WO2005065705A1 - カルシトニン類のプレフィルドシリンジ製剤 - Google Patents
カルシトニン類のプレフィルドシリンジ製剤 Download PDFInfo
- Publication number
- WO2005065705A1 WO2005065705A1 PCT/JP2003/016940 JP0316940W WO2005065705A1 WO 2005065705 A1 WO2005065705 A1 WO 2005065705A1 JP 0316940 W JP0316940 W JP 0316940W WO 2005065705 A1 WO2005065705 A1 WO 2005065705A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- calcitonin
- sterilization
- sterilized
- preparation according
- syringe
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a prefilled syringe preparation filled with calcitonin, and more particularly, to a sterile calcitonin preparation which assures sterility and which is clear and calcitonin does not adhere to a container, and its production.
- BACKGROUND ART Calcitonin is a peptide hormone related to blood calcium concentration, and is a medicament used for treatment of hypertensive lucidemia, bone pageet disease or osteoporosis, or amelioration of pain in osteoporosis.
- calcitonins are degraded by digestive juices in the gastrointestinal tract and cannot be administered orally, they are generally administered by injection. However, it is known that calcitonin easily adheres to the container wall surface, and that adhesion to the outer wall is promoted by external factors such as shaking. As a result, the content of calcitonins in the pharmaceutical solution may decrease, and the expected effect may not be obtained.
- glass has been used for injection containers because of its poor reactivity and the property of shielding from the outside.
- glass is heavy and it is inconvenient to transport it.
- the glass may be damaged by impact during manufacturing or transportation, and foreign matter such as glass fragments may be mixed during cutting.
- injection containers using a lightweight and less breakable resinous base material have been developed and used.
- containers for injections must be sterilized by their nature, and sterilization methods such as heat sterilization, steam sterilization, gas sterilization, and gamma-ray sterilization are generally performed.
- sterilization methods such as heat sterilization, steam sterilization, gas sterilization, and gamma-ray sterilization are generally performed.
- resin containers have poor heat resistance due to their properties, so heat sterilization may cause deterioration, deformation and breakage of the containers.
- a stable calcitonin preparation can be obtained by filling a sterilized calcitonin into a container which has been steam-sterilized in advance (Japanese Patent Application Laid-Open No. 200-303). 1 1 3 1 1 2).
- the container to be sterilized is placed in a sterilization room, the environment is filled with steam, and the operation is performed at 80 to 120 ° C for about 180 minutes. It is everywhere.
- calcitonins are peptides and are very sensitive to temperature, they must be completely brought to room temperature before they can be filled into steam-sterilized containers. In addition, there is a possibility that water droplets may adhere to the container, which may cause problems. Disclosure of the invention
- the present inventor has conducted various studies to solve the above-mentioned problems relating to injectables of calcitonin, and as a result of adopting sterilization by gas or gamma ray as a method of sterilizing an injection cylinder for filling calcitocinin, I learned that sterilization of containers became easier and that sterility could be maintained over a long period of time. Then, they found that a highly practical injection of calcitocinins could be obtained by reducing the adsorptivity to the wall surface and filling a sterilized calcitonin solution with a sterilized container, and completed the present invention.
- the present invention was previously sterilized, particularly by gamma sterilization or gas sterilization.
- This is a prefilled syringe preparation in which a syringe is filled with a sterilized calcitonin injection solution, which has reduced adsorbability to the wall surface.
- Calcitonin which is an active ingredient of the injection solution of the present invention, is a polypeptide consisting of 32 amino acids.
- porcine calcitonin derived from bushu porcine calcitonin derived from bushu
- salmon calcitonin derived from salmon and elcatonin (calcitonin obtained by replacing the disulfide bond of calcitonin derived from eel with an ethylene bond) are known in the present invention. Any of them may be used, and human calcitonin obtained by recombination may be used.
- calcitonins are effective in a very small amount. For example, a single dose of about 10 to 160 units of calcitonin may be administered by injection. Therefore, in the calcitonin injection solution of the present invention, calcitonin may be added in an amount of 0.01 to 100,000 units Zm1, and it is 5 to 80 units per prefilled syringe preparation. Is preferred.
