JPWO2019220654A1 - Formulation in which the N-formylpiperidine content is reduced and/or collapse or contraction of the freeze-dried cake is suppressed - Google Patents

Abstract

A formulation having a reduced N-formylpiperidine content and/or suppressed collapse or shrinkage of a freeze-dried cake. A freeze-dried preparation containing a teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, and further contains at least one component of (1) to (4). A freeze-dried preparation: (1) sodium glutamate or a hydrate thereof; (2) succinic acid; (3) sorbitol; (4) sodium acetate or a hydrate thereof.

Description

  The present invention has a reduced N-formylpiperidine content, and/or the collapse or shrinkage of a freeze-dried cake (hereinafter sometimes simply referred to as cake or cake) is suppressed, Regarding the formulation.

N-formylpiperidine (NFP may be hereinafter referred to as NFP) is a substance sometimes referred to as 1-formylpiperidine, and its CAS number is 2591-86-8. .. The structural formula is shown below.

  A rubber stopper is often used for the purpose of improving the sealing property of a drug filled in an injectable container such as a vial or a prefilled syringe (Patent Document 1).

  The drug with which the container for injection is filled may be freeze-dried at the time of its production for the purpose of improving stability, and when used, it is dissolved with glucose injection solution or physiological saline solution before use. Obtained (Non-patent documents 2-3).

  The drug may include a nonionic surfactant (Patent Documents 2 to 4). Preparations containing thrombomodulin or teriparatide are also known (Patent Documents 5 to 6, Non-Patent Documents 2 to 3).

  Further, an elcatonin formulation in which shrinkage of the freeze-dried cake is suppressed is known (Patent Document 7).

JP 2001-87351 A International Publication No. 95/16460 JP, 2005-168654, A JP, 2016-222663, A International Publication No. 2013/073545 International Publication No. 2012/169435 Japanese Patent Laid-Open No. 05-345729 Japanese Patent Publication No. 2016-505543

Journal of the Rubber Society of Japan, Vol. 53, No. 12 (1980) pp. 719-727 56.5 μg package insert for subcutaneous administration of Teribon (registered trademark) (revised in May 2017 (4th edition revision accompanied by changes in dosage and administration)) Licomodulin (registered trademark) 12800 package insert for intravenous infusion (revised April 2016 (8th edition))

  An object of the present invention is a freeze-dried preparation which is sealed with a rubber stopper and is filled in a medical container and which contains teriparatide acetate as an active ingredient, wherein NFP in the preparation is preserved when the preparation is stored. It is an object of the present invention to provide a freeze-dried preparation in which increase over time is suppressed, and a method for suppressing increase in NFP over time.

  Another object of the present invention is a lyophilized formulation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, and which contains NFP in the formulation when the formulation is stored. It is an object of the present invention to provide a freeze-dried preparation in which increase over time is suppressed, and a method for suppressing increase in NFP over time.

  Another object of the present invention is to provide a method for suppressing a time-dependent increase of NFP in a lyophilized preparation which is sealed with a rubber stopper and is filled in a medical container, during storage thereof. is there.

  Another object of the present invention is a method for producing a lyophilized preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container. It is intended to provide a method for producing a freeze-dried preparation in which an increase in NFP in the preparation over time is suppressed when stored.

  Another object of the present invention is a freeze-dried preparation which is sealed with a rubber stopper and is filled in a medical container, which contains teriparatide acetate as an active ingredient, and a freeze-dried cake when the preparation is stored. A lyophilized preparation in which collapse or contraction of (lyo cake) is suppressed, and a method for producing the same.

  Another object of the present invention is to provide a quality inspection method for a freeze-dried preparation which is sealed with a rubber stopper and filled in a medical container. Another object of the present invention is to provide a method for preparing a high-quality drug solution by using a freeze-dried preparation which is sealed with a rubber stopper and is filled in a medical container. Another object of the present invention is to provide a method for suppressing NFP in a drug solution obtained by dissolving a freeze-dried preparation, which is sealed with a rubber stopper and is filled in a medical container, with a solvent.

  One embodiment of the lyophilized preparation of the present invention is a lyophilized preparation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container. Alternatively, it is a freeze-dried preparation containing additives. Further, one aspect of the production method of the present invention is a method for producing a lyophilized formulation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, wherein Before the freeze-drying treatment in the manufacturing process, the step of incorporating a specific excipient and/or additive into the preparation is included. The freeze-dried preparation of the present aspect and the freeze-dried preparation obtained by the production method of the present aspect suppress an increase in the amount of NFP in the preparation during storage over time.

  Another embodiment of the lyophilized preparation of the present invention is a lyophilized preparation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, which comprises a specific excipient and/or It is a freeze-dried preparation containing additives. Further, one embodiment of the suppression method of the present invention is to increase the time-dependent increase of N-formylpiperidine in a freeze-dried preparation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and filled in a medical container. A method of inhibiting, which comprises the step of incorporating a specific nonionic surfactant into the formulation before freeze-drying treatment in the manufacturing process of the formulation. The freeze-dried preparation of the present aspect and the freeze-dried preparation obtained by the suppression method of the present aspect also suppress the increase in the amount of NFP in the preparation during storage over time.

  Another embodiment of the freeze-dried preparation of the present invention is a freeze-dried preparation which is filled with a medical container, which is sealed with a rubber stopper using a specific material and/or having specific physical properties. Also in the freeze-dried preparation of this aspect, the increase in the amount of NFP in the preparation during storage is suppressed.

  Another aspect of the production method of the present invention is a method for producing a lyophilized preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container. , A step of incorporating sodium chloride into the preparation before freeze-drying treatment in the manufacturing process of the preparation. The freeze-dried preparation obtained by the production method of the present embodiment also suppresses an increase in the amount of NFP in the preparation during storage over time.

  Another aspect of the freeze-dried preparation of the present invention is a freeze-dried preparation containing a teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, wherein 1) teriparatide acetate and A lyophilized formulation comprising a specific excipient and no additive, or 2) teriparatide acetate and a specific excipient and a specific additive. Another aspect of the production method of the present invention is a method for producing a lyophilized preparation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container. A step of freeze-drying a drug solution containing teriparatide acetate and a specific excipient and containing no additive, or 2) a drug solution containing teriparatide acetate and a specific excipient and a specific additive .. The freeze-dried preparation of the present aspect and the freeze-dried preparation obtained by the production method of the present aspect suppress the collapse or shrinkage of the freeze-dried cake (lyo cake) in the preparation during storage.

  One aspect of the quality inspection method of the present invention is a quality inspection method for a freeze-dried preparation which is sealed with a rubber stopper and is filled in a medical container, wherein the presence of NFP in the preparation is confirmed, and/or Quantifying the abundance. Moreover, one aspect of the drug solution preparing method of the present invention is a step of adding a solvent to the freeze-dried preparation sealed with a rubber stopper and filled in a medical container, and a step of twisting the medical container. including. Furthermore, another embodiment of the freeze-dried preparation of the present invention is a freeze-dried preparation which is sealed with a rubber stopper and contains teriparatide acetate as an active ingredient, which contains a specific excipient and contains additives. It is a lyophilized preparation not containing or a lyophilized preparation containing a specific excipient and a specific additive. The medicinal solution obtained through the quality inspection method of the present aspect, the medicinal solution obtained by the medicinal solution preparation method of the present aspect, and the medicinal solution obtained from the freeze-dried preparation of the present aspect have suppressed NFP content in the medicinal solution. And is of high quality.

That is, the present invention relates to the following inventions.
[1]
A freeze-dried preparation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, and further contains at least one component of (1) to (4). Lyophilized formulation:
(1) Sodium glutamate or its hydrate;
(2) succinic acid;
(3) sorbitol;
(4) Sodium acetate or its hydrate.
[2]
The lyophilized preparation according to the above [1], containing 67.9 μg of teriparatide acetate.
[3]
The freeze-dried preparation according to the above [1] or [2], wherein the material of the rubber stopper is butyl rubber.
[4]
A lyophilized preparation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, further containing the component (1):
(1) A nonionic surfactant having an HLB (Hydrophilic-Lipophilic Balance) value of 10.5 or more.
[5]
The freeze-dried preparation according to the above [4], wherein the component (1) is a polyoxyethylene (POE) sorbitan fatty acid ester or POE hydrogenated castor oil.
[6]
The freeze-dried preparation according to the above [4] or [5], wherein the content of the component (1) is 0.1 mg or more.
[7]
The freeze-dried preparation according to any one of [4] to [6] above, wherein thrombomodulin is a peptide represented by any of the following amino acid sequences and has thrombomodulin activity:
(1) the amino acid sequence of SEQ ID NO: 2;
(2) An amino acid sequence in which one or more amino acids of the amino acid sequence shown in SEQ ID NO: 2 is substituted, deleted or added;
(3) An amino acid sequence having 80% or more homology to the amino acid sequence set forth in SEQ ID NO: 2.
[8]
The freeze-dried preparation according to any one of [4] to [7] above, wherein the material of the rubber stopper is butyl rubber.
[9]
The freeze-dried preparation according to any one of [1] to [8] above, wherein the medical container is a vial.
[10]
A freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, which contains at least one excipient of (1) to (4) and is added. Freeze-dried formulation without substances:
(1) Glycine;
(2) sodium glutamate;
(3) Trehalose;
(4) Purified white sugar.
[11]
A freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, which contains purified sucrose and is at least one additive of (1) to (6). Lyophilized formulations, including:
(1) Histidine, a salt thereof, or a hydrate thereof;
(2) Ascorbic acid;
(3) Sodium acetate or its hydrate;
(4) sodium bisulfite;
(5) benzalkonium chloride;
(6) Methionine.
[12]
The freeze-dried preparation according to the above [10] or [11], wherein the amount of teriparatide acetate in the freeze-dried preparation is 67.9 μg.
[13]
A method for suppressing an increase with time of N-formylpiperidine in a lyophilized preparation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, comprising: (1) To (4), the method for suppressing, comprising the step of including at least any one of the components in the formulation before lyophilization in the production process of the formulation:
(1) Sodium glutamate or its hydrate;
(2) succinic acid;
(3) sorbitol;
(4) Sodium acetate or its hydrate.
[14]
The suppression method according to the above [13], wherein the amount of teriparatide acetate in the freeze-dried preparation is 67.9 μg.
[15]
The suppressing method according to the above [13] or [14], wherein the material of the rubber stopper is butyl rubber.
[16]
A method for suppressing an increase with time of N-formylpiperidine in a freeze-dried preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container. And a method of suppressing sodium chloride in the preparation of the preparation before freeze-drying in the manufacturing process of the preparation.
[17]
The suppressing method according to [16], wherein the material of the rubber stopper is butyl rubber.
[18]
A method for suppressing an increase with time of N-formylpiperidine in a freeze-dried preparation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, comprising the component (1) Suppressing method, characterized in that the product is contained in the preparation before freeze-drying treatment in the manufacturing process of the preparation:
(1) A nonionic surfactant having an HLB (Hydrophilic-Lipophilic Balance) value of 10.5 or more.
[19]
The method of [18], wherein the component (1) is polyoxyethylene (POE) sorbitan fatty acid ester or POE hydrogenated castor oil.
[20]
The method of suppressing according to [18] or [19] above, wherein the content of the component (1) is 0.1 mg or more.
[21]
The suppression method according to any one of [18] to [20], wherein the material of the rubber stopper is butyl rubber.
[22]
A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper made of halogenated butyl rubber;
Step 2) Tighten the formulation with an aluminum cap.
[23]
A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper that satisfies the following conditions 1 to 3;
Condition 1) The material of the rubber stopper is butyl rubber;
Condition 2) A rubber stopper is laminated;
Condition 3) The water vapor permeability of the rubber stopper is less than 0.57 (g/m ² ·24h);
Step 2) Tighten the formulation with an aluminum cap.
[24]
A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper having a dehydration rate of 33%/h or less according to the following definition;
Definition) This is the rate of change in the amount of water contained in the rubber stopper, which is obtained after sterilizing the rubber stopper for 30 minutes as a water-containing treatment and performing a drying treatment for 1 hour. Water content of rubber stopper after treatment/water content of rubber stopper after water treatment×100 (%/hour);
Step 2) Tighten the formulation with an aluminum cap.
[25]
A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper that satisfies the following conditions 1 and 2;
Condition 1) The material of the rubber stopper is butyl rubber or polyisobutylene;
Condition 2) the density of the rubber plug is less than 1.3 g/cm ³ .
Step 2) Tighten the formulation with an aluminum cap.
[26]
The suppression method according to any one of [13] to [25], wherein the medical container is a vial.
[27]
A method for inspecting the quality of a freeze-dried preparation, which is sealed with a rubber stopper and filled in a medical container, wherein the presence of N-formylpiperidine in the preparation is confirmed and/or the amount thereof is quantified. An inspection method including a step of performing.
[28]
A method for preparing a drug solution, which includes the following steps:
Step 1) A step of adding a solvent to the freeze-dried preparation, which is sealed with a rubber stopper and filled in a medical container;
Step 2) A step of twisting the medical container, wherein the number of times is 1 to 5 times.
[29]
A method for suppressing the N-formylpiperidine content in a drug solution obtained by dissolving a lyophilized preparation in a solvent, which comprises the following steps:
Step 1) A step of adding a solvent to the freeze-dried preparation, which is sealed with a rubber stopper and is filled in a medical container;
Step 2) A step of twisting the medical container, wherein the number of times is 1 to 5 times.
[30]
A method for producing a freeze-dried preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, wherein sodium chloride is freeze-dried in the production process of the preparation. A method for producing, which comprises the step of incorporating into the preparation before treatment.
[31]
The production method according to [30], wherein the material of the rubber stopper is butyl rubber.
[32]
A method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and filled in a medical container, comprising teriparatide acetate and at least any one of (1) to (4). A freeze-dried preparation, which comprises a step of freeze-drying a drug solution containing an excipient and does not contain an additive, wherein collapse or contraction of a freeze-dried cake (lyo cake) in the freeze-dried preparation is suppressed. Production method:
(1) Glycine;
(2) sodium glutamate;
(3) Trehalose;
(4) Purified white sugar.
[33]
A method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, comprising at least one of teriparatide acetate, purified sucrose, and (1) to (6). A method for producing a freeze-dried preparation, comprising the step of freeze-drying a drug solution containing the additive of claim 1 or 2, wherein collapse or shrinkage of the freeze-dried cake in the freeze-dried preparation is suppressed.
(1) Histidine, a salt thereof, or a hydrate thereof;
(2) Ascorbic acid;
(3) Sodium acetate or its hydrate;
(4) sodium bisulfite;
(5) benzalkonium chloride;
(6) Methionine.

