WO2012169435A1 - 高純度pth含有凍結乾燥製剤およびその製造方法 - Google Patents
高純度pth含有凍結乾燥製剤およびその製造方法 Download PDFInfo
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- WO2012169435A1 WO2012169435A1 PCT/JP2012/064229 JP2012064229W WO2012169435A1 WO 2012169435 A1 WO2012169435 A1 WO 2012169435A1 JP 2012064229 W JP2012064229 W JP 2012064229W WO 2012169435 A1 WO2012169435 A1 WO 2012169435A1
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- WIPO (PCT)
- Prior art keywords
- pth
- pth peptide
- freeze
- peptide
- related substance
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Images
Classifications
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- 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
- 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
-
- 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 physiologically active equivalent thereof (hereinafter collectively referred to as “PTH peptide”) as an active ingredient.
- PTH parthyroid hormone
- PTH peptide a physiologically active equivalent thereof
- the present invention also relates to a method for producing a lyophilized preparation containing a PTH peptide.
- the present invention relates to a test or quality assurance method for a lyophilized preparation containing a PTH peptide.
- Parathyroid hormone along with calcitonin and vitamin D, is a hormone involved in the regulation of blood calcium concentration. Therefore, the PTH peptide is used as a diagnostic agent for hypoparathyroidism. Parathyroid hormone is also known to have an action of promoting calcium absorption in the intestinal tract by increasing the production of active vitamin D3 in the kidney in vivo (Non-patent Document 1). In addition, by administering subcutaneously 100 or 200 units of PTH per administration over a 26-week administration period to an osteoporosis patient once a week, the bone density of the sea surface bone of the osteoporosis patient is increased. And a method for treating osteoporosis that does not reduce the bone density of cortical bone is disclosed (Patent Document 7).
- Patent Document 1 Patent Document 1
- Patent Document 2 the freeze-dried pharmaceutical composition characterized by containing a monosaccharide or a disaccharide, and sodium chloride is also known (patent document 3).
- an ordinary pharmaceutical manufacturing facility has realized an aseptic environment with a flow of aseptic air having a constant wind speed through a HEPA filter. Use the area. That is, in the pharmaceutical manufacturing facility in the aseptic environment, typically, the aseptic filtration of the solution following the preparation step of the active ingredient-containing solution to the filling step into the container, the carrying step into the freeze-dryer of the filling vessel, And the manufacturing process which consists of a capping process of a container (vials etc.) from a freeze-drying process is implemented.
- Japanese Unexamined Patent Publication No. 63-60940 Japanese Patent Laid-Open No. 2-111 JP-A-5-306235 Japanese Unexamined Patent Publication No. 64-16799 WO02 / 002136 JP 2003-095974 A JP-A-8-73376 WO00 / 10596 WO10 / 30670
- the active ingredients of pharmaceuticals are obtained by chemical synthesis from raw materials, isolation / purification of biological substances, or genetic engineering production and product isolation / purification.
- the purity of the raw material itself, incomplete reaction, decomposition in the isolation / purification process, etc. the purity of 100% as a pharmaceutical active ingredient to be produced It is often difficult to obtain.
- a diagnostic or therapeutic drug contains impurities beyond the allowable amount, the possibility of adverse effects on the diagnosis or treatment cannot be ruled out, so that a safe and effective drug can still be produced.
- One important factor is to obtain a highly pure product.
- the administration period may be long, so the preparation containing the PTH peptide needs to be particularly high purity. It will be said.
- PTH related substance a substance in which the chemical structure of the active ingredient (PTH peptide) is changed (hereinafter referred to as “PTH related substance”). It was discovered that a preparation containing “.” was produced. In particular, when the production scale is increased, the production amount of the PTH-related substance is likely to increase to an extent that is substantially unacceptable as the production quantity increases. Furthermore, although the amount of the PTH related substance produced was not always constant and varied depending on the production place, time, time, etc., the cause of the production of the PTH related substance was not specified. For this reason, we faced a serious problem that we could not manage the amount of production.
- an object of the present invention is to provide a PTH peptide-containing lyophilized preparation that has a high purity, that is, a level that is low to an acceptable level of PTH-related substances. Furthermore, this invention makes it a subject to provide the manufacturing method of the said highly purified PTH peptide containing freeze-dried formulation. Another object of the present invention is to provide a method for examining a PTH-related substance for the purpose of confirming the purity of a freeze-dried preparation containing a PTH peptide.
- the present inventors have become concerned that the production scale will increase, and the production amount of PTH related substances will increase to an extent that is substantially unacceptable as the production quantity increases, and the PTH related substances will be isolated. Succeeded in characterization. Furthermore, it discovered that the production
- the structural characteristics of the PTH related substances characterized above and the generation of the related substances can be prevented / reduced by suppressing exposure to the air environment in the pharmaceutical manufacturing facility. From these facts, it was estimated that the production of these PTH related substances was caused by substances having an oxidizing ability present in the air environment in the pharmaceutical manufacturing facility.
- the air environment of a pharmaceutical manufacturing facility may contain gaseous substances having soot and oxidizing ability in addition to high cleanliness (grade A, etc.).
- pharmaceutical manufacturing facilities may be fumigated with a sterilizing agent such as formaldehyde or ozone in order to realize a more thorough aseptic environment.
- the fumigation disinfection residue may contain an oxidizing gas such as formaldehyde or ozone.
- ozone is present in the atmosphere at a concentration of 0.001 to 0.02 ppm, depending on the location, time, and season, with or without fumigation.
- the present inventors have also confirmed that the production of the PTH-related substance revealed in the present invention is reproduced by bringing the PTH peptide into contact with air containing ozone.
- the present invention includes the following aspects and preferred embodiments.
- the PTH peptide-containing lyophilized preparation produced by the method, wherein exposure of the PTH peptide-containing solution before lyophilization to an air environment in a pharmaceutical production facility is suppressed.
- the PTH analog is 1) Related substances 1: A digest having a mass number 64 Da larger than the mass number of the PTH peptide contained in the preparation, and corresponding to the following fragments (1-a) to (1-c) when the related substance is trypsin-digested An oxide of the PTH peptide that yields (1-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys (SEQ ID NO: 1) mass number +16 Da, (1-b) His-Leu-Asn-Ser-Met-Glu-Arg (SEQ ID NO: 2) mass number +16 Da, and (1-c) Val-Glu-Trp-Leu-Arg (SEQ ID NO: 3) Mass number + 4 Da; 2) Related substances 2: A digest having a mass number 36 Da larger than the mass number of the PTH peptide contained in the preparation, and corresponding to the following fragments (2-a) to (2-c) when the related substance is tryp
- the PTH analog is 1) Related substances 1 ': Residues corresponding to positions 8 and 18 methionine of human PTH (1-34) were changed to methionine sulfoxide residues, and residues corresponding to position 23 tryptophan were changed to residues represented by the following structural formula (a). An oxide of the PTH peptide, ; 2) Related substances 2 ': Residues corresponding to positions 8 and 18 methionine of human PTH (1-34) were changed to methionine sulfoxide residues, and residues corresponding to position 23 tryptophan were changed to residues represented by the following structural formula (b).
- the high purity is such that the amount of at least one or more of the related substances 1 to 11 in the preparation is 1.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount in the preparation. And / or the total amount of the related substance amounts 1 to 11 is 5.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount. Lyophilized formulation.
- the high purity is such that the amount of at least one of the related substances 1 ′ to 11 ′ in the preparation is 1.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount in the preparation. And / or the total amount of the related substance amounts 1 ′ to 11 ′ is 5.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount, according to [3] A lyophilized preparation containing PTH peptide.
- Suppression of exposure of the PTH peptide-containing solution to the air environment in the pharmaceutical manufacturing facility before lyophilization is any of the PTH peptide-containing solution preparation step, the aseptic filtration step, the chemical solution filling step, and the lyophilization means loading step.
- the PTH peptide-containing lyophilized preparation according to any one of [1] to [7], which is performed in one or more steps.
- the freeze-dried product is produced by a method including suppressing exposure to an air environment in a pharmaceutical production facility, [8] A freeze-dried preparation containing the PTH peptide according to 1.
- the suppression of the exposure is performed by using a freeze-drying chamber provided with a means for suppressing air in the pharmaceutical manufacturing facility from flowing into the freeze-drying means.
- the freeze-drying means has an easily openable and closable sub-door provided in an opening formed in a small door portion that opens when a container containing the PTH peptide-containing solution before freeze-drying is carried into and out of the means.
- This is a freeze-drying cabinet, which prevents the exposure of the PTH peptide-containing solution before freeze-drying to the air environment in the pharmaceutical manufacturing facility by opening the auxiliary door only at the time of carrying in the container and quickly closing it after carrying in the carrying-in process.
- the freeze-drying means is a freeze-drying warehouse having an opening formed in a small door portion that opens when a container containing the PTH peptide-containing solution before freeze-drying is carried into and out of the means, and air in a pharmaceutical manufacturing facility
- the carrying-in step suppresses exposure of the PTH peptide-containing solution before lyophilization to an air environment in a pharmaceutical production facility by replacing the lyophilization means with an inert gas, [10] A freeze-dried preparation containing the PTH peptide according to 1.
- the freeze-drying means has an easily openable and closable sub-door provided in an opening formed in a small door portion that is opened when the container containing the PTH peptide-containing solution before freeze-drying is carried into and out of the means. It is a freeze-drying chamber, so that in the carrying-in process, the subdoor is opened only at the time of carrying in the container and quickly closed after carrying in, and the inside of the freeze-drying means is replaced with an inert gas, so that the PTH peptide before freeze-drying is contained.
- the freeze-drying means has an opening formed in a small door portion that is opened when a container for storing the PTH peptide-containing solution before freeze-drying is carried in and out of the means, and further provided with a wind regulation cover in the opening.
- a freeze-drying cabinet whereby in the carrying-in step, the conditioned cover changes the flow of flowing air in a direction not to go into the cabinet, and the inside of the freeze-drying means is replaced with an inert gas before PTH before freeze-drying.
- the PTH peptide-containing lyophilized preparation according to any one of [10] to [16], wherein the carrying-in step is a step over 3 hours or more.
- a freeze-dried preparation containing a high-purity PTH peptide as an active ingredient is placed in an air environment in a pharmaceutical manufacturing facility when a PTH peptide-containing solution before freeze-drying is carried into a freeze-drying means.
- the high purity is the amount of at least one PTH analog relative to the sum of the amount of PTH peptide and the total amount of PTH analog in the formulation Is 1.0% or less, and / or that the total PTH related substance amount is 5.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount, and the carrying-in step is 3 hours or more
- the air environment is an environment in which clean air that has passed through the HEPA filter is maintained as a one-way airflow from the top to the bottom, and the HE A lyophilized preparation containing PTH peptide, wherein the airflow at a position 20 cm directly under the PA filter is a flow velocity airflow of 0.2 to 1.0 m / s.
- a method for producing a PTH peptide-containing lyophilized preparation wherein the PTH peptide-containing solution is prepared in one or more steps from the start of the PTH peptide-containing solution preparation step to the end of the carry-in step to the freeze-drying means.
- the auxiliary door is opened only at the time of carrying in the container, and then quickly closed after carrying in, thereby suppressing exposure of the PTH peptide-containing solution before lyophilization to the air environment in the pharmaceutical production facility, [24 ] Or the method according to [25].
- the freeze-drying means is a freeze-drying warehouse having an opening formed in a small door portion that is opened when a container containing the PTH peptide-containing solution before freeze-drying is carried in and out of the means, and air in a pharmaceutical manufacturing facility
- the method according to [24] or [25] wherein the means for suppressing the flow of the air into the freeze-drying means is a wind regulation cover that changes the flow of the flowing air in a direction not from the opening to the inside of the storage.
- the exposure of the PTH peptide-containing solution before lyophilization to an air environment in a pharmaceutical production facility is suppressed by replacing the lyophilization means with an inert gas. The method described.
- the sub-door is opened only at the time of carrying the solution container and quickly closed after carrying in, and the freeze-drying means is replaced with an inert gas to replace the pharmaceutical product of the pre-lyophilized PTH peptide-containing solution.
- the freeze-drying means has an opening formed in a small door portion that is opened when a container for storing the PTH peptide-containing solution before freeze-drying is carried in and out of the means, and further provided with a wind regulation cover in the opening.
- a freeze-drying cabinet whereby in the carrying-in step, the conditioned cover changes the flow of flowing air in a direction not to go into the cabinet, and the inside of the freeze-drying means is replaced with an inert gas before PTH before freeze-drying.
- the air environment in the pharmaceutical manufacturing facility is 1) Grade A air, and 2) Clean air that has passed through a HEPA filter that has a performance of capturing particles with a particle size of 0.3 ⁇ m with an efficiency of 99.97% or more. Is maintained as a one-way airflow from the top to the bottom, and 3) any one of [21] to [33], which is an air environment having a contained ozone concentration of 0.001 to 0.1 ppm The method described in 1.
- the amount of at least one PTH related substance relative to the sum of the PTH peptide amount and the total PTH related substance amount in the PTH peptide-containing lyophilized preparation is 1.0% or less, and / or the PTH peptide amount and the total PTH related substance amount
- a method for producing a lyophilized preparation containing a high-purity PTH peptide as an active ingredient comprising the steps of: air in a pharmaceutical production facility when a PTH peptide-containing solution before lyophilization is carried into a lyophilization means It is a method characterized by suppressing exposure to the environment, wherein the high purity means at least one PTH analog relative to the sum of the amount of PTH peptide and the total amount of PTH analog in the preparation At least 1.0% and / or the total amount of PTH related substance to the sum of the amount of PTH peptide and the total amount of PTH related substance is 5.0% or less.
- the air environment is an environment in which the clean air that has passed through the HEPA filter is maintained as a one-way air flow from top to bottom,
- the present invention contemplates an inspection method that is important for guaranteeing the suitability of a freeze-dried preparation containing a PTH peptide as a pharmaceutical product and complying with laws and regulations.
- the inspection method is characterized by confirming the presence and / or quantifying the presence of any one or more of the PTH-related substances or all of them.
- the aspects and preferred embodiments include the following.
- a method for examining a freeze-dried preparation containing PTH peptide the method confirming the presence of at least one or more of PTH-related substances 1 to 11 according to [2] in the freeze-dried preparation containing PTH peptide And / or quantifying the abundance.
- a method for testing a freeze-dried preparation containing PTH peptide comprising the presence of at least one or more of the PTH-related substances 1 ′ to 11 ′ according to [3] in the freeze-dried preparation containing PTH peptide And / or quantifying the abundance.
- the purity of the PTH peptide in the PTH peptide-containing lyophilized preparation can be determined by comparing the peak area corresponding to the PTH peptide or the peak area of the PTH peptide with the sum of the peak areas of all other PTH related substances detected The method according to [43], comprising calculating.
- the amount of at least one PTH related substance relative to the sum of the PTH peptide amount and the total PTH related substance amount in the freeze-dried preparation containing PTH peptide is 1.0% or less, and / or the PTH peptide amount and the total PTH related substance amount [41]
- the method according to any one of [41] to [45], for ensuring that the total amount of PTH-related substances relative to the sum of the amounts is 5.0% or less.
- a method for producing a pharmaceutical product comprising a PTH peptide-containing lyophilized preparation comprising a step of performing the test method according to any one of [41] to [48].
- PTH peptide-containing lyophilized preparation wherein at least one PTH related substance is 1.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount, and / or the total PTH related substance
- PTH peptide-containing freeze-dried preparation characterized in that the amount is 5.0% or less with respect to the sum of the amount of PTH peptide and the amount of all PTH-related substances.