- the calcitocinin injection solution used in the present invention is a calcitonin solution (hereinafter, referred to as “adsorption-inhibited calcitonin injection solution”) in which adsorption to the wall surface of a glass or resin injection cylinder is prevented.
- This antiadhesion calcitonin injection solution contains the above calcitonins and an antiadsorption component.
- the anti-adhesion component used here is a compound that is hydrophobically bonded to the wall surface of the syringe to prevent adsorption. More specifically, a compound having a hydrophobic group in the molecule and having a surface-active action, It is an ion-charged protein.
- the former include polyoxyethylene alcohol ether, polyoxyethylene fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester.
- anion-charged protein include: Include gelatin, albumin, polygenin and the like. Also, although economics will decrease, calcitonins can be used as an anti-adsorption component in some cases.
- gelatin among the above-mentioned adsorption preventing components examples include gelatin purified by the Japanese Pharmacopoeia, but are not limited thereto.
- Gelatins as the anti-adsorption component may be used alone or in combination of two or more.
- the gelatin concentration is preferably about 0.01 to 5 O WZV ⁇ , particularly 0.1 to 5 O WZV ⁇ . More preferably, it is about 2.0 ⁇ %.
- albumin examples include those having no antigenicity for humans, and the concentration thereof is preferably about 0.1 to 50 WZV%, particularly about 0.1 to 2.0 WZV%. Is more preferable.
- any solvent can be used as long as it is physiologically acceptable as a solvent for injections.
- any solvent can be used as long as it is physiologically acceptable as a solvent for injections.
- Japanese Pharmacopoeia water for injection, physiological saline and the like can be mentioned.
- the above-mentioned anti-adsorption calcitonin injection solution contains, as necessary, a pH adjuster (hydrochloric acid, sodium hydroxide, etc.), a buffering agent (a citrate, a tartrate, a phosphate, etc.) which is usually used in the injection. Acetate, etc.) and tonicity agents (eg, sodium chloride, glycerin).
- a pH adjuster hydrochloric acid, sodium hydroxide, etc.
- a buffering agent a citrate, a tartrate, a phosphate, etc.
- tonicity agents eg, sodium chloride, glycerin.
- the pH of the above-mentioned injection solution can be appropriately set depending on the type of calcitonin, but is preferably in the range of 2.5 to 8.
- the above-mentioned anti-adsorption calcitonin injection solution is sterilized by filtration sterilization.
- a syringe (syringe) used as a container for filling a calcitonin solution in the present invention is made of glass or resin, and both can be used for the pre-filled syringe formulation of the present invention. Glass and cyclic polyolefin are more preferred.
- the capacity of the syringe may be selected depending on the amount of the drug solution to be filled, and a capacity of about 1 m1 and about 5 m1 is preferably used.
- the above syringes must be sterilized by gamma sterilization or gas sterilization.
- gamma ray sterilization can be performed by a method of irradiating gamma rays with cobalt 60 as a radiation source.
- the irradiation amount of gamma rays in this sterilization may be about 5 to 10 OkGy, preferably 10 to 50 kGy.
- the gas sterilization uses a gas such as ethylene oxide (EOG), formaldehyde, daliside aldehyde, methyl bromide, ozone, hydrogen peroxide gas (VHP), etc., and the shape and material of the container and the gas used for sterilization.
- EOG ethylene oxide
- formaldehyde, daliside aldehyde, methyl bromide, ozone, hydrogen peroxide gas (VHP), etc. ethylene oxide
- VHP hydrogen peroxide gas
- gamma-ray sterilization is preferably used for sterilizing plastic syringes
- gas sterilization is preferably used for glass syringes, especially using EOG gas.
- a sterilization method is employed.
- the prefilled syringe formulation of the present invention obtained as described above can almost completely prevent the problem of calcitonin adsorption on the wall surface, which has been a problem in the prior art.
- the sterilization method of the present invention is simpler than the sterilization method already disclosed, which is advantageous from the viewpoint of cost.
- Elcatonin 0.2 mg (5000 international units mg), sodium chloride 500 mg and gelatin 80 Omg were dissolved in water for injection.
