US20140088014A1 - Freeze-dried preparation containing high-purity pth and method for producing same - Google Patents

Freeze-dried preparation containing high-purity pth and method for producing same Download PDF

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US20140088014A1
US20140088014A1 US14/116,483 US201214116483A US2014088014A1 US 20140088014 A1 US20140088014 A1 US 20140088014A1 US 201214116483 A US201214116483 A US 201214116483A US 2014088014 A1 US2014088014 A1 US 2014088014A1
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freeze
pth
pth peptide
analog
peptide
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Fumihide Nishio
Takuji Maejima
Yoshiro Mitome
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Asahi Kasei Pharma Corp
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Asahi Kasei Pharma Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
    • B65B55/02—Sterilising, e.g. of complete packages
    • B65B55/04—Sterilising wrappers or receptacles prior to, or during, packaging
    • B65B55/10—Sterilising wrappers or receptacles prior to, or during, packaging by liquids or gases
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
    • B65B55/02—Sterilising, e.g. of complete packages
    • B65B55/12—Sterilising contents prior to, or during, packaging
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B63/00—Auxiliary devices, not otherwise provided for, for operating on articles or materials to be packaged
    • B65B63/08—Auxiliary devices, not otherwise provided for, for operating on articles or materials to be packaged for heating or cooling articles or materials to facilitate packaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph

Definitions

  • the present invention relates to a freeze-dried preparation containing PTH (parathyroid hormone) or a substance of equivalent physiologic activity (collectively referred to hereinafter as “PTH peptide”) as an active ingredient.
  • PTH parthyroid hormone
  • PTH peptide a substance of equivalent physiologic activity
  • the present invention also relates to a method for producing a freeze-dried preparation containing PTH peptide.
  • the present invention also relates to a method for testing and assuring the quality of freeze-dried preparations containing PTH peptide.
  • Parathyroid hormone is a hormone that participates in regulating the calcium concentration in the blood. Therefore, PTH peptide is used as a diagnostic for hypoparathyroidism. Parathyroid hormone is also known to accelerate the absorption of calcium in the intestine by increasing active vitamin D3 production in the kidneys (Non-patent Reference 1). A method of treating osteoporosis that increases the density of cancellous bone and does not decrease the density of the cortical bone of osteoporosis patients by subcutaneous administration of 100 or 200 units/time of PTH once a week over a period of 26 weeks to osteoporosis patients has also been disclosed (Patent Reference 7).
  • a method of combining mannitol or another such saccharide or gelatin or another such macromolecular substance as a stabilizer is generally used when making a trace of PTH peptide into a freeze-dried preparation to be dissolved at the time of use (Patent References 1 and 2).
  • a freeze-dried pharmaceutical composition characterized in containing a monosaccharide or disaccharide and sodium chloride is also known (Patent Reference 3).
  • a manufacturing process in a pharmaceutical production facility under this sterile environment typically consists of a step for preparing an active ingredient solution, followed by a step for aseptically filtering of the solution and dispensing it into containers, a step for loading the filled containers into a freeze-drying chamber, and a step for sealing the containers (vials and the like) after the freeze-drying step.
  • the active ingredient of a pharmaceutical is obtained by chemical synthesis from raw materials, by isolation and refining of a biological product, by production by genetic engineering and isolation and refining of the product, and the like. It is generally difficult to obtain 100% purity of the pharmaceutical active ingredient produced due to the purity of the raw materials themselves, incomplete reactions, decomposition during isolation and refining, and other such factors, in any method, including genetic recombination. On the other hand, since the possibility of undesirable effects on diagnosis and treatment cannot be ruled out when diagnostic and therapeutic drugs contain more than the acceptable amount of impurities, the fact remains that obtaining a high-purity product is an important factor for producing a safe, effective drug. When preparations containing PTH peptide are used in the treatment/prevention of osteoporosis in particular, high purity can be said to be especially necessary for preparations containing PTH peptide because the duration of administration extends over a long period of time.
  • the purpose of the present invention is to provide a freeze-dried preparation containing PTH peptide of high purity, that is, in which the content of PTH analogs is kept to an acceptably low level. Another purpose of the present invention is to provide a method for producing this high-purity freeze-dried preparation containing PTH peptide. Yet another purpose of the present invention is to provide a test method for PTH analogs for purposes such as checking the purity of a freeze-dried preparation containing PTH peptide.
  • the present inventors were concerned that the amount of PTH analogs produced would rise to an essentially unacceptable level as the production scale increased and the production volume rose and succeeded in isolating and characterizing these PTH analogs. They also discovered that controlling the exposure of solution containing PTH peptide and the like to air environments within a pharmaceutical production facility greatly inhibits and decreases the production of these PTH analogs.
  • ozone is present in a concentration of 0.001-0.02 ppm, approximately 0.02-0.1 ppm depending on the time, location, and season, in the atmosphere regardless of fumigation and disinfection.
  • the present inventors also confirmed that the production of the PTH analogs elucidated by the present invention can be reproduced by bringing PTH peptide into contact with air containing ozone.
  • a freeze-dried preparation containing high-purity PTH peptide as an active ingredient wherein “high-purity” means at least that the amount of at least one PTH analog versus the sum of the amount of PTH peptide and the total amount of PTH analogs in the preparation is 1.0% or less and/or that the total amount of PTH analogs versus the sum of the amount of PTH peptide and the total amount of PTH analogs is 5.0% or less; the freeze-dried preparation containing PTH peptide being produced by a method characterized in that the exposure of the solution containing PTH peptide prior to freeze drying to air environments within a pharmaceutical production facility is controlled.
  • freeze-dried preparation containing PTH peptide according to any of [1] to [7], characterized in that exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying is controlled in any one or more steps selected from a step for preparing a solution containing PTH peptide, an aseptic filtration step, a drug solution dispensing step, and a step for loading into a freeze drying means.
  • freeze-dried preparation containing PTH peptide set forth in [8] characterized in being produced using a method that also includes control of exposure of the freeze-dried product to air environments within a pharmaceutical production facility in a vial sealing step after freeze drying.
  • freeze-dried preparation containing PTH peptide set forth in [11] characterized in that the freeze-drying means is a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by opening this sub-door only during container loading and quickly closing the sub-door after loading.
  • freeze-drying means is a freeze-drying chamber having an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, and the means for controlling the ingress of air within a pharmaceutical production facility into the freeze-drying means is an airflow-adjusting cover that can change the air flow to a direction not directed from this opening to the inside of the chamber.
  • the freeze-drying means is a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by opening this sub-door only
  • the freeze-drying means is a freeze-drying chamber having an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, this opening being equipped with an airflow-adjusting cover, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by changing the direction of the airflow-adjusting
  • freeze-dried preparation containing PTH peptide according to any of [8] to [17] wherein time from the beginning of the step for preparing a solution containing PTH peptide to the end of the step for loading into the freeze-drying means spans three or more hours, and production is performed using a method for controlling exposure of the solution containing PTH peptide to an air environment within a pharmaceutical production facility in one or more steps during the time.
  • a freeze-dried preparation containing PTH peptide according to any of [14] to [18] wherein the inert gas is nitrogen gas.