  According to the present invention, a freeze-dried preparation or the like having a reduced NFP content and/or suppressed collapse or shrinkage of the freeze-dried cake is provided.

FIG. 1 is a graph showing the relationship between the polysorbate 80 content (surfactant amount (mg)) contained in the freeze-dried preparation and the NFP content (μg/vial) in the preparation after 2 weeks from the production. . FIG. 2 is a graph showing the relationship between the dehydration rate (%/hour) of the rubber stopper used to seal the formulation and the NFP content (μg/vial) in the formulation after storage for 1 week. FIG. 3 is a graph showing the relationship between the density (g/cm ³ ) of the butyl rubber stopper and the polyisobutylene stopper used for sealing the preparation and the NFP content (μg/vial) in the preparation after storage for 1 week. .. FIG. 4 shows the relationship between the material of the rubber stopper used for sealing the formulation and the NFP content (μg/vial) in the formulation after storage for 1 week. FIG. 5 shows the rubber plug No. The high performance liquid chromatography result of 1 sample is shown. The peak observed at the elution time of 4.682 minutes is the NFP-derived peak. FIG. 6 is a result of photographing the freeze-dried cake of the freeze-dried preparation containing a surfactant with an electron microscope (magnification is 60 times). FIG. 7 is a result of photographing an freeze-dried cake of a freeze-dried preparation containing no surfactant with an electron microscope (a magnification of 60 times). FIG. 8 is a result of photographing a freeze-dried cake of a freeze-dried preparation containing a surfactant with an electron microscope (a magnification of 300 times). The upper row is a photograph of the inside of the cake, and the lower row is a photograph of the surface of the cake. FIG. 9 is a result of photographing an freeze-dried cake of a freeze-dried preparation containing no surfactant with an electron microscope (magnification of 300 times). The upper row is a photograph of the inside of the cake, and the lower row is a photograph of the surface of the cake. FIG. 10 shows the results of photographing a freeze-dried cake of a freeze-dried preparation containing a surfactant with an electron microscope (magnification: 1000 times). The upper row is a photograph of the inside of the cake, and the lower row is a photograph of the surface of the cake. FIG. 11 is a result of photographing the freeze-dried cake of the freeze-dried preparation containing no surfactant with an electron microscope (magnification of 1000 times). The upper row is a photograph of the inside of the cake, and the lower row is a photograph of the surface of the cake. FIG. 12 is a graph showing the relationship between the HLB of a freeze-dried preparation containing a non-surfactant and the NFP content (μg/vial) in the preparation after 2 weeks from the production. FIG. 13 shows the results of measuring the NFP content in the lyophilized formulations (formulations 21 to 31) containing various excipients/additives after storage. The upper number shown at the bottom of the graph is the formulation number, and the lower number is the NFP content (NFP content in 1 vial; μg). FIG. 14 is a photograph of the freeze-dried preparation after storing the freeze-dried preparation (formulations 25 to 28) containing various excipients and additives. Each formulation is sealed with a rubber stopper and filled in a vial container. In the photograph, the formulation marked with "5" is the freeze-dried formulation after storage (formulation 25), and the formulation marked with "6" is the freeze-dried formulation after storage (formulation 26), "7". The formulation marked with indicates the freeze-dried preparation after storage (formulation 27), and the formulation marked "8" indicates the freeze-dried preparation after storage (formulation 28). FIG. 15 shows the results of measuring the NFP content in the teriparatide freeze-dried preparations (formulations 32 to 46) containing various excipients/additives after storage. The upper number shown at the bottom of the graph is the formulation number, and the lower number is the NFP content (NFP content in 1 vial; μg). FIG. 16 is a photograph of a freeze-dried preparation after storing the freeze-dried preparation of teriparatide (formulations 33, 39, 40, 41, 45) containing various excipients and additives. Each formulation is sealed with a rubber stopper and filled in a vial container. In the photograph, the preparation marked with “2” is the freeze-dried preparation after storage (formulation 33), and the preparation marked with “8” is the freeze-dried preparation after storage (formulation 39) is “9”. The formulation marked with is the freeze-dried formulation after storage (formulation 40), the formulation marked "10" is the freeze-dried formulation after storage (formulation 41), the formulation marked "14" is , And the freeze-dried preparation after storage (formulation 45). FIG. 17 is a photograph of the freeze-dried preparation after storing the freeze-dried teriparatide preparation containing various excipients and additives. Each formulation is sealed with a rubber stopper and filled in a vial container. In the photograph, the formulations marked with “1” to “15” represent the freeze-dried formulations after storage (formulations 32 to 46), respectively.

  Hereinafter, the present invention will be described in detail 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 present invention.

1. Lyophilized formulation:
(1) Medicinal component (component 1):
The active ingredient according to the present invention is not particularly limited and may be an ingredient effective for treatment, prevention, diagnosis and the like for mammals including humans. The structure of the medicinal component is not particularly limited, and may be a low molecular weight compound, peptide, protein, nucleic acid compound, polysaccharide and the like. The medicinal component is preferably a peptide or protein, more preferably a bioactive peptide or bioactive protein.

  Examples of the physiologically active peptide or protein include thrombomodulin, interleukin, colony stimulating factor, interferon, tumor necrosis factor, insulin, glucagon, parathyroid hormone (PTH), teriparatide or a salt thereof, gastrin and selectin. Among them, thrombomodulin, parathyroid hormone (PTH), and derivatives thereof are preferable as the medicinal component.

(1-1) Thrombomodulin:
Thrombomodulin is known as a substance that specifically binds to thrombin and inhibits the blood coagulation activity of thrombin, and at the same time has an action of significantly promoting the protein C activation ability of thrombin, and is known to have a strong blood coagulation inhibitory action. (Patent Document 5).

  The thrombomodulin according to the present invention preferably has the action of (1) selectively binding to thrombin and (2) promoting the activation of protein C by thrombin, and further (3) extending the coagulation time by thrombin. More preferably, it has an action and (4) also has an action of suppressing platelet aggregation by thrombin. In addition to the actions (1) to (4), the thrombomodulin of the present invention more preferably has (5) an anti-inflammatory action. Any one or more actions selected from (1) to (5) may be referred to as thrombomodulin activity.

  The binding action of thrombomodulin with thrombin is, for example, Thrombosis and Haemostasis 1993 70(3):418-422 and The Journal of Biological Chemistry 1989 264(9):4872-4876 and other tests described in various known documents. It can be confirmed by the method. The action of stimulating the activation of protein C by thrombin is, for example, the action of accelerating the activation of protein C by the test methods clearly described in various known documents including JP-A-64-6219. The amount of activity and the presence or absence thereof can be easily confirmed. Further, the effect of prolonging the coagulation time by thrombin and/or the effect of suppressing platelet aggregation by thrombin can be similarly easily confirmed. Furthermore, the anti-inflammatory effect can be confirmed by the test methods described in various known documents including Blood 2008 112:3361-3670 and The Journal of Clinical Investigation 2005 115(5):1267-1274.

  The thrombomodulin in the present embodiment is not particularly limited as long as it has thrombomodulin activity, but it is preferably water-soluble soluble thrombomodulin in the absence of a surfactant. A preferable example of the solubility of soluble thrombomodulin is 1 mg/mL in water, for example, distilled water for injection (in the absence of a surfactant such as Triton X-100 or polidocanol, usually around neutrality). Or more, or 10 mg/mL or more, preferably 15 mg/mL or more, or 17 mg/mL or more, more preferably 20 mg/mL or more, 25 mg/mL or more, or 30 mg/mL or more, and particularly It is preferably 60 mg/mL or more, and in some cases, 80 mg/mL or more, or 100 mg/mL or more, respectively. In determining whether or not soluble thrombomodulin could be dissolved, it was clear that it was clear when observed with the naked eye at a brightness of about 1000 lux, for example, directly under a white light source after dissolution. It is understood that the absence of such a level of insoluble matter is a direct indicator. It is also possible to confirm the presence or absence of a residue by filtering.

  The molecular weight of thrombomodulin according to the present invention is not limited, but is preferably 100,000 or less, more preferably 90,000 or less, further preferably 80,000 or less, particularly preferably 70,000 or less. Further, the molecular weight of thrombomodulin is more preferably 50,000 or more, particularly preferably 60,000 or more.

  The molecular weight of the soluble thrombomodulin according to the present invention can be easily measured by an ordinary method for measuring the molecular weight of a protein, but it is preferably measured by mass spectrometry and measured by the MALDI-TOF-MS method. Is more preferable. Soluble thrombomodulin can be obtained by culturing transformed cells prepared by transfecting a host cell with a DNA encoding soluble thrombomodulin, and further performing a fractionation treatment by column chromatography or the like to obtain a desired product. Soluble thrombomodulin having a molecular weight of

  The thrombomodulin according to the present invention includes the amino acid sequence of positions 19 to 132 of SEQ ID NO: 1 (hereinafter, also referred to as human TRM19-132) which is known as the central site of thrombomodulin activity in human thrombomodulin. Preferably. Further, the thrombomodulin according to the present invention is an amino acid sequence in which one or more amino acids are substituted, deleted, or added in human TRM19-132, and has a certain homology to human TRM19-132 (example : 50% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more), and a thrombomodulin variant exhibiting thrombomodulin activity.