- PTH peptide-containing lyophilized preparation wherein each PTH related substance is 1.0% or less with respect to the sum of the amount of PTH peptide and the total PTH related substance, and / or the total PTH related substance
- the amount of the related substance relative to the sum of the PTH peptide amount and the total PTH related substance amount is at least the following relationship: 1 amount of related substance is 0.04% or less; The total amount of related substance 3 and related substance 4 is 0.11% or less; The amount of related substance 5 is 0.26% or less; The amount of the related substance 7 is 0.33% or less; The PTH peptide-containing lyophilized preparation according to [52], wherein the amount of the related substance 8 is a percentage arbitrarily selected from 0.21 to 1.00%; and the amount of the related substance 9 is 0.68% or less.
- the amount of the related substance relative to the sum of the PTH peptide amount and the total PTH related substance amount is at least the following relationship:
- Related substance 1 'content is 0.04% or less;
- the total amount of related substance 3 ′ and related substance 4 ′ is 0.11% or less;
- the amount of the related substance 9 and the total amount of the related substance 10 and the related substance 11 are 1.0% or less with respect to the sum of the amount of the PTH peptide and the total amount of the PTH related substance, containing the PTH peptide according to [52] Lyophilized formulation.
- the amount of the related substance 8 ′, the amount of the related substance 9 ′, and the total amount of the related substance 10 ′ and the related substance 11 ′ are 1.0% or less with respect to the sum of the PTH peptide amount and the total PTH related substance amount.
- the present invention provides a freeze-dried preparation containing high-purity PTH. That is, it is confirmed that the PTH-containing lyophilized preparation is produced in the present invention, and undesirable production of the characterized PTH-related substance during pharmaceutical production is prevented / reduced.
- by quantifying the PTH-related substance it is possible to produce the preparation suitable as a pharmaceutical while confirming and verifying the quality of the PTH-containing lyophilized preparation simply, quickly and reliably.
- the horizontal axis represents time (minutes) and the vertical axis represents absorption intensity.
- the large peak that appeared at 21.157 minutes (retention time) is human PTH (1-34).
- subjected to the high performance liquid chromatography (HPLC) as a sample, and the ultraviolet part (214 nm) absorption was measured is shown.
- the horizontal axis represents time (minutes) and the vertical axis represents absorption intensity.
- a large peak appearing at 20.279 minutes (retention time) is human PTH (1-34).
- “5 (circled number)” refers to the related substance 6 (related substance 6 ′), and the meanings of the other circled numbers are the same as those in FIG.
- a PTH peptide freeze-dried preparation exposed to ozone is used as a sample and subjected to high performance liquid chromatography (HPLC), and a chromatogram when measuring ultraviolet (214 nm) absorption is shown.
- the horizontal axis represents time (minutes) and the vertical axis represents absorption intensity.
- a large peak appearing at 22.670 minutes (retention time) is human PTH (1-34).
- the meaning of the circled numbers is the same as in Fig. 2.
- the structure of a methionine oxidant is shown.
- the structure of a tryptophan variant is shown.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 1 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 2 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the mixture of the related substance 3 and the related substance 4 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 5 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 6 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 7 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 8 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the related substance 9 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- the result of the high performance liquid chromatography-mass spectrometry (LC / MS) of the mixture of the related substances 10 and 11 is shown.
- the horizontal axis represents time (minutes), and the vertical axis represents detected intensity.
- PTH Peptide is used as a general term for natural PTH and its physiologically active equivalents.
- the physiological activity of PTH is characterized as having a serum calcium raising effect.
- Suitable PTH peptides include natural PTH or partial peptides thereof and may be peptides having a molecular weight of about 4,000 to 10,000.
- the PTH peptide is one in which all of the constituent amino acid residues are not chemically modified as compared with the natural product, and does not include the (2) PTH related substance described later.
- Specific examples of the partial peptide include human PTH (1-34), human PTH (1-35), human PTH (1-36), human PTH (1-37), human having 34 to 84 amino acid sequences.
- human PTH (1-38), human PTH (1-84) and the like can be mentioned. That is, human PTH (1-34) is a partial peptide of the natural type sequence corresponding to amino acid numbers 1 to 34 of natural type human PTH. Human PTH (1-34) and human PTH (1-84) are preferable, and human PTH (1-34) is particularly preferable.
- the amino acid sequence of human-PTH (1-34) is as follows:
- the PTH peptide of the present invention may exist as a salt formed with one or more volatile organic acids. Examples of the volatile organic acid include trifluoroacetic acid, formic acid, acetic acid and the like, and preferred examples include acetic acid, but are not limited thereto.
- the ratio between the free PTH peptide and the volatile organic acid forming a salt is not particularly limited as long as it forms a possible salt.
- human-PTH (1-34) has 9 basic amino acid residues and 4 acidic amino acid residues in its molecule, and therefore, taking into account salt formation in those molecules, 5 amino acid residues can be the chemical equivalent of acetic acid.
- the acetic acid content expressed as acetic acid weight ⁇ 100 (%) / peptide weight of human-PTH (1-34) is used as the amount of acetic acid
- one theory is that human-PTH (1- The chemical equivalent of acetic acid to 34) is about 7.3% (% by weight).
- teriparatide acetate human-PTH (1-34) which is a free form is sometimes referred to as “teriparatide”, and teriparatide acetate is sometimes referred to as “teriparatide acetate”.
- the acetic acid content in teriparatide acetate is not particularly limited as long as teriparatide and acetic acid form a salt, and may be, for example, the above theoretical chemical equivalent of 7.3% or more. If it exceeds, it may be less than 1%.
- the acetic acid content in teriparatide acetate may be exemplified by 1 to 7%, preferably 2 to 6%.
- the amount of PTH peptide, the amount of each PTH related substance, the amount of the PTH related substance mixture and the total PTH related substance in the preparation of the present invention are HPLC. It should be noted that any PTH peptide or PTH analog in that case can be quantified in the test and is quantified as a free mass.
- PTH-related substance in the present invention refers to a PTH peptide that is an active ingredient on the chromatogram when a sample derived from a lyophilized preparation containing PTH peptide is subjected to HPLC.
- PTH-related substance refers to a PTH peptide that is an active ingredient on the chromatogram when a sample derived from a lyophilized preparation containing PTH peptide is subjected to HPLC.
- HPLC HPLC
- a mixture of multiple chemical substances that can be detected as a single peak on the HPLC chromatogram is sometimes referred to as a “related substance”.
- a single peak composed of such a mixture is regarded as one “related substance” for convenience and purity confirmation and purity calculation are performed, the present invention also provides a given condition. It is not precluded from comprehensively considering a mixture of multiple chemicals detected as a single peak in the lower HPLC as a single “PTH analog”.
- PTH-related substances that were found to be produced during the production of PTH peptide-containing lyophilized preparations were characterized as shown in Table 1 below.
- T1 to T3 are typical fragments generated when trypsin digests each related substance, and are described below based on the amino acid number of the human PTH (1-34) sequence.
- the number of the amino acid to be changed is expressed as the amino acid number of the corresponding human PTH (1-34) sequence, and the same notation is used unless otherwise specified in this specification.
- human PTH (1-34) -Met8 [O] -Met18 [O] -Trp23 [dioxide] (related substance 1 ′) is the 8-position of human PTH (1-34).
- residue corresponding to 18-position methionine is a methionine sulfoxide residue
- residue corresponding to position 23 tryptophan is a residue (Trp23 oxidation (a) residue) represented by the following structure (a):
- Other structures refer to PTH analogs that are identical to the original PTH peptide.
- human PTH (1-34) -Met8 [O] -Met18 [O] -Trp23 [dioxide-formic acid elimination] (analogous substance 2 ′) means positions 8 and 18 of human PTH (1-34).
- Residues corresponding to methionine are methionine sulfoxide residues
- residues corresponding to tryptophan at position 23 are residues shown in the following structure (b) (Trp23 oxidation (b) residue)
- other structures Means a PTH analog that is identical to the original PTH peptide.
- human PTH (1-34) -Met8 [O] -Met18 [O] is a group in which residues corresponding to 8- and 18-position methionine of human PTH (1-34) are It is a methionine sulfoxide residue, and refers to a PTH analog whose other structure is identical to the original PTH peptide.
- human PTH (1-34) -Met8 [O] -Trp23 [dioxide] is a methionine sulfoxide residue corresponding to 8-position methionine of human PTH (1-34).
- the residue corresponding to tryptophan at position 23 is a Trp23 oxidation (a) residue
- the other structure means a PTH analog having the same structure as the original PTH peptide.
- the related substance 3 ′ and the related substance 4 ′ can be easily detected as a single peak.
- the PTH related substance is used as a mixture of the related substance 3 ′ and the related substance 4 ′. It may be defined.
- Human PTH (1-34) -Met18 [O] -Trp23 [dioxide] (related substance 5 ′) is a methionine sulfoxide residue corresponding to the 18-position methionine of human PTH (1-34); A residue corresponding to tryptophan at position 23 is a Trp23 oxidized (a) residue, and the other structure means a PTH analog having the same structure as the original PTH peptide.
- Human PTH (1-34) -Met18 [O] -Trp23 [dioxide-formic acid elimination] (related substance 6 ′) is a residue corresponding to methionine at position 18 in human PTH (1-34). It is a group, and the residue corresponding to tryptophan at position 23 is a Trp23 oxidation (b) residue, and the other structure means a PTH analog having the same structure as the original PTH peptide.
- Human PTH (1-34) -Met8 [O] (related substance 7 ′) is a residue that corresponds to methionine 8-position of human PTH (1-34) is a methionine sulfoxide residue. Means the same PTH analog as the PTH peptide.
- Human PTH (1-34) -Met18 [O] (related substance 8 ') is a methionine sulfoxide residue corresponding to 18-position methionine of human PTH (1-34). Means the same PTH analog as the PTH peptide.
- Human PTH (1-34) -Trp23 [dioxide] (related substance 9 ′) is a residue corresponding to tryptophan at position 23 of human PTH (1-34) is a Trp23 oxidized (a) residue. Structure refers to a PTH analog that is identical to the original PTH peptide.
- Human PTH (1-34) -Trp23 [monoxide] (related substance 10 ′) is a residue corresponding to tryptophan at position 23 of human PTH (1-34) having the following structure (c) -1 or (c ) -2 (Trp23 oxidation (c) residue), and other structures mean PTH analogs having the same structure as the original PTH peptide.
- Human PTH (1-34) -Trp23 [dioxide-formic acid elimination] (related substance 11 ′) is a residue corresponding to tryptophan at position 23 of human PTH (1-34), which is a Trp23 oxidized (b) residue.
- other structures refer to PTH analogs that are identical to the original PTH peptide.
- the related substance 10 ′ and the related substance 11 ′ are easily detected as a single peak.
- the PTH related substance is a mixture of the related substance 10 ′ and the related substance 11 ′. Can be defined.
- the PTH peptide is changed so that a modified amino acid residue generated by oxidation of methionine or tryptophan is introduced. Therefore, it seems reasonable to infer that the production of the PTH-related substance of the present invention is initiated by the contact of the substance having oxidizing ability and the PTH peptide. That is, in the present specification, the “substance having oxidation ability” means a substance having the ability to oxidize the constituent amino acids of the PTH peptide, particularly methionine and tryptophan.
- the “substance having oxidizing ability” in the present specification is as described above.
- Substances that can oxidize methionine and tryptophan, which are sometimes contained in air in various pharmaceutical manufacturing facilities, are interesting.
- the definition of the PTH related substance as described above can be applied even when the PTH peptide contained as an active ingredient is other than human PTH (1-34).
- the corresponding related substance 1 ′ can also be expressed as human PTH (1-84) -Met8 [O] -Met18 [O] -Trp23 [dioxide].
- the 8th and 18th methionine residues of human PTH (1-84) are methionine sulfoxide residues
- the 23th tryptophan residue is a Trp23 oxidized (a) residue
- the other structure is human.
- PTH analogs that are identical to PTH (1-84) can be specified.
- PTH-related substances in PTH-containing lyophilized preparations are prepared by dissolving the preparations in an appropriate solvent (such as a phosphate buffer containing benzalkonium chloride).
- an appropriate solvent such as a phosphate buffer containing benzalkonium chloride.
- the sample can be detected or quantified, for example, by subjecting the sample to HPLC under the following conditions.
- Detector UV absorption photometer (measurement wavelength: 214 nm)
- Column A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm is filled with 3.5 ⁇ m of octadecylsilylated silica gel for liquid chromatography (Zorbax 300SB-C18 manufactured by Agilent Technologies, or equivalent).
- Mobile phase Mobile phase A: 28.4 g of anhydrous sodium sulfate is dissolved in 900 mL of water, phosphoric acid is added to adjust the pH to 2.3, and then water is added to 1000 mL. Add 100 mL of acetonitrile to 900 mL of this solution.
- Mobile phase B 28.4 g of anhydrous sodium sulfate is dissolved in 900 mL of water, phosphoric acid is added to adjust the pH to 2.3, and then water is added to make 1000 mL. Add 500 mL of acetonitrile to 500 mL of this solution.
- the measurement wavelength is not particularly limited as long as it can detect PTH peptides and PTH-related substances. For example, if one or more wavelengths in the range of 210 to 360 nm, preferably 210 to 280 nm, more preferably 210 to 254 nm are selected. Good. An example of a suitable wavelength is 214 nm. It is possible to create a chromatogram based on the measured value of the ultraviolet absorption.
- the amount of PTH related substance and the amount of PTH peptide based on the chromatogram obtained by carrying out the above HPLC can be obtained by calculating each peak area on the chromatogram (for example, by an automatic integration method). it can. And based on the said calculated value, each PTH related substance amount (%) and total PTH related substance amount (%) can be quantified and compared by the following formulas 1 and 2, respectively.
- the “total peak area” in the formula is a value obtained by adding the peak area of the PTH peptide on the above chromatogram and the peak areas of all other PTH related substances detected. Therefore, the “total peak area” corresponds to “the sum of the PTH peptide amount and the total PTH related substance amount”. Further, unless otherwise specified in the present invention, “%” has the meaning of the following formula.
- PTH peptide-containing lyophilized preparation means a lyophilized preparation containing a PTH peptide as an active ingredient.
- the amount of a certain PTH related substance in the preparation is 1.0% or less with respect to “the sum of the PTH peptide amount and the total PTH related substance amount”, and / or The total amount of PTH related substances in the preparation is also a PTH peptide-containing lyophilized preparation that is 5.0% or less with respect to “the sum of the PTH peptide amount and the total PTH related substance amount”.
- the amount of each PTH related substance in the preparation is 1.0% or less with respect to “the sum of the PTH peptide amount and the total PTH related substance amount”. And / or a PTH peptide-containing freeze-dried preparation in which the total amount of PTH related substances in the preparation is 5.0% or less with respect to the “sum of the amount of PTH peptides and the total amount of PTH related substances”.
- the PTH-related substance may not be contained in the PTH peptide-containing lyophilized preparation of the present invention at all, or may be contained in the% or less. It means that there is also.
- At least one or more PTH analogs are not contained in excess of 1.0% with respect to the “sum of the PTH peptide amount and the total PTH analog amount”.
- not all PTH related substances are contained in excess of 1.0% with respect to “the sum of the PTH peptide amount and the total PTH related substance amount”.
- the single peak is regarded as one related substance. More preferably, the amount is not more than 1.0% with respect to “the sum of the amount and the total amount of PTH related substances”.
- the amount of each PTH related substance in the preparation is preferably “1.0% or less”, but 0.9% or less, 0.8% or less, 0.7% or less, or 0.6% or less. Even if it exists, it is preferable. Further, the total amount of PTH-related substances is preferably “5.0% or less”, but may be 4.5% or less, 4.0% or less, 3.5% or less, or 3.0% or less.
- Table 4 below also illustrates preferred PTH peptide-containing lyophilized preparations of the present invention.
- the “total amount of PTHs” in the table means “the sum of the amount of PTH peptide and the amount of all PTH related substances”.)
- the PTH peptide-containing lyophilized preparation of the present invention will be further described.
- the PTH peptide-containing lyophilized preparation of the present invention can contain various additives. Examples of the additive include saccharides, amino acids, and sodium chloride.