  • a freeze-dried preparation containing high-purity PTH peptide as an active ingredient the PTH-peptide-containing freeze-dried preparation manufactured using a method characterized in that exposure of a solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying is controlled during loading into the freeze-drying means; wherein “high-purity” means at least that the amount of at least one PTH analog versus the sum of the amount of PTH peptide and the total amount of PTH analogs in the preparation is 1.0% or less and/or that the total amount of PTH analogs versus the sum of the amount of PTH peptide and the total amount of PTH analogs is 5.0% or less; the loading step is a step that spans three or more hours; the air environment is an environment that maintains one-way air flow of clean air that has passed through an HEPA filter downward from above; and the velocity of the air flow 20 cm directly under the HEPA filter is 0.2-1.0 m/s.
  • a method for producing a freeze-dried preparation containing PTH peptide the method being characterized in that exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility is controlled in one or more steps from the beginning of the step for preparing a solution containing PTH peptide to the end of the step for loading into a freeze-drying means.
  • freeze-drying means is a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded and unloaded, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by opening this sub-door only during container loading and quickly closing the sub-door after loading.
  • freeze-drying means is a freeze-drying chamber having an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, and the means for controlling the ingress of air within a pharmaceutical production facility into the freeze-drying means is an airflow-adjusting cover that can change the air flow to a direction not directed from this opening to the inside of the chamber.
  • freeze-drying means is a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded and unloaded, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by opening this sub-door only during container loading and quickly closing the sub-door after loading and purging the inside of the freeze-drying means with an inert gas in the loading step.
  • freeze-drying means is a freeze-drying chamber having an opening created in a small door unit opened when containers housing the solution containing PTH peptide prior to freeze drying are loaded into and unloaded from this means, this opening being equipped with an airflow-adjusting cover, thereby controlling exposure of the solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying by changing the airflow-adjusting cover to a direction in which the air flow is not directed into the chamber and purging the inside of the freeze-drying means with an inert gas in the loading step.
  • the air environment within a pharmaceutical production facility is an air environment in which 1) the air is of grade A, 2) clean air that has passed through an HEPA filter having the ability to trap particles having a particle size of 0.3 ⁇ m at an efficiency of 99.97% or higher is maintained as a one-way air flow downward from above, and 3) the ozone concentration is 0.001-0.1 ppm.
  • a method for producing a freeze-dried preparation containing high-purity PTH peptide as an active ingredient the method characterized in that exposure of a solution containing PTH peptide to air environments within a pharmaceutical production facility prior to freeze drying is controlled during loading into the freeze-drying means; wherein “high-purity” means at least that the amount of at least one PTH analog versus the sum of the amount of PTH peptide and the total amount of PTH analogs is 1.0% or less and/or that the total amount of PTH analogs versus the sum of the amount of PTH peptide and the total amount of PTH analogs is 5.0% or less in the preparation; the loading step is a step that spans three or more hours; the air environment is an environment in which clean air that has passed through an HEPA filter is maintained as a one-way air flow downward from above; and the velocity of the air flow 20 cm directly under the HEPA filter is 0.2-1.0 m/s.
  • the present invention also intends a test method that is important for compliance with laws and regulations and assurance of compatibility of the freeze-dried preparation containing PTH peptide as a pharmaceutical.
  • This test method is characterized in confirming the presence of any one or more or all of the above PTH analogs and/or determines the amounts present.
  • the following are also encompassed as aspects and preferred embodiments.
  • a method for testing a freeze-dried preparation containing PTH peptide the method being characterized in confirming the presence of at least one or more of the PTH analogs 1 to 11 of [2] and/or determining the amounts present in the freeze-dried preparation containing PTH peptide.
  • a method for testing a freeze-dried preparation containing PTH peptide the method being characterized in confirming the presence of at least one or more of the PTH analogs 1′ to 11′ of [3] and/or determining the amounts present in the freeze-dried preparation containing PTH peptide.
  • determination of the PTH analogs includes calculating the area of the peak corresponding to the PTH analog on a chromatogram when the ultraviolet absorption of a sample derived from a freeze-dried preparation containing PTH peptide is measured by high-performance liquid chromatography.
  • a method for producing a pharmaceutical comprising a freeze-dried preparation containing PTH peptide including a step to carry out the test method of any of [41] to [48].
  • freeze-dried preparations containing PTH peptide of the present invention are also intended as preferred freeze-dried preparations containing PTH peptide of the present invention.
  • a freeze-dried preparation containing PTH peptide the freeze-dried preparation containing PTH peptide being characterized in that at least one or more PTH analogs is 1.0% or less versus the sum of the amount of PTH peptide and the total amount of PTH analogs and/or the total amount of PTH analogs is 5.0% or less versus the sum of the amount of PTH peptide and the total amount of PTH analogs.
  • a freeze-dried preparation containing PTH peptide the freeze-dried preparation containing PTH peptide being characterized in that any of the respective PTH analogs is 1.0% or less versus the sum of the amount of PTH peptide and the total amount of PTH analogs and/or the total amount of PTH analogs is 5.0% or less versus the sum of the amount of PTH peptide and the total amount of PTH analogs.
  • the amount of analog 1 is 0.04% or less
  • the total amount of analog 3 and analog 4 is 0.11% or less
  • the amount of analog 5 is 0.26% or less
  • the amount of analog 7 is 0.33% or less
  • the amount of analog 8 is a percentage selected arbitrarily from 0.21-1.00%.
  • the amount of analog 9 is 0.68% or less.
  • the amount of analog 1′ is 0.04% or less
  • the total amount of analog 3′ and analog 4′ is 0.11% or less;
  • the amount of analog 5′ is 0.26% or less
  • the amount of analog 7′ is 0.33% or less
  • the amount of analog 8′ is a percentage selected arbitrarily from 0.21-1.00%.
  • the amount of analog 9′ is 0.68% or less.
  • freeze-dried preparation containing PTH peptide according to any of [50] to [57] wherein the freeze-dried preparation containing PTH peptide is a preparation housed in a stoppered glass container.
  • a freeze-dried preparation containing PTH peptide according to any of [50] to [58] wherein the freeze-dried preparation containing PTH peptide is a glass vial preparation.
  • a freeze-dried preparation containing high-purity PTH is provided by the present invention. Specifically, the production of PTH analogs characterized and confirmed to be produced in the freeze-dried preparation containing PTH which is undesirable during pharmaceutical manufacture is inhibited and decreased in the present invention. A preparation qualified as a pharmaceutical can also be produced while confirming and assuring the quality of the freeze-dried preparation containing PTH simply, rapidly, and accurately by determining the PTH analogs.
  • FIG. 1 shows the chromatograms when the ultraviolet (214 nm) absorbance was measured by high-performance liquid chromatography (HPLC) taking as the sample a PTH peptide used as a raw material of a PTH peptide freeze-dried preparation produced as a working example and comparative example.
  • the horizontal axis represents the time (min), and the vertical axis represents the absorption intensity.
  • the large peak appearing at approximately 20-21 minutes is human PTH (1-34).
  • “6 (encircled number)” corresponds to analog 7 (analog 7′), and “7 (encircled number)” corresponds to analog 8 (analog 8′).