The thrombomodulin according to the present invention may be a peptide represented by any of the following amino acid sequences A to C and further showing a thrombomodulin activity.
Sequence A: The amino acid sequence shown by SEQ ID NO:2.
Sequence B: An amino acid sequence obtained by substituting, deleting, or adding one or more amino acids in the amino acid sequence shown by SEQ ID NO:2.
Sequence C: an amino acid having a certain homology (eg, 50% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more) with the amino acid sequence represented by SEQ ID NO: 2. Array.

  The amount of thrombomodulin contained in the freeze-dried preparation of the present invention is not particularly limited, but it is preferable to include 12,800 active units (about 2 mg) of thrombomodulin. The amount of thrombomodulin per single dose contained in the freeze-dried preparation of the present invention is not particularly limited, but for example, when used for intravenous infusion, the upper limit is preferably 1 mg/kg or less, and among them, 0. 5 mg/kg or less, 0.1 mg/kg or less, and 0.08 mg/kg or less are particularly preferable. Further, the lower limit is particularly preferably 0.005 mg/kg or more, 0.01 mg/kg or more, 0.02 mg/kg or more. The amount of thrombomodulin contained in the freeze-dried preparation for intravenous administration of the present invention is preferably 0.06 mg/kg. When administered to patients with a body weight of more than 100 kg, it may be preferable to administer a fixed dose of 6 mg from the viewpoint that the blood volume is not proportional to the body weight and the blood volume relative to the body weight decreases relatively. ..

(1-2) Teriparatide or a salt thereof:
In the present invention, human PTH(1-34) is composed of amino acid residues from the 1st to the 34th amino acid residues in the amino acid sequence of human PTH(1-84), which is a human parathyroid hormone. It is a peptide represented by a partial amino acid sequence. In the present invention, teriparatide means free human PTH(1-34). Teriparatide can also be in salt form.

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

  The amount of teriparatide or a salt thereof contained in the freeze-dried preparation of the present invention is not particularly limited, but it is preferably 63.3 μg as teriparatide or 67.9 μg as teriparatide acetate. The amount of teriparatide or a salt thereof per single dose contained in the freeze-dried preparation of the present invention is not particularly limited, but teriparatide is preferably 56.5 μg.

(2) Other components (component 2):
The lyophilized preparation of the present invention may contain any other pharmacologically or physiologically acceptable component in addition to the above medicinal components.

  As other components of the present invention, for example, 1 or 2 or more kinds of excipients can be mentioned, and further 1 or 2 or more kinds of solubilizers, stabilizers, antioxidants, Additives such as anti-aggregating agents, tonicity adjusting agents, pH adjusting agents, preservatives (preservatives) can be included in the freeze-dried preparation of the present invention.

(2-1) Excipients and additives:
The excipient used in the freeze-dried preparation of the present invention is not particularly limited, but by itself or in combination with an additive, an increase in NFP over time during the storage process of the freeze-dried preparation of the present invention is suppressed. It is preferable that the obtained excipient is.

  The additive used in the freeze-dried preparation of the present invention is also not particularly limited, but by itself or in combination with an excipient or other additives, the increase of NFP in the freeze-dried preparation of the present invention is suppressed. It is preferably an additive that can be added. In addition, the additive used in the freeze-dried preparation of the present invention does not adversely affect the quality and safety of the freeze-dried preparation of the present invention, and/or reacts with excipients and other additives. It is preferable that the additive does not cause/is unlikely to cause. Unfavorable reactions may include cake collapse or shrinkage, which may be observed immediately after manufacture of the lyophilized formulation or after its storage. The cake is sometimes referred to as a porous, dry "lyo cake". When the cake collapses or shrinks, it becomes difficult or impossible to dissolve (reconstitute) the cake, and thus the collapse or shrinkage of the cake is not preferable.

  The excipients and additives used in the freeze-dried preparation of the present invention are not limited to one kind of excipients and additives, and may be two or more kinds of excipients and additives.

  Examples of excipients include sugar alcohols (mannitol, inositol, sorbitol, etc.), monosaccharides (glucose, fructose, etc.), disaccharides (maltose, lactose, sucrose, trehalose, etc.), amino acids (glycine, glutamic acid or salts thereof, asparagine). Acids or salts thereof, glutamine or hydrochlorides thereof, arginine or hydrochlorides thereof), celluloses (ethyl cellulose, crystalline cellulose, carboxymethyl cellulose etc.), citric acid or salts thereof (calcium citrate or disodium citrate etc.), chloride Sodium, etc. can be mentioned. Here, the amino acid may be D-form or L-form, but L-form is preferable. The sugar alcohol may be either D-form or L-form, but the D-form is preferable. These may be hydrates.

  As excipients, among others, inositol, glycine, sodium glutamate, maltose or hydrates thereof, mannitol, lactose or hydrates thereof, trehalose or hydrates thereof, arginine hydrochloride, and sucrose (eg, purified white sugar) And glycine, sodium glutamate, trehalose or a hydrate thereof, arginine hydrochloride, and sucrose (eg, purified sucrose) can be further preferably mentioned.

  As additives, for example, amino acids or salts thereof (eg: histidine, cysteine, methionine, or salts thereof), sugar alcohols (eg: mannitol, inositol, sorbitol), citric acid, sodium hydrogen carbonate, ascorbic acid, succinic acid, Sodium acetate, α-thioglycerin, phosphoric acid, sodium dihydrogen phosphate, sodium carbonate, trometamol, sodium dihydrogen phosphate, tartaric acid, sodium thioglycolate, sodium bisulfite, benzalkonium chloride, surfactants, etc. Can be mentioned. Here, the amino acid may be D-form or L-form, but L-form is preferable. The sugar alcohol may be either D-form or L-form, but the D-form is preferable. These may be hydrates.

(2-2) Glycine:
When glycine is used as an excipient, it is preferable that one or more polar amino acids are further contained in the preparation as an additive. Examples of polar amino acids include, for example, histidine, cysteine, or their hydrochlorides or their salts. The hydrate of the above can be mentioned. Here, the polar amino acid may be D-form or L-form, but L-form is preferable. When glycine is used as an excipient for the purpose of suppressing collapse or shrinkage of the lyophilized cake during storage, a mode in which no additive is contained is also preferable.

(2-3) Glutamic acid or a salt thereof:
When glutamic acid or a salt thereof is used as an excipient, it is preferable that one or more components selected from ascorbic acid, succinic acid and sodium acetate be added to the formulation as an additive. Alternatively, as another embodiment, a formulation that uses glutamic acid or a salt thereof as an excipient and does not use an additive can be preferably mentioned.

(2-4) Maltose or a hydrate thereof:
When maltose or its hydrate is used as an excipient for the purpose of suppressing collapse or shrinkage of a lyophilized cake during storage, α-thioglycerin, phosphoric acid and phosphorous are added as additives. It is preferable that one or more components selected from sodium dihydrogen acid are included in the preparation.

(2-5) Mannitol:
When mannitol is used as an excipient for the purpose of suppressing collapse or shrinkage of the lyophilized cake during storage, one or two selected from sodium hydrogen carbonate, trometamol and methionine as an additive. It is preferable to include the above components in the preparation. Here, methionine may be D-form or L-form, but L-form is preferable.

(2-6) Lactose or its hydrate:
When lactose or its hydrate is used as an excipient for the purpose of suppressing the collapse or shrinkage of the lyophilized cake during storage, as additives, sodium dihydrogen phosphate, tartaric acid and thiol are further added. It is preferable to include one or more components selected from sodium glycolate in the preparation.

(2-7) Trehalose or its hydrate:
When trehalose or a hydrate thereof is used as an excipient for the purpose of suppressing the increase of NFP in the preparation over time, D-sorbitol and/or sodium bisulfite may be added to the preparation as an additive. preferable. When trehalose or its hydrate is used as an excipient for the purpose of suppressing collapse or shrinkage of the lyophilized cake during storage, it is preferable that no additive is contained.

(2-8) Arginine or its hydrochloride:
When arginine or its hydrochloride is used as an excipient, it is preferable to include benzalkonium or its chloride and/or a surfactant in the formulation. Further, when arginine or its hydrochloride is used as an excipient for the purpose of suppressing collapse or shrinkage of a lyophilized cake during storage, a mode in which no additive is contained can be preferably exemplified.

(2-9) Sucrose (eg, purified white sugar):
When sucrose (eg, refined sucrose) is used as an excipient for the purpose of suppressing the increase of NFP in the preparation, succinic acid, sodium acetate or a hydrate thereof, D-sorbitol, and It is preferable that one or more components selected from and sodium chloride are contained in the preparation.

  When sucrose (eg, refined sucrose) is used as an excipient for the purpose of suppressing collapse or shrinkage of the lyophilized cake during storage, addition of succinic acid or D-sorbitol as an additive It is not preferable to include the product in the formulation, 1) histidine, a salt thereof, or a hydrate thereof, 2) ascorbic acid, 3) sodium acetate or a hydrate thereof, 4) sodium bisulfite, 5) benzalco. It is preferred that the formulation contains one or more additives selected from the group consisting of titanium or its chloride and 6) methionine. Here, each of methionine and histidine may be D-form or L-form, but L-form is preferable.

  When sucrose (eg, refined sucrose) is used as an excipient for the purpose of suppressing collapse or shrinkage of a lyophilized cake during storage, a mode in which additives are not included in the formulation can be preferably exemplified.

(2-10) Excipients and additives when the medicinal component is thrombomodulin:
When the medicinal component contained in the freeze-dried preparation of the present invention is thrombomodulin, the excipient contained in the preparation is not particularly limited, but one or more amino acids are preferable, and among them, glutamine or its hydrochloride, And/or arginine or its hydrochloride is preferred, and arginine or its hydrochloride is most preferred.

  When the medicinal component contained in the freeze-dried preparation of the present invention is thrombomodulin, the additive contained in the preparation is not particularly limited, but it is preferable to include a surfactant also from the viewpoint of solubilization aid and anti-aggregation. .

(2-11) Excipient or additive when the medicinal component is teriparatide or a salt thereof:
When the medicinal component contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the excipient contained in the preparation is not particularly limited, but glycine, glutamic acid or a salt thereof, trehalose or a hydrate thereof, arginine. Alternatively, it is preferably one or more kinds of excipients selected from its hydrochloride and sucrose (eg, purified sucrose), and among them, glutamic acid or its salt or sucrose (eg, purified sucrose). Is more preferable. Suitable examples of glutamic acid or a salt thereof include sodium glutamate.

  The medicinal ingredient contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the additive contained in the preparation is not particularly limited, but for the purpose of suppressing the increase of NFP in the preparation over time, succinic acid, The formulation preferably contains one or more additives selected from sodium acetate hydrate, sorbitol, and sodium chloride, for the purpose of suppressing collapse or shrinkage of a lyophilized cake during storage. In, 1) histidine, a salt thereof, or a hydrate thereof, 2) ascorbic acid, 3) sodium acetate or a hydrate thereof, 4) sodium bisulfite, 5) benzalkonium or a chloride thereof, 6) It is preferable to include one or more additives selected from methionine in the preparation.

(2-12) Content of excipients and additives:
The content of excipients and additives contained in the freeze-dried preparation of the present invention is not particularly limited, and can be designed according to, for example, the size and physical properties of the medicinal component, medical container, and the like.

  When the medicinal component contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the content of the additive is the mass of the freeze-dried preparation (here, medical containers and packages such as rubber stoppers, vials and ampoules). 10 times or less, preferably 5.0 times or less, 1:1 or less, or 0.5 times or less, and 0.001 times or more. In particular, it is preferably 0.005 times or more, or 0.01 times or more.

  When the medicinal component contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the content of the additive is 1000 times or less with respect to the mass of the medicinal component (component 1) contained in the freeze-dried preparation. It is possible that it is preferably 100 times or less, 50 times or less or 10 times or less, and 0.1 times or more, and preferably 0.5 times or more, or 1 time or more. ..

  When the medicinal component contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the content of the additive may be, for example, 100 mg or less, and particularly 50 mg or less, 10 mg or less, or 5 mg or less. It may be 0.01 mg or more, preferably 0.05 mg or more, 0.08 mg or more, or 0.1 mg or more.

