stability of the liquid pharmaceutical preparation of the present invention can be evaluated by measuring / quantifying the total amount of component 1 analogues or the like, which may be relative to the content).
• the total amount of teriparatide or a salt thereof (component 1) in the liquid pharmaceutical preparation of the present invention and the amount of component 1 are detected and known using, for example, known techniques by LC / MS / MS (liquid chromatography / tandem mass spectrometry) It can be quantified.
• Method of suppressing the formation of the oxidant of Component 1 It is also known that addition of methionine to teriparatide aqueous solution stabilizes teriparatide, and that teriparatide aqueous solution filled in a radiation-sterilized resin-made prefilled syringe is stabilized by methionine contained in the same solution (patent documents 2 to 6). 3).
• the oxidized form of component 1 means an oxidized form of at least one or more of various types of oxidized component 1 For example, preferred are 8 oxidants, 18 oxidants, 8-18 oxidants, and 23 oxidants.
• the term “8-oxidant” refers to an oxidized form of teriparatide or a salt thereof (component 1) in which the methionine residue at the eighth position from the N-terminus is sulfoxidated
• the term “18-oxidant” refers to the 18th And the 8-18 oxidized form mean the oxidized form in which the 8th and 18th methionine residues from the N terminus of the component 1 are both sulfoxided, respectively.
• 23-oxidant means an oxidized form in which the 23rd tryptophan residue from the N-terminus of teriparatide or a salt thereof (component 1) is oxidized.
• any of the analogues 9 'to 11' described in Patent Document 5 can be preferably exemplified.
• the analogue 9 'described in Patent Document 5 is a teriparatide analog (human) in which the residue corresponding to tryptophan 23 of teriparatide is the following (a) residue and the other structure is identical to that of the original teriparatide (human PTH (1-34) -Trp23 [dioxide]).
• the related substance 10 ' is a residue corresponding to tryptophan 23 of teriparatide is a residue shown by the following (c) -1 or (c) -2 below, and the other structure is identical to the original teriparatide Indicates teriparatide analogue (human PTH (1-34) -Trp23 [mono-oxidation]).
• the analogue 11 ' is a teriparatide analog (human PTH (1-34)-) whose residue corresponding to tryptophan 23 in teriparatide is the following residue (b) and the other structure is identical to that of the original teriparatide: Trp23 [dioxide-formic acid elimination] is meant.
• the suppression of the formation of the oxidized form of Component 1 in the liquid pharmaceutical preparation of the present invention may be, for example, the suppression of the formation of the oxidized form of Component 1 in the preparation at the time of production of the liquid pharmaceutical preparation of the present invention. It may be suppression of the formation of the oxidized form of component 1 in the preparation during transport / storage of the pharmaceutical preparation.
• methionine component 3
• / or mannitol component 4
• component 3 is used as a preparation in order to suppress the formation of at least one or more of the 8 oxidized form, 18 oxidized form and 8-18 oxidized form. It is preferable to contain it.
• the content of the component 3 is not particularly limited, it is preferable that the mass ratio of the component 1: component 3 is 1: 0.5 or more.
• the upper limit of the addition amount of the component 3 is not particularly limited, it is preferably 100 times or less, 50 times or less, 10 times or less, or 5 times or less of the component 1 and is preferably 1 time or less. That is, it is preferable to incorporate Component 1 and Component 3 in the liquid pharmaceutical preparation so that the mass ratio of Component 1: Component 3 is 1: 0.2 to 1.0.
• the pH can be neutral or acidic (pH is 8.0 or less), and the lower limit is, for example, 3.0 or more, 3.6 or more, 3.8 or more, 4.0 or more, or 4. More than 0, 4.1 or more, 4.2 or more, or 4.4 or more is preferable.
• the upper limit may be, for example, 7.0 or less, less than 7.0, 6.0 or less, 5.0 or less, less than 5.0, 4.9 or less, 4.8 or less, or 4.6 or less preferable.