  • FIG. 2 shows the chromatogram when the ultraviolet (214 nm) absorbance was measured by high-performance liquid chromatography (HPLC) taking as the sample a PTH peptide freeze-dried preparation produced as Example 1.
  • the horizontal axis represents the time (min), and the vertical axis represents the absorption intensity.
  • the large peak appearing at 21.157 min (retention time) is human PTH (1-34).
  • “1 (encircled number)” corresponds to analog 1 (analog 1′); “2 (encircled number)” corresponds to analog 2 (analog 2′); “3 (encircled number)” corresponds to a mixture of analog 3 and analog 4′ (mixture of analog 3′ and analog 4′); “4 (encircled number)” corresponds to analog 5 (analog 5′); “6 (encircled number)” corresponds to analog 7 (analog 7′); “7 (encircled number)” corresponds to analog 8 (analog 8′); “8 (encircled number)” corresponds to analog 9 (analog 9′); “9 (encircled number)” corresponds to a mixture of analog 10 and analog 11 (mixture of analog 10′ and mixture 11′).
  • FIG. 3 shows the chromatogram when the ultraviolet (214 nm) absorbance was measured by high-performance liquid chromatography (HPLC) taking as the sample a PTH peptide freeze-dried preparation produced as Comparative Example 1.
  • the horizontal axis represents the time (min), and the vertical axis represents the absorption intensity.
  • the large peak appearing at 20.279 min (retention time) is human PTH (1-34).
  • “5 (encircled number)” corresponds to analog 6 (analog 6′); the meaning of the other encircled numbers is the same as in FIG. 2 .
  • FIG. 4 shows the chromatogram when the ultraviolet (214 nm) absorbance was measured by high-performance liquid chromatography (HPLC) taking as the sample a PTH peptide freeze-dried preparation exposed to ozone as in Test Example 2.
  • the horizontal axis represents the time (min), and the vertical axis represents the absorption intensity.
  • the large peak appearing at 22.670 min (retention time) is human PTH (1-34).
  • the meaning of the encircled numbers is the same as in FIG. 2 .
  • FIG. 5 shows the structure of a methionine oxide compound.
  • FIG. 6 shows the structure of a tryptophan variant.
  • FIG. 7 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 1.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 8 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 2.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 9 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of a mixture of analog 3 and analog 4.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 10 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 5.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 11 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 6.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 12 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 7.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 13 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 8.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 14 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of analog 9.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 15 shows the results of high-performance liquid chromatography-mass spectrometry (LC/MS) of a mixture of analogs 10 and 11.
  • the horizontal axis represents the time (min), and the vertical axis represents the detection intensity.
  • FIG. 16 is a schematic diagram showing an example of preferred freeze-drying means of the present invention.
  • FIG. 17 is a schematic diagram showing an example of preferred freeze-drying means of the present invention.
  • PTH peptide in the present invention is used as a collective term for natural PTH and substances of equivalent physiologic activity.
  • the physiologic activity of PTH is characterized as acting to raise the serum calcium.
  • Preferred PTH peptides encompass natural PTH and partial peptides thereof, which may be peptides having a molecular weight of from about 4000 to 10,000.
  • PTH peptides are those wherein any of the constituent amino acid residues have not been chemically modified at all in comparison to the natural form; they do not include the (2) PTH analogs discussed later.
  • partial peptides include human PTH (1-34), human PTH (1-35), human PTH (1-36), human PTH (1-37), human PTH (1-38), human PTH (1-84), and the like, all of which have a sequence of 34-84 amino acids.
  • human PTH (1-34) is a partial peptide of the natural form sequence corresponding to amino acids numbers 1-34 of natural human PTH.
  • Human PTH (1-34) and human PTH (1-84) are preferred, and human PTH (1-34) is especially preferred.
  • the amino acid sequence of human PTH (1-34) is as follows:
  • the PTH peptide of the present invention may also be present as a salt formed with one or more volatile organic acids.
  • volatile organic acids include trifluoroacetic acid, formic acid, acetic acid, and the like.
  • Acetic acid can be given as a preferred example, but preferred examples are not limited to this.
  • the ratio of the two when free PTH peptide and a volatile organic acid form a salt is not particularly restricted as long as a salt forms. For example, since human PTH (1-34) has nine basic amino acid residues and four acidic amino acid residues in its molecule, taking into consideration salt formation in these molecules, the basic amino acid 5 residue can be made into a chemical equivalent of acetic acid.
  • acetic acid content represented by the acetic acid weight ⁇ 100(%)/peptide weight of human PTH (1-34)
  • amount of acetic acid as one theory, the chemical equivalent of acetic acid versus free human PTH (1-34) becomes approximately 7.3% (wt %).
  • free human PTH (1-34) sometimes is also called “teriparatide,” and the acetate of teriparatide is sometimes also called “teriparatide acetate.”
  • the acetic acid content in teriparatide acetate is not particularly restricted as long the teriparatide and acetic acid form a salt.
  • acetic acid content in teriparatide acetate may be 7.3%, which is the above theoretical chemical equivalent, or higher, or it may be from more than 0% to less than 1%. More concrete examples of the acetic acid content in teriparatide acetate are 1-7%, preferably 2-6%.
  • the amount of PTH peptide in the preparation of the present invention can be determined by HPLC testing. It should be noted that in this case the PTH peptide and PTH analogs are all determined as free compounds.
  • PTH analog in the present invention is defined in the broad sense as one detected as a peak different from the PTH peptide which is the active ingredient on the chromatogram when a sample from a freeze-dried preparation containing PTH peptide is subjected to HPLC. Therefore, if detected as one peak different from the original PTH peptide on the chromatogram, all of the chemical substances included in this peak may be regarded together as a single “PTH analog” even when two or more separate chemical substances are present in mixture within the peak.
  • the PTH analogs discovered to be produced during the production of a freeze-dried preparation containing PTH peptide were characterized as shown in Table 1 below.
  • T1-T3 are typical fragments produced when each analog is digested by trypsin and are as follows when listed based on the amino acid sequence of the human PTH (1-34) sequence.
  • T1 (corresponding to positions 1-13 of human PTH (1-34) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu- Gly-Lys (SEQ ID NO: 1)
  • T2 (corresponding to positions 14-20 of human PTH (1-34) His-Leu-Asn-Ser-Met-Glu-Arg (SEQ ID NO: 2)
  • T3 (corresponding to positions 21-25 of human PTH (1-34) Val-Glu-Trp-Leu-Arg (SEQ ID NO: 3)
  • human PTH (1-34)-Met 8 [O]-Met 18 [O]-Trp 23 [dioxidation] (analog 1′) means a PTH analog in which the residues corresponding to the position 8 and 18 methionine of human PTH (1-34) are each methionine sulfoxide residues, the residue corresponding to the position 23 tryptophan is a residue shown by the following structure (a) (Trp 23 oxidation (a) residue), and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Met 8 [O]-Met 18 [O]-Trp 23 [dioxidation-formic acid elimination] (analog 2′) means a PTH analog in which the residues corresponding to the position 8 and 18 methionine of human PTH (1-34) are each methionine sulfoxide residues, the residue corresponding to the position 23 tryptophan is a residue shown by the following structure (b) (Trp 23 oxidation (b) residue), and the other structures are the same as the original PTH peptide.