  When the medicinal component contained in the freeze-dried preparation of the present invention is thrombomodulin, the content of the additive is the mass of the freeze-dried preparation (here, the mass of the medical container such as a rubber stopper, a vial or an ampoule and the packaging is Excluding), the amount may be equal to or less than the above, and may be 0.5 or less, 0.1 or less, 0.05 or less, 0.01 or less, or 0.005 or less, among others. Preferably, it is 0.0001 times or more, 0.0005 times or more, 0.001 times or more, or 0.002 times or more. The ratio of the mass of the freeze-dried preparation of the present invention to the mass of the amount of surfactant contained in the freeze-dried preparation is preferably 1:0.001 to 0.05, for example.

  When the medicinal component contained in the freeze-dried preparation of the present invention is thrombomodulin, the content of the additive is 0.5 times or less the mass of the medicinal component (component 1) contained in the freeze-dried preparation. In particular, it is preferably 0.1 times or less, 0.05 times or less, or 0.02 times or less, and 0.001 times or more, 0.005 times or more, or 0.01 times or more. Is preferred. The ratio of the mass of the medicinal component (component 1) of the present invention to the mass of the surfactant is preferably, for example, 1:0.01 to 0.2.

  When the medicinal component contained in the freeze-dried preparation of the present invention is teriparatide or a salt thereof, the content of the excipient may be 1 mg or more, and preferably 5 mg or more, or 10 mg or more, and It may be 100 mg or less, and preferably 50 mg or less, or 20 mg or less.

  When the medicinal ingredient contained in the freeze-dried preparation of the present invention is thrombomodulin, the content of the excipient may be 1 mg or more, preferably 10 mg or more, or 20 mg or more, and 100 mg or less. It is possible, and in particular, it is preferably 80 mg or less, or 50 mg or less.

(2-13) Surfactant:
Surfactants can be roughly classified into ionic surfactants and nonionic surfactants. Ionic surfactants are classified into anionic surfactants, cationic surfactants and amphoteric surfactants. obtain. Preferred examples of the surfactant contained in the freeze-dried preparation of the present invention include anionic surfactants and nonionic surfactants.

  As the nonionic surfactant, polyoxyethylene (hereinafter sometimes referred to as POE)-polyoxypropylene (hereinafter sometimes referred to as POP) block copolymer, POE-POP block copolymer adduct, Examples thereof include POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE alkyl ether, POE/POP alkyl ether, POE alkylphenyl ether, polyethylene glycol monostearate, glycerin fatty acid ester, and sorbitan fatty acid ester.

  Examples of the anionic surfactant include alkyl allyl sulfonate, alkyl sulfate, POE alkyl ether phosphate, fatty acid or a salt thereof, and sodium alkylbenzene sulfonate, sodium lauryl sulfate and POE cetyl ether phosphate, respectively. Preferred examples are sodium and ursodesoxycholic acid.

  As the nonionic surfactant, POE sorbitan fatty acid ester is preferable, and among them, POE(20) sorbitan monolaurate (polysorbate 20), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80) is suitable. Polysorbate 80 is a substance described in the Japanese Pharmacopoeia, and polysorbates 20, 40, 60, and 65 are substances described in the standard of pharmaceutical additives, and these are all widely used as pharmaceutical additives.

Further, as the nonionic surfactant, POE hydrogenated castor oil is preferable, and among them, POE (5) hydrogenated castor oil, POE (10) hydrogenated castor oil, POE (20) hydrogenated castor oil (for example, NIKKOL HCO-20 ^(registered trademark)). ^Trademarks) , POE(40) hydrogenated castor oil (eg NIKKOL HCO-40 ^{(registered trademark)} ), POE(50) hydrogenated castor oil (eg NIKKOL HCO-50 ^{(registered trademark)} ), POE(60) hydrogenated. Castor oil (for example, NIKKOL HCO-60 ^{(registered trademark)} ), POE (100) hydrogenated castor oil are suitable.

Alternatively, a nonionic surfactant having an HLB (Hydrophilic-Lipophilic Balance) value of 10.5 or more according to the following Griffin's method is suitable, and among them, a nonionic surfactant having 11 or more or 14 or more is preferable. Preferred are surfactants. The upper limit of HLB is not particularly limited as long as it is 20 or less, but among them, a nonionic surfactant having 19 or less, 18 or less, or 17 or less is preferable.

Further, an anionic surfactant having an HLB value of 5 or more according to the following Davis method formula is preferable, and among them, an anionic interface having 10 or more, 20 or more, 30 or more, or 35 or more is preferable. Activators are preferred. The upper limit of HLB is not particularly limited as long as it is 40 or less.

(Formula for obtaining the balance between hydrophilicity and lipophilicity on the basis that sodium dodecyl sulfate is 40 and oleic acid is 1)

  The amount of the surfactant contained in the freeze-dried preparation of the present invention is not particularly limited, but with respect to the mass of the freeze-dried preparation (here, excluding the mass of medical containers and packages such as rubber stoppers, vials and ampoules). It may be equal to or less than the above, preferably 0.5 times or less, 0.1 times or less, 0.05 times or less, 0.01 times or less, or 0.005 times or less, and It is preferably 0.0001 times or more, 0.0005 times or more, 0.001 times or more, or 0.002 times or more. The ratio of the mass of the freeze-dried preparation of the present invention to the mass of the amount of surfactant contained in the freeze-dried preparation is preferably 1:0.001 to 0.05, for example.

  The amount of the surfactant contained in the freeze-dried preparation of the present invention is not particularly limited, but may be 0.5 times or less the amount of the medicinal component (ingredient 1) contained in the freeze-dried preparation, and among others, It is preferably 0.1 times or less, 0.05 times or less, or 0.02 times or less, and 0.001 times or more, 0.005 times or more, or 0.01 times or more. preferable. The ratio of the mass of the medicinal component (component 1) of the present invention to the mass of the surfactant is preferably, for example, 1:0.01 to 0.2.

  Although the amount of the surfactant contained in the freeze-dried preparation of the present invention is not particularly limited, for example, 0.003 mg or more, 0.01 mg or more, 0.03 mg or more, 0.1 mg or more, 0.11 mg or more, 0.12 mg. As described above, it can be 0.13 mg or more or 1.0 mg or more, and above all, it is preferably 0.1 mg or more, and can be 0.1 to 1.0 mg.

  The method of adding the surfactant to the freeze-dried preparation of the present invention is not particularly limited, but a preferred embodiment is one in which the surfactant is also dissolved in advance in a solution containing component 1 and the like to be subjected to the freeze-drying treatment. That is, it is preferable that a surfactant is included in a solution together with other components, and the solution is freeze-dried to produce the freeze-dried preparation of the present invention.

(3) Rubber stopper:
The freeze-dried preparation of the present invention is preferably sealed with a rubber stopper. Here, the closure can be easily understood by those skilled in the art, and means to seal the mouth of the container filled with the freeze-dried preparation (see Patent Document 6, etc.).

  The material of the rubber stopper according to the present invention is not particularly limited, and examples thereof include butyl rubber, chlorinated butyl rubber, brominated butyl rubber, butyl rubber such as divinylbenzene terpolymer butyl rubber, and polyisoprene rubber (high to low cis 1,4). Bond), polybutadiene rubber (high to low cis 1,4 bond), conjugated diene rubber such as styrene-butadiene copolymer rubber, ethylene-propylene-diene terpolymer rubber (EPDM), and the like.

  The rubber stopper used in the freeze-dried preparation of the present invention does not show an increase in NFP over time during storage of the preparation, or an increase in NFP is observed, but the increase in NFP occurs over time when another rubber stopper is used. It is preferable that the rubber stopper is suppressed compared with the increase.

  Here, as the rubber plug according to the present invention, a rubber plug whose material is halogenated butyl rubber can be preferably exemplified, and among them, chlorinated butyl rubber and brominated butyl rubber are more suitable. In the freeze-dried preparation sealed with such a rubber stopper, an increase in the amount of NFP in the preparation over time is suppressed.

  Further, the rubber stopper according to the present invention may be a rubber stopper having a low dehydration rate, for example, a rubber stopper having a low dehydration rate and made of butyl rubber is preferable. The dehydration rate of the rubber stopper is, for example, by subjecting the rubber stopper to be inspected to a high humidity or high humidity/high temperature environment for a predetermined period to carry out a water-containing treatment, and then performing a drying treatment for a predetermined time. It can be known by measuring the rate of change of the amount of water contained in the rubber stopper by a method known per se. In the freeze-dried preparation sealed with such a rubber stopper, an increase in the amount of NFP in the preparation over time is suppressed.

  For example, after the sterilizing treatment at 121° C. for 30 minutes as the water-containing treatment, after performing the drying treatment for 1 hour, the rate of change of the water content contained in the rubber stopper (water content of the rubber stopper after the drying treatment/after sterilizing treatment) The water content of the rubber stopper×100 (%/hour)) can be used as the dehydration rate and can be measured by the Karl Fischer titration method.

  More specifically, the water content immediately after sterilization treatment related to high humidity or high humidity/high temperature is 5.32 mg/rubber stopper, and the water content after 1 hour of drying treatment is 1.92 mg/rubber stopper. In this case, the dehydration rate of the single rubber stopper is 1.92/5.32×100 (%/hour), that is, about 36 (%/hour). Alternatively, when the water content immediately after the sterilization treatment related to high humidity or high humidity/high temperature is 2.54 mg/rubber stopper and the water content after the drying treatment for 1 hour is 0.83 mg/rubber stopper, The dehydration rate of one rubber plug is 0.83/2.54×100 (%/hour), that is, about 33 (%/hour).

  When the rate of change of the water content in the rubber stopper is calculated after the water-containing treatment is sterilized at 121°C for 30 minutes and the drying treatment is performed for 1 hour, the dehydration rate of the rubber stopper is 33 (%/hour). It can be less than, and is preferably 32 (%/hour) or less, 31 (%/hour) or less, or 30 (%/hour) or less.

The rubber stopper according to the present invention is preferably a rubber stopper made of butyl rubber or polyisobutylene having a low density. The density can be measured, for example, by the JISK6268 test method (a method for measuring the density of vulcanized rubber, which is defined by Japanese Industrial Standards). The density can be less than 1.3 (g/cm ³ ), among which 1.2 (g/cm ³ ) or less, 1.1 (g/cm ³ ) or less, or 1.0 (g/cm ³ ). It is preferably not more than cm ³ ). The lower limit of the density is not particularly limited, but can be, for example, 0.5 (g/cm ³ ) or more, and particularly 0.7 (g/cm ³ ) or more, or 0.9 (g/cm ^{3 ).} ) Or more is preferable. In the freeze-dried preparation sealed with such a rubber stopper, an increase in the amount of NFP in the preparation over time is suppressed.

Alternatively, the rubber plug according to the present invention may be a rubber plug made of butyl rubber having a low water vapor permeability and having a top surface laminated (for example, with a material such as polytetrafluoroethylene (PTFE)). The water vapor permeability can be measured by, for example, the JISZ0208 test method (commonly called a cup method; Non-Patent Document 1). The water vapor permeability can be less than 0.57 (g/m ² ·24h), among which 0.46 (g/m ² ·24h) or less, 0.4 or less, 0.33 (g/m). ² ·24h) or less, 0.3(g/m ² ·24h) or less, 0.1(g/m ² ·24h) or less, 0.05(g/m ² ·24h) or less, or 0.04 It is preferably (g/m ² ·24h) or less. In the freeze-dried preparation sealed with such a rubber stopper, an increase in the amount of NFP in the preparation over time is suppressed.

  The material of the rubber stopper according to the present invention is butyl rubber, and the freeze-dried preparation of the present invention filled in a medical container suppresses an increase in NFP in the preparation when the preparation is stored. It is preferable to include one or more kinds of excipients and/or additives capable of Above all, when the material is butyl rubber and the rubber plug is a rubber plug satisfying at least one of the following conditions 1 to 3, it is more preferable to use the above-mentioned excipient and/or additive.