- saccharides When saccharides are used as additives, mannitol, glucose, sorbitol, inositol, sucrose, maltose, lactose, and trehalose are added as saccharides in an amount of 1 weight or more (preferably 50 to 1000 weights) relative to 1 weight of the PTH peptide. It is preferable. When saccharide and sodium chloride are used as additives, it is preferable to add 1/1000 to 1/5 weight (preferably 1/100 to 1/10 weight) of sodium chloride with respect to 1 weight of saccharide.
- the container used for the PTH peptide-containing lyophilized preparation of the present invention is not particularly limited, but the preparation is a PTH peptide-containing lyophilized preparation filled in a glass container having a stopper. Is preferred.
- the material of the stopper is not particularly limited, but is preferably made of rubber. It is preferred that the stopper is washed, sterilized and / or dried.
- the freeze-dried preparation containing PTH peptide filled in the glass container having the stopper of the present invention includes, for example, a freeze-dried preparation containing PTH peptide (glass vial preparation) filled in a glass vial having a rubber stopper, and a rubber stopper.
- a kit preparation comprising an ampoule filled with a PTH peptide-containing freeze-dried preparation and an aqueous solution for dissolution aseptically filled in a glass vial, and a kit preparation comprising a prefilled syringe filled with an aseptic solution containing a PTH peptide-containing freeze-dried preparation and an aqueous solution for dissolution
- a glass double-chamber formulation one syringe has two chambers, one chamber contains a PTH-containing lyophilized product, and the other chamber contains an aqueous solution for dissolution.
- the PTH peptide-containing lyophilized preparation of the present invention a glass vial preparation is most preferred.
- the rubber plug material include chlorinated butyl rubber, normal butyl rubber, butadiene rubber, isoprene rubber, silicone rubber, and elastomer. Borosilicate glass is preferred as the glass.
- lyophilized preparation containing PTH peptide is typically produced by a process including all or any of the following steps depending on the use.
- the PTH peptide-containing lyophilized preparation of the present invention can also be produced according to the following steps. That is, the production scheme of the PTH peptide-containing freeze-dried preparation of the present invention includes at least an active ingredient-containing solution preparation step and a freeze-drying step, which will be described below.
- an active ingredient-containing solution preparation step, an aseptic filtration / chemical solution filling step, a carry-in step, a freeze-drying step, and a packaging step are included.
- Active ingredient solution preparation step This step is a step of dissolving the active ingredient drug substance and various additives as required in a solvent (eg, water for injection). Moreover, you may adjust pH of a solution, liquid volume adjustment, etc. as needed.
- the time required for this step is not particularly limited as long as it is within the time allowed for industrial production, but in some cases is 0.5 to 5 hours, usually about 1 to 3 hours.
- the PTH peptide of the present invention When the PTH peptide of the present invention is used as an active ingredient, it is preferable to preliminarily dissolve the PTH peptide drug substance and add it to a solvent in which various additives are dissolved.
- various additives include excipients, stabilizers, solubilizers, antioxidants, soothing agents, tonicity agents, pH adjusters, and preservatives.
- Aseptic filtration / chemical solution filling step This step is suitable for aseptic filtration of the active ingredient-containing solution prepared in the above step and for carrying out the freeze-drying step described below for the sterile filtered solution (chemical solution). Including filling the container.
- Typical aseptic filtration in this process is performed using a filter.
- Various commercially available filters can be used for aseptic filtration.
- the pore size of the filter is preferably 0.2 ⁇ m or less or 0.22 ⁇ m or less.
- specific devices for performing aseptic filtration are well known to those skilled in the art.
- medical solution for manufacturing the lyophilized formulation utilized as a pharmaceutical can be prepared by carrying out aseptic filtration.
- Typical chemical filling in this process is also well known to those skilled in the art.
- the chemical solution after the aseptic filtration of the active ingredient solution is directly filled into individual containers.
- a large amount of solution may be once aseptically filtered at once, and then dispensed into a container suitable for use in the following steps.
- these containers include glass vials that can be stoppered with a rubber stopper or the like. The use of such glass vials is advantageous in the production of glass vial formulations.
- the time required for this step is not particularly limited as long as it is within the time allowed for industrial production, but in some cases, the filtration step is 0.5 to 2 hours, usually 0.5 to 1 hour.
- the filling step is 3 to 10 hours, usually 6 to 10 hours.
- the PTH peptide-containing lyophilized preparation of the present invention is used as a glass vial preparation, for example, 1 g (preferably 0.3 g) of the solution after aseptic filtration containing the PTH peptide is contained in one glass vial. About 3 g, more preferably about 0.5 g to 0.6 g).
- the carrying-in process is a series of transporting (conveying) the filled containers prepared as described above to the freeze-drying means used in the next process, and carrying them into the means. Means the process.
- opening means that the stopper is fully open
- half opening means that the stopper is not opened but not closed.
- the chemical solution can be dried in a vacuum after freezing.
- the product to be manufactured is a glass vial preparation
- the glass vial is filled with a sterile filtrate (medical solution), and then the filled vial is half-plugged with a rubber stopper.
- a step for half-plugging in such a manner is also included in the carrying-in step.
- the freeze-drying means is a means capable of drying a frozen solution under vacuum. It is preferable that the means for industrial production also has a cooling function sufficient to freeze the solution, and a function to appropriately warm the lyophilized product during the treatment in order to promote lyophilization. It is preferable to provide.
- a typical freeze-drying means suitable for industrial production is also referred to as a large door (hereinafter referred to as “large door”) corresponding to almost the entire front surface of the means for carrying the freeze-dried material into the warehouse. ).
- a typical lyophilization means is a lyophilizer (also referred to as a “lyophilizer”), and many forms are commercially available.
- the preparation to be produced is a glass vial preparation
- the drug solution-filled glass vial obtained in the step “2)” is half-capped and lyophilized.
- This process corresponds to this process in which the vials are transported to the means, and each of the vials is sequentially or collectively bundled in a certain quantity unit into the freeze-drying warehouse and arranged. Note that the case of “sequentially carrying in” each of the vials will be described below.
- each vial is continuously filled with a chemical solution by the above-described chemical solution filling step, and then each vial is It is sometimes half-plugged and transported (conveyed) to the freeze-drying means.
- the freeze-drying means since all the vials that can be processed at one time by the freeze-drying means are transferred to the freeze-drying means before the next freeze-drying process is started, they are transported as described above. Each vial that has been received is placed one after another (ie “sequentially loaded”) into the freeze-drying means until it reaches the quantity that can be handled at one time, and is often placed in the means.
- the “loading process” of the present invention starts after the chemical filling process for a certain (first) vial is completed, and together with the (first) vial. This means the process until the last vial to be lyophilized (that is, once) is loaded and placed in the lyophilization means.
- the freeze-drying chamber has a plurality of shelves, and each shelf is filled with a plurality of chemical solutions.
- the shelf can be moved up and down for the convenience of carrying in the medicine-filled vials.
- the “loading process” starts after the chemical filling process for a certain (first) vial is completed, and the last vial to be lyophilized together with the (first) vial is loaded into the lyophilization means. It means a process until it is arranged.
- the drug-filled vial can be left in the half-plugged state before the start of the subsequent lyophilization process and exposed to the air environment in the pharmaceutical manufacturing facility described below. It is.
- the time required for this step is not particularly limited as long as it is within the time allowed for industrial production, but in some cases, it is 3 to 10 hours, usually about 6 to 10 hours.
- Freeze-drying step This is a step of sublimating water from a frozen material to be dried under reduced pressure by the freeze-drying means.
- the vial is opened or semi-opened during decompression (for example, the vial is half stoppered), and the vial gap is replaced with nitrogen at the end of freeze-drying. Can then be sealed.
- the time required for this step varies depending on the ability of the freeze-drying means and the amount of the material to be lyophilized, but may be within the time allowed for industrial production and is usually about 24 to 72 hours.
- Tightening step This step can be included when producing a freeze-dried preparation in a glass vial.
- the glass vial obtained after the freeze-drying process obtained in the step “4)” is wound with an aluminum cap using a press-type cap winder or the like.
- the manufacturing facility When manufacturing a freeze-dried preparation as a pharmaceutical, the manufacturing facility will be required to be a facility compatible with the pharmaceutical GMP.
- the facility is equipped with chemical preparation equipment, sterile filtration equipment and freeze-drying equipment (means), as well as water production equipment for injection, vial filling / plugging equipment, cap tightening, for carrying out the processes described above. Machine, labeler, etc.
- the air environment in the facility for producing the lyophilized preparation containing the PTH peptide of the present invention is also at least equivalent to the air environment in the sterile injection production facility described above, and more preferably, particles having a particle size of 0.3 ⁇ m are 99.
- the environment should be such that clean air that has passed through a HEPA filter having a performance of capturing at an efficiency of 97% or more is maintained as a one-way air flow from the top to the bottom.
- the wind speed of the air current is preferably 0.2 to 1.0 m / s at a position 20 cm directly below the HEPA filter, and preferably 0.1 to 0.8 m / s at the position where the manufacturing work is performed, and 20 cm directly below the HEPA filter. More preferably, the flow rate is 0.4 to 0.7 m / s at the position of 0.3 and 0.5 to 0.5 m / s at the position where the manufacturing work is performed.
- ozone formaldehyde, hydrogen peroxide, peracetic acid, chlorine dioxide, glutaraldehyde
- ozone formaldehyde, hydrogen peroxide, peracetic acid, chlorine dioxide, glutaraldehyde
- the residual formaldehyde concentration after fumigation with formaldehyde should be controlled to 0.1 ppm or less, preferably 0.08 ppm or less.
- ozone it is usually present in the outside air at a concentration of 0.001 to 0.02 ppm as an average daily value. Also, depending on the location, time and season, it may temporarily exist at a concentration of about 0.02 to 0.1 ppm.
- the method for producing a lyophilized preparation containing a PTH peptide is a method for preparing a PTH peptide (active ingredient) -containing solution preparation process, particularly at the end of a chemical solution filling process, in the air environment in the pharmaceutical production facility described above.
- a substantial time elapse is required from when the solution is lyophilized to the start of the freeze-drying process (that is, the carrying-in process)
- the PTH peptide-containing solution is exposed to the air environment in the pharmaceutical manufacturing facility during the process. Characterized by suppression.
- “suppressing exposure to an air environment in a pharmaceutical manufacturing facility” and “suppressing exposure to an air environment in a pharmaceutical manufacturing facility” mean PTH peptide drug substance, PTH peptide-containing solution, PTH peptide lyophilized preparation
- the contact is substantially limited (for example, time and contact amount).
- fluid air an environment where clean air that has passed through the HEPA filter is maintained as a one-way airflow from the top to the bottom
- the air flow of the air in the facility is maintained in a normal pharmaceutical manufacturing facility, a large amount of air that may fall as the air flow comes into contact with the PTH peptide-containing solution, and the oxidation contained in the air flow It can be inferred that the PTH-related substance in the solution is increased due to a cause such as a reactive gaseous substance (such as ozone) reacting with the PTH peptide in the solution.
- a reactive gaseous substance such as ozone
- the means for suppressing contact of the PTH peptide-containing solution with the flowing air in the present invention is not particularly limited.
- means for suppressing the fluidity and flow rate of air around the PTH peptide-containing solution and the PTH peptide-containing solution A means for replacing the periphery with an inert gas can be exemplified.
- a normal lyophilizer has a door for carrying a container filled with a solution to be lyophilized, and the door is a lyophilizer. It is often a door (large door) that can cover the entire front surface of the door, but in the case of the present invention, a part of the large door is a shelf on the shelf (freeze-dried on it)
- a freeze-drying chamber that further includes a small door having a size substantially corresponding to that on which the product-filled container is placed, and that can be easily opened and closed when the container is carried in and out is preferable.
- the freeze-drying cabinet having the small door has an opening for carrying in (hereinafter referred to as “hereinafter,“ It also has a sub-door that can be easily opened and closed provided in the “small door opening”, and means that the sub-door is not opened at all times but is opened only when the container is loaded, and is quickly closed after loading. it can.
- the sub door is divided into two to five so that only a portion necessary for the carry-in can be opened in an area corresponding to the small door opening.
- the auxiliary door which can be opened only at a necessary place at times is preferable, and it is preferably divided into two or three. Examples of secondary doors that can be easily opened and closed include a secondary door with a hinge provided at the top of the secondary door and a small door opening, a secondary door that slides left and right, and a secondary door that slides up and down Is mentioned.
- the preparation equipment (tank or container, etc.) is closed.
- a preferable example is sealing or replacing the inside of the preparation vessel with an inert gas at the time of preparation.
- the inside of the preparation equipment is added when the prepared PTH peptide-containing solution is sterilized by filtration in the aseptic filtration / chemical solution filling step.
- the pressure gas is passed through a sterile filter and sent to a container or tank for filling. In such a case, it is preferable to use an inert gas as the gas for pressurization.
- the air in the chemical solution filling equipment (tank or container, etc.) is previously replaced with an inert gas in the sterile filtration / chemical solution filling step.
- the glass container filled with the PTH peptide-containing solution is replaced with an inert gas in advance.
- the voids (the portion of air that is not a chemical solution) in the glass container filled with the PTH peptide-containing solution are not used.
- a preferable example is substitution with an active gas.
- a glass container filled with a PTH peptide-containing solution may be transported.
- the environment during transport may be brought under an inert gas stream. It can preferably be exemplified as a means for suppressing this.
- a flap for changing the flow of flowing air toward the inside and a wind regulation cover (FIG. 17) can be installed.
- the shape of the flap and the air conditioning cover can be appropriately selected depending on the size of the freeze dryer and the small door opening, and the material thereof may be a vinyl sheet, metal, resin, or the like.
- the suppression of flowing air from the small door opening of the freeze-drying chamber into the freeze-drying chamber means that the contact between the PTH peptide-containing solution and the flowing air is substantially suppressed.
- the inflow is controlled, and the inflow speed of the flowing air from the small door opening is preferably 0.2 m / s or less, more preferably 0.1 m / s or less, particularly preferably 0.0 m / s. It can be controlled to be: The control can be suitably performed by appropriately arranging a flap, a wind regulation cover and the like in the vicinity of the small door.
- the means for replacing the periphery of the PTH peptide-containing solution with an inert gas is a means for replacing the air in the freeze-drying chamber used in the freeze-drying process with the inert gas, in addition to the means for replacing with the inert gas described above.
- it may be a means for causing an inert gas to flow into the freeze-drying chamber from the carry-in port when the PTH peptide-containing solution container is loaded into the freeze-drying chamber used in the freeze-drying step.
- the flow rate of the inert gas when flowing in is preferably 0.1 to 5 Nm 3 / min, more preferably 0.2 to 3 Nm 3 / min, and particularly preferably 0.3 to 1 Nm 3 / min.
- Nitrogen and argon can be illustrated as an inert gas when substituting with the inert gas, preferably nitrogen.
- (B) A step of taking a means for suppressing the PTH peptide-containing solution from coming into contact with the flowing air
- the “means for suppressing the PTH peptide-containing solution from coming into contact with the flowing air” in (A) above is the preparation of the PTH peptide-containing solution. It can be taken in all or part of the steps included from the start of the step to the start of the freeze-drying step of the solution, and may be taken from the start of the PTH peptide-containing solution preparation step.
- the method for producing the lyophilized preparation containing PTH peptide of the present invention as a pharmaceutical comprises the steps of preparing a solution containing PTH peptide, opening the semi-opened glass container into the lyophilizer, or carrying the solution filled in a half-opened glass container, and lyophilizing.
- the above-mentioned means (A) can be taken in part or all of the process of carrying in the solution filled in a glass container that is opened or semi-opened into a freeze-drying warehouse.
- (C) Time of the step of taking a means for suppressing the PTH peptide-containing solution from contacting with flowing air
- the lower limit 1 hour or more, preferably 3 hours or more, more preferably 6 hours or more can be exemplified, and the upper limit is 20 hours or less, preferably 12 hours or less, more preferably 10 hours or less, most preferably Is 9 hours or less.