  • human PTH (1-34)-Met 8 [O]-Met 18 [O] (analog 3′) means a PTH analog in which residues corresponding to the position 8 and 18 methionine of human PTH (1-34) are each methionine sulfoxide residues and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Met 8 [O]-Trp 23 [dioxidation] (analog 4′) means a PTH analog in which the residue corresponding to the position 8 methionine of human PTH (1-34) is a methionine sulfoxide residue, the residue corresponding to the position 23 tryptophan is a Trp 23 oxidation (a) residue, and the other structures are the same as the original PTH peptide. Furthermore, analog 3′ and analog 4′ tend to be detected as a single peak, depending on the HPLC conditions. In this case, the PTH analog may be defined as a mixture of analog 3′ and analog 4′ as discussed above.
  • Human PTH (1-34)-Met 18 [O]-Trp 23 [dioxidation] (analog 5′) means a PTH analog in which the residue corresponding to the position 18 methionine of human PTH (1-34) is a methionine sulfoxide residue, the residue corresponding to the position 23 tryptophan is a Trp 23 oxidation (a) residue, and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Met 18 [O]-Trp 23 [dioxidation-formic acid elimination] (analog 6′) means a PTH analog in which the residue corresponding to the position 18 methionine of human PTH (1-34) is a methionine sulfoxide residue, the residue corresponding to the position 23 tryptophan is a Trp 23 oxidation (b) residue, and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Met 8 [O] (analog 7′) means a PTH analog in which the residue corresponding to the position 8 methionine of human PTH (1-34) is a methionine sulfoxide residue and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Met 18 [O] (analog 8′) means a PTH analog in which the residue corresponding to the position 18 methionine of human PTH (1-34) is a methionine sulfoxide residue and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Trp 23 [dioxidation] (analog 9′) means a PTH analog in which the residue corresponding to the position 23 tryptophan of human PTH (1-34) is a Trp 23 oxidation (a) residue and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Trp 23 [monoxidation] (analog 10′) means a PTH analog in which the residue corresponding to the position 23 tryptophan of human PTH (1-34) is a residue shown by the following structure (c)-1 or (c)-2 (Trp 23 oxidation (c) residue) residue and the other structures are the same as the original PTH peptide.
  • Human PTH (1-34)-Trp 23 [dioxidation-formic acid elimination] (analog 11′) means a PTH analog in which the residue corresponding to the position 23 tryptophan of human PTH (1-34) is a Trp 23 oxidation (b) residue and the other structures are the same as the original PTH peptide. Furthermore, analog 10′ and analog 11′ tend to be detected as a single peak, depending on the HPLC conditions. In this case, the PTH analog may be defined as a mixture of analog 10′ and analog 11′ as discussed above
  • the PTH peptide changes in that modified amino acid residues produced by oxidation of either methionine or tryptophan are introduced. It is therefore logical to assume that the production of the PTH analogs of the present invention is begun by contact between a substance having oxidizing capability and the PTH peptide.
  • a “substance having oxidizing capability” means a substance having the capacity to oxidize a structural amino acid of the PTH peptide, especially methionine or tryptophan.
  • the above definition of PTH analogs can be applied even when the PTH peptide contained as an active ingredient is other than human PTH (1-34).
  • the corresponding analog 1′ can also be expressed as human PTH (1-84)-Met 8 [O]-Met 18 [O]-Trp 23 [dioxidation].
  • the analog can be specified as one in which the position 8 and 18 methionine residues of human PTH (1-84) are each methionine sulfoxide residues, the position 23 tryptophan residue is a Trp 23 oxidation (a) residue, and the other structures are the same as human PTH (1-84).
  • the PTH analogs in a freeze-dried preparation containing PTH can be detected or determined by producing a sample by dissolving the preparation in a suitable solvent (phosphate buffer containing benzalkonium chloride or the like) and subjecting this sample to HPLC under, for example, the following conditions.
  • a suitable solvent phosphate buffer containing benzalkonium chloride or the like
  • Mobile phase A Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water and bring to 1000 mL by adding water after adding phosphoric acid to adjust the pH to 2.3. Add 100 mL of acetonitrile to this 900 mL of liquid.
  • Mobile phase B Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water and bring to 1000 mL by adding water after adding phosphoric acid to adjust the pH to 2.3 Add 500 mL of acetonitrile to 500 mL of this liquid.
  • the measurement wavelength is not particularly restricted as long as it allows detection of the PTH peptide and PTH analogs.
  • One or more wavelengths may be selected, for example, in the range of 210-360 nm, preferably 210-280 nm, and more preferably 210-254 nm.
  • One example of a suitable wavelength is 214 nm.
  • a chromatogram can be produced based on the measured values of this ultraviolet absorption.
  • the amount of each PTH analog and the amount of PTH peptide can be determined by calculating each peak area (e.g., by automatic integration) on the chromatogram based on the chromatogram obtained by performing HPLC as discussed above.
  • the amount of each PTH analog (%) and the total amount of PTH analogs (%) can then be determined and compared based on the calculated values by the following formulas 1 and 2.
  • the “total peak area” in the formulas is a value determined by adding the peak area of PTH peptide and the peak areas of all other PTH analogs detected on the chromatogram. Therefore, the “total peak area” corresponds to the “sum of the amount of PTH peptide and total amount of PTH analogs.”
  • “%” has the meaning of the following formula in the present invention.
  • analogs 3 and 4 produced from human PTH (1-34) elute as a single peak, as was mentioned above, when HPLC is carried out under the above conditions. Since regarding this single peak as one analog does not affect the results when used to confirm the purity or measure the preparation in this case, the mixed peak of analogs 3 and 4 (analogs 3′ and 4′) may be regarded as one analog. The same is also true of analogs 10 and 11 (analogs 10′ and 11′).
  • Table 3 shows a typical measurement example when HPLC was performed under the above conditions on a sample derived from a freeze-dried preparation containing human PTH (1-34). Furthermore, the notation “approximate relative retention time” in the table is because the relative retention time also sometimes changes depending on the column used or the mobile phase flow rate. Nonetheless, each analog can be identified and determined based on the pattern of the chromatogram taking this relative retention time as a criterion even in this case.
  • a freeze-dried preparation containing PTH peptide of the present invention means a freeze-dried preparation containing PTH peptide as an active ingredient.
  • freeze-dried preparation containing PTH peptide of the present invention is a freeze-dried preparation containing PTH peptide wherein the amount of a PTH analog in the preparation is 1.0% or less versus the “sum of the amount of PTH peptide and total amount of PTH analogs” and/or the total amount of PTH analogs in the preparation is 5.0% or lower versus the “sum of the amount of PTH peptide and total amount of PTH analogs.”
  • freeze-dried preparation containing PTH peptide of the present invention is a freeze-dried preparation containing PTH peptide wherein the amount of any of the respective PTH analogs is 1.0% or less versus the “sum of the amount of PTH peptide and total amount of PTH analogs” and/or the total amount of PTH analogs in the preparation is 5.0% or lower versus the “sum of the amount of PTH peptide and total amount of PTH analogs.”