• a buffer may or may not be substantially contained in the preparation for enhancing the suppression of the formation of the oxidized form of component 1 in the liquid pharmaceutical preparation of the present invention. In order to enhance the suppression of the formation of the oxidized form of component 1 in the liquid pharmaceutical preparation of the present invention, it is preferred that the buffer be substantially not contained.
• the amount of oxidized form of teriparatide or a salt thereof (component 1) is detected and known using, for example, a known technique by LC / MS / MS (liquid chromatography / tandem mass spectrometry) It can be quantified.
• the method is particularly advantageous for storing the liquid pharmaceutical preparation according to the invention, in particular for the purpose of maintaining its quality when stored at room temperature or under refrigeration, for a period of three months or more. And so on.
• a test of a liquid pharmaceutical preparation containing component 1 comprising the step of detecting or quantifying the presence of the following analogues (1) to (4) and at least any one of them:
• a method e.g. a quality inspection method
• a deamidated form (N16 ⁇ iso-D16) is a deamidated form in which the asparagine residue present 16th from the N-terminus of teriparatide is changed to an isoaspartic acid residue, and the other residues correspond to teriparatide Deamidate, which is identical to the residue.
• a deamidated form (N16 ⁇ D16) is a deamidated form in which an asparagine residue present 16th from the N-terminus of teriparatide is changed to an aspartic acid residue, and the other residues are the corresponding residues of teriparatide Means a deamidated form which is identical to
• Asp isomer (D30 ⁇ iso-D30) is an isomer in which the aspartic acid residue located 30th from the N-terminus of teriparatide is changed to an isoaspartic acid residue, and the other residues are teriparatide Means an isomer which is identical to the corresponding residue of
• the deamidated form (N10) -Asp isomerized form (D30 ⁇ iso-D30) is a deamidated form produced by deamidating an asparagine residue present 10th from the N-terminus of teriparatide, As a result, it is a deamidated form in which the same residue is changed to an aspartic acid residue or an isoaspartic acid residue, and an aspartic acid residue present 30th from the N terminus of teriparatide is an isoaspartic acid residue It refers to an aspartic acid residue isomerization product that changes.
• Analogs can be detected or quantified using well known techniques, for example by LC / MS / MS (liquid chromatography / tandem mass spectrometry). The methods and analogs are useful, for example, to control the quality of liquid pharmaceutical formulations containing ingredient 1.
• a liquid pharmaceutical preparation comprising component 1 in which the content of at least one of the above-mentioned analogues (1) to (4) is reduced.
• the content of each analog is not particularly limited, but is 5% or less, 4% or less, 3% or less, or 2% or less as a percentage (%) based on 100% of the total mass of teriparatide and its analogues Is preferably, and more preferably 1% or less.
• Light stabilization method It is preferable that at least several thousands items of medical pharmaceuticals requiring shading storage exist and are stored under sufficiently light stable conditions for proper management of pharmaceutical preparations.
• Non-patent Document 12 a PTH aqueous solution stable to light and heat is disclosed.
• the light stability of the liquid pharmaceutical preparation of the present invention can be improved by shielding it from light, for example, by storing it in a box-packed state.
• the material, structure, and shape of the box used for packaging are not particularly limited, but the box may be a pharmaceutical individual box collectively packaging one or more liquid pharmaceutical preparations, and one or more pharmaceutical individual packaging It may be an original cardboard box for packaging a box.
• the pharmaceutical packaging case can be a paper box that prevents damage to the pharmaceutical preparation, contamination of foreign matter, and the like, and that includes the package insert. Preferably, perforations, zippers and the like are provided in the unsealing portion.
• the paper quality of the pharmaceutical packaging box may be cardboard or may be paper.
• the liquid pharmaceutical preparation may be blister-packed or pillow-packaged as part of a measure against damage to the medicine or contamination of foreign matter, and then packaged in a medicine packaging box.