- Examples of the time for the step (A) include 1 to 20 hours, preferably 3 to 12 hours, more preferably 6 to 10 hours, and most preferably 6 to 9 hours.
- the PTH peptide-containing lyophilized preparation of the present invention can contain a pharmaceutically effective amount of PTH peptide.
- the lyophilized preparation is dissolved in a suitable solvent at the time of use. And can be used for the treatment of osteoporosis.
- the method for inhibiting the production of PTH analogues according to the present invention is at least one of PTH peptide drug substance, PTH peptide-containing solution, and PTH peptide lyophilized preparation.
- a substance having an oxidizing ability in particular, means for suppressing contact with air containing the substance.
- generation of a PTH related substance can be illustrated by substituting the air which contacts a PTH peptide containing solution for the inert gas (preferably nitrogen).
- At least the related substances 1 to 11 or the related substances by means for suppressing contact between the PTH peptide-containing solution and flowing air or by means for replacing the air in contact with the PTH peptide-containing solution with an inert gas (preferably nitrogen).
- an inert gas preferably nitrogen
- Examples thereof include a method for suppressing the production of any one or more PTH-related substances among substances 1 ′ to 11 ′.
- production control methods can be carried out in a freeze-dried preparation manufacturing facility under the air environment in the pharmaceutical manufacturing facility as described above.
- the elapsed time from the start of the PTH peptide-containing solution preparation process to the start of the lyophilization process of the solution is a predetermined time or more, and the solution is prevented from contacting the solution with flowing air in the course of the process.
- These generations can be suppressed.
- the preferable aspect about this means is the same as the preferable specific aspect of the manufacturing method of the corresponding freeze-dried preparation containing PTH peptide of this invention.
- Example 1 About 50 kg of water for injection at about 25 ° C. is placed in a 50 L stainless steel container, and 540 g of purified white sugar and 27 g of sodium chloride are weighed and dissolved therein, and then human PTH (1-34) is 3541 mg as an acetate salt (Lot A; 860 mg). , Lot B; 2591 mg, lot C; 90 mg) were added and dissolved, and then water for injection was added to correct the weight to 27 kg to obtain a PTH peptide-containing aqueous solution. The obtained PTH peptide-containing aqueous solution was aseptically filtered using a filtration filter while applying nitrogen pressure, and liquid-fed to a stainless steel 50 L filling tank filled with nitrogen in advance.
- a sub-door corresponding to the width of the tray provided at the opening when the small door of the freeze-drying chamber is opened (the one similar to the sub-door in FIG. 16 is commercially available. It was attached to the freeze-drying chamber by itself.) After opening the tray and carrying the tray into the freeze-drying chamber, the sub door was quickly closed. The same process was repeated, and the half-opened vial was carried into the freeze-drying chamber over about 9 hours. Freeze the PTH-containing solution and sublimate the water under reduced pressure by vacuum lyophilization. After drying, replace the glass vial with nitrogen, seal with a rubber stopper, tighten with an aluminum cap and freeze with PTH peptide A dry formulation was obtained.
- Example 2 About 20 kg of water for injection at about 25 ° C. is put into a 20 L stainless steel container, and 280 g of purified white sugar and 14 g of sodium chloride are weighed and dissolved therein. Next, water for injection is added to correct the weight to 14 kg, and the additive solution is prepared. Prepared. 1780 mg (lot D) of human PTH (1-34) as an acetate salt was weighed and dissolved in 13 kg of the additive solution to obtain a PTH peptide-containing aqueous solution. The obtained PTH peptide-containing aqueous solution was aseptically filtered using a filtration filter while being pressurized with nitrogen, and fed to a 50 L filling tank filled with nitrogen in advance.
- Example 3 About 19 kg of water for injection at about 25 ° C. was placed in a 30 L stainless steel container, and 460 g of purified sucrose and 23 g of sodium chloride were added and dissolved therein, and then water for injection was added to adjust the weight to 23 kg to prepare a placebo solution. 2979 mg (lot D) of human PTH (1-34) as an acetate salt was weighed and dissolved in 22 kg of the above placebo solution to obtain an aqueous solution containing a PTH peptide. The obtained PTH peptide-containing aqueous solution was aseptically filtered using a filtration filter while being pressurized with nitrogen, and fed to a stainless steel filling tank filled with nitrogen in advance.
- a semi-open vial was obtained using a dry rubber stopper.
- a semi-opened vial is transferred to a Grade A zone and is a freeze-dried chamber (manufactured by ULVAC (type: DFB shelf area: 22 m 2 )) filled with nitrogen in advance, and the small door opening of the freeze-dried chamber is Using a vinyl sheet that changes the flow of flowing air in the opposite direction (the one that conforms to the air-conditioning cover in FIG.
- Example 4 About 50 kg of water for injection at about 25 ° C. is put in a 50 L stainless steel container, and 540 g of purified white sugar and 27 g of sodium chloride are added and dissolved therein, and then 3525 mg (lot C; 1880 mg) of human PTH (1-34) as an acetate salt. , Lot E; 1645 mg) was added and dissolved, and then water for injection was added to correct the weight to 27 kg to obtain a PTH peptide-containing aqueous solution. The obtained PTH peptide-containing aqueous solution was aseptically filtered using a filtration filter while being pressurized with nitrogen, and liquid-fed to a stainless steel 50 L filling tank previously filled with nitrogen.
- the PTH peptide-containing aqueous solution is washed and Fill the dried vial with 0.56g, and use the washed and dried rubber stopper to obtain half-opened vials. About 1000 of them are aligned on a stainless steel tray. The product was transferred to the front of a freeze-dried product made of ULVAC (type: DFB shelf area: 24 m 2 ) previously filled with nitrogen.
- ULVAC type: DFB shelf area: 24 m 2
- a sub-door corresponding to the width of the tray provided at the opening when the small door of the freeze-drying chamber is opened (the one similar to the sub-door in FIG. 16 is commercially available. It was attached to the freeze-drying chamber by itself.) After opening the tray and carrying the tray into the freeze-drying chamber, the sub door was quickly closed. The same process was repeated, and the half-opened vial was carried into the lyophilization cabinet over about 8 hours. Freeze PTH peptide-containing solution and vacuum freeze-dry by sublimating water under reduced pressure. After drying, replace the glass vial with nitrogen, seal with a rubber stopper, tighten with an aluminum cap and freeze with PTH A dry formulation was obtained.
- Example 5 About 18 kg of water for injection at about 25 ° C. is put in a 50 L stainless steel container, 540 g of purified white sugar and 27 g of sodium chloride are added and dissolved therein, and then 3566 mg (lot H) of human PTH (1-34) is added as an acetate salt. Then, water for injection was added to correct the weight to 27 kg to obtain a PTH peptide-containing aqueous solution. The obtained PTH peptide-containing aqueous solution was aseptically filtered using a filtration filter while being pressurized with nitrogen, and liquid-fed to a stainless steel 50 L filling tank previously filled with nitrogen.
- the PTH peptide-containing aqueous solution is washed and Fill the dried vial with 0.56g, and use the washed and dried rubber stopper to obtain half-opened vials. About 1000 of them are aligned on a stainless steel tray. Ltd. ULVAC filled beforehand with nitrogen (type: DFB shelf area: 24m 2) was transferred to pre-lyophilization chamber.
- a sub-door corresponding to the width of the tray provided at the opening when the small door of the freeze-drying chamber is opened (the one similar to the sub-door in FIG. 16 is commercially available. It was attached to the freeze-drying chamber by itself.) After opening the tray and carrying the tray into the freeze-drying chamber, the sub door was quickly closed. The same process was repeated, and the semi-opened vial was carried into the lyophilization cabinet over about 7 hours. Freeze PTH peptide-containing solution and vacuum freeze-dry by sublimating water under reduced pressure. After drying, replace the glass vial with nitrogen, seal with a rubber stopper, tighten with an aluminum cap and freeze with PTH A dry formulation was obtained.
- Test Example 1 As a method for evaluating the purity and the amount of a related substance of a PTH peptide-containing lyophilized preparation, the area percentage method in the HPLC method is simple. Weigh 0.25 g of benzalkonium chloride and add 50 mM sulfate buffer (pH 2.3) to make 50 mL. Each of the preparations of Examples and Comparative Examples is dissolved in 1 mL of physiological saline solution, and the solution and the additive solution mixed at a ratio of 9: 1 are used as a sample solution. 100 ⁇ L of the sample solution was tested by HPLC under the following conditions. In addition, benzalkonium chloride was used for the purpose of preventing the peptide to be measured from being adsorbed to an instrument or the like during the analysis operation.
- Detector UV absorptiometer (measurement wavelength: 214 nm)
- Column A stainless steel tube having an inner diameter of 4.6 mm and a length of 150 mm is packed with 3.5 ⁇ m of octadecylsilylated silica gel.
- Mobile phase A 28.4 g of anhydrous sodium sulfate is dissolved in 900 mL of water, phosphoric acid is added to adjust to pH 2.3, and then water is added to 1000 mL.
- Mobile phase B in which 100 mL of acetonitrile is added to 900 mL of this solution: 28.4 g of anhydrous sodium sulfate is dissolved in 900 mL of water, phosphoric acid is added to adjust to pH 2.3, and then water is added to 1000 mL.
- Transferring mobile phase by adding 500 mL of acetonitrile to 500 mL of this solution Time after injection for controlling the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as follows: Flow rate: 1.0 mL per minute Sample temperature: Constant temperature detection around 5 ° C .: 45 minutes after sample solution injection. However, from the back of the solvent peak.
- Calculation method The amount of related substances of each PTH and the total amount thereof are calculated by performing the liquid chromatography test under the above conditions, measuring each peak area by the automatic integration method, and using the formulas 1 and 2. Quantified.
- the total peak area was the sum of the areas of all peaks detected by conducting a liquid chromatography test under the above conditions. That is, the total peak area represents the sum of the amounts of PTH peptide and all PTH-related substances in the preparation.
- Test Example 2 The structure of each related substance in Table 6 was obtained by estimation according to Test Example 2 below.
- Test Example 2 For the purpose of estimating the structure of each related substance obtained in Test Example 1, a human PTH (1-34) related substance was produced and collected, and an analytical test of the fraction was performed.
- Test Example 1 ⁇ Test conditions> The test conditions were the same as those in Test Example 1 except for the following conditions.
- each related substance (undigested product) and forced degradation solution were analyzed by HPLC, and the retention time of human PTH (1-34) in the forced degradation solution was set to 1. ) Relative retention time was calculated.
- Detector UV absorption photometer (measurement wavelength: 210 nm)
- Column A stainless steel tube having an inner diameter of 1.5 mm and a length of 150 mm is packed with 5 ⁇ m of octadecylsilylated silica gel.
- test conditions were the same as the LC / MS / MS except for the following conditions.
- Mobile phase feeding Time after injection in which the concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows: ⁇ Result> The results of structural analysis of nine related substances in Test Example 2 are shown below.
- ⁇ Related substances 1> In Table 8, the related substance showing relative retention time 0.43 in the column of “related substance (undigested product)” is referred to as related substance 1, and Table 13 shows the mass of related substance 1 (digested product) in LC / MS / MS The measurement results are shown.
- Table 21 shows the results of comparison of the mass obtained by LC / MS of related substance 5 (undigested product) with the theoretical mass of 4115.1309 of human PTH (1-34).
- related substance 5 unigested product
- peaks of +48 Da and +20 Da were confirmed compared to the theoretical mass, and +48 Da was considered to be the main peak from the size of the peak as shown in FIG.
- Table 23 shows the results of comparison of the mass obtained by LC / MS of related substance 6 (undigested product) with the theoretical mass of 4115.1309 of human PTH (1-34).
- related substance 6 (undigested product)
- a peak of +20 Da was confirmed compared with the theoretical mass.
- Table 29 shows the results of comparison of the mass obtained by LC / MS of the related substance 9 (undigested product) with the theoretical mass of 4115.1309 of human PTH (1-34).
- the related substance 9 (undigested product)
- peaks of +32 Da and +4 Da were observed compared to the theoretical mass, and +32 Da was considered to be the main peak as shown in FIG.
- Table 33 shows the relative retention time and estimated structure results of each related substance.
- the oxidation of methionine residues in the table is shown in FIG. 5, and a), b) and c) in the table are shown in FIG.
- the relative retention time of each related substance in the table indicates the relative retention time when the retention time of human PTH (1-34) is 1.
- a lyophilized preparation containing a high-purity PTH peptide is provided, so that the present invention can be used in the pharmaceutical manufacturing industry.