  • “1.0% or less” and “5.0% or less” mean when absolutely no PTH analogs are contained in the freeze-dried preparation containing PTH peptide of the present invention or when that % or less is contained.
  • the freeze-dried preparation containing PTH peptide of the present invention does not contain any more than 1.0% of at least one or more PTH analogs versus the “sum of the amount of PTH peptide and total amount of PTH analogs,” and more preferably does not contain more than 1.0% of any PTH analog versus the “sum of the amount of PTH peptide and total amount of PTH analogs.”
  • the single peak is regarded as one analog, and the analog regarded in this way is more preferably not contained in an amount exceeding 1.0% versus the “sum of the amount of PTH peptide and total amount of PTH analogs.”
  • the amount of each PTH analog in the preparation is preferably “1.0% or less,” but 0.9% or less, 0.8% or less, 0.7% or less, and 0.6% or less are also preferred.
  • the total amount of PTH analogs is preferably “5.0% or less,” but 4.5% or less, 4.0% or less, 3.5% or less
  • the freeze-dried preparation containing PTH peptide of the present invention can contain various additives.
  • additives include sugars, amino acids, sodium chloride, and the like.
  • sugars are used as additives, mannitol, glucose, sorbitol, inositol, sucrose, maltose, lactose, or trehalose is preferably added in an amount of 1 weight or more (preferably 50-1000 weights) per weight of PTH peptide.
  • sugars and sodium chloride are used as additives, sodium chloride is preferably added in an amount of 1/1000-1/5 weight (preferably 1/100 to 1/10 weight) per weight of sugars.
  • the container used for the freeze-dried preparation containing PTH peptide of the present invention is not particularly restricted, but the preparation is preferably a freeze-dried preparation containing PTH peptide housed in a stoppered glass container.
  • the material of the stopper is not particularly restricted, but rubber is preferred.
  • the stopper is preferably washed, sterilized, and/or dried.
  • the freeze-dried preparation containing PTH peptide of the present invention housed in a stoppered glass container is, for example, a freeze-dried preparation containing PTH peptide housed in a glass vial having a rubber stopper (glass vial preparation), kit preparation comprising a freeze-dried preparation containing PTH peptide housed in a glass vial having a rubber stopper and an ampule sterilely filled with aqueous solution for dissolution, kit preparation comprising a freeze-dried preparation containing PTH peptide and prefilled syringe sterilely filled with aqueous solution for dissolution, or glass double chamber preparation (two chambers are present in one syringe, one chamber containing freeze-dried preparation containing PTH peptide and the other containing aqueous solution for dissolution).
  • a glass vial preparation is most preferred as the freeze-dried preparation containing PTH peptide of the present invention.
  • the material of the rubber stopper include chlorinated butyl rubber, normal butyl rubber, butadiene rubber, isoprene rubber, silicone rubber, elastomer, and the like. Silicate glass is preferred as the glass.
  • a freeze-dried preparation is produced by a process typically including any or all of the following steps, depending on its use.
  • the freeze-dried preparation containing PTH peptide of the present invention can also be produced according to the following steps.
  • the production scheme of the freeze-dried preparation containing PTH peptide of the present invention includes at least an active ingredient-containing solution preparation step and a freeze drying step explained below. It usually includes an active ingredient-containing solution preparation step, loading step, and freeze drying step, and preferably includes an active ingredient-containing solution preparation step, aseptic filtration and drug solution dispensing step, loading step, freeze drying step, and packaging step.
  • This step dissolves a bulk compound of the active ingredient and various additives as needed in a solvent (e.g., water for injection). Adjustment of the pH of the solution, adjustment of the volume of the solution, and the like may be performed as needed.
  • the time necessary for this step is not particularly restricted as long as it is within the acceptable range for industrial production, but it may be 0.5-5 hours, usually about 1-3 hours.
  • the PTH peptide of the present invention is the active ingredient, it is preferable to dissolve the bulk PTH peptide in advance and add it to a solution in which the various additives have been dissolved.
  • additives include excipients, stabilizers, dissolution auxiliaries, antioxidants, analgesics, isotonifying agents, pH regulators, and preservatives.
  • This step includes aseptic filtration of the active ingredient-containing solution prepared in the above step and filling a container suited to the performance of the freeze drying step explained below with this aseptic filtered solution (drug solution).
  • aseptic filtration is carried out using a filter.
  • Various commercial products can be used as the filter for aseptic filtration.
  • the pore size of the filter is preferably 0.2 ⁇ m or less or 0.22 ⁇ m or less.
  • Specific equipment and the like for performing aseptic filtration is well known to those skilled in the art.
  • Such aseptic filtration makes it possible to prepare a drug solution for producing a freeze-dried preparation to be utilized as a pharmaceutical.
  • Typical drug solution filling in this step is also well known to those skilled in the art.
  • individual containers are filled directly with drug solution after aseptic filtration of the solution of the active ingredient.
  • a large amount of solution may be aseptically filtered at once and subsequently dispensed into containers suited to use in the following step.
  • An example of these containers is a glass vial that can be stoppered by a rubber stopper or the like. The use of such glass vials is advantageous in the production of a preparation in a glass vial.
  • the time necessary for this step is also not particularly restricted as long as it is within the acceptable range for industrial production, but it may be 0.5-2 hours, usually 0.5-1 hour, as the filtration step and 3-10 hours, usually 6-10 hours, as the filling step.
  • one glass vial can be filled, for example, with about 1 g (preferably 0.3-3 g, more preferably 0.5-0.6 g) of aseptically filtered solution containing PTH peptide.
  • loading step means a series of steps whereby the filled containers prepared as described above are transported (transferred) to the freeze-drying means used in the next step and loaded and placed in that means.
  • the stoppers of the filled containers are usually open or partially open to dry by vacuum the filled solution frozen in a subsequent step in the production of a freeze-dried preparation.
  • An open stopper means that the stopper is completely open, and a partially open stopper means that the stopper is not open but not closed. This makes it possible to vacuum dry the drug solution in the container after freezing.
  • a partially open stoppered state as above is created by stoppering the filled vial partially using a rubber stopper after filling the glass vial by aseptically filtered solution (drug solution).
  • a step to provide partial stoppering in this way is also included in this loading step.
  • a freeze drying means is means making it possible to dry the frozen solution under vacuum.
  • Means for industrial production is preferably also provided with an adequate cooling function to freeze the solution or preferably provided with a function to properly heat the material to be freeze dried during this treatment to accelerate freeze drying. Since the material to be freeze dried is loaded into a chamber in a typical freeze-drying means suited to industrial production, this means has a large door (also referred to as “large door” hereinafter) corresponding to basically its entire front surface.
  • a typical freeze-drying means is a freeze-drying chamber (also called a “freeze dryer”), and many forms of these are marketed.
  • this step by way of example, taking a preparation in glass vials as an example of the preparation to be produced, a process whereby glass vials filled with drug solution obtained in the above step “2)” are partially stoppered and transported to the freeze-drying means and each vial is loaded sequentially or a quantity unit is loaded together at one time into the freeze-drying chamber and placed therein corresponds to this step.
  • each vial is “loaded sequentially,” depending on the layout of the pharmaceutical production facility, this can mean that each vial is filled one after another continuously by the above drug solution dispensing step, and each vial is then sequentially partially stoppered and transferred (transported) to the freeze-drying means.