• the material of the blister package and the pillow package is not particularly limited, but examples thereof include plastic materials.
• the material, structure, shape, etc. of the original cardboard are not particularly limited, but may be, for example, A flute (A / F), B flute (B / F), or double flute (AB / F).
• the surface liner can be, for example, C5, K5, K6 or K7 and the core can be S120 or S160.
• a reinforced core (such as P160) may be used instead of the core.
• the surface liner may be single-sided (single-sided cardboard) or double-sided (double-sided cardboard).
• a flute (K6xS120xK6) can be illustrated preferably.
• the liquid pharmaceutical preparation preferably contains methionine, and further preferably contains sodium chloride or mannitol.
• the photostability can be measured using, as an indicator, the amount of the analogue of Component 1 contained after storage of the liquid pharmaceutical preparation, in particular, the amount of 8-oxidant and / or 18-oxidant. That is, the degree of light stabilization can be measured by using the suppression of generation of these oxidants as an index.
• the liquid pharmaceutical preparation is preferably a preparation filled in a plastic or glass vial or a prefilled syringe.
• Example 1 Preparation of a Liquid Pharmaceutical Preparation: (1) Preparation of a liquid pharmaceutical preparation subjected to a test for suppressing the formation of a deamidated form and an aspartic acid residue isomerized form: (1-1) Production 1: Formulations 1 to 11 were prepared according to Table 1 below.
• each additive solution described in the “Additive” column in the table is mixed with water for injection, 1 mL of teriparatide acetate solution (2820 ⁇ g / mL as teriparatide) is added to the mixture, and about 19 mL of drug solution a is added Prepared. Furthermore, the pH adjustment agent described in the "pH adjustment agent” column in the table is added to the chemical solution a to adjust to the pH described in the "pH” column in the table, and each formulation of 20 mL is prepared. Prepared.
• each formulation was filter-sterilized and then 0.2 mL each was filled in a plastic syringe to produce a plastic syringe (prescription formulation) filled with each formulation, which was then subjected to a deamidation product formation inhibition test.
• composition of each formulation is as described in the "final content” column in the table.
• Control formulation 12 to control formulation 17 were prepared according to Table 2 below.
• each formulation is as follows. First, a solution containing each additive solution described in the "additive" column in the table and a solution obtained by dissolving a solution of teriparatide acetate (28.2 mg as teriparatide) were mixed to prepare a total of 175 mL of a chemical solution a. Thereafter, the pH adjuster described in the "pH adjuster" column in the table is added to the chemical solution a to adjust to the pH described in the "pH” column in the table, and each formulation of 200 mL in total is prepared. did.
• each formulation was filter-sterilized and then 0.2 mL each was filled in a plastic syringe to produce a plastic syringe (prescription formulation) filled with each formulation, which was then subjected to a deamidation product formation inhibition test.
• composition of each formulation is as described in the "final content” column in the table.
• each additive solution / additive described in the “Additive” column in the table is mixed with water for injection, 1 mL of teriparatide acetate solution (2820 ⁇ g / mL as teriparatide) is added to the mixture, and approximately 19 mL of A drug solution a was prepared. Furthermore, the pH adjustment agent described in the "pH adjustment agent” column in the table is added to the chemical solution a to adjust to the pH described in the "pH” column in the table, and each formulation of 20 mL is prepared. Prepared.
• each formulation was filter-sterilized and then 0.2 mL each was filled in a plastic syringe to produce a plastic syringe (prescription formulation) filled with each formulation, which was then subjected to a deamidation product formation inhibition test.
• composition of each formulation is as described in the "final content” column in the table.
• Formulations 30-32 were prepared according to Table 4 below.
• each formulation is as follows. First, each additive described in the "additive" column in the table and teriparatide acetate (141 mg as teriparatide) were mixed with water for injection, and after dissolution was confirmed, a total amount of 980 g of drug solution a was prepared using water for injection. Thereafter, hydrochloric acid was added to the drug solution a to adjust to the pH described in the “pH” column in the table, and then a formulation of 1000 g in total was prepared using water for injection.