- An appropriate amount of hydrochloric acid was added thereto to adjust the pH to 5.0, and the total amount was adjusted to 5 OmL with water for injection. This was further sterile-filtered using a 0.22 m filter to obtain an L-potency tonin injection.
- the glass syringe was left in a sterilization room at a temperature of 50 :, 20% EG / 80% CO 2 for 12 hours and sterilized with ethylene oxide gas (EG).
- EG ethylene oxide gas
- the glass syringe was filled with the above-mentioned injection solution by ImL to prepare a prefilled syringe.
- a syringe made of a cyclic polyolefin resin was irradiated with gamma rays of 25 kGy using cobalt 60 and sterilized. Each of the sterilized syringes was filled with I mL of an erythrotonin injection solution prepared in the same manner as in Example 1 to obtain a pre-filled syringe.
- Example 3
- the ratio of the peak height means the peak height of elcatonin Z and the peak height of the internal standard.
- a filled syringe formulation was made. Also, for each example or comparative example,
- Example 4 Example 5
- Example 6 Comparative example 1 L-tonin 0 units 0 units 10 units 0 units Adsorption inhibitor
- the syringes prepared in Examples 1 to 3 were stored at 40 ° C. and 75% RH for 6 months. The residual rate was determined when the quantitative value of elcatonin added as an active ingredient at the start of the test was 100%. The results are shown in Table 3.
- Example 4 Yes-100% 83.9% None 100% 78.0%
- Example 5 Yes 100% 94.8% None 100% 81.0%
- Example 6 Yes 100% 91.2% None 100% 79.0% Comparative Example 1 Yes 100% 40.6% None 100% 30.4%
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Medicinal Preparation (AREA)
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP2003/016940 WO2005065705A1 (ja) | 2003-12-26 | 2003-12-26 | カルシトニン類のプレフィルドシリンジ製剤 |
AU2003292649A AU2003292649A1 (en) | 2003-12-26 | 2003-12-26 | Prefilled syringe preparation of calcitonins |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP2003/016940 WO2005065705A1 (ja) | 2003-12-26 | 2003-12-26 | カルシトニン類のプレフィルドシリンジ製剤 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005065705A1 true WO2005065705A1 (ja) | 2005-07-21 |
Family
ID=34746771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2003/016940 WO2005065705A1 (ja) | 2003-12-26 | 2003-12-26 | カルシトニン類のプレフィルドシリンジ製剤 |
Country Status (2)
Country | Link |
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AU (1) | AU2003292649A1 (ja) |
WO (1) | WO2005065705A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008077155A1 (en) * | 2006-12-21 | 2008-06-26 | Genentech, Inc. | Sterilization of objects containing biological molecules |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000044487A (ja) * | 1998-05-29 | 2000-02-15 | Taiyo Yakuhin Kogyo Kk | カルシトニン類のプレフィルドシリンジ製剤 |
JP2002241264A (ja) * | 2001-02-19 | 2002-08-28 | Asahi Kasei Corp | エルカトニンのプレフィルドシリンジ製剤 |
JP2003113112A (ja) * | 2001-10-05 | 2003-04-18 | Asahi Kasei Corp | 無菌カルシトニン製剤及びその製造方法 |
-
2003
- 2003-12-26 AU AU2003292649A patent/AU2003292649A1/en not_active Abandoned
- 2003-12-26 WO PCT/JP2003/016940 patent/WO2005065705A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000044487A (ja) * | 1998-05-29 | 2000-02-15 | Taiyo Yakuhin Kogyo Kk | カルシトニン類のプレフィルドシリンジ製剤 |
JP2002241264A (ja) * | 2001-02-19 | 2002-08-28 | Asahi Kasei Corp | エルカトニンのプレフィルドシリンジ製剤 |
JP2003113112A (ja) * | 2001-10-05 | 2003-04-18 | Asahi Kasei Corp | 無菌カルシトニン製剤及びその製造方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008077155A1 (en) * | 2006-12-21 | 2008-06-26 | Genentech, Inc. | Sterilization of objects containing biological molecules |
Also Published As
Publication number | Publication date |
---|---|
AU2003292649A1 (en) | 2005-08-12 |
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