  • each of the vials transported as described above is introduced one after another (that is, “sequential loading”) and placed into the freeze-drying means until reaching the quantity that can be treated at once.
  • the “loading step” of the present invention means a step that begins with a certain (first) vial after the drug solution dispensing step has been completed until the final vial to be freeze dried together with this (first) vial (that is, at once) has been loaded and placed in the freeze-drying means.
  • Loading the vials “in a quantity unit together at one time” can mean, for example, that there are multiple trays in the freeze-drying chamber and multiple drug solution-filled vials are placed together on each tray when placing them in the freeze-drying chamber, and sometimes these trays can be moved up and down for the sake of convenience when loading the drug solution-filled vials.
  • the “loading step” of the present invention means a step that begins with a certain (first) vial after the drug solution dispensing step has been completed until the final vial to be freeze dried together with this (first) vial has been loaded and placed in the freeze-drying means.
  • the drug solution-filled vials are left in a partially open state in this step until the subsequent freeze drying step begins and may be exposed to the air environment within a pharmaceutical production facility explained below.
  • the time necessary for this step also is not particularly restricted as long as it is within the range acceptable for industrial production, but is 3-10 hours, usually about 6-10 hours.
  • the vials can be placed in an open or partially open state under reduced pressure (for example, with the vials partially stoppered), and sealed at the end of freeze drying after the space in the vial has been purged by nitrogen.
  • the time necessary for this step varies depending on the capabilities of the freeze drying means, amount of substance to be freeze dried, and the like and should be within the range acceptable for industrial production. It is usually about 24-72 hours.
  • This step can be included when producing a freeze-dried preparation in a glass vial. Specifically, it is a step whereby the freeze-dried glass vials obtained in the above step “4)” are closed by an aluminum cap by a press-type capping machine, or the like.
  • the production facility When a freeze-dried preparation is produced as a pharmaceutical, the production facility must be a facility that meets the pharmaceutical GMP. This facility has drug solution preparation equipment, aseptic filtration equipment, and freeze drying equipment (means) and, in addition to these, water for injection production equipment, vial filling and stoppering equipment, capping machines, labelers, and the like to implement the steps explained above.
  • This facility has drug solution preparation equipment, aseptic filtration equipment, and freeze drying equipment (means) and, in addition to these, water for injection production equipment, vial filling and stoppering equipment, capping machines, labelers, and the like to implement the steps explained above.
  • all of the above steps 1)-6) or at least from the end of the aseptic filtration step to the beginning of the freeze drying step should be carried out in air environments within a pharmaceutical production facility. That is, the air environment of the pharmaceutical production facility differs from the simple outside air environment. Specifically, it is required that the air environment inside a facility for production of a sterile injection (pharmaceutical) be “a critical area of high cleanliness (the content of suspended microparticles 0.5 ⁇ m or greater in size per m 3 of air is to be 3520 or fewer during both work and non-work times).” This air quality corresponds to grade A (termed class 100 or ISO 5) according to current, commonly-used domestic and international air quality standards.
  • the air environment inside the facility that produces a freeze-dried preparation containing PTH peptide of the present invention should be at least equivalent to the air environment inside the above sterile injection production facility, more preferably an environment that maintains a unidirectional flow downward from above of clean air that has passed through HEPA filters capable of trapping particles of 0.3 ⁇ m in size at an efficiency of 99.97% or greater.
  • the air flow speed is preferably 0.2-1.0 m/s at a location 20 cm below the HEPA filter and 0.1-0.8 m/s at the location where the production work is carried out, more preferably 0.4-0.7 m/s at a location 20 cm below the HEPA filter and 0.3-0.5 m/s at the location where the production work is carried out.
  • bacteria suspended in the air and bacteria adhered to machinery, walls, floors, and other such installations are sterilized using ozone or formaldehyde or chemicals having oxidizing capability, such as hydrogen peroxide, peracetic acid, chlorine dioxide, glutaraldehyde, and the like, as disinfectants.
  • the residual formaldehyde concentration after fumigation and sterilization by formaldehyde should usually be kept to 0.1 ppm or lower, preferably 0.08 ppm or lower.
  • ozone is usually present even in the outside air in a concentration of 0.001-0.02 ppm as an average daily value. Concentrations of approximately 0.02-0.1 ppm are also sometimes present temporarily depending on the time, location, and season.
  • a method for producing a freeze-dried preparation containing PTH peptide is characterized in that exposure of the solution containing PTH peptide to the air environment within a pharmaceutical production facility is controlled during the process of the course when a substantial time is required under the air environment within a pharmaceutical production facility as described above at the beginning of the step for preparing a solution of PTH peptide (active ingredient), especially from the end of the drug solution dispensing step to the beginning of the drug solution freeze drying step (that is, loading step).
  • exposure to air environments within a pharmaceutical production facility is controlled” and “control of exposure to air environments within a pharmaceutical production facility” mean both that at least one or more of the PTH peptide bulk drug, solution containing PTH peptide, and PTH peptide freeze-dried preparation have absolutely no contact with air environments within a pharmaceutical production facility and that this contact is substantially (e.g., time and level of contact) restricted.
  • this contact is substantially (e.g., time and level of contact) restricted.
  • flowing air includes provision of a means to control the time in contact with this flowing air and the contacted air flow rate. Specific examples appear below.
  • the present inventors discovered that the generation of impurities (PTH analogs) in solution containing PTH peptide can be controlled by providing means for controlling contact of the solution containing PTH peptide with flowing air. Since flow of the air within the facility is maintained in an ordinary pharmaceutical production facility, it can be deduced that a large amount of air that pours down as air flow comes into contact with the solution containing PTH peptide and that gaseous substances having oxidizing capability (ozone and the like) contained in this air flow increase the PTH analogs in the solution by causing reactions and the like with the PTH peptide in the solution.
  • gaseous substances having oxidizing capability ozone and the like
  • the means for controlling contact of the solution containing PTH peptide with flowing air in the present invention is not particularly restricted. Examples include a means for controlling the fluidity and flow of the air in the vicinity of the solution containing PTH peptide and a means for purging the vicinity of the solution containing PTH peptide with an inert gas.
  • an ordinary freeze-drying chamber has a door in the front surface for loading the containers filled with the solution to be freeze dried.
  • This door is often a door (large door) that can cover the entire front surface of the freeze-drying chamber.
  • the present invention additionally provides a small door of a size roughly corresponding to one of the trays placed in the freeze-drying chamber (with the filled containers to be freeze dried disposed on top of it), and a freeze-drying chamber having a small door that can be opened and closed easily to load the containers is preferred.
  • a more preferred example is the above freeze-drying chamber with a small door having sub-doors that can be opened and closed easily provided with openings for loading (also referred to hereinafter as “small door openings”) to create small door units to open when loading and unloading the containers filled with the material to be freeze dried into the freeze-drying chamber and a means to open the sub-door only during container loading without leaving it constantly open and to close it quickly after loading.
  • These sub-doors are provided divided into 2-5 levels among the zones corresponding to the small door openings so that only the necessary unit may be opened for loading. Sub-doors that make it possible to open only the necessary location for loading the containers are preferred, and division into 2-3 levels is preferred.