-Condition 1: Not laminated, or the water vapor permeability of the rubber plug is 0.57 (g/m ² ·24h) or more.
-Condition 2: The dehydration rate of the rubber stopper exceeds 33%/h (however, the dehydration rate means that the rubber stopper is sterilized at 121°C for 30 minutes as a water-containing treatment for 1 hour. The rate of change in the amount of water contained in the rubber stopper obtained after performing the drying treatment of 1. The water content of the rubber stopper after the drying treatment/the water content of the rubber stopper after the water treatment×100 (%/hour) ).
-Condition 3: The density of the rubber plug is 1.3 g/cm ³ or more.

(4) Medical container:
The freeze-dried preparation of the present invention is preferably filled in a medical container. The medical container is not particularly limited, but an infusion bag, a syringe, a vial, an ampoule and the like are preferable, and a vial is particularly preferable. The material of the medical container is not particularly limited, and may be, for example, glass or plastic.

  When the freeze-dried preparation of the present invention is used for human treatment, prevention or diagnosis, the freeze-dried preparation of the present invention is preferably sterilized. The sterilization method is not particularly limited, and examples thereof include a hot water immersion sterilization method, a hot water shower sterilization method, and a high pressure steam sterilization (autoclave) method. Further, if desired, the lyophilized preparation of the present invention (specifically, the drug solution corresponding to the lyophilized preparation before being lyophilized) can be filtered with a dust filter or the like when the medical container is filled.

  When the medical container is a vial, the drug solution is dispensed into the vial, the opening can be sealed with a rubber stopper after the freeze-drying process, and in addition, it is sealed with an aluminum cap or the like, The lyophilized formulation of the present invention can be manufactured.

(5) NFP content:
The freeze-dried preparation of the present invention is preferably a preparation having a reduced NFP content at the time of its production, over its storage period, or during use after its storage.

  The amount of NFP contained in the freeze-dried preparation of the present invention is not particularly limited, but the amount of NFP contained in the freeze-dried preparation of the present invention administered per day is reduced to, for example, 1 to 10 μg. Is preferred.

The amount of NFP contained in the freeze-dried preparation of the present invention is not particularly limited, but relative to the mass of the freeze-dried preparation of the present invention (here, the mass of medical containers and packages such as rubber stoppers, vials and ampoules is excluded). May be 2×10 ⁻³ % or less, preferably 1×10 ⁻³ % or less, 5×10 ⁻⁴ % or less, 3×10 ⁻⁴ % or less, or 2×10 ⁻⁴ % or less. ..

The amount of NFP contained in the freeze-dried preparation of the present invention is not particularly limited, but it may be 2×10 ⁻² % or less with respect to the mass of the medicinal component (ingredient 1) contained in the freeze-dried preparation of the present invention. It is preferably ×10 ⁻² % or less, 8×10 ⁻³ % or less, 5×10 ⁻³ % or less, 3×10 ⁻³ % or less, or 2×10 ⁻³ % or less.

  Although the amount of NFP contained in the freeze-dried preparation of the present invention is not particularly limited, it may be, for example, 20 μg or less, and above all, 10 μg or less, 8 μg or less, 5 μg or less, 1 μg or less, 0.5 μg or less, 0.2 μg or less, 0. It is preferably 15 μg or less, 0.12 μg or less, 0.1 μg or less, 0.08 μg or less, 0.07 μg or less, 0.05 μg or less, 0.02 μg or less, or 0.01 μg or less. Of course, the embodiment in which the freeze-dried preparation of the present invention contains no NFP is most preferable.

  NFP in the formulation can be detected or quantified by high performance liquid chromatography, mass spectrometry, or the like.

(6) Suppression of collapse or shrinkage of the freeze-dried cake:
The freeze-dried preparation of the present invention is preferably a preparation in which collapse or shrinkage of the freeze-dried cake is suppressed at the time of its production, its storage period, or use after storage.

  Regarding the collapse or shrinkage of the freeze-dried cake, the presence or absence and the degree thereof can be easily determined by observing the appearance of the freeze-dried cake.

  In order to suppress the collapse or shrinkage of the freeze-dried cake, it is preferable to appropriately select the excipients and additives used in the freeze-dried preparation of the present invention.

  When trehalose or its hydrate is used as an excipient, it is preferable that sorbitol or sodium bisulfite is not used together as an additive, and if the medicinal ingredient is teriparatide or its salt, no additive is contained. Aspects are even more preferred.

  When sodium bisulfite is used as an additive, it is preferable not to use trehalose or its hydrate together as an excipient, and when the medicinal ingredient is teriparatide or a salt thereof, sucrose (ex: An embodiment using purified sucrose) is more preferable.

  When succinic acid is used as an additive, it is preferable that sucrose (eg, purified sucrose) is not used as an excipient, and sodium glutamate is used as an excipient. When succinic acid is used as an additive and sodium glutamate is used as an excipient, a mode in which ascorbic acid or sodium acetate hydrate is further added as an additive is more preferable.

  When sucrose (eg, purified sucrose) is used as an excipient, it is preferable that cysteine, its salt, hydrates thereof, succinic acid and sorbitol are not used as an additive, 1) histidine, its salt, Or a hydrate thereof, 2) ascorbic acid, 3) sodium acetate or a hydrate thereof, 4) sodium bisulfite, 5) benzalkonium, and 6) one or more additives selected from methionine are contained in the preparation. It is preferable to be strict.

  Patent Document 7 reports that shrinkage of the freeze-dried cake was not observed in almost all formulations using sugars such as sucrose and mannitol. On the other hand, in the freeze-dried preparation of the present application, when sucrose or trehalose (or a hydrate thereof) is used as an excipient, in view of suppressing collapse or shrinkage of the freeze-dried cake, selection of a specific additive or The use of no additives is preferred.

  Patent Document 8 discloses that the lyophilized cake shrinks by replacing sodium chloride in the preparation with another salt, potassium chloride. On the other hand, in the freeze-dried preparation of the present application, when salts such as histidine hydrochloride, sodium acetate, sodium bisulfite, and benzalkonium chloride were used, in all cases, the shrinkage of the freeze-dried cake was visually observed. There wasn't.

  When additives are added to excipients such as sucrose or trehalose (or its hydrate) for the purpose of suppressing collapse or shrinkage of the freeze-dried cake, sucrose or trehalose (or its hydrate) It is preferable that the ratio of the amount of the excipient to the additive is 1:0.005-0.2. That is, it is preferable to add about 0.5 to 20% of the additive amount of the excipient such as sucrose or trehalose (or its hydrate) to the preparation. Further, the mass of the additive in the preparation is preferably 0.05 to 2.0 mg.

  In Patent Document 7, when the content of sodium chloride in the preparation is 25% or more by weight with respect to the sugar in the preparation, shrinkage of the cake after freeze-drying is recognized. On the other hand, in the freeze-dried preparation of the present application, the shrinkage of the cake is also observed by setting the additive succinic acid to the excipient sucrose in a mass ratio of about 5%. Therefore, even when the above-mentioned excipient amount and additive mass ratio are established, when sucrose or trehalose (or its hydrate) is used as an excipient, suppression of collapse or shrinkage of the freeze-dried cake is suppressed. From the viewpoint of, the selection of specific additives is preferable.

(7) Use:
The freeze-dried preparation of the present invention is a freeze-dried preparation that is used (treatment, prevention, diagnosis for mammals including human) after being dissolved with water for injection, glucose injection, physiological saline or the like before use. You can

  When the dissolved lyophilized formulation (medicine solution) is administered to humans, it can be administered parenterally, for example, intravenously, intramuscularly, or subcutaneously. In the case of intravenous administration, the desired amount can be administered once (intravenous rapid administration) or intravenous drip can be administered.

2. Method of suppressing increase in NFP amount over time:
In one embodiment of the freeze-dried preparation of the present invention, the material of the rubber stopper used for sealing the preparation is halogenated butyl rubber. In one embodiment of the freeze-dried preparation of the present invention, the dehydration rate of the rubber stopper used for sealing the preparation is below a certain threshold. In one embodiment of the freeze-dried preparation of the present invention, the density of the rubber stopper used for sealing the preparation is a certain threshold value or less, and the material is butyl rubber or polyisobutylene. In one embodiment of the freeze-dried preparation of the present invention, the water vapor permeability of the rubber stopper used for sealing the preparation is below a certain threshold, and the rubber stopper is laminated (top surface, foot portion, or both). , Its material is butyl rubber.

  In these freeze-dried preparations, an increase in the amount of NFP in the preparation over time can be suppressed.

  In one embodiment of the freeze-dried preparation of the present invention, it contains the specific excipients and additives exemplified above. Also in these freeze-dried preparations, an increase in the amount of NFP in the preparation over time can be suppressed.

  Here, the suppression of the increase over time means the increase in the NFP content over time in comparison with the increase in the NFP content over time in the above-mentioned rubber stopper or the freeze-dried preparation that does not use a specific excipient or additive. It means that the increase is gradual, the NFP content does not change over time, or the NFP content decreases over time. Here, the time scale is not particularly limited, but it may be, for example, suppression of increase with time when stored at room temperature to about 80° C. for several days to several months.

  The method for incorporating a specific excipient or additive into the preparation for the purpose of suppressing the increase in NFP content in the freeze-dried preparation of the present invention over time is not particularly limited, but it is one of the steps for producing the preparation. Include it in the preparation before the freeze-drying process (Example: Prepare an aqueous solution containing the medicinal components, excipients, and additives, and after pre-treating the aqueous solution, such as filtration, place the aqueous solution in a medical container. (Filling) is preferable.

  The presence and/or NFP content of NFP in the freeze-dried preparation can be confirmed and quantified by a method known per se such as high performance liquid chromatography. The conditions of high performance liquid chromatography are as follows, for example.

(1) Detector: ultraviolet absorptiometer (measurement wavelength: 214 nm).
(2) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 150 mm was packed with 5 μm of octadecylsilylated silica gel for liquid chromatography (YMC-Pack ODS-AM manufactured by YMC, or an equivalent product).
(3) Column temperature: A constant temperature around 40°C.
(4) Mobile phase:
Mobile phase A: Prepared by adding 1 mL of acetic acid (100) to 1000 mL of water.
Mobile phase B: Prepared by adding 1 mL of acetic acid (100) to 1000 mL of acetonitrile.
(5) Liquid transfer of mobile phase:
The mixing ratio of mobile phase A and mobile phase B is set to 81:19.
(6) Flow rate: The NFP holding time is adjusted to be about 4.5 minutes.
(7) Detection time: About twice the holding time of NFP.

  A sample to be applied to high performance liquid chromatography can be prepared by dissolving the freeze-dried preparation in a suitable solvent, but the preparation method is not particularly limited. For example, a solution obtained by dissolving the freeze-dried preparation in physiological saline can be used as a sample to be applied to high performance liquid chromatography.

  The mechanism of the increase in NFP content in the lyophilized formulation over time is not clear. However, during the period during which the freeze-dried preparation of the present invention is stored or allowed to stand, the inventor gradually migrates NFP from the rubber stopper used for the closure to the surface of the preparation or the inside thereof (eg, inside cake) This allows for the possibility that the NFP content in the formulation may increase over time.

  That is, a rubber stopper using a halogenated butyl rubber as a material, a rubber stopper having a dehydration rate equal to or lower than a certain threshold value, or a density of the rubber stopper equal to or less than a certain threshold value, and the material being a butyl rubber or a polyisobutylene rubber stopper, Alternatively, the water vapor permeability of the rubber stopper is below a certain threshold, laminated, the freeze-dried preparation sealed with a rubber stopper whose material is butyl rubber, for example, physical properties different from these rubber stoppers, Compared to a freeze-dried preparation that is sealed with a rubber stopper made of butyl rubber, NFP that migrates from the rubber stopper to the freeze-dried preparation can be suppressed over a period during which the preparation is stored or allowed to stand. The inventor thinks.

  The mechanism by which the lyophilized preparation contains a specific excipient or additive to suppress the increase in NFP content in the lyophilized preparation over time is not clear, but one theory is that some interaction ( (Example: chemical interaction inside the freeze-dried cake) or the mechanism of collapse or shrinkage of the freeze-dried cake is considered by the inventor.