• each formulation was filter-sterilized and then 0.2 mL each was filled in a plastic syringe to produce a plastic syringe (prescription formulation) filled with each formulation, which was subjected to a methionine effect test.
• composition of each formulation is as described in the "final content” column in the table.
• Formulations 33-40 were prepared according to Table 5 below.
• each additive described in the "additive" column in the table was mixed with water for injection to prepare a total of 3000 mL of solution a.
• Teriparatide acetate (282 mg as teriparatide) was dissolved in 1600 mL of the solution a to prepare a drug solution a.
• a drug solution a was prepared using said solution a.
• composition of each formulation is as described in the "final content” column in the table.
• Formulations 41 and 42 were prepared according to Table 6 below.
• each additive solution / additive described in the “Additive” column in the table is mixed with water for injection, and a solution containing teriparatide acetate described in the “Teriparatide added amount” column in the table is added to the mixed liquid Was added to prepare about 19 mL of a drug solution a. Since the pH of the drug solution a was the pH described in the “pH” column in the table, the pH adjustment with a pH adjuster was not performed, and further, the solution solution a was subjected to a dose-up and 20 mL of each formulation Prepared.
• each formulation was filter-sterilized and then 0.2 mL each was filled in a plastic syringe to produce a plastic syringe (formulation formulation) filled with each formulation, which was subjected to a stability test for control comparison.
• each additive solution / additive described in the “Additive” column in the table is mixed with water for injection, 1 mL of teriparatide acetate solution (2820 ⁇ g / mL as teriparatide) is added to the mixture, and approximately 19 mL of A drug solution a was prepared. Furthermore, the pH adjustment agent described in the "pH adjustment agent” column in the table is added to the chemical solution a to adjust to the pH described in the "pH” column in the table, and each formulation of 20 mL is prepared. Prepared.
• the formulation filled with each formulation was manufactured by filling each in 0.4 mL glass vials, and the formulation was subjected to a stability test for additive evaluation.
• composition of each formulation is as described in the "final content” column in the table.
• pH adjustment with the pH adjuster was not performed, and only the measurement was performed to adjust to the pH described in the “pH” column. .
• the formulation 60 and the formulation 61 were prepared according to Table 8 below.
• the specific preparation method of each formulation is as follows. After weighing the teriparatide amount described in the "Additive” column in the table, dissolve with the solvent described in the “Solvent” column in the table, and measure up to the volume described in the "Mess up” column in the table. The formulation was prepared.
• each formulation was filter-sterilized and then filled with 0.4 mL each in a glass vial to produce a formulation filled with each formulation, which was then subjected to a stability test for additive evaluation.
• each additive described in the "additive" column in the table was mixed with water for injection to prepare a total of 3000 g of solution a.
• the formulation 62 was prepared by dissolving teriparatide acetate (352.5 mg as teriparatide) in 2480 g of solution a, and using solution a to make the total amount 2500 g.
• formulation 62 was filter-sterilized, 0.2 mL each was filled in a plastic syringe, and the syringe filled with the formulation 62 was used as a formulation 62 formulation.
• Example 2 (Test for suppressing formation of deamidated form and aspartic acid residue isomerized form): (1) Test method: Production of deamidated and aspartic acid isomer isomer using Formulation 1 to 29 prepared in the above-mentioned "Liquid pharmaceutical preparation subjected to the test for suppressing formation of deamidated compound and aspartic acid residue isomer" A suppression test was performed.
• Test results The test results are described in Tables 10-14 below. The numerical values in the table indicate the percentage (%) when the total amount of teriparatide and its related substances contained in the formulation is 100.
• the “deamidated form (N16 ⁇ iso-D16)” in the table is a deamidated form produced by deamidating an asparagine residue present 16th from the N-terminus of teriparatide, as a result, A deamidated form in which the residue is changed to an isoaspartic acid residue is meant.