  • sub-doors that can opened and closed easily include a sub-door that provides a hinge (hinge) at the top of the sub-door and is installed in the small door opening, a sub-door that slides to the right and left, a sub-door that slides up and down, and the like.
  • Preferred examples of other means of controlling contact of the solution containing PTH peptide and the like with flowing air include sealing the equipment for preparation (tank or container and the like) after the PTH peptide has been dissolved in the solvent in the solution containing PTH peptide preparation step or purging the interior of the container used for preparation by an inert gas during preparation.
  • the inside of the preparation equipment (tank or container and the like) is sometimes pressurized and the prepared solution containing PTH peptide is passed through a sterile filter and fed to the container or tank for dispensing in the aseptic filtration and drug solution dispensing step.
  • a means for controlling contact of the solution containing PTH peptide with flowing air is to use an inert gas as the gas for pressurization in this case.
  • Another preferred example of a means for controlling contact of the solution containing PTH peptide with flowing air is to purge the air inside the drug solution dispensing equipment (tank or container and the like) with an inert gas in advance in the aseptic filtration-drug solution dispensing step and to purge the glass container to be filled with the solution containing PTH peptide with an inert gas in advance.
  • Another preferred example of means for controlling contact of the solution containing PTH peptide with flowing air is to purge the space inside the glass container (part containing air and no drug solution) filled with the solution containing PTH peptide with an inert gas in the aseptic filtration-drug solution dispensing step.
  • the glass containers filled with the solution containing PTH peptide are sometimes transported from the aseptic filtration-drug solution dispensing equipment to near the freeze-drying chamber during the time after the end of the aseptic filtration-drug solution dispensing step up to loading of the solution containing PTH peptide housed in the open or partially open glass containers into the freeze drying means.
  • Placing the environment during transport under an inert gas flow can also be given as a preferred example of a means for controlling contact of the solution containing PTH peptide with flowing air in such cases.
  • a flap or airflow-adjusting cover ( FIG. 17 ) that can change the flow of the flowing air from the opening into the chamber can be installed to control the influx of flowing air from the small opening of the freeze-drying chamber into the freeze-drying chamber as a means for controlling contact of the solution containing PTH peptide with flowing air.
  • the shape of this flap or airflow-adjusting cover can be selected as is appropriate to the size of the freeze dryer and small door opening. It may be made of a vinyl sheet, metal, resin, or the like.
  • controlling the influx of flowing air from the small door opening of the freeze-drying chamber into the freeze-drying chamber means that the influx of flowing air is controlled to the point that contact between the solution containing PTH peptide and flowing air is substantially controlled, preferably controlled so that the inflow speed of flowing air from the small door opening is 0.2 m/s or less, more preferably 0.1 m/s or less, and most preferably 0.0 m/s or less.
  • This control can be achieved by proper placement of a flap or airflow-adjusting cover or the like near the small door.
  • the means for purging the vicinity of the solution containing PTH peptide with inert gas can be means for purging the air inside the freeze-drying chamber used in the freeze drying step using an inert gas or means for causing an inert gas to flow from the loading port into the freeze-drying chamber when loading the containers of solution containing PTH peptide into the freeze-drying chamber used in the freeze drying step.
  • the flow rate of the inert gas during influx is preferably 0.1-5 Nm 3 /min, more preferably 0.2-3 Nm 3 /min, and most preferably 0.3-1 Nm 3 /min.
  • Examples of the inert gas in purging by an inert gas include nitrogen and argon; nitrogen can be given as a preferred example.
  • the “means for controlling contact of the solution containing PTH peptide with flowing air” of (A) above can be provided in all or some steps included from the beginning of the step for preparing a solution containing PTH peptide to the beginning of the freeze drying step of this solution, and may be provided from the beginning of the step for preparing a solution containing PTH peptide.
  • the method for producing a freeze-dried preparation containing PTH peptide as a pharmaceutical of the present invention includes a step for preparing a solution containing PTH peptide, a step for loading this solution housed in open or partially open glass containers into a freeze-drying chamber, and a freeze drying step
  • the means of (A) above can be provided in some or all of the step for loading this solution housed in open or partially open glass containers into a freeze-drying chamber.
  • the duration of the step that provides “means for controlling contact of the solution containing PTH peptide with flowing air” of (A) above can have, for example, as the lower limit, one hour or more, preferably three hours or more, and more preferably six hours or more, and, as the upper limit, 20 hours or less, preferably 12 hours or less, more preferably 10 hours or less, and most preferably nine hours or less.
  • Examples of the duration of the step that provides a means of (A) above include 1-20 hours, preferably 3-12 hours, more preferably 6-10 hours, and most preferably 6-9 hours.
  • the freeze-dried preparation containing PTH peptide of the present invention can contain a pharmaceutically effective amount of PTH peptide and, for example, the freeze-dried preparation can be dissolved in a suitable solvent at the time of use to make an injection and used in the treatment of osteoporosis.
  • the method for controlling the production of PTH analogs of the present invention is a method that provides means for controlling contact of at least one of the PTH peptide bulk drug, solution containing PTH peptide, and freeze-dried preparation containing PTH peptide with substances having oxidizing capability, especially with air containing these substances.
  • a preferred example of a method for controlling the production of PTH analogs is to provide a means for purging air in contact with solution containing PTH peptide by an inert gas (preferably nitrogen).
  • a more preferred example is a method for controlling the production of any one or more PTH analogs among the aforementioned analogs 1 to 11 and analogs 1′ to 11′ by means for controlling contact of the solution containing PTH peptide with flowing air or means for purging the air in contact with the solution containing PTH peptide by an inert gas (preferably nitrogen).
  • an inert gas preferably nitrogen
  • production control methods can be implemented in freeze-dried preparation production facilities in air environments within pharmaceutical production facilities as described above.
  • their production in the solution can be controlled by means for controlling contact of the solution with flowing air during the course of the process for a predetermined time or longer from the beginning of the step for preparing a solution containing PTH peptide to the beginning of the freeze drying step of this solution.
  • Preferred embodiments of this means are the same as the preferred embodiments of the corresponding methods for production a freeze-dried preparation containing PTH peptide of the present invention.
  • a PTH peptide-containing aqueous solution was obtained by weighing out 1780 mg (lot D) of human PTH (1-34) as an acetate and dissolving it in 13 kg of the additive solution.
  • the PTH peptide-containing aqueous solution obtained was aseptically filtered using a filter while pressurizing by nitrogen and fed to a 50 L stainless steel filling tank previously filled with nitrogen.
  • a PTH peptide-containing aqueous solution was obtained by weighing out 2979 mg (lot D) of human PTH (1-34) as an acetate and dissolving it in 22 kg of the placebo solution.
  • the PTH peptide-containing aqueous solution obtained was aseptically filtered using a filter while pressurizing by nitrogen and fed to a stainless steel filling tank previously filled with nitrogen.
  • the area percentage method using HPLC is a simple method for assessing the purity of a freeze-dried preparation containing PTH peptide and the amount of analogs.
  • a solution obtained by weighing out 0.25 g of benzalkonium chloride and bringing it to 50 mL by adding 50 mM sulfate buffer (pH 2.3) serves as the loading buffer.