3. Storage method of lyophilized formulation:
As one aspect of the present invention, there is provided a method for storing a freeze-dried preparation which is sealed with a rubber stopper, wherein the increase in the amount of NFP in the freeze-dried preparation is suppressed.

  As described above, the increase in the amount of NFP can be suppressed by using a rubber stopper used for sealing or a specific rubber stopper containing a surfactant to be contained in the freeze-dried preparation (eg, a rubber stopper having a specific physical property, a specific material). It can be carried out by using a rubber stopper manufactured in 1) or a surfactant.

  The storage conditions are not particularly limited, and may be stored at room temperature or under refrigeration, but refrigeration is preferred. The storage period is not particularly limited, and examples thereof include storage periods of 1 month, 3 months, 6 months, 12 months, 18 months, or 24 months.

4. Quality inspection method for freeze-dried preparations:
It is known that the quality of injectables is tested from the viewpoint of the size and number of insoluble foreign matters and fine particles (Patent Document 1).

  As one aspect of the present invention, there is provided a method for inspecting the quality of a freeze-dried preparation of the present invention, which comprises a step of confirming the presence of NFP in the preparation and/or quantifying the amount thereof. It

  The presence of NFP can be confirmed by supplying a sample derived from the freeze-dried preparation of the present invention to high performance liquid chromatography. INDUSTRIAL APPLICABILITY The quality inspection method of the present invention can be usefully used for the purpose of inspecting the presence or absence of deterioration of the quality of a lyophilized preparation when the lyophilized preparation is stored for a long period of time, and the like.

5. How to prepare the drug solution:
As one aspect of the present invention, there is provided a method for preparing a drug solution, which comprises the steps of
1) A step of adding a solvent to the freeze-dried preparation of the present invention (here, the freeze-dried preparation is filled in a medical container).
2) A step of twisting the medical container filled with the freeze-dried preparation, the step being 2 to 4 times.

  The solvent used here is not particularly limited, and may be, for example, water for injection or physiological saline. The medical container is not particularly limited here, and an infusion bag, a syringe, a vial, an ampoule and the like can be preferably used.

  The specific mode of twisting is not particularly limited, and for example, the medical container can be grasped by hand, the elbow can be almost fixed, and the wrist can be rotated while twisting clockwise or counterclockwise. When the wrist is rotated clockwise or counterclockwise, the physical structure of the upper arm or wrist is forced to invert at some place, but the number of inversions is about 1 to 5 times, especially about 2 to 4 times. preferable. The speed of twisting is also not particularly limited, but it is preferable to twist so as to invert about once per second.

  The freeze-dried preparation used in the preparation method of the present invention may be a preparation containing no surfactant.

6. A method for producing a freeze-dried preparation containing teriparatide acetate in which collapse or shrinkage of a freeze-dried cake is suppressed:
As one aspect of the present invention, there is provided a method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, comprising teriparatide acetate, purified sucrose, and (1) to There is provided a production method including a step of freeze-drying a drug solution containing at least any one of the additives (6).
(1) Histidine, a salt thereof, or a hydrate thereof.
(2) Ascorbic acid.
(3) Sodium acetate or its hydrate.
(4) Sodium hydrogen sulfite.
(5) Benzalkonium chloride.
(6) Methionine.

As an aspect of the present invention, there is provided a method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, comprising teriparatide acetate and (1) to (4). There is provided a manufacturing method including a step of freeze-drying a drug solution containing at least any one of these excipients and containing no additive.
(1) Glycine.
(2) Sodium glutamate.
(3) Trehalose.
(4) Purified white sugar.

  In these manufacturing methods, for example, the above-mentioned drug solution is prepared, the drug solution is filled in a medical container, and the filled drug solution half-capped with a rubber stopper is freeze-dried in a freeze dryer, and after the freeze-drying is completed. After re-pressurizing with nitrogen, the cap and aluminum cap can be tightened.

  Freeze-drying can go through, for example, three steps of freezing, primary drying, and secondary drying. In the freezing step, the freezing step of lowering the temperature for about 1 to 3 hours and the lowered temperature of 1 are carried out. Freezing steps maintained for ~3 hours can be formed in combination.

  The rubber stopper to be used is preferably washed and sterilized before use, and it is also preferable to carry out a drying treatment in advance for the purpose of suppressing collapse or shrinkage of the freeze-dried cake. The drying condition is not particularly limited, but it is preferable to dry the rubber stopper, for example, under a temperature condition of 90 to 120° C. for 2 to 10 hours.

  The medical container to be used is preferably washed and sterilized in advance before use, and it is also preferably preliminarily dried for the purpose of suppressing collapse or shrinkage of the freeze-dried cake. The drying condition is not particularly limited, but it is preferable to dry the medical container for 10 to 120 minutes under a temperature condition of 250 to 400° C., for example.

  Hereinafter, the present invention will be described in more detail 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 present invention.

  In addition, in the following examples, "prescription" and "prescription formulation" may be described as a word corresponding to the "lyophilized formulation" of the present invention.

Example 1 (Production of thrombomodulin):
DNA encoding the amino acid sequence of SEQ ID NO: 2 (specifically, consisting of the nucleotide sequence of SEQ ID NO: 3) is transfected into Chinese hamster ovary (CHO) cells, and the culture medium of this transformed cell is purified. , 20 mmol/L phosphate buffer (pH 7.3) containing 50 mmol/L sodium chloride (NaCl) was used to collect the active fraction. The recovered solution was further concentrated using an ultrafiltration membrane to obtain a 11.0 mg/mL thrombomodulin solution.

Example 2 (Production of freeze-dried preparation and liquid preparation):
(1) Preparation of lyophilized preparations 1-4:
Regarding the lyophilized formulations 1 to 4, first, the respective drug solutions were prepared by the following procedure.

  In the production of the freeze-dried preparation 1, a 60 mg/mL thrombomodulin aqueous solution prepared in advance, a 1 mg/mL polysorbate 80 aqueous solution, and a 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide. After adding 5 mL of each, drug solution 1 was prepared by measuring up to 50 mL with water for injection.

  In the production of the lyophilized preparation 2, 5 mg of polysorbate 80 aqueous solution of 1 mg/mL prepared in advance and 5 mg of L-arginine hydrochloride aqueous solution of 250 mg/mL whose pH was adjusted to about 7 with sodium hydroxide were added, respectively, The drug solution 2 was prepared by making up to 50 mL with water for injection.

  In producing the freeze-dried preparation 3, 5 mL of a previously prepared 60 mg/mL thrombomodulin aqueous solution and 5 mL of a 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide were added, and then 50 mL of water for injection was added. The drug solution 3 was prepared by measuring up to 1.

  In the production of the lyophilized preparation 4, the drug solution 4 was prepared by making up 5 mL of a 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide prepared in advance to 50 mL with water for injection.

  Each of the drug solutions 1 to 4 was sterilized by filtration, and then 1.2 mL each was filled in a glass vial. Then, the rubber stopper was capped halfway and freeze-dried with a freeze dryer. After the freeze-drying was completed, each freeze-dried preparation was manufactured by restoring the pressure with nitrogen, sealing the rubber stopper completely, and tightening the aluminum cap.

Lyophilized formulations 1 to 4 shown in Table 1 below were obtained in accordance with the above production method.

(2) Preparation of freeze-dried preparations 5-10:
Regarding the freeze-dried preparations 5 to 10, first, respective drug solutions were prepared by the following procedure.

  In producing the freeze-dried preparation 5, 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide prepared in advance was added, and then the volume of the solution was increased to 50 mL with water for injection to prepare the drug solution 5. Was prepared.

  In producing the freeze-dried preparation 6, 15 μL of 10 mg/mL aqueous solution of polysorbate 80 prepared in advance and 5 mL of 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide were added respectively, and then water for injection was added. The drug solution 6 was prepared by measuring up to 50 mL with.

  In producing the lyophilized preparation 7, after adding 50 μL of a 10 mg/mL aqueous solution of polysorbate 80 previously prepared and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide, water for injection was added respectively. The drug solution 7 was prepared by measuring the volume to 50 mL with.

  In producing the freeze-dried preparation 8, after adding 150 μL of a 10 mg/mL aqueous solution of polysorbate 80 prepared in advance and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride adjusted to about 7 with sodium hydroxide, water for injection was added respectively. The drug solution 8 was prepared by measuring up to 50 mL with.

  In producing the freeze-dried preparation 9, after adding 500 μL of a 10 mg/mL aqueous solution of polysorbate 80 previously prepared and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride adjusted to about 7 with sodium hydroxide, water for injection was added respectively. The chemical solution 9 was prepared by measuring the volume to 50 mL with.

  In producing the freeze-dried preparation 10, 5 mL of a previously prepared 10 mg/mL polysorbate 80 aqueous solution and 5 mL of 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide were added respectively, and then water for injection was added. The drug solution 10 was prepared by measuring up to 50 mL.

  Each of the chemical solutions 5 to 10 was sterilized by filtration, and then 1.2 mL each was filled in a glass vial. Then, the rubber stopper was capped halfway and freeze-dried with a freeze dryer. After the freeze-drying was completed, each freeze-dried preparation was manufactured by restoring the pressure with nitrogen, sealing the rubber stopper completely, and tightening the aluminum cap.

The freeze-dried preparations 5 to 10 shown in Table 2 below were obtained according to the above production method.

(3) Preparation of solution formulations 11 to 13:
Solution formulation 11 was produced by adding 1.2 mL of water for injection to the freeze-dried formulation 1 in Table 1 with a syringe without opening the rubber stopper. Solution formulation 12 was produced by adding 1.2 mL of water for injection to the freeze-dried formulation 3 in Table 1 with a syringe without opening the rubber stopper.

According to the above-mentioned manufacturing method, solution formulations 11 to 12 shown in Table 3 below were obtained.

(4) Preparation of freeze-dried preparations 13 to 19:
With respect to the freeze-dried preparations 13 to 19, first, respective drug solutions were prepared by the following procedure.

  In the production of the freeze-dried preparation 13, 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide prepared in advance was added, and then the solution was made up to 50 mL with water for injection. Was prepared.

  In producing the freeze-dried preparation 14, 5 mL of a 1 mg/mL aqueous solution of polysorbate 80 prepared in advance and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide were added respectively, and then water for injection was added. The drug solution 14 was prepared by measuring up to 50 mL.

  In the production of the lyophilized preparation 15, 5 mL of a 1 mg/mL aqueous solution of polysorbate 20 prepared in advance and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide were added, and then water for injection was added. The drug solution 15 was prepared by measuring up to 50 mL.

  In producing the freeze-dried preparation 16, 5 mL of a 1 mg/mL aqueous solution of polysorbate 60 prepared in advance and 5 mL of a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide were added, and then water for injection was added. The drug solution 16 was prepared by measuring up to 50 mL.

  In the production of the freeze-dried preparation 17, 5 mL of a previously prepared 1 mg/mL polysorbate 65 white turbid solution and 5 mL of 250 mg/mL L-arginine hydrochloride aqueous solution whose pH was adjusted to about 7 with sodium hydroxide were added respectively, and then water for injection was added. The drug solution 17 was prepared by measuring up to 50 mL with.

In the production of the freeze-dried preparation 18, 250 mg/mL L of which pH was adjusted to about 7 with a previously prepared 1 mg/mL POE(60) hydrogenated castor oil (NIKKOL HCO-60 ^{(registered trademark)} ) aqueous solution and sodium hydroxide was used. -Medical solution 19 was prepared by adding 5 mL of each arginine hydrochloride aqueous solution and then measuring to 50 mL with water for injection.

  In the production of the freeze-dried preparation 19, 5 mL of a 1 mg/mL aqueous solution of sodium dodecyl sulfate and a 250 mg/mL aqueous solution of L-arginine hydrochloride whose pH was adjusted to about 7 with sodium hydroxide were added respectively, and then water for injection was added. The drug solution 20 was prepared by measuring the volume to 50 mL with.