• the “deamidated form (N16 ⁇ D16)” in the table is a deamidated form produced by deamidating an asparagine residue present 16th from the N-terminus of teriparatide, and as a result, the same residue Means a deamidated form converted to an aspartic acid residue.
• Asp isomerate (D30 ⁇ iso-D30)” in the table means aspartate isomerization in which the aspartic acid residue present 30 from the N-terminus of teriparatide is changed to an isoaspartic acid residue Means the body.
• deamidated form (N10) -Asp isomerized form (D30 ⁇ iso-D30) is formed by deamidating an asparagine residue present 10th from the N-terminus of teriparatide
• a deamidated form which is a deamidated form in which the same residue is changed to an aspartic acid residue or an isoaspartic acid residue, and an aspartic acid residue present 30th from the N-terminus of teriparatide It means an aspartic acid residue isomerized form in which a group is changed to an isoaspartic acid residue.
• deamidated form means deamidated form (N10) —Asp isomerized form (D30 ⁇ iso-D30), deamidated form (N16 ⁇ iso-D16), and deamidated form (N16 ⁇ D16) (Namely, the numerical value in the table of the deamidated form means the total of the three compounds).
• Asp isomerate in the table means a generic name of deamidated form (N10) -Asp isomerate (D30 ⁇ iso-D30) and Asp isomerate (D30 ⁇ iso-D30) (ie, The numerical value in the table of the Asp isomerized form means the total amount of the above two compounds).
• Example 3 effect test of methionine: (1) Test method: The methionine effect test was conducted using the formulations 30 to 32 prepared in the above-mentioned “Liquid pharmaceutical preparation subjected to methionine effect test”.
• each formulation was stored in a stability tester at 5 ° C., and then sampling was performed at 6 months, and the stability was measured by high performance liquid chromatography.
• Test results The test results are described in Tables 15 and 16 below.
• the “analog mass” in the table indicates the percentage (%) when the total amount of teriparatide and its analogue contained in the formulation is 100.
• the content at the beginning of the table indicates the percentage (%) of the amount of teriparatide remaining in the sixth month when the amount of teriparatide before storage is 100.
• the "8 oxidized form” in the table refers to teriparatide oxidized form in which the methionine residue from the N-terminus to the 8th of teriparatide is sulfoxided
• the "18 oxidized form” in the table refers to the 18th
• Example 4 Stability Test on a Filled Container (1) Test method: Formulation 33-40 ampoule formulation prepared in the above-mentioned "Liquid pharmaceutical preparation subjected to stability test on filled container", and formulation prepared in the above "liquid pharmaceutical preparation subjected to stability test on filled container” Stability studies were performed using a 33-40 syringe formulation.
• each formulation was stored in a stability tester at 25 ° C./60% RH, then sampling was performed at three months, and the stability was measured by high performance liquid chromatography.
• Test results The test results are described in Tables 17 and 18 below.
• the “content to start with” in the table indicates the percentage (%) of the amount of teriparatide remaining in the third month when the amount of teriparatide before storage is 100.
• the “total amount of related substances” in the table means the percentage (%) of the total amount of related substances present in the third month, assuming that the existing in the third month (the amount of teriparatide and the total amount of the related substances) is 100. Show.
• Example 5 (stability test for control comparison): (1) Test method: Formulations 41 to 42 prepared in the above-mentioned “Liquid pharmaceutical preparation subjected to stability test for control comparison” and the formulations prepared in the above “Liquid pharmaceutical preparation subjected to stability test on filled container” 38 Stability studies were performed using a syringe formulation.
• each formulation was stored in a stability tester at 25 ° C./60% RH, then sampling was performed at 1 and 3 months, and the stability was measured by high performance liquid chromatography.
• Test results The test results are described in Table 19 below. "Content to start (after 3 months storage)” in the table indicates the percentage (%) of the amount of teriparatide remaining in the third month when the amount of teriparatide before storage is 100.