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Abstract
Description
1)類縁物質1:
製剤に含有されたPTHペプチドの質量数より64Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(1-a)~(1-c)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(1-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、
(1-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(1-c) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
2)類縁物質2:
製剤に含有されたPTHペプチドの質量数より36Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(2-a)~(2-c)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(2-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、
(2-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(2-c) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
3)類縁物質3:
製剤に含有されたPTHペプチドの質量数より32Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(3-a)~(3-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(3-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、及び
(3-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da;
4)類縁物質4:
製剤に含有されたPTHペプチドの質量数より48Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(4-a)~(4-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(4-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、及び
(4-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
5)類縁物質5:
製剤に含有されたPTHペプチドの質量数より48Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(5-a)~(5-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(5-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(5-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
6)類縁物質6:
製剤に含有されたPTHペプチドの質量数より20Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(6-a)~(6-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(6-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(6-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
7)類縁物質7:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(7-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(7-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da;
8)類縁物質8:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(8-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(8-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da;
9)類縁物質9:
製剤に含有されたPTHペプチドの質量数より32Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(9-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(9-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
10)類縁物質10:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(10-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(10-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+16Da;又は
11)類縁物質11:
製剤に含有されたPTHペプチドの質量数より4Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(11-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(11-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da、
のうちの少なくとも1種以上である、[1]記載のPTHペプチド含有凍結乾燥製剤。
1)類縁物質1’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が下記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物、
;
2)類縁物質2’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が下記構造式(b)で示される残基に変化した前記PTHペプチドの酸化物、
;
3)類縁物質3’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
4)類縁物質4’:
ヒトPTH(1-34)の8位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
5)類縁物質5’:
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
6)類縁物質6’:
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造(b)で示される残基に変化した前記PTHペプチドの酸化物;
7)類縁物質7’
ヒトPTH(1-34)の8位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
8)類縁物質8’
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
9)類縁物質9’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
10)類縁物質10’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が下記構造式(c-1)又は(c-2)で示されるトリプトファン一酸化物残基に変化した前記PTHペプチドの酸化物;
;又は
11)類縁物質11’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が上記構造式(b)で示される残基に変化した前記PTHペプチドの酸化物、
のうちの少なくとも1種以上である、[1]記載のPTHペプチド含有凍結乾燥製剤。
[14] 前記搬入工程が、凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、[10]に記載のPTHペプチド含有凍結乾燥製剤。
[17] 前記搬入工程が3時間以上にわたる該工程である、[10]乃至[16]のいずれか1つに記載のPTHペプチド含有凍結乾燥製剤。
[21] PTHペプチド含有凍結乾燥製剤の製造方法であって、PTHペプチド含有溶液調製工程の開始から凍結乾燥手段への搬入工程終了の間の1以上の工程においてPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする方法。
[28] 凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、[23]又は[25]に記載の方法。
[30] 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部を有し、更に該開口部に整風カバーを備える凍結乾燥庫であり、それにより前記搬入工程において、該整風カバーが流動空気の流れを庫内に向かわない方向に変えること、並びに凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、[23]又は[25]に記載の方法。
[40] 高純度のPTHペプチドを有効成分として含有する凍結乾燥製剤の製造方法であって、該製造方法は、凍結乾燥前PTHペプチド含有溶液を凍結乾燥手段へ搬入する際に医薬品製造施設内空気環境に対して暴露されるのを抑制したことを特徴とする方法であり、但し前記高純度とは、当該製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量が1.0%以下であり、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量が5.0%以下であることを少なくとも意味し、前記搬入工程は3時間以上にわたる工程であり、且つ前記空気環境はHEPAフィルターを通過した清浄な空気が上から下方に向かって一方向の気流として維持されている環境であり、該HEPAフィルター直下20cmの位置の気流が0.2~1.0m/sの流速気流である、前記製造方法。
類縁物質1量が0.04%以下;
類縁物質3と類縁物質4の合計量が0.11%以下;
類縁物質5の量が0.26%以下;
類縁物質7の量が0.33%以下;
類縁物質8の量が0.21~1.00%から任意に選ばれる百分率以下;及び
類縁物質9の量が0.68%以下
にある、[52]記載のPTHペプチド含有凍結乾燥製剤。
類縁物質1’量が0.04%以下;
類縁物質3’と類縁物質4’の合計量が0.11%以下;
類縁物質5’の量が0.26%以下;
類縁物質7’の量が0.33%以下;
類縁物質8’の量が0.21~1.00%から任意に選ばれる百分率以下;及び
類縁物質9’の量が0.68%以下
にある、[53]記載のPTHペプチド含有凍結乾燥製剤。
本発明において「PTHペプチド」の用語は、天然型のPTH及びその生理学的活性同等物の総称として用いる。PTHの生理学的活性は血清カルシウム上昇作用を有するものとして特徴付けられる。好適なPTHペプチドは、天然型PTHまたはその部分ペプチド類を包含し、分子量約4,000から10,000のペプチド類であってよい。ただしPTHペプチドは、すべての構成アミノ酸残基が天然体と比較して化学修飾されていないものであり、後述する(2)PTH類縁物質を含まないものである。部分ペプチドの具体例としては、34~84個のアミノ酸配列を有するヒトPTH(1-34)、ヒトPTH(1-35)、ヒトPTH(1-36)、ヒトPTH(1-37)、ヒトPTH(1-38)、ヒトPTH(1-84)等があげられる。すなわち、ヒトPTH(1-34)とは、天然型のヒトPTHのアミノ酸番号1~34に対応する当該天然型配列の部分ペプチドである。好適には、ヒトPTH(1-34)、ヒトPTH(1-84)が好ましく、特に好ましくはヒトPTH(1-34)である。ヒト-PTH(1-34)のアミノ酸配列は以下のとおりである:
また、本発明のPTHペプチドは、1種又は2種以上の揮発性有機酸と形成した塩として存在してもよい。揮発性有機酸としては、トリフルオロ酢酸、蟻酸、酢酸などが例示され、好ましくは酢酸を挙げることができるが、それに限定されない。フリー体のPTHペプチドと揮発性有機酸が塩を形成する際の両者の比率も、可能な塩を形成する限りにおいて特に限定されない。例えば、ヒト-PTH(1-34)は、その分子中に9分子の塩基性アミノ酸残基と4分子の酸性アミノ酸残基を有するため、それらの分子内における塩形成を考慮に入れると、塩基性アミノ酸5残基を酢酸の化学当量とすることができる。例えば、酢酸量に酢酸重量×100(%)/ヒト-PTH(1-34)のペプチド重量、で表される酢酸含量を用いれば、一つの理論として、フリー体であるヒト-PTH(1-34)に対する酢酸の化学当量は約7.3%(重量%)となる。本願明細書において、フリー体であるヒト-PTH(1-34)は「テリパラチド」と称され、またテリパラチドの酢酸塩は「テリパラチド酢酸塩」と称されることもある。テリパラチド酢酸塩における酢酸含量は、テリパラチドと酢酸が塩を形成する限りにおいて特に限定されず、例えば、前記の理論化学等量である7.3%以上であってもよく、場合によっては0%を超えれば1%未満でも差し支えない。典型的には、テリパラチド酢酸塩における酢酸含量として、1~7%、好ましくは2~6%が例示され得る。
本発明にける「PTH類縁物質」は、広義には、PTHペプチド含有凍結乾燥製剤由来の試料をHPLCに付した際に、当該クロマトグラム上で有効成分であるPTHペプチドとは異なるピークとして検出されるものとして定義される。従って、当該クロマトグラム上で元来のPTHペプチドと異なる1つのピークとして検出されるならば、そのピーク内において2以上の別個の化学物質が混在している場合でも、当該ピークに含まれる全ての化学物質をまとめて1つの「PTH類縁物質」と見做してよい。つまり、一般的な凍結乾燥製剤の純度確認や測定の目的においては、HPLCのクロマトグラム上で単一ピークとして検出可能な複数の化学物質の混合物も包括的に「類縁物質」ということがあり、且つそのような混合物から成る単一ピークを便宜的に1つの「類縁物質」と見做して純度確認や純度計算等をすることが広く行われているから、本発明においても所与の条件下のHPLCにおいて単一ピークとして検出される複数の化学物質の混合物を包括的して1種の「PTH類縁物質」と見做すことを妨げられない。
上記の表1において、T1~T3は、各類縁物質をトリプシン消化した際に生じる代表的なフラグメントであり、ヒトPTH(1-34)配列のアミノ酸番号に基づき記載すると下記のとおりである。
また、表1において被変化アミノ酸の番号は、対応するヒトPTH(1-34)配列のアミノ酸番号として表記されており、本明細書において特段の断りがない場合は同様の表記である。
また、ヒトPTH(1-34)-Met8[O]-Met18[O]-Trp23[二酸化―ギ酸脱離](類縁物質2’)とは、ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がそれぞれメチオニンスルホキシド残基であり、23位トリプトファンに対応する残基が以下の構造(b)で示される残基(Trp23酸化(b)残基)であり、その他の構造は元のPTHペプチドと同一であるPTH類縁物質を意味する。
同様に、ヒトPTH(1-34)-Met8[O]-Met18[O](類縁物質3’)とは、ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がそれぞれメチオニンスルホキシド残基であり、その他の構造は元のPTHペプチドと同一であるPTH類縁物質を意味する。また、ヒトPTH(1-34)-Met8[O]-Trp23[二酸化](類縁物質4’)とは、ヒトPTH(1-34)の8位メチオニンに対応する残基がメチオニンスルホキシド残基であり、23位トリプトファンに対応する残基がTrp23酸化(a)残基であり、その他の構造は元のPTHペプチドと同一であるPTH類縁物質を意味する。なお、HPLC条件によっては、類縁物質3’と類縁物質4’が単一のピークとして検出され易く、その場合、前記のとおりに当該類縁物質3’と類縁物質4’の混合物としてPTH類縁物質を定義してもよい。
ヒトPTH(1-34)-Trp23[二酸化―ギ酸脱離](類縁物質11’)とは、ヒトPTH(1-34)の23位トリプトファンに対応する残基がTrp23酸化(b)残基であり、その他の構造は元のPTHペプチドと同一であるPTH類縁物質を意味する。なお、HPLC条件によっては、類縁物質10’と類縁物質11’が単一のピークとして検出され易く、その場合、前記のとおりに当該類縁物質10’と類縁物質11’の混合物としてPTH類縁物質が定義できる。
PTH含有凍結乾燥製剤中のPTH類縁物質は、当該製剤を適当な溶媒(塩化ベンザルコニウムを含む燐酸緩衝液など)に溶液して試料を作製し、当該試料を、例えば下記の条件下のHPLCに付すことにより、検出または定量できる。
a)検出器:紫外吸光光度計(測定波長:214nm)
b)カラム:内径4.6mm、長さ150mmのステンレス管に3.5μmの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填(Agilent Technologies社製のZorbax 300SB-C18、又は同等品)
c)カラム温度:40℃付近の一定温度
d)移動相:
移動相A:無水硫酸ナトリウム28.4gを水900mLに溶かし、リン酸を加えてpH2.3に調整した後、水を加えて1000mLとする。この液900mLにアセトニトリル100mLを加える。
各PTH類縁物質量(%)=(各類縁物質のピーク面積/総ピーク面積)×100
<式2>
全PTH類縁物質量(%)=(各類縁物質のピーク面積の総和/総ピーク面積)×100
なお、上記の条件下でHPLCを実施した場合に、前記のとおりヒト-PTH(1-34)から生成する類縁物質3と4(類縁物質3'と4’)は単一のピークとして溶出されてくるが、その場合には当該単一ピークを1つの類縁物質と見做しても製剤の純度確認乃至測定の用に供する際には結果に影響を与えないから、当該類縁物質3と4(類縁物質3'と4’)の混合ピークを1つの類縁物質と見做してもよい。類縁物質10と11(類縁物質10'と11’)についても同様である。
(4) PTHペプチド含有凍結乾燥製剤
本発明のPTHペプチド含有凍結乾燥製剤とはPTHペプチドを有効成分として含有する凍結乾燥製剤を意味する。
本発明のPTHペプチド含有凍結乾燥製剤について更に説明すると、本発明のPTHペプチド含有凍結乾燥製剤は各種添加剤を含有することができる。添加剤として例えば、糖類、アミノ酸、又は塩化ナトリウム等を挙げることができる。添加剤として糖類を用いる場合には、糖類として、マンニトール、グルコース、ソルビトール、イノシトール、シュークロース、マルトース、ラクトース、トレハロースをPTHペプチド1重量に対して1重量以上(好ましくは50~1000重量)添加することが好ましい。添加剤として糖類及び塩化ナトリウムを用いる場合には、糖類1重量に対して1/1000~1/5重量(好ましくは1/100~1/10重量)の塩化ナトリウムを添加することが好ましい。
本発明のPTHペプチド含有凍結乾燥製剤に用いる容器は特に限定されないが、当該製剤は栓を有するガラス容器に充填されたPTHペプチド含有凍結乾燥製剤であることが好ましい。栓の材質は特に限定されないがゴム製が好ましい。栓が洗浄、滅菌、および/または乾燥されていることが好ましい。
凍結乾燥製剤は、その用途により、典型的には以下の工程の全て又はいずれかを含む過程により製造される。特に注記されない限り、本発明のPTHペプチド含有凍結乾燥製剤も以下の工程に準じて製造できる。すなわち、本発明のPTHペプチド含有凍結乾燥製剤の製造スキームは、少なくとも以下で説明する有効成分含有溶液調製工程と凍結乾燥工程を含み、通常は有効成分含有溶液調製工程、搬入工程、および凍結乾燥工程を含み、好ましくは有効成分含有溶液調製工程、無菌ろ過・薬液充填工程、搬入工程、凍結乾燥工程、および包装工程を含む。
本工程は有効成分の原薬と必要により各種添加剤を溶媒(例:注射用水)に溶解させる工程である。また必要に応じて溶解液のpH調整や溶解液の液量調整等を行ってもよい。当該工程の所要時間は、工業生産的に許容される時間内であれば特に限定されないが、場合により0.5~5時間、通常は1~3時間程度である。
本工程は、上記の工程で調製した有効成分含有溶を無菌ろ過すること、及び当該無菌ろ過した液(薬液)を以下で説明する凍結乾燥工程の実施に適した容器に充填することを含む。
充填工程として3~10時間、通常は6~10時間である。
ここでいう搬入工程は、前記のようにして用意された充填後の容器を、次の工程で利用する凍結乾燥手段まで運搬(搬送)し、当該手段内に搬入・配置する一連の工程を意味する。
前記の凍結乾燥手段により、凍結状態の被乾燥物から、減圧下で水を昇華させる工程である。ガラス製バイアル入りの凍結乾燥製剤を製造する場合、減圧中は当該バイアルを開栓又は半開栓状態にして(例えば、バイアルを半打栓しておき)、凍結乾燥の終了時にバイアル空隙を窒素置換した後に封栓することができる。
ガラス製バイアル入りの凍結乾燥製剤を製造する場合に含めることができる工程である。具体的には、例えば、前記「4)」の工程で得られた凍結乾燥処理後のガラス製バイアルをプレス方式のキャップ巻き締め機等でアルミキャップにて巻き締めする工程である。
製剤に対してラベルを添付して紙箱等に包装する工程である。
上記のとおり、本発明者らは、PTHペプチド含有溶液が流動空気と接触することを抑制する手段を講じることにより、PTHペプチド含有溶液中における不純物(PTH類縁物質)の発生も抑制できることを見出した。前記のとおり通常の医薬品製造施設では該施設内空気の気流が維持されているために、該気流として降り注ぐことのある大量の空気がPTHペプチド含有溶液と接触し、そして該気流内に含まれる酸化能を有する気体性物質(オゾン等)が該溶液中のPTHペプチドと反応するなどの原因により溶液中のPTH類縁物質が増大していると推論できる。
上記(A)の「PTHペプチド含有溶液が流動空気と接触することを抑制する手段」は、PTHペプチド含有溶液調製工程開始時から該溶液の凍結乾燥工程開始迄に含まれる工程全てあるいはその一部において講じることができ、PTHペプチド含有溶液調製工程開始時から講じていてもよい。本発明のPTHペプチド含有凍結乾燥製剤の医薬品としての製造方法が、PTHペプチド含有溶液調製工程、凍結乾燥庫への開栓又は半開栓のガラス容器に充填された該溶液の搬入工程、および凍結乾燥工程を含む場合、上記(A)の手段は、凍結乾燥庫への開栓又は半開栓のガラス容器に充填された該溶液の搬入工程の一部又は全部で講じることができる。
上記(A)の「PTHペプチド含有溶液が流動空気と接触することを抑制する手段」を講じる工程の時間として、下限として、1時間以上、好ましくは3時間以上、さらに好ましくは6時間以上を例示することができ、上限として、20時間以下、好ましくは12時間以下、さらに好ましくは10時間以下、最も好ましくは9時間以下である。上記(A)の手段を講じる工程の時間として、例えば、1~20時間、好ましくは3~12時間、さらに好ましくは6~10時間、最も好ましくは6~9時間を挙げることができる。
本発明のPTHペプチド含有凍結乾燥製剤は、医薬的有効量のPTHペプチドを含有することができ、例えば、用時に適当な溶媒で当該凍結乾燥製剤を溶解して注射剤とし、骨粗鬆症治療に用いることができる。