  Each of the drug solutions 13 to 19 was sterilized by filtration, and then 1.2 mL each was filled in a glass vial. Then, the rubber stopper was capped halfway and freeze-dried with a freeze dryer. After the freeze-drying was completed, each freeze-dried preparation was manufactured by restoring the pressure with nitrogen, sealing the rubber stopper completely, and tightening the aluminum cap.

Lyophilized formulations 13 to 19 shown in Table 4 below were obtained according to the above production method.

Example 3 (Production of teriparatide freeze-dried preparation):
50 g of purified sucrose and 2.5 g of sodium chloride were added to about 1.0 kg of water for injection to dissolve it, and the weight was adjusted to 2.5 kg with water for injection to obtain a preconditioning solution A. After adding 267 mg of teriparatide acetate in 250 mL of this pre-prepared solution A to dissolve it, the total amount of pre-prepared solution A was adjusted to 2.2 kg to obtain a drug solution.

  After subjecting this chemical solution to filtration sterilization, 0.56 g each was filled in a glass vial. Then, the rubber stopper was capped halfway and freeze-dried with a freeze dryer. After the freeze-drying was completed, each formulation was manufactured by restoring the pressure with nitrogen, sealing the rubber stopper completely, and tightening the aluminum cap.

A freeze-dried preparation 20 shown in Table 5 below was obtained according to the above production method.

Example 4 (Production of lyophilized preparation containing various excipients/additives):
For each lyophilized formulation described in Table 6 below, a drug solution having the composition described in Table 6 below was prepared, 0.56 g of each drug solution was filled in a glass vial, and then a rubber stopper was half-capped and frozen. It was produced by freeze-drying in a dryer. After the freeze-drying was completed, the pressure was restored with nitrogen, and the rubber stopper was fully capped, and the aluminum cap was wound.

  The preparation amount of the drug solution was 20 mL in all cases. At the time of preparation of each drug solution, the additive weighing amount was as shown in Table 6 below, and the excipient weighing amount was 1090.9 mg (formulation 29) or 407.3 mg (formulation 21). 28, 30-31).

Example 5 (Production of teriparatide freeze-dried preparation containing various excipients/additives):
For each lyophilized formulation described in the following table, a drug solution having the composition described in the following table was prepared, 0.56 g of each drug solution was filled in a glass vial, and then a rubber stopper was half-stopped, and a freeze dryer was used. It was produced by freeze-drying in. After the freeze-drying was completed, the pressure was restored with nitrogen, and the rubber stopper was fully capped, and the aluminum cap was wound.

  Formulations 32 to 34 were prepared by weighing 203.6 mg of each excipient, adding distilled water to 5 mL, and adding 5 mL of the teriparatide acetic acid solution and stirring. The teriparatide acetic acid solution here was prepared by dissolving 19.8 mg of teriparatide acetate in 80 mL of distilled water.

  For the chemical solutions of the prescriptions 35 to 46, each additive was weighed in the weighed amount described in the following table, 1 mL of the purified sucrose solution was added, and then distilled water was further added to 5 mL, and then 5 mL of the teriparatide acetic acid solution was added. It was prepared by adding and stirring. The purified sucrose solution was prepared by dissolving 2.646 g of the purified sucrose in 13 mL of distilled water.

Example 6 (Search for components affecting increase in NFP content over time):
(1) Test method:
Using the freeze-dried preparations 1 to 4 produced in the above-mentioned Example 2, “Production of freeze-dried preparation and liquid preparation”, the components affecting the increase in NFP content in each preparation over time were searched for. Specifically, it is as follows.

  The lyophilized formulations 1 to 4 were stored in a stability tester at 80° C., and then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 8 below.

Example 7 (Confirmation of the effect of components affecting the increase in NFP content over time):
(1) Test method:
In the above-mentioned Example 6, it was suggested that the component which influences the increase in NFP content in the preparation over time is a surfactant. Therefore, using the freeze-dried preparations 1 and 3 produced in the above-mentioned Example 2 “Production of freeze-dried preparation and liquid preparation”, the effect of suppressing the increase in NFP content over time, which is suggested by the surfactant, was observed after the preparation of the preparation. I reconfirmed by changing the period and elapsed conditions. Specifically, it is as follows.

  The lyophilized preparations 1 and 3 were stored in a stability tester at 60° C., then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 9 below.

Example 8 (Evaluation of the effect of the amount of surfactant on the effect of suppressing increase in NFP content over time):
(1) Test method:
In Examples 6 to 7 described above, it was revealed that the component that affects the increase in NFP content in the preparation over time is a surfactant. Therefore, by using the freeze-dried preparations 5 to 10 produced in the above-mentioned Example 2 “Production of freeze-dried preparation and liquid preparation”, the amount of the surfactant was increased with respect to the effect of suppressing the increase in NFP content over time exhibited by the surfactant. The effect on it was evaluated. Specifically, it is as follows.

  The freeze-dried preparations 5 to 10 were stored in a stability tester at 60° C., then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 10 below.

The relationship between the polysorbate 80 content (surfactant amount (mg)) and the NFP content after 2 weeks (μg/vial) in the above table is shown in FIG.
The time-dependent increase of NFP in the freeze-dried preparation was suppressed depending on the amount of polysorbate 80 added, and the time-dependent increase of NFP was almost not observed with the addition of about 0.1 mg or more.

Example 9 (Evaluation of the influence of the dosage form of the preparation on the effect of suppressing increase in NFP content over time):
(1) Test method:
In Examples 6 to 7 described above, it was revealed that the component that affects the increase in NFP content in the preparation over time is a surfactant. Therefore, by using the solution formulations 11 to 12 produced in the above-mentioned Example 2 “Production of lyophilized formulation and solution”, the formulation of the formulation gives the effect of suppressing the increase in NFP content over time exhibited by the surfactant. The impact was evaluated. Specifically, it is as follows.

  The solution formulations 11 to 12 were stored in stability testers at 40° C., 60° C. and 80° C., respectively, and then sampled over time to measure the NFP content by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 11 below.

Example 10 (Evaluation of effect of rubber plug type on increase in NFP content over time):
(1) Test method:
The effect of the type of rubber stopper on the increase in NFP content in the preparation over time was evaluated. The rubber stoppers used in the test are shown in Table 12 below.

  1 mL of water for injection was added to a glass vial, each of which was sealed with each of the various rubber stoppers shown in Table 13, and wound with an aluminum cap. These samples were stored in a stability tester at 80° C. and sampled one week later, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 13 below.

Rubber stopper Nos. in Tables 12 to 13 above. For the rubber plug Nos. 1 to 4 and 7, the rubber plug dehydration rate (%/hour) and the NFP content (μg/vial) are shown in FIG. Regarding the rubber plug Nos. 1 to 3 and 7, the relationship between the rubber plug density (g/cm ³ ) and the NFP content (μg/vial) is shown in FIG. Regarding 1 to 6, the relationship between the rubber stopper material and the NFP content (μg/vial) is shown in FIG. 4, respectively. In FIG. 5, rubber stopper No. The high performance liquid chromatography result of 1 sample is shown.

Example 11 (Evaluation of effect of rubber plug replacement after production on effect of suppressing increase in NFP content over time):
(1) Test method:
In the above-mentioned Examples 6 to 8, it was revealed that the component affecting the change over time of NFP contained in the preparation is a surfactant. Therefore, using the freeze-dried preparations 1 and 3 produced in the above-mentioned Example 2 “Production of freeze-dried preparation and liquid preparation”, the rubber after preparation of the preparation against the effect of suppressing increase in NFP content over time exhibited by the surfactant. The effect of plug replacement was evaluated. Specifically, it is as follows.

  Remove the aluminum cap and rubber stopper of freeze-dried formulations 1 and 3. Immediately thereafter, another rubber stopper was completely plugged and wound with an aluminum cap. The freeze-dried preparations 1 and 3 with these rubber stoppers replaced were stored in a stability tester at 60° C., then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 14 below.

Example 12 (Evaluation of effect of surfactant on cake shape of formulation):
(1) Test method:
Using the freeze-dried preparations 1 and 3 produced in the above-mentioned Example 2, “Production of freeze-dried preparation and liquid preparation”, the cake of each preparation was observed by an electron microscope. Specifically, the aluminum cap and the rubber stopper of the freeze-dried preparation 1 or 3 were removed, and a part of the cake was quickly taken out with a spatula. The taken-out cake was subjected to platinum vapor deposition with ION SPUTTER (E-1010, manufactured by HITACHI) for 120 seconds. The platinum vapor-deposited sample was subjected to scanning Electron Microscope (S-2380N, manufactured by HITACHI), and an electron micrograph was taken.

(2) Test results:
The results of photographing the cake of the freeze-dried preparation 1 with an electron microscope are shown in FIG. 6 (60 times), FIG. 8 (300 times) and FIG. 10 (1000 times). Similarly, the results of photographing the cake of the freeze-dried preparation 3 with an electron microscope are shown in FIG. 7 (60 times), FIG. 9 (300 times) and FIG. 11 (1000 times). From these results, it was found that the surfactant in the formulation did not substantially affect the shape of the cake in the formulation.

Example 13 (Evaluation of influence of timing of addition of surfactant on inhibitory effect on increase in NFP content over time):
(1) Test method:
Using the freeze-dried preparations 1 and 3 produced in the above-mentioned Example 2, “Production of freeze-dried preparation and liquid preparation”, addition of the same to the preparation against the effect of suppressing increase of NFP content over time exhibited by the surfactant. We evaluated the impact of timing.

  Specifically, the aluminum caps and rubber stoppers of freeze-dried preparations 1 and 3 are removed. After that, the cake was rapidly stirred with a spatula, and then the rubber stopper was completely capped and wound with an aluminum cap to obtain freeze-dried preparations 1-1 and 3-1. Then, the aluminum cap and the rubber stopper of the freeze-dried preparation 3 are removed. Then, 0.1 mg of polysorbate 80 was dropped into the vial, and the cake was immediately stirred with a spatula. Then, the rubber stopper was completely capped and the aluminum cap was wound up to obtain a freeze-dried preparation 3-2. The lyophilized formulations 1-1, 3-1 and 3-2 were stored in a stability tester at 60° C., and then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 15 below.

  The effect of suppressing the increase in NFP content over time exhibited by the surfactant contained in the freeze-dried preparation is that the surfactant is added to the preparation (more specifically, to the drug solution corresponding to the preparation) before freeze-drying. It was found to be an effect recognized by.

Example 14 (Evaluation of the effect of the type of surfactant on the effect of suppressing increase in NFP content over time):
(1) Test method:
Using the freeze-dried preparations 14 to 20 produced in the above-mentioned Example 2, “Production of freeze-dried preparation and liquid preparation”, the kind of the surfactant was compared against the effect of suppressing increase of NFP content over time exhibited by the surfactant. The effect on it was evaluated.

  Specifically, the freeze-dried preparations 13 to 19 were stored in a stability tester at 60° C., then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 16 below.

For the freeze-dried preparations containing the non-surfactant in the above table, the relationship between HLB and NFP content (μg/vial) after 2 weeks has been illustrated in FIG.
From this result, it was revealed that the effect of suppressing the increase of NFP in the freeze-dried preparation with time by the surfactant is remarkable in the nonionic surfactant having HLB of 10.5 or more.

Example 15 (Evaluation of the effect of the dissolution method on the effect of suppressing increase in NFP content over time):
(1) Test method:
Using the freeze-dried preparations 1 and 3 produced in the above-mentioned Example 2, “Production of freeze-dried preparation and liquid preparation”, the influence of the method for dissolving the freeze-dried preparation on the NFP content in the solution was evaluated.

  Specifically, 1.2 mL of water for injection was added to freeze-dried formulations 1 and 3 with a syringe without opening the rubber stopper. Then, the cake was dissolved by shaking by hand at a speed of about once per second for 60 seconds or 3 seconds. This solution was sampled and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 17 below.

Example 16 (Evaluation of effect of medicinal component on increase in NFP content over time):
(1) Test method:
Using the freeze-dried preparation 20 produced in the above-mentioned Example 3, “Production of teriparatide freeze-dried preparation”, the effect of the medicinal component on the increase in NFP content over time was evaluated. Specifically, the freeze-dried preparation 20 was stored in a stability tester at 40° C. and 75% RH, then sampled over time, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
The test results are shown in Table 18 below.