• the “total amount of related substances (after 3 months storage)” in the table means the total amount of related substances present in the third month when the amount of teriparatide and the total amount of related substances present in the third month is 100. Indicates the percentage (%) of
• Example 6 Stability test for specific analogue suppression: (1) Test method: Using formulations 33 and 38 prepared in “Preparation of liquid pharmaceutical formulation subjected to stability test on filled container” described above, and formulation 62 prepared in “Preparation of control liquid pharmaceutical formulation” described above Stability studies on specific analog suppression were performed.
• Detector Ultraviolet absorptiometer (measurement wavelength: 214 nm)
• Column A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm is packed with 3.5 ⁇ m octadecylsilylated silica gel for liquid chromatography (Agilent Tech Zorbax 300SB-C18 manufactured by nologies, or equivalent) (3)
• Column temperature Constant temperature around 40 ° C.
• Mobile phase Mobile phase
• Mobile phase A Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, adjust to pH 2.3 with phosphoric acid and then add water. Make up to 1000 mL.
• Mobile phase B Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, adjust to pH 2.3 with phosphoric acid, and add water to make 1000 mL. Add 500 mL of acetonitrile to 500 mL of this solution.
• Transfer of Mobile Phase The concentration ratio is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 20 below. (6) Flow rate: 1.0 mL per minute (7) Detection time: 45 minutes after injection of the sample solution. However, it is from behind the solvent peak.
• Test results The amounts of related substances with a relative retention time of 0.72 for each formulation are shown in Table 21 below.
• the “starting content” in the table indicates the proportion (%) of the relative substance mass having a relative retention time of 0.72 that was present when the amount before storage (the amount of teriparatide and the total amount of related substances) was 100.
• the “3 months content” in the table means the relative substance with a relative retention time of 0.72 existing in the 3rd month, assuming that the 3rd month (the amount of teriparatide and the total amount of related substances) is 100. Indicates the percentage (%) of the amount.
• the analogue 9 'described in Patent Document 5 is a teriparatide analog (human) in which the residue corresponding to tryptophan 23 of teriparatide is the above-mentioned (a) residue and the other structure is identical to that of the original teriparatide (human PTH (1-34) -Trp23 [dioxide]) is meant.
• the related substance 10 ' is a residue corresponding to tryptophan 23 of teriparatide is the residue shown in (c) -1 or (c) -2 above, and the other structure is identical to the original teriparatide Indicates teriparatide analogue (human PTH (1-34) -Trp23 [mono-oxidation]).
• the analogue 11 is a teriparatide analog (human PTH (1-34)-) whose residue corresponding to tryptophan 23 in teriparatide is the above residue (b) and the other structure is identical to that of the original teriparatide Trp23 [dioxide-formic acid elimination] is meant.
• Example 7 (stability test for additive evaluation): (1) Test method: A stability test for additive evaluation was conducted using formulations 43 to 61 prepared in the "Preparation of liquid pharmaceutical preparation subjected to stability test for additive evaluation" described above.
• Test results The test results are shown in Table 22 below. In the table, "-" means the fact that it was not measured.
• the “starting content” in the table indicates the percentage (%) of the total amount of related substances that were present when the amount of teriparatide and the total amount of related substances before storage was 100.
• the “one month content” in the table means the percentage (%) of the total amount of related substances present in the first month when the amount of teriparatide and the total amount of related substances present in the first month is 100.
• the “3 months content” in the table means the percentage (%) of the total amount of related substances present in the third month, assuming that the present (the amount of teriparatide and the total amount of related substances) present in the third month is 100. Show.
• Example 8 (light stability test): (1) Test method: Formulation 38 Syringe preparation prepared in the above-mentioned “Liquid pharmaceutical preparation subjected to stability test for filled containers” or the same preparation packaged in a paper box or the like is used for a commercial light stability test device, and D65 lamp is used as a light source (Illuminance: 2500 lx), 20 days as a period satisfying 1.2 million lx ⁇ hr and 200 w ⁇ h / m 2 under conditions of 5 ° C. ⁇ 3 ° C., or 10 days as a period satisfying 600,000 lx ⁇ hr It was exposed to light.