  • Each preparation of the examples and comparative examples is dissolved by 1 mL of physiological saline solution, and a 9:1 mixture of this solution and the loading buffer serves as the sample solution.
  • a quantity of 100 ⁇ L of sample solution is tested by HPLC under the following conditions.
  • benzalkonium chloride was used to prevent the peptide that is the target of measurement from attaching to the instrument and the like.
  • Mobile phase Mobile phase A: Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water and bring to 1000 mL by adding water after adding phosphoric acid to adjust the pH to 2.3. Add 100 mL of acetonitrile to this 900 mL of liquid.
  • Mobile phase B Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water and bring to 1000 mL by adding water after adding phosphoric acid to adjust the pH to 2.3 Add 500 mL of acetonitrile to 500 mL of this liquid.
  • Mobile phase feed Concentration gradient control is provided by varying the mixture ratio of mobile phase A and mobile phase B as follows.
  • Detection time 45 minutes after injection of the sample solution. However, this is from the back of the solvent peak.
  • Calculation method The amount of each PTH analog and the total amount thereof was determined by performing liquid chromatography under the above conditions, measuring each peak area by automatic integration, and performing calculation using Formulas 1 and 2. Furthermore, the total peak area was the sum total of the area of all peaks detected by performing liquid chromatography under the above conditions. In other words, the total peak area shows the sum total of PTH peptide and all PTH analogs in the preparation.
  • Amount of each PTH analog (%) (peak area of each analog/total peak area) ⁇ 100 Formula 1:
  • Table 6 shows the results obtained by assessing the amount of analogs of the human PTH (1-34) (bulk drug) used in the examples.
  • FIG. 1 shows an HPLC chart.
  • Table 7 shows the results obtained by assessing the purity of the freeze-dried preparations containing PTH peptide and the amount of analogs in the test example.
  • FIG. 2 shows an HPLC chart of Example 1
  • FIG. 3 shows an HPLC chart of Comparative Example 1. The structure of each analog in Table 6 was obtained by estimation using Test Example 2 below.
  • a quantity of 4.00 g of sucrose and 0.20 g of sodium chloride were weighed out and dissolved by adding water for injection to make a placebo solution.
  • Human PTH (1-34) was weighed out exactly and dissolved by adding 100 mL of placebo solution to make a reaction stock solution.
  • An environment having an ozone concentration of approximately 0.08 ppm by ozone concentration meter was produced using an ozone generator and a blower (initial wind speed approximately 7.2 m/s) to circulate the ozone and make the concentration uniform in a tray having a 40 cm long ⁇ 90 cm wide ⁇ 100 cm high glass door.
  • Approximately 15 mL of the reaction stock solution was dispensed into each 20 mL vial.
  • a stirrer was introduced into the vial, and degradation was carried out while stirring by stirrer until the purity was approximately 20% (in other words, the total amount of human PTH (1-34) analogs was 80%) by exposure (for about 20 hours) to an ozone atmosphere of approximately 0.08 ppm. Furthermore, the purity was confirmed in accordance with the test conditions of Test Example 1.
  • the degraded solution was freeze dried, and a solution dissolved by a suitable amount of water for injection was taken as a forced-degradation solution.
  • the analogs were fractionated under the following conditions using this solution.
  • test conditions other than the following were the same as the test conditions in Test Example 1.
  • FIG. 4 shows a chromatogram of the forced-degradation solution.
  • the elution times of the human PTH (1-34) peaks differ slightly owing to the differing compositions of the charged solutions in FIGS. 3 and 4 , but the corresponding analogs of FIGS. 3 and 4 were assumed to be the same given that the elution patterns and weight percent of each analog were the same on each chart.
  • the ozone exposure test here appeared to be a test that substantially reproduces the PTH analog production reactions triggered when solution containing PTH peptide is produced in an air environment inside a pharmaceutical production facility.
  • Mobile phase Mobile phase A: Mixed aqueous solution containing trifluoroacetic acid (1:1000)
  • Mobile phase feed Concentration gradient control is provided by varying the mixture ratio of mobile phase A and mobile phase B as follows.
  • Detection time 45 minutes after injection of the sample solution. However, this is from the back of the solvent peak
  • Mobile phase feed Concentration gradient control is provided by varying the mixture ratio of mobile phase A and mobile phase B as follows.
  • Table 11 shows the expected fragments of human PTH (1-34) produced by trypsin digestion.
  • Table 12 shows the results of measurement of the mass of each fragment confirmed in LC/MS/MS of the standard solution (digested compound). The measured values of each fragment in the standard solution (digested compound) were compared with the calculated mass, and it was confirmed that five fragments of estimated structure were obtained in human PTH (1-34).
  • Table 14 shows the results obtained by MS/MS analysis of fragments confirmed to have changes in mass. As a result of comparison with the standard solution (digested compound), changes in mass of +16 Da in Met 18 in T2, +4 Da in Trp 23 in T3, and +16 Da in Met 8 in T1 were confirmed.
  • Table 15 shows the results obtained by comparing the mass of analog 1 (undigested compound) obtained by LC/MS with the calculated value of 4115.1309 of human PTH (1-34).
  • analog 1 (undigested compound) peaks of +64 Da and +36 Da were confirmed in comparison to the calculated mass, and the +64 Da peak appeared to be the main peak based on the size of the peaks, as shown in FIG. 7 .
  • the molecular weight of the undigested compound is approximately 4000 Da, but since the mass of a multivalent ion is obtained as the measured value in LC/MS, an error of about ⁇ 1 Da was anticipated in the process of calculating the mass of the undigested compound from the mass of the multivalent ion. Corrected values are listed in parentheses for estimated differences in mass when an error arose in structural analysis. The same is true in subsequent structural analyses.
  • T2+16 Da: T2 and T3+4 Da: T3 were each present in an approximately 1:1 ratio, and T2+16 Da: T3+4 Da: T1+16 Da were present in an approximately 1:1:2 ratio.
  • Analogs 3 and 4 were estimated to be human PTH (1-34)+32 Da and human PTH (1-34)+48 Da, respectively.
  • Table 31 shows the results obtained by MS/MS analysis of fragments confirmed to have changes in mass.
  • a change in mass of +16 Da in Trp 23 in one T3 was confirmed as a result of comparison with the standard solution (digested compound).
  • the structure of the changed form of +16 Da in Trp was expected to be c) in FIG. 6 .
  • a change in mass of +4 Da in Trp 23 was estimated from the results of analysis of analogs 1-8.
  • Table 32 shows the results of comparing the mass of a mixture of analogs 10 and 11 (undigested compound) obtained by LC/MS with the calculated mass of 4115.1309 of human PTH (1-34).
  • peaks of +16 Da and +4 Da were observed comparison to the calculated masses, as shown in FIG. 15 .
  • Table 33 shows the relative retention time and estimated structure results of each analog.
  • FIG. 5 shows the oxidation of the methionine residues in the table
  • FIG. 6 shows a), b), and c) in the table.
  • the relative retention time of each analog in the table shows the relative retention time taking the retention time of human PTH (1-34) as 1.
  • the present invention can be used in the pharmaceutical manufacturing industry.

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