本発明のPTH類縁物質の生成を抑制する方法は、PTHペプチド原薬、PTHペプチド含有溶液、PTHペプチド凍結乾燥製剤の少なくとも1以上と酸化能を有する物質、特に当該物質を含有する空気の接触を抑制する手段を講じる方法である。好ましくは、PTHペプチド含有溶液と接する空気を不活性化ガス(好ましくは窒素)に置換することを手段とする、PTH類縁物質の生成を抑制する方法を例示できる。さらに好ましくは、PTHペプチド含有溶液と流動空気の接触を抑制する手段またはPTHペプチド含有溶液と接する空気を不活性化ガス(好ましくは窒素)に置換する手段による、少なくとも前記類縁物質1乃至11又は類縁物質1’乃至11’のいずれか1以上のPTH類縁物質の生成を抑制する方法を例示することができる。
50Lステンレス容器に約25℃の注射用水約18kgを入れ、そこに秤量した精製白糖540gおよび塩化ナトリウム27gを加えて溶解し、次いでヒトPTH(1-34)を酢酸塩として3541mg(ロットA;860mg、ロットB;2591mg、ロットC;90mg)加えて溶解し、その後、注射用水を加え27kgに重量補正をしてPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を窒素加圧しながらろ過フィルターを用いて無菌ろ過し、あらかじめ窒素を満たしたステンレス製の50L充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有する区域にて、当該無菌ろ過済みPTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得て、その約1000本ずつをステンレス製のトレイに整列させ、整列後のトレイをグレードAの区域で、あらかじめ窒素で満たしたULVAC製(型:DFB 棚面積:24m2)凍結乾燥庫の前まで移送した。窒素で凍結乾燥庫内をパージし続けながら、前記凍結乾燥庫の小扉が開いた際の開口部に設けた、トレイの幅に合わせた副扉(図16の副扉に準ずるものを市販の前記凍結乾燥庫に自作で取り付けた。)を開き、トレイを凍結乾燥庫に搬入した後、速やかに副扉を閉めた。同様の工程を繰り返して半開栓バイアルを約9時間かけて凍結乾燥庫内に搬入した。PTH含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後ガラスバイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTHペプチド含有凍結乾燥製剤を得た。
20Lステンレス容器に約25℃の注射用水約10kgを入れ、そこに秤量した精製白糖280gおよび塩化ナトリウム14gを加えて溶解し、次に注射用水を加えて14kgに重量補正をして添加剤溶液を調製した。ヒトPTH(1-34)を酢酸塩として1780mg(ロットD)量り、前記の添加剤溶液13kgに溶解してPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、あらかじめ窒素を満たした50Lの充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有する区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したガラスバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得て、その約1000本ずつをステンレス製のトレイに整列させ、整列後のトレイをグレードAの区域で、あらかじめ窒素で満たしたULVAC製(型:DFB 棚面積:24m2)凍結乾燥庫の前まで移送した。窒素で凍結乾燥庫内をパージし続けながら、前記凍結乾燥庫の小扉が開いた際の開口部に設けた、トレイの幅に合わせた副扉(図16の副扉に準ずるものを市販の前記凍結乾燥庫に自作で取り付けた。)を開き、トレイを凍結乾燥庫に搬入した後、速やかに副扉を閉めた。同様の工程を繰り返して、半開栓バイアルを約6時間かけて凍結乾燥庫内に搬入した。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後ガラスバイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTHペプチド含有凍結乾燥製剤を得た。
30Lステンレス容器に約25℃の注射用水約19kgを入れ、そこに秤量した精製白糖460gおよび塩化ナトリウム23gを加えて溶解し、次いで注射用水を加え23kgに重量補正をしてプラセボ溶液を調製した。ヒトPTH(1-34)を酢酸塩として2979mg(ロットD)量り、前記のプラセボ溶液22kgに溶解してPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を、窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、あらかじめ窒素を満たしたステンレス製の充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有する区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得た。半開栓バイアルをグレードAの区域を移送し、あらかじめ窒素で満たした凍結乾燥庫(ULVAC製(型:DFB 棚面積:22m2))であり、且つ該凍結乾燥庫の小扉の開口部とは逆の方向に流動空気の流れを変えるビニル製シート(図17の整風カバーに準ずるものを市販の凍結乾燥庫に自作で取り付けた。)を用いて小扉の開口部から凍結乾燥庫内に気流が入らないようにした凍結乾燥庫内に、全てのバイアルを約6時間かけて搬入した。なお、当該流動空気の流れを変えるビニル製シートも、市販の前記凍結乾燥庫に自作で取り付けたものであり、小扉の開口部の上部から斜め下方に向けてビニルシートを張り、上から下に向けて流れる流動空気の方向を変えて開口部から流入することを防いだ。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後バイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTH含有凍結乾燥製剤を得た。
50Lステンレス容器に約25℃の注射用水約18kgを入れ、そこに秤量した精製白糖540gおよび塩化ナトリウム27gを加えて溶解し、次いでヒトPTH(1-34)を酢酸塩として3525mg(ロットC;1880mg、ロットE;1645mg)加えて溶解し、その後、注射用水を加え27kgに重量補正をしてPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を、窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、あらかじめ窒素を満たしたステンレス製の50L充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有し、ホルマリンの濃度を0.08ppm以下とした区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得て、その約1000本ずつをステンレス製のトレイに整列させ、整列後のトレイをグレードAの区域であらかじめ窒素で満たしたULVAC製(型:DFB 棚面積:24m2)凍結乾燥庫の前まで移送した。窒素で凍結乾燥庫内をパージし続けながら、前記凍結乾燥庫の小扉が開いた際の開口部に設けた、トレイの幅に合わせた副扉(図16の副扉に準ずるものを市販の前記凍結乾燥庫に自作で取り付けた。)を開き、トレイを凍結乾燥庫に搬入した後、速やかに副扉を閉めた。同様の工程を繰り返して、半開栓バイアルを約8時間かけて凍結乾燥庫内に搬入した。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後ガラスバイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTH含有凍結乾燥製剤を得た。
50Lステンレス容器に約25℃の注射用水約18kgを入れ、そこに秤量した精製白糖540gおよび塩化ナトリウム27gを加えて溶解し、次いでヒトPTH(1-34)を酢酸塩として3566mg(ロットH)加えて溶解し、その後、注射用水を加え27kgに重量補正をしてPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を、窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、あらかじめ窒素を満たしたステンレス製の50L充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有し、ホルマリンの濃度を0.08ppm以下とした区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得て、その約1000本ずつをステンレス製のトレイに整列させ、整列後のトレイをグレードAの区域であらかじめ窒素で満たしたULVAC製(型:DFB 棚面積:24m2)凍結乾燥庫の前まで移送した。窒素で凍結乾燥庫内をパージし続けながら、前記凍結乾燥庫の小扉が開いた際の開口部に設けた、トレイの幅に合わせた副扉(図16の副扉に準ずるものを市販の前記凍結乾燥庫に自作で取り付けた。)を開き、トレイを凍結乾燥庫に搬入した後、速やかに副扉を閉めた。同様の工程を繰り返して、半開栓バイアルを約7時間かけて凍結乾燥庫内に搬入した。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後ガラスバイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTH含有凍結乾燥製剤を得た。
10Lステンレス容器に約25℃の注射用水約5000gを入れ、そこに秤量した精製白糖120gおよび塩化ナトリウム6gを加えて溶解し、次いでヒトPTH(1-34)を酢酸塩として909mg(ロットF;335mg、ロットG;574mg)加えて溶解し、その後、注射用水を加え6000gに重量補正をしてPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、ステンレス製の充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有する区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得た。半開栓バイアルをグレードAの区域を移送し、小扉を有する凍結乾燥機(ULVAC製(型:DFB 棚面積:22m2))に全体で約4時間かけて順次搬入した。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後バイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTHペプチド含有凍結乾燥製剤を得た。
10Lステンレス容器に約25℃の注射用水約2000gを入れ、そこに秤量した精製白糖100gおよび塩化ナトリウム5gを加えて溶解し、次いでヒトPTH(1-34)を酢酸塩として515mg(ロットD)加えて溶解し、その後、注射用水を加え4000gに重量補正をしてPTHペプチド含有水溶液を得た。得られたPTHペプチド含有水溶液を窒素で加圧しながらろ過フィルターを用いて無菌ろ過し、ステンレス製の5L充てん用タンクに液送した。医薬品製造施設内のグレードA(風速が約0.2~0.4m/s)の環境を有する区域にて、該PTHペプチド含有水溶液を、洗浄・乾燥したバイアルに0.56g充填し、洗浄・乾燥したゴム栓を用いて半開栓バイアルを得た。半開栓バイアルをグレードAの区域を移送し、小扉を有する凍結乾燥機(共和真空技術製(型:RL 棚面積:9m2))に全体で約3時間かけて順次搬入した。PTHペプチド含有溶液を凍結させて減圧下で水を昇華させる真空凍結乾燥を行い、乾燥終了後バイアル中を窒素で置換した後にゴム栓で封栓し、アルミキャップにて巻き締めてPTHペプチド含有凍結乾燥製剤を得た。
PTHペプチド含有凍結乾燥製剤の純度および類縁物質量を評価する手法としては、HPLC法における面積百分率法が簡便である。塩化ベンザルコニウム0.25gを秤量し、50mM硫酸緩衝液(pH2.3)を加えて50mLとしたものを添加液とする。実施例及び、比較例の各々の製剤を生理食塩液1mLで溶解し、さらにその溶解液と添加液を9:1の割合で混合したものを試料溶液とする。試料溶液100μLにつき、以下に示す条件でHPLCにより試験を行った。なお、塩化ベンザルコニウムは、測定対象のペプチドが分析操作中に器具等に吸着するのを防止する目的で使用した。
検出器:紫外吸光光度計(測定波長:214nm)
カラム:内径4.6mm、長さ150mmのステンレス管に3.5μmのオクタデシルシリル化シリカゲルを充填する。
移動相:移動相A:無水硫酸ナトリウム28.4gを水900mLに溶かし、リン酸を加えてpH2.3に調整した後、水を加えて1000mLとする。この液900mLにアセトニトリル100mLを加える
移動相B:無水硫酸ナトリウム28.4gを水900mLに溶かし、リン酸を加えてpH2.3に調整した後、水を加えて1000mLとする。この液500mLにアセトニトリル500mLを加える
移動相の送液:移動相A及び移動相Bの混合比を次のように変えて濃度勾配制御する
注入後の時間:
流量:毎分1.0mL
試料温度:5℃付近の一定温度
検出時間:試料溶液注入後45分間。ただし溶媒ピークの後ろからとする。
式2: 全PTH類縁物質量(%)=(各類縁物質のピーク面積の総和/総ピーク面積)×100
<結果>
実施例で用いたヒト-PTH(1-34)の類縁物質量(原薬)を評価した結果を表6に、HPLCのチャートを図1に示す。また、試験例で実施したPTHペプチド含有凍結乾燥製剤の純度および類縁物質量を評価した結果を表7に示す。また、実施例1のHPLCのチャートを図2に、比較例1のHPLCのチャートを図3に示す。表6中の各類縁物質の構造は下記試験例2による推定により得られた。
[試験例2]
試験例1で得られた各類縁物質の構造を推定することを目的に、ヒトPTH(1-34)類縁物質を生成、分取し、さらに、分取物の分析試験を実施した。
精製白糖4.00gと塩化ナトリウム0.20gを量り、注射用水を加えて溶解し、プラセボ溶液とした。ヒトPTH(1-34)を精密に量り、プラセボ液100mLを加えて溶解し、反応原液とした。縦40cm×横90cm×高さ100cmのガラス戸のついた棚中に、オゾン発生装置およびオゾンを循環させ濃度を均一にする送風機(初期風速が約7.2m/s)を用いて、オゾン濃度計によりオゾン濃度が約0.08ppmとなる環境を作製した。反応原液を容量20mLのバイアルに約15mLずつ分注し、バイアルに撹拌子を入れてスターラーで撹拌しながら、純度が約20%(すなわち、ヒトPTH(1-34)類縁物質総量が80%)となるまで、約0.08ppmのオゾン雰囲気下に曝露(約20時間)し劣化させた。なお、純度の確認は試験例1の試験条件に従った。劣化させた溶液を凍結乾燥し、適当量の注射用水で溶解した溶液を、強制劣化溶液とした。この溶液を用いて、以下に示す条件で類縁物質の分取をおこなった。
下記の条件以外は試験例1の試験条件と同じであった。
カラム:内径9.4mm、長さ250mmのステンレス管に5μmのオクタデシルシリル化シリカゲルを充填する。
なお、上記の条件が試験例1とは異なっていたにも拘らず、クロマトグラムのパターンに大きな差は観察されなかった。
強制劣化溶液中の各類縁物質の相対保持時間とほぼ完全に一致していることを確認した。相対保持時間の結果を表8に、強制劣化溶液のクロマトグラムを図4に示した。図3と図4ではチャージした液の組成が異なるためにヒトPTH(1-34)ピークの溶出時間が微妙に異なるが、各チャートにおける各類縁物質の溶出パターン及び量率が同じであることから図3と図4の対応する類縁物質は同じものであると推察された。これらの結果から、ここでのオゾン曝露試験は、医薬品製造施設内の空気環境化においてPTHペプチド含有溶液を製造する際に誘発されるPTH類縁物質の生成反応を実質的に再現する試験であると考えられた。
(2)各類縁物質の構造推定分析
上記の各類縁物質(未消化品)及びヒトPTH(1-34)標準物質をトリプシンで消化し、類縁物質(消化品)及び標準溶液(消化品)とした。これら10の試料を以下に示す条件でLC/MS/MSで解析した。
検出器:紫外吸光光度計(測定波長:210nm)
カラム:内径1.5mm、長さ150mmのステンレス管に5μmのオクタデシルシリル化シリカゲルを充填する。
移動相:移動相A:トリフルオロ酢酸を含む水混液(1:1000)
移動相B:アセトニトリル
移動相の送液:移動相A及び移動相Bの混合比を次のように変えて濃度勾配制御する
注入後の時間:
流量:毎分0.1mL
試料温度:5℃付近の一定温度
検出時間:試料溶液注入後45分間。ただし溶媒ピークの後ろからとする。
各類縁物質(未消化品)を以下に示す条件でLC/MSで解析した。
下記の条件以外はLC/MS/MSの試験条件と同じであった。
表11にトリプシン消化で生じるヒトPTH(1-34)の予想フラグメントを示した。
標準溶液(消化品)のLC/MS/MSにおいて確認された各フラグメントの質量測定結果を表12に示した。標準溶液(消化品)の各フラグメントの実測値を理論質量と比較し、ヒトPTH(1-34)では推定構造の5つのフラグメントが得られたことが確認された。
<類縁物質1>
表8の「類縁物質(未消化品)」の列で相対保持時間=0.43を示す類縁物質を類縁物質1とし、表13に類縁物質1(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質1(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Da、T3で+4Da、T1で+16Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果を表14に示した。標準溶液(消化品)と比較した結果、T2ではMet18で+16Da、T3ではTrp23で+4Da、T1ではMet8で+16Daの質量変化が確認された。
また類縁物質1(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表15に示した。類縁物質1(未消化品)では、理論質量と比較して+64Da及び+36Daのピークが確認され、図7に示すようにピークの大きさから+64Daがメインピークと考えられた。未消化品の分子量は約4000Daであるが、LC/MSにおいて実測値としては多価イオンの質量が得られるため、多価イオンの質量から未消化品の質量を計算する過程で±1Da程度の誤差が生じることが予想された。構造解析上、誤差が生じていると推定された質量差については( )内に補正した値を記載した。以降の構造解析でも同様に記載した。
MS/MS解析の結果から、ヒトPTH(1-34)+36Da=(Met18+16Da)+(Trp23+4Da)+(Met8+16Da)と推定された。また、Trpにおける+4Da変化体の構造は図6のb)であり、その前駆体a)の質量変化は+32Daであると予想された。トリプシン消化等の操作の過程でTrp23がa)→b)へと変化したと仮定し、類縁物質1(未消化品)のメインピークは、ヒトPTH(1-34)+64Da=(Met18+16Da)+(Trp23+32Da)+(Met8+16Da)と推定された。すなわち、類縁物質1はヒト-PTH(1-34)-Met8[O]-Met18[O]-Trp23[二酸化]であると推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.44を示す類縁物質を類縁物質2とし、表16に類縁物質2(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質2(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Da、T3で+4Da、T1で+16Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果、類縁物質1と同じく、T2ではMet18で+16Da、T3ではTrp23で+4Da、T1ではMet8で+16Daの質量変化が確認された。また類縁物質2(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表17に示した。類縁物質2(未消化品)では、理論質量と比較して+24Da及び+92Daのピークが確認されたが、図8に示したようにほぼピーク形状をなしていないことや、MS/MS解析の結果を支持する質量が得られなかったことから、確認されたこれらの質量の信頼性は低いと考えられた。
MS/MS解析の結果から、類縁物質2は少なくとも、ヒトPTH(1-34)+36Da=(Met18+16Da)+(Trp23+4Da)+(Met8+16Da)の質量変化をしたものであると推定された。すなわち、類縁物質2はヒト-PTH(1-34)-Met8[O]-Met18[O]-Trp23[二酸化―ギ酸脱離]であると推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.46を示すピークは、以下で説明するとおりに類縁物質3及び4の混合物由来のものであった。表18に類縁物質3及び4の混合物(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質3及び4の混合物(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Da、T3で+4Da、T1で+16Daの質量変化が確認された。また、質量変化を伴わないT2及びT3フラグメントも確認された。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果、類縁物質1と同じく、T2ではMet18で+16Da、T3ではTrp23で+4Da、T1ではMet8で+16Daの質量変化が確認された。また類縁物質3及び4の混合物(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表19に示した。類縁物質3及び4の混合物(未消化品)では、理論質量と比較して+32Da、+48Da及び+20Daのピークが確認され、図9に示すようにピークの大きさから+32Da及び+48Daが約1:1の割合でメインピークと考えられた。
類縁物質3及び4の混合物(消化品)のLC/MS/MSクロマトグラムでは、T2+16Da:T2とT3+4Da:T3がそれぞれ約1:1の割合で存在し、T2+16Da:T3+4Da:T1+16Daは約1:1:2の割合で存在していた。従ってMS/MS解析の結果から、ヒトPTH(1-34)+32Da=(Met18+16Da)+(Met8+16Da)、ヒトPTH(1-34)+20Da=(Trp23+4Da)+(Met8+16Da)と推定され、後者に関しては類縁物質1と同じくトリプシン消化等の操作の過程においてTrp23でa)→b)という変化が起きたと仮定し、ヒトPTH(1-34)+48Da=(Trp23+32Da)+(Met8+16Da)と推定された。類縁物質3及び4は、それぞれ、ヒトPTH(1-34)+32Da及びヒトPTH(1-34)+48Daと推定された。すなわち、表8の相対保持時間=0.46のピークは、ヒト-PTH(1-34)-Met8[O]-Met18[O]とヒト-PTH(1-34)-Met8[O]-Trp23[二酸化]を含む混合物のピークと推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.49を示す類縁物質を類縁物質5とし、表20に類縁物質5(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質5(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Da、T3で+4Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果、類縁物質1と同じく、T2ではMet18で+16Da、T3ではTrp23で+4Daの質量変化が確認された。また類縁物質5(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表21に示した。類縁物質5(未消化品)では、理論質量と比較して+48Da及び+20Daのピークが確認され、図10に示すようにピークの大きさから+48Daがメインピークと考えられた。