  Not only when the drug component contained in the freeze-dried preparation was thrombomodulin, but also when the drug component contained in the freeze-dried preparation was teriparatide acetate, an increase in NFP content in the preparation was observed.

Example 17 (Effects of Excipient/Additive Type, etc. on NFP Increase over Time in Formulation Storage and Lyophilized Cake of Formulation):
(1) Test method:
Using the freeze-dried preparations 21 to 31 produced in the above-mentioned Example 4 “Production of freeze-dried preparation containing various excipients/additives”, various excipients, additives, etc. were freeze-dried preparations. Was evaluated for its effect on NFP content after storage.

  Specifically, the freeze-dried preparations 21 to 31 were stored in a stability tester at 60° C. for 2 weeks, sampled, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
FIG. 13 shows the results of measuring the NFP content in the freeze-dried preparations 21 to 31 after storage. The upper number shown at the bottom of the graph is the formulation number, and the lower number is the NFP content (NFP content in 1 vial; μg). It was revealed that Formulations 22, 23, 27, and 28 suppressed the increase in NFP after storage.

  FIG. 14 shows photographs of freeze-dried preparations 25 to 28 after storage. Each formulation is sealed with a rubber stopper and filled in a vial container. In the photograph, the formulation marked with "5" is the freeze-dried formulation after storage (formulation 25), and the formulation marked with "6" is the freeze-dried formulation after storage (formulation 26), "7". The formulation marked with indicates the freeze-dried preparation after storage (formulation 27), and the formulation marked "8" indicates the freeze-dried preparation after storage (formulation 28). It can be seen that the lyo cake of each of Formulations 25, 26 and 28 is collapsed or contracted after storage. On the other hand, it can be seen that the freeze-dried cake of formulation 27 has collapsed after its storage. In Formulation 27, it is highly possible that this large shape change of the freeze-dried cake had an influence on the suppression of NFP increase after storage.

Example 18 (Effects of Excipient/Additive Type, etc. on NFP Increase over Time in Storage of Teriparatide Formulation and Lyophilized Cake of Formulation):
(1) Test method:
Using the freeze-dried preparations 32 to 46 produced in the above-mentioned Example 5 “Production of teriparatide freeze-dried preparation containing various excipients/additives”, various excipients were added to the teriparatide freeze-dried preparation. The effect of additives and the like on the NFP content after storage of the freeze-dried preparation was evaluated.

  Specifically, the freeze-dried preparations 32 to 46 were stored in a stability tester at 60° C. for 2 weeks, sampled, and the NFP content was measured by high performance liquid chromatography.

(2) Test results:
FIG. 15 shows the results of measuring the NFP content in the teriparatide freeze-dried preparations 32 to 46 after storage. The upper number shown at the bottom of the graph is the formulation number, and the lower number is the NFP content (NFP content in 1 vial; μg). It was revealed that Formulations 33, 39, 40, and 41 suppressed the increase in NFP after storage.

  FIG. 16 shows photographs of freeze-dried teriparatide formulations 33, 39, 40, 41, and 46 after storage. Each formulation is sealed with a rubber stopper and filled in a vial container. In the photograph, the preparation marked with “2” is the freeze-dried preparation after storage (formulation 33), and the preparation marked with “8” is the freeze-dried preparation after storage (formulation 39) is “9”. The formulation marked with is the freeze-dried formulation after storage (formulation 40), the formulation marked "10" is the freeze-dried formulation after storage (formulation 41), the formulation marked "14" is , And the freeze-dried preparation after storage (formulation 45). It can be seen that the freeze-dried cakes of Formulations 33, 40 and 45 are suppressed from collapsing or shrinking after storage. On the other hand, it can be seen that the freeze-dried cakes of each of the formulations 39 and 41 have collapsed or contracted after their storage. In Formulations 39 and 41, it is highly possible that this large shape change of the freeze-dried cake had an influence on the suppression of NFP increase after storage.

  FIG. 17 shows a photograph of the teriparatide freeze-dried preparation (prescription 32-46; total 15 preparations) after storage. It can be seen that the freeze-dried cakes of the formulations 32-34, 36-38, 40, 42-46 (13 formulations in total) are suppressed in collapse or shrinkage after storage. On the other hand, it can be seen that the freeze-dried cakes of each of the formulations 35, 39, and 41 have collapsed or contracted after their storage.

  The freeze-dried preparation of the present invention has a reduced N-formylpiperidine content and is useful as a high-quality drug.

Claims (33)

A freeze-dried preparation containing a teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, and further contains at least one component of (1) to (4). Lyophilized formulation:
(1) Sodium glutamate or its hydrate;
(2) succinic acid;
(3) sorbitol;
(4) Sodium acetate or its hydrate.   The lyophilized formulation according to claim 1, comprising 67.9 μg teriparatide acetate.   The freeze-dried preparation according to claim 1 or 2, wherein the material of the rubber stopper is butyl rubber. A freeze-dried preparation containing a thrombomodulin as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, and further contains the component (1):
(1) A nonionic surfactant having an HLB (Hydrophilic-Lipophilic Balance) value of 10.5 or more.   The freeze-dried preparation according to claim 4, wherein the component (1) is polyoxyethylene (POE) sorbitan fatty acid ester or POE hydrogenated castor oil.   The freeze-dried preparation according to claim 4 or 5, wherein the content of the component (1) is 0.1 mg or more. The freeze-dried preparation according to any one of claims 4 to 6, wherein thrombomodulin is a peptide represented by any of the following amino acid sequences and has thrombomodulin activity:
(1) the amino acid sequence of SEQ ID NO: 2;
(2) An amino acid sequence in which one or more amino acids of the amino acid sequence shown in SEQ ID NO: 2 is substituted, deleted or added;
(3) An amino acid sequence having 80% or more homology to the amino acid sequence set forth in SEQ ID NO: 2.   The freeze-dried preparation according to any one of claims 4 to 7, wherein the material of the rubber stopper is butyl rubber.   The freeze-dried preparation according to any one of claims 1 to 8, wherein the medical container is a vial. A freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, which contains at least one excipient of (1) to (4) and is added. Freeze-dried formulation without substances:
(1) Glycine;
(2) sodium glutamate;
(3) Trehalose;
(4) Purified white sugar. A freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, which contains purified sucrose and is at least one additive of (1) to (6). Lyophilized formulations, including:
(1) Histidine, a salt thereof, or a hydrate thereof;
(2) Ascorbic acid;
(3) Sodium acetate or its hydrate;
(4) sodium bisulfite;
(5) benzalkonium chloride;
(6) Methionine.   The freeze-dried preparation according to claim 10 or 11, wherein the amount of teriparatide acetate in the freeze-dried preparation is 67.9 µg. A method for suppressing an increase with time of N-formylpiperidine in a lyophilized preparation containing teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and is filled in a medical container, comprising: (1) To (4), the method for suppressing, comprising the step of including at least any one of the components in the formulation before lyophilization in the production process of the formulation:
(1) Sodium glutamate or its hydrate;
(2) succinic acid;
(3) sorbitol;
(4) Sodium acetate or its hydrate.   The method according to claim 13, wherein the amount of teriparatide acetate in the freeze-dried preparation is 67.9 μg.   The suppression method according to claim 13 or 14, wherein the material of the rubber stopper is butyl rubber.   A method for suppressing an increase with time of N-formylpiperidine in a freeze-dried preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container. And a method of suppressing sodium chloride in the preparation of the preparation before freeze-drying in the manufacturing process of the preparation.   The suppressing method according to claim 16, wherein the material of the rubber stopper is butyl rubber. A method for suppressing an increase with time of N-formylpiperidine in a freeze-dried preparation containing thrombomodulin as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, comprising the component (1) Suppressing method, characterized in that the product is contained in the preparation before freeze-drying treatment in the manufacturing process of the preparation:
(1) A nonionic surfactant having an HLB (Hydrophilic-Lipophilic Balance) value of 10.5 or more.   The suppression method according to claim 18, wherein the component (1) is a polyoxyethylene (POE) sorbitan fatty acid ester or POE hydrogenated castor oil.   The suppression method according to claim 18 or 19, wherein the content of the component (1) is 0.1 mg or more.   The suppression method according to any one of claims 18 to 20, wherein the material of the rubber stopper is butyl rubber. A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper made of halogenated butyl rubber;
Step 2) Tighten the formulation with an aluminum cap. A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper that satisfies the following conditions 1 to 3;
Condition 1) The material of the rubber stopper is butyl rubber;
Condition 2) A rubber stopper is laminated;
Condition 3) The water vapor permeability of the rubber stopper is less than 0.57 (g/m ² ·24h);
Step 2) Tighten the formulation with an aluminum cap. A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper having a dehydration rate of 33%/h or less according to the following definition;
Definition) The rate of change in the amount of water contained in the rubber stopper, which is obtained after performing a sterilization treatment at 121°C for 30 minutes as a water-containing treatment on the rubber stopper and performing a drying treatment for 1 hour. Water content of rubber stopper after treatment/water content of rubber stopper after water treatment×100 (%/hour);
Step 2) Tighten the formulation with an aluminum cap. A method for suppressing an increase in N-formylpiperidine with time in a preparation sealed with a rubber stopper and filled in a medical container, the manufacturing method of the preparation including the following steps 1 and 2. :
Step 1) Seal the formulation with a rubber stopper that satisfies the following conditions 1 and 2;
Condition 1) The material of the rubber stopper is butyl rubber or polyisobutylene;
Condition 2) the density of the rubber plug is less than 1.3 g/cm ³ .
Step 2) Tighten the formulation with an aluminum cap.   The suppression method according to any one of claims 13 to 25, wherein the medical container is a vial.   A method for inspecting the quality of a freeze-dried preparation, which is sealed with a rubber stopper and filled in a medical container, wherein the presence of N-formylpiperidine in the preparation is confirmed and/or the amount thereof is quantified. An inspection method including a step of performing. A method for preparing a drug solution, which includes the following steps:
Step 1) A step of adding a solvent to the freeze-dried preparation, which is sealed with a rubber stopper and filled in a medical container;
Step 2) A step of twisting the medical container, wherein the number of times is 1 to 5 times. A method for suppressing the N-formylpiperidine content in a drug solution obtained by dissolving a lyophilized preparation in a solvent, which comprises the following steps:
Step 1) A step of adding a solvent to the freeze-dried preparation, which is sealed with a rubber stopper and is filled in a medical container;
Step 2) A step of twisting the medical container, wherein the number of times is 1 to 5 times.   A method for producing a lyophilized preparation containing 67.9 μg of teriparatide acetate as an active ingredient, which is sealed with a rubber stopper and filled in a medical container, wherein sodium chloride is lyophilized in the production process of the preparation. A method for producing, which comprises the step of incorporating into the preparation before treatment.   The manufacturing method according to claim 30, wherein the material of the rubber stopper is butyl rubber. A method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and filled in a medical container, comprising teriparatide acetate and at least any one of (1) to (4). A freeze-dried preparation, which comprises a step of freeze-drying a drug solution containing an excipient and does not contain an additive, wherein collapse or shrinkage of a freeze-dried cake (lyo cake) in the freeze-dried preparation is suppressed. Production method:
(1) Glycine;
(2) sodium glutamate;
(3) Trehalose;
(4) Purified white sugar. A method for producing a freeze-dried preparation containing teriparatide acetate, which is sealed with a rubber stopper and is filled in a medical container, comprising at least one of teriparatide acetate, purified sucrose, and (1) to (6). A method for producing a freeze-dried preparation, comprising a step of freeze-drying a drug solution containing the additive of claim 1 or 2, wherein collapse or contraction of a freeze-dried cake (lyo cake) in the freeze-dried preparation is suppressed.
(1) Histidine, a salt thereof, or a hydrate thereof;
(2) Ascorbic acid;
(3) Sodium acetate or its hydrate;
(4) sodium bisulfite;
(5) benzalkonium chloride;
(6) Methionine.