• Test method Formulation 38 Syringe preparation prepared in the above-mentioned “Liquid pharmaceutical preparation subjected to stability test for filled containers” or the same preparation packaged in a paper box or the like is used for a commercial light stability test device, and D65 lamp is used as a light source (Illuminance: 2500 lx), 20 days as a period
• the same preparation packaged in a paper box or the like refers to a syringe preparation incorporated in a device, which is further blister-packaged and enclosed in a separate box.
• Test results The measurement results are shown in the following table. Each numerical value in the measurement time column indicates the ratio (%) of the corresponding oxidized form amount when the value before storage (the amount of teriparatide and the total amount of related substances) is 100.
• the liquid pharmaceutical preparation of the present invention is excellent in terms of physical properties and pharmacokinetics.
• Each method (deamidation reaction suppression method, storage method, and analog formation suppression method) of the present invention is also a revolutionary key drug control method.
• the present invention is very useful in the pharmaceutical industry.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Endocrinology (AREA)
• Inorganic Chemistry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Zoology (AREA)
• Gastroenterology & Hepatology (AREA)
• Diabetes (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Dermatology (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=65811407

Family Applications (1)

Country Status (6)

Cited By (3)

Families Citing this family (7)

Citations (20)

Family Cites Families (39)

• 2018
  • 2018-09-20 JP JP2018558440A patent/JP6577683B2/ja active Active
  • 2018-09-20 EP EP18859204.2A patent/EP3685849A4/en not_active Withdrawn
  • 2018-09-20 CN CN202311111773.2A patent/CN116898955A/zh active Pending
  • 2018-09-20 CN CN201880053788.9A patent/CN110996988A/zh active Pending
  • 2018-09-20 US US16/649,254 patent/US20200289621A1/en not_active Abandoned
  • 2018-09-20 CA CA3075977A patent/CA3075977C/en active Active
  • 2018-09-20 WO PCT/JP2018/034887 patent/WO2019059302A1/ja not_active Ceased
• 2019
  • 2019-01-22 JP JP2019008797A patent/JP6714738B2/ja active Active
  • 2019-01-22 JP JP2019008790A patent/JP6585317B2/ja active Active
  • 2019-03-06 JP JP2019041011A patent/JP6817358B2/ja active Active
  • 2019-03-06 JP JP2019040987A patent/JP6826140B2/ja active Active
  • 2019-03-25 JP JP2019057398A patent/JP6581741B2/ja active Active
  • 2019-03-25 JP JP2019057412A patent/JP6781790B2/ja active Active
  • 2019-03-25 JP JP2019057434A patent/JP6646173B2/ja active Active
  • 2019-03-25 JP JP2019057438A patent/JP2019089865A/ja active Pending
  • 2019-03-25 JP JP2019057408A patent/JP6634175B2/ja active Active
  • 2019-04-26 JP JP2019085817A patent/JP6825034B2/ja active Active
  • 2019-12-19 JP JP2019228968A patent/JP6739612B2/ja active Active
• 2020
  • 2020-03-24 JP JP2020053255A patent/JP6766286B2/ja active Active
  • 2020-08-20 JP JP2020139570A patent/JP6818928B2/ja active Active
  • 2020-12-03 JP JP2020201121A patent/JP6851536B2/ja active Active
  • 2020-12-28 JP JP2020218741A patent/JP6977137B2/ja active Active
• 2021
  • 2021-03-09 JP JP2021036829A patent/JP2021088606A/ja active Pending
  • 2021-03-19 US US17/206,987 patent/US20210205418A1/en active Pending

Patent Citations (22)

Non-Patent Citations (9)

Also Published As

Similar Documents

Legal Events