MS/MS解析の結果から、ヒトPTH(1-34)+20Da=(Met18+16Da)+(Trp23+4Da)と推定された。類縁物質1と同じくトリプシン消化等の操作の過程においてTrp23でa)→b)という変化が起きたと仮定し、類縁物質5(未消化品)のメインピークは、ヒトPTH(1-34)+48Da=(Met18+16Da)+(Trp23+32Da)と推定された。すなわち、類縁物質5はヒト-PTH(1-34)-Met18[O]-Trp23[二酸化]と推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.51を示す類縁物質を類縁物質6とし、表22に類縁物質6(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質6(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Da、T3で+4Daの質量変化が確認された。また、質量変化を伴わないT1フラグメントも確認された。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果、類縁物質1と同じく、T2ではMet18で+16Da、T3ではTrp23で+4Daの質量変化が確認された。また類縁物質6(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表23に示した。類縁物質6(未消化品)では、理論質量と比較して+20Daのピークが確認された。
MS/MS解析の結果から、類縁物質6は、ヒトPTH(1-34)+20Da=(Met18+16Da)+(Trp23+4Da)と推定された。すなわち、類縁物質6はヒト-PTH(1-34)-Met18[O]-Trp23[二酸化―ギ酸脱離]と推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.55を示す類縁物質を類縁物質7とし、表24に類縁物質7(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質7(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T1で+16Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析を行った結果、類縁物質1と同じく、T1ではMet8で+16Daの質量変化が確認された。また類縁物質7(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表25に示した。図12に示すように、類縁物質7(未消化品)では、理論質量と比較して+16Daのピークが確認された。
MS/MS解析の結果から、類縁物質7は、ヒトPTH(1-34)+16Da=(Met8+16Da)と推定された。すなわち、類縁物質7は、ヒト-PTH(1-34)-Met8[O]と推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.62を示す類縁物質を類縁物質8とし、表26に類縁物質8(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質8(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T2で+16Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析を行った結果、類縁物質1と同じく、T2ではMet18で+16Daの質量変化が確認された。また類縁物質8(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表27に示した。図13に示すように、類縁物質8(未消化品)では、理論質量と比較して+16Daのピークが確認された。
MS/MS解析の結果から、類縁物質8は、ヒトPTH(1-34)+16Da=(Met18+16Da)と推定された。すなわち、類縁物質8は、ヒト-PTH(1-34)-Met18[O]と推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.65を示す類縁物質を類縁物質9とし、表28に類縁物質9(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質9(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T3で+4Daの質量変化が確認された。
質量変化が確認されたフラグメントについてMS/MS解析を行った結果、類縁物質1と同じく、T3ではTrp23で+4Daの質量変化が確認された。また類縁物質9(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表29に示した。類縁物質9(未消化品)では、理論質量と比較して+32Da、+4Daのピークが観察され、図14に示すようにピークの大きさから+32Daがメインピークと考えられた。
MS/MS解析の結果から、ヒトPTH(1-34)+4Da=(Trp23+4Da)と推定された。類縁物質1と同じくトリプシン消化等の操作の過程においてTrp23でa)→b)という変化が起きたと仮定し、類縁物質9(未消化品)のメインピークは、ヒトPTH(1-34)+32Da=(Trp23+32Da)と推定された。すなわち、類縁物質9は、ヒト-PTH(1-34)-Trp23[二酸化]と推定された。
表8の「類縁物質(未消化品)」の列で相対保持時間=0.70を示すピークは、以下で説明するとおりに類縁物質10及び11の混合物由来のものであった。表30に類縁物質10及び11の混合物(消化品)のLC/MS/MSにおける質量測定結果を示した。類縁物質10及び11の混合物(消化品)では標準溶液(消化品)の該当フラグメントの実測値と比較して、T3で+16Da及び+4Daの質量変化を別々のフラグメントとして確認した。
質量変化が確認されたフラグメントについてMS/MS解析をおこなった結果を表31に示した。標準溶液(消化品)と比較した結果、一方のT3ではTrp23で+16Daの質量変化が確認された。Trpでの+16Da変化体の構造は図6のc)であると予想された。もう一方のT3では被変化アミノ酸を特定できるデータが得られなかったが、類縁物質1~8の解析結果からTrp23で+4Daの質量変化をしていると推定された。
また類縁物質10及び11の混合物(未消化品)のLC/MSで得られた質量を、ヒトPTH(1-34)の理論質量4115.1309と比較した結果を表32に示した。図15に示すように、類縁物質10及び11の混合物(未消化品)では、理論質量と比較して+16Da、+4Daのピークが観察された。
MS/MS解析の結果から、ヒトPTH(1-34)+16Da=(Trp23+16Da)、ヒトPTH(1-34)+4Da=(Trp23+4Da)と帰属され、表8の「類縁物質(未消化品)」の列で相対保持時間=0.70を示すピークは、類縁物質10及び11の混合物と推定された。すなわち、類縁物質10はヒト-PTH(1-34)-Trp23[一酸化]と、類縁物質11はヒト-PTH(1-34)-Trp23[二酸化―ギ酸脱離]と推定された。
2:小扉
3:副扉(開いた状態)
4:副扉(閉じた状態)
5:整風カバー
Claims (49)
- 高純度のPTHペプチドを有効成分として含有する凍結乾燥製剤であって、但し高純度とは、当該製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量が1.0%以下であり、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量が5.0%以下であることを少なくとも意味し、該凍結乾燥製剤は、凍結乾燥前のPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制したことを特徴とする方法により製造される、前記PTHペプチド含有凍結乾燥製剤。
- 前記PTH類縁物質が、
1)類縁物質1:
製剤に含有されたPTHペプチドの質量数より64Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(1-a)~(1-c)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(1-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、
(1-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(1-c) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
2)類縁物質2:
製剤に含有されたPTHペプチドの質量数より36Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(2-a)~(2-c)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(2-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、
(2-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(2-c) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
3)類縁物質3:
製剤に含有されたPTHペプチドの質量数より32Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(3-a)~(3-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(3-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、及び
(3-b) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da;
4)類縁物質4:
製剤に含有されたPTHペプチドの質量数より48Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(4-a)~(4-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(4-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da、及び
(4-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
5)類縁物質5:
製剤に含有されたPTHペプチドの質量数より48Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(5-a)~(5-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(5-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(5-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
6)類縁物質6:
製剤に含有されたPTHペプチドの質量数より20Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(6-a)~(6-b)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(6-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da、及び
(6-b) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
7)類縁物質7:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(7-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(7-a) Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys(配列番号:1)の質量数+16Da;
8)類縁物質8:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(8-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(8-a) His-Leu-Asn-Ser-Met-Glu-Arg(配列番号:2)の質量数+16Da;
9)類縁物質9:
製剤に含有されたPTHペプチドの質量数より32Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(9-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(9-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da;
10)類縁物質10:
製剤に含有されたPTHペプチドの質量数より16Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(10-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(10-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+16Da;又は
11)類縁物質11:
製剤に含有されたPTHペプチドの質量数より4Da大きな質量数を有し、且つ当該類縁物質をトリプシン消化した際に、以下の(11-a)のフラグメントに対応する消化物を生じる前記PTHペプチドの酸化物、
(11-a) Val-Glu-Trp-Leu-Arg(配列番号:3)の質量数+4Da、
のうちの少なくとも1種以上である、請求項1記載のPTHペプチド含有凍結乾燥製剤。 - 前記PTH類縁物質が、
1)類縁物質1’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が下記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物、
;
2)類縁物質2’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が下記構造式(b)で示される残基に変化した前記PTHペプチドの酸化物、
;
3)類縁物質3’:
ヒトPTH(1-34)の8位および18位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
4)類縁物質4’:
ヒトPTH(1-34)の8位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
5)類縁物質5’:
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
6)類縁物質6’:
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に、並びに23位トリプトファンに対応する残基が上記構造(b)で示される残基に変化した前記PTHペプチドの酸化物;
7)類縁物質7’
ヒトPTH(1-34)の8位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
8)類縁物質8’
ヒトPTH(1-34)の18位メチオニンに対応する残基がメチオニンスルホキシド残基に変化した前記PTHペプチドの酸化物;
9)類縁物質9’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が上記構造式(a)で示される残基に変化した前記PTHペプチドの酸化物;
10)類縁物質10’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が下記構造式(c-1)又は(c-2)で示されるトリプトファン一酸化物残基に変化した前記PTHペプチドの酸化物;
;又は
11)類縁物質11’:
ヒトPTH(1-34)の23位トリプトファンに対応する残基が上記構造式(b)で示される残基に変化した前記PTHペプチドの酸化物、
のうちの少なくとも1種以上である、請求項1記載のPTHペプチド含有凍結乾燥製剤。 - 前記高純度が、製剤中の少なくとも1種以上の上記類縁物質1乃至11の量が該製剤中のPTHペプチド量と全PTH類縁物質量の和に対して1.0%以下であり、及び/又は上記類縁物質量1乃至11の合計量がPTHペプチド量と全PTH類縁物質量の和に対して5.0%以下であることを意味する、請求項2に記載のPTHペプチド含有凍結乾燥製剤。
- 前記高純度が、製剤中の少なくとも1種以上の上記類縁物質1’乃至11’の量が該製剤中のPTHペプチド量と全PTH類縁物質量の和に対して1.0%以下であり、及び/又は上記類縁物質量1’乃至11’の合計量がPTHペプチド量と全PTH類縁物質量の和に対して5.0%以下であることを意味する、請求項3に記載のPTHペプチド含有凍結乾燥製剤。
- 前記PTHペプチドがヒトPTH(1-34)である、請求項1乃至5いずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- PTHペプチド含有凍結乾燥製剤がガラス製バイアルに収容された製剤である、請求項1乃至6のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- 凍結乾燥前のPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露の抑制が、PTHペプチド含有溶液調製工程、無菌濾過工程、薬液充填工程、及び凍結乾燥手段への搬入工程のいずれか1以上の工程で行われることを特徴とする、請求項1乃至7のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- 更に、凍結乾燥後のバイアル封栓工程においても凍結乾燥物が医薬品製造施設内空気環境に暴露されることを抑制することを含む方法により製造されることを特徴とする、請求項8に記載のPTHペプチド含有凍結乾燥製剤。
- 凍結乾燥前のPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露の抑制が、凍結乾燥手段への搬入工程で行われることを特徴とする、請求項1乃至9のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- 前記暴露の抑制が、医薬品製造施設内空気が凍結乾燥手段内へ流入することを抑制する手段が講じられた凍結乾燥庫を用いることで行われることを特徴とする、請求項10に記載のPTHペプチド含有凍結乾燥製剤。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部に備えられた容易に開閉可能な副扉を有する凍結乾燥庫であり、それにより前記搬入工程において、該副扉を容器搬入時のみ開け且つ搬入後は速やかに閉めることで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項11に記載のPTHペプチド含有凍結乾燥製剤。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部を有する凍結乾燥庫であり、医薬品製造施設内空気が凍結乾燥手段内へ流入することを抑制する手段が、流動空気の流れを該開口部から庫内に向かわない方向に変える整風カバーである、請求項11に記載のPTHペプチド含有凍結乾燥製剤。
- 前記搬入工程が、凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項10に記載のPTHペプチド含有凍結乾燥製剤。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部に備えられた容易に開閉可能な副扉を有する凍結乾燥庫であり、それにより前記搬入工程において、該副扉を容器搬入時のみ開け搬入後は速やかに閉めること、並びに凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項10に記載のPTHペプチド含有凍結乾燥製剤。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部を有し、更に該開口部に整風カバーを備える凍結乾燥庫であり、それにより前記搬入工程において、該整風カバーが流動空気の流れを庫内に向かわない方向に変えること、並びに凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項10に記載のPTHペプチド含有凍結乾燥製剤。
- 前記搬入工程が3時間以上にわたる該工程である、請求項10乃至16のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- PTHペプチド含有溶液調製工程の開始から凍結乾燥手段への搬入工程の終了までが3時間以上にわたる、その間の1以上の工程においてPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露が抑制される方法により製造されることを特徴とする、請求項8乃至17のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- 前記不活性ガスが窒素ガスである、請求項14乃至18のいずれか1項に記載のPTHペプチド含有凍結乾燥製剤。
- 高純度のPTHペプチドを有効成分として含有する凍結乾燥製剤であって、該凍結乾燥製剤は、凍結乾燥前PTHペプチド含有溶液を凍結乾燥手段へ搬入する際に医薬品製造施設内空気環境に対して暴露されるのを抑制したことを特徴とする方法で製造され、但し前記高純度とは当該製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量が1.0%以下であり、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量が5.0%以下であることを少なくとも意味し、前記搬入工程は3時間以上にわたる工程であり、且つ前記空気環境はHEPAフィルターを通過した清浄な空気が上から下方に向かって一方向の気流として維持されている環境であり、該HEPAフィルター直下20cmの位置の気流が0.2~1.0m/sの流速気流である、PTHペプチド含有凍結乾燥製剤。
- PTHペプチド含有凍結乾燥製剤の製造方法であって、PTHペプチド含有溶液調製工程の開始から凍結乾燥手段への搬入工程終了の間の1以上の工程においてPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする方法。
- 更に、凍結乾燥後のバイアル封栓工程においても凍結乾燥物が医薬品製造施設内空気環境に暴露されることを抑制することを含む、請求項21に記載の方法。
- 凍結乾燥手段への搬入工程においてPTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項21又は22に記載の方法。
- 前記暴露の抑制が、医薬品製造施設内空気が凍結乾燥手段内へ流入することを抑制する手段が講じられた凍結乾燥庫を用いることを特徴とする、請求項23に記載の方法。
- 凍結乾燥手段への搬入工程が3時間以上にわたる該工程である、請求項23又は24に記載の方法。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を搬出入する際に開く小扉部分に生じる開口部に備えられた容易に開閉可能な副扉を有する凍結乾燥庫であり、それにより前記搬入工程において、該副扉を容器搬入時のみ開け搬入後は速やかに閉めることで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制する、請求項24又は25に記載の方法。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部を有する凍結乾燥庫であり、医薬品製造施設内空気が凍結乾燥手段内へ流入することを抑制する手段が、流動空気の流れを該開口部から庫内に向かわない方向に変える整風カバーである、請求項24又は25に記載の方法。
- 凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項23又は25に記載の方法。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を搬出入する際に開く小扉部分に生じる開口部に備えられた容易に開閉可能な副扉を有する凍結乾燥庫であり、それにより前記搬入工程において、該副扉を溶液容器搬入時のみ開け搬入後に速やかに閉めること、並びに凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項23又は25に記載の方法。
- 前記凍結乾燥手段が、凍結乾燥前PTHペプチド含有溶液を収容する容器を該手段に搬出入する際に開く小扉部分に生じる開口部を有し、更に該開口部に整風カバーを備える凍結乾燥庫であり、それにより前記搬入工程において、該整風カバーが流動空気の流れを庫内に向かわない方向に変えること、並びに凍結乾燥手段内を不活性ガスで置換することで凍結乾燥前PTHペプチド含有溶液の医薬品製造施設内空気環境への暴露を抑制することを特徴とする、請求項23又は25に記載の方法。
- 前記不活性ガスが窒素である、請求項28乃至30のいずれか1項に記載の方法。
- 前記PTHペプチド含有溶液を収容する容器がガラス製バイアルである、請求項21乃至31のいずれか1項に記載の方法。
- 前記PTHがヒトPTH(1-34)である、請求項21乃至32のいずれか1項に記載の方法。
- 医薬品製造施設内空気環境が、1)グレードAの空気であり、2)粒径0.3μmの粒子を99.97%以上の効率で捕らえる性能を有するHEPA フィルターを通過した清浄な空気が上から下方に向かって一方向の気流として維持されており、且つ、3)含有オゾン濃度が0.001~0.1ppmの空気環境である、請求項21乃至33のいずれか1項に記載の方法。
- 医薬品製造施設内空気環境が、含有ホルムアルデヒド濃度0.1ppm以下の空気環境である、請求項21乃至34のいずれか1項に記載の方法。
- PTHペプチド含有凍結乾燥製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量を1.0%以下とし、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量を5.0%以下とするための、請求項21乃至35のいずれか1項に記載の方法。
- 請求項2に記載のPTH類縁物質1乃至11の生成を抑制するための、請求項21乃至36のいずれか1項に記載の方法。
- 請求項3に記載のPTH類縁物質1’乃至11’の生成を抑制するための、請求項21乃至36のいずれか1項に記載の方法。
- 請求項21~38のいずれか1項に記載の方法により製造された、PTHペプチド含有凍結乾燥製剤。
- 高純度のPTHペプチドを有効成分として含有する凍結乾燥製剤の製造方法であって、該製造方法は、凍結乾燥前PTHペプチド含有溶液を凍結乾燥手段へ搬入する際に医薬品製造施設内空気環境に対して暴露されるのを抑制したことを特徴とする方法であり、但し前記高純度とは、当該製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量が1.0%以下であり、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量が5.0%以下であることを少なくとも意味し、前記搬入工程は3時間以上にわたる工程であり、且つ前記空気環境はHEPAフィルターを通過した清浄な空気が上から下方に向かって一方向の気流として維持されている環境であり、該HEPAフィルター直下20cmの位置の気流が0.2~1.0m/sの流速気流である、前記製造方法。
- PTHペプチド含有凍結乾燥製剤の検査方法であって、該方法は、該PTHペプチド含有凍結乾燥製剤中における請求項2に記載のPTH類縁物質1乃至11の少なくとも1種以上の存在を確認、及び/又は存在量を定量することを特徴とする方法。
- PTHペプチド含有凍結乾燥製剤の検査方法であって、該方法は、該PTHペプチド含有凍結乾燥製剤中における請求項3に記載のPTH類縁物質1’乃至11’の少なくとも1種以上の存在を確認、及び/又は存在量を定量することを特徴とする方法。
- 前記PTH類縁物質の定量が、PTHペプチド含有凍結乾燥製剤に由来する試料を高速液体クロマトグラフィーに付して紫外部吸収を測定した際のクロマトグラム上における前記PTH類縁物質に相当するピークの面積を計算することを含む、請求項41又は42に記載の方法。
- PTHペプチド含有凍結乾燥製剤に由来する試料を高速液体クロマトグラフィーに付して紫外部吸収を測定した際のクロマトグラム上における前記PTH類縁体に相当するピークの面積と、同一クロマトグラム上におけるPTHペプチドに相当するピーク面積或いはPTHペプチドのピーク面積とそれ以外に検出された全てのPTH類縁物質のピーク面積の和を比較することで当該PTHペプチド含有凍結乾燥製剤中のPTHペプチドの純度を算出することを含む、請求項43に記載の方法。
- 前記クロマトグラム上で前記PTH類縁物質のいずれか2種以上が1又は2以上の単一ピークとして検出されるクロマトグラフィー条件を適用した場合において、当該ピークの面積と、同一クロマトグラム上におけるPTHペプチドに相当するピーク面積或いはPTHペプチドのピーク面積とそれ以外に検出された全てのPTH類縁物質のピーク面積の和を比較することで当該PTHペプチド含有凍結乾燥製剤中のPTHペプチドの純度を算出することを含む、請求項44に記載の方法。
- PTHペプチド含有凍結乾燥製剤中のPTHペプチド量と全PTH類縁物質量の和に対する少なくとも1種のPTH類縁物質の量が1.0%以下、及び/又はPTHペプチド量と全PTH類縁物質量の和に対する全PTH類縁物質量が5.0%以下であることを保証するための、請求項41乃至45のいずれか1項に記載の方法。
- 更に、高速液体クロマトグラフィー質量分析計を用いて前記PTH類縁物質の質量数を検出することを含む、請求項41乃至46のいずれか1項に記載の方法。
- 更に、前記クロマトグラム上で単一ピークを与える物質を分取し、当該物質をトリプシン消化して生じるフラグメントの質量数を同定することを含む、請求項41乃至47のいずれか1項に記載の方法。
- 請求項41乃至48のいずれか1項に記載の検査方法を実施する工程を含む、PTHペプチド含有凍結乾燥製剤から成る医薬品の製造方法。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019059302A1 (ja) | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
WO2019059303A1 (ja) | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | 薬物動態及び/又は安全性に優れるテリパラチド含有液状医薬組成物 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150116467A (ko) * | 2011-06-07 | 2015-10-15 | 아사히 가세이 파마 가부시키가이샤 | 고순도 pth 함유 동결 건조 제제 및 그의 제조 방법 |
US9919939B2 (en) | 2011-12-06 | 2018-03-20 | Delta Faucet Company | Ozone distribution in a faucet |
US11458214B2 (en) | 2015-12-21 | 2022-10-04 | Delta Faucet Company | Fluid delivery system including a disinfectant device |
KR102606317B1 (ko) | 2016-06-02 | 2023-11-23 | 에스케이온 주식회사 | 리튬 이차 전지용 음극 활물질, 이를 포함하는 음극 및 리튬 이차 전지 |
CN110917150A (zh) * | 2019-12-31 | 2020-03-27 | 北京博康健基因科技有限公司 | 一种pth冻干制剂及其制备方法 |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6360904A (ja) | 1986-08-29 | 1988-03-17 | Yoshiaki Matsuo | 農作物等植物栽培用生育促進補助水 |
JPS6416799A (en) | 1987-07-10 | 1989-01-20 | Toyo Jozo Kk | H-pth (1-34) composition and its preparation |
JPH02111A (ja) | 1987-08-03 | 1990-01-05 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド製剤 |
JPH05306235A (ja) | 1991-12-09 | 1993-11-19 | Asahi Chem Ind Co Ltd | パラサイロイドホルモン類の安定化組成物 |
JPH0873376A (ja) | 1994-09-07 | 1996-03-19 | Asahi Chem Ind Co Ltd | 骨粗鬆症治療薬 |
JPH09506869A (ja) * | 1993-12-23 | 1997-07-08 | アレリックス・バイオファーマスーティカルス・インコーポレーテッド | 副甲状腺ホルモン製剤 |
WO2000010596A1 (en) | 1998-08-19 | 2000-03-02 | Eli Lilly And Company | Method of increasing bone toughness and stiffness and reducing fractures |
WO2002002136A1 (fr) | 2000-06-30 | 2002-01-10 | Suntory Limited | Constituants medicinaux comportant de l'hormone parathyroidienne humaine et compositions medicinales pour l'administration nasale contenant lesdits constituants |
JP2002512973A (ja) * | 1998-04-28 | 2002-05-08 | エヌピーエス アレリックス コーポレーション | タンパク質製剤 |
JP2003095974A (ja) | 2001-09-27 | 2003-04-03 | Asahi Kasei Corp | 骨形成を安全に促進させる医薬複合剤 |
WO2010030670A2 (en) | 2008-09-10 | 2010-03-18 | Genentech, Inc. | Compositions and methods for the prevention of oxidative degradation of proteins |
JP2010509563A (ja) * | 2006-11-07 | 2010-03-25 | アイエムエイ エドワーズ インコーポレイテッド | 凍結乾燥機のバリアシステム |
JP2010216664A (ja) * | 2009-03-12 | 2010-09-30 | Ulvac Japan Ltd | 凍結真空乾燥装置 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK137287B (da) | 1970-08-25 | 1978-02-13 | Atlas As | Frysetørringsapparat. |
JPS5568572A (en) | 1978-11-16 | 1980-05-23 | Ishikawajima Harima Heavy Ind | Method of and apparatus for drying waterrcontaining article having oxidizability |
JPS55112980A (en) | 1979-02-26 | 1980-09-01 | Nippon Oxygen Co Ltd | Freezing drier |
JPS5671931A (en) | 1979-11-19 | 1981-06-15 | Canon Inc | Film formation |
JPS6267099A (ja) * | 1985-09-19 | 1987-03-26 | Toyo Jozo Co Ltd | 〔Nleb,21,〕−r−PTH(1−34)ペプチド誘導体 |
JPH0116799Y2 (ja) | 1986-02-05 | 1989-05-17 | ||
JPS6360940A (ja) | 1986-09-01 | 1988-03-17 | Toyo Jozo Co Ltd | 白内障の予防または治療剤 |
US5059587A (en) | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
JPH0532696A (ja) * | 1990-09-28 | 1993-02-09 | Takeda Chem Ind Ltd | 副甲状腺ホルモン誘導体 |
US5208041A (en) * | 1991-05-23 | 1993-05-04 | Allelix Biopharmaceuticals Inc. | Essentially pure human parathyroid hormone |
CA2123430C (en) * | 1991-12-06 | 2004-02-10 | Cornelia M. Gorman | Prohormone convertase transformed cells |
WO1993011785A1 (en) | 1991-12-09 | 1993-06-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
DE19538687A1 (de) | 1995-10-17 | 1997-04-24 | Boehringer Mannheim Gmbh | Stabile pharmazeutische Darreichungsformen enthaltend Parathormon |
WO2001021198A1 (en) * | 1999-09-20 | 2001-03-29 | Eli Lilly And Company | Method for reducing the risk of cancer |
HU229310B1 (en) * | 1999-10-29 | 2013-10-28 | Nektar Therapeutics | Dry powder compositions having improved dispersivity |
US6838264B2 (en) * | 2000-12-05 | 2005-01-04 | Immutopics, Inc. | Antibodies and peptide antigens for producing antibodies having a selective binding specificity to bioactive intact parathyroid hormone (PTH) 1-84 |
BRPI0509788A (pt) * | 2004-05-13 | 2007-10-23 | Alza Corp | aparato e método para liberação transdérmica de agentes de hormÈnio paratireóides |
PE20061107A1 (es) | 2005-03-14 | 2006-12-08 | Wyeth Corp | Composiciones de tigeciclina y metodos para su preparacion |
WO2007095288A2 (en) * | 2006-02-13 | 2007-08-23 | Nektar Therapeutics | Methionine-containing protein or peptide compositions and methods of making and using |
CN1861790A (zh) * | 2006-04-25 | 2006-11-15 | 华东理工大学 | 重组人甲状旁腺激素1-84的制备方法 |
SI2034951T1 (sl) * | 2006-06-22 | 2013-06-28 | Biocompatibles Uk Limited | Rehidrirajoč farmacevtski proizvod |
UA98776C2 (ru) * | 2006-10-03 | 2012-06-25 | Радиус Хелс, Инк. | СПОСОБ ДОСТАВКИ лекарственного ПРЕПАРАТА ДЛЯ УСИЛЕНИЯ СИНТЕЗА БЕЛКА В КОСТЯХ |
EP2106788A1 (en) | 2008-04-04 | 2009-10-07 | Ipsen Pharma | Liquid and freeze dried formulations |
JP5568572B2 (ja) | 2008-11-18 | 2014-08-06 | バル・ラヴィ・クリシュナン | 固体有機材料を炭素または活性炭に変換するための方法および装置 |
KR20150116467A (ko) * | 2011-06-07 | 2015-10-15 | 아사히 가세이 파마 가부시키가이샤 | 고순도 pth 함유 동결 건조 제제 및 그의 제조 방법 |
JP6416799B2 (ja) | 2016-01-19 | 2018-10-31 | 株式会社ユニバーサルエンターテインメント | 遊技機 |
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Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6360904A (ja) | 1986-08-29 | 1988-03-17 | Yoshiaki Matsuo | 農作物等植物栽培用生育促進補助水 |
JPS6416799A (en) | 1987-07-10 | 1989-01-20 | Toyo Jozo Kk | H-pth (1-34) composition and its preparation |
JPH02111A (ja) | 1987-08-03 | 1990-01-05 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド製剤 |
JPH05306235A (ja) | 1991-12-09 | 1993-11-19 | Asahi Chem Ind Co Ltd | パラサイロイドホルモン類の安定化組成物 |
JPH09506869A (ja) * | 1993-12-23 | 1997-07-08 | アレリックス・バイオファーマスーティカルス・インコーポレーテッド | 副甲状腺ホルモン製剤 |
JPH0873376A (ja) | 1994-09-07 | 1996-03-19 | Asahi Chem Ind Co Ltd | 骨粗鬆症治療薬 |
JP2002512973A (ja) * | 1998-04-28 | 2002-05-08 | エヌピーエス アレリックス コーポレーション | タンパク質製剤 |
WO2000010596A1 (en) | 1998-08-19 | 2000-03-02 | Eli Lilly And Company | Method of increasing bone toughness and stiffness and reducing fractures |
WO2002002136A1 (fr) | 2000-06-30 | 2002-01-10 | Suntory Limited | Constituants medicinaux comportant de l'hormone parathyroidienne humaine et compositions medicinales pour l'administration nasale contenant lesdits constituants |
JP2003095974A (ja) | 2001-09-27 | 2003-04-03 | Asahi Kasei Corp | 骨形成を安全に促進させる医薬複合剤 |
JP2010509563A (ja) * | 2006-11-07 | 2010-03-25 | アイエムエイ エドワーズ インコーポレイテッド | 凍結乾燥機のバリアシステム |
WO2010030670A2 (en) | 2008-09-10 | 2010-03-18 | Genentech, Inc. | Compositions and methods for the prevention of oxidative degradation of proteins |
JP2010216664A (ja) * | 2009-03-12 | 2010-09-30 | Ulvac Japan Ltd | 凍結真空乾燥装置 |
Non-Patent Citations (6)
Title |
---|
ADVANCES IN ENZYMOLOGY, vol. 32, 1969, pages 221 - 296 |
CURRENT OSTEOPOROSIS REPORTS, vol. 6, 2008, pages 12 - 16 |
J. BIOL. CHEM., vol. 266, 1991, pages 2831 - 2835 |
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 98, no. 12, 2009, pages 4485 - 4500 |
M. TAKEI ET AL., PEPTIDE CHEMISTRY, 1980, pages 187 - 192 |
See also references of EP2719393A4 * |
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WO2019059303A1 (ja) | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | 薬物動態及び/又は安全性に優れるテリパラチド含有液状医薬組成物 |
JP2019065042A (ja) * | 2017-09-22 | 2019-04-25 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
JP2019073543A (ja) * | 2017-09-22 | 2019-05-16 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
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