WO2003002139A1

WO2003002139A1 - Method for improving stability of protein preparation

Info

Publication number: WO2003002139A1
Application number: PCT/JP2002/006599
Authority: WO
Inventors: Kohji Hitomi; Hiroshi Asai
Original assignee: Asahi Kasei Kabushiki Kaisha
Priority date: 2001-06-29
Filing date: 2002-06-28
Publication date: 2003-01-09
Also published as: JP4225416B2; JPWO2003002139A1

Abstract

A method for improving the stability of a protein preparation packed in a container made of a resin which comprises shielding the light to the preparation and/or reducing the contact of the preparation with oxygen. The method allows the improvement of the stability, in particular, the light stability of a protein preparation packed in a container made of a resin.

Description

To improve the stability of porous preparations

[Technical field]

The present invention relates to improving the stability of a protein preparation filled in a resin container. More specifically, the present invention relates to a method for improving the photostability of a protein preparation filled in a resin container, and to a protein preparation stabilized by light by such a method.

book

[Background technology]

In general, there is a problem in that protein preparations are affected by heat, light, and the like during storage for a long period of time, causing degradation such as protein aggregation, denaturation, and a decrease in content due to degradation. To prevent this, formulation additives are added, or lyophilized to form a powdered product without moisture, and stored in a glass or resin container, stored and distributed in the same manner as general products. It is used.

Glass as a container has good airtightness, but is heavy and inconvenient to transport, and may be damaged during manufacturing, transport and use. On the other hand, a resin container compensates for the drawbacks of such a glass container, but in some cases the stability is worse than when the container is filled in a glass container.

[Brief description of drawings]

FIG. 1 shows the light transmittance of the package material of the example of the present invention. [Disclosure of the Invention]

An object of the present invention is to provide a protein preparation having improved stability, particularly light stability, in a resin container.

The present inventors have conducted intensive studies to solve this problem, and as a result, It has been discovered that the cause of reduced photostability in cases is the synergistic effect of oxygen and light, and to minimize the contact with protein preparations, at least by either oxygen or light, to prevent glass containers. The present inventors have found that the same stability as in the case of filling into a container can be ensured, and have reached the present invention.

That is, for example, when the drug to be filled is calcitonin, various studies have been conducted on the formulation filled in a glass container in order to ensure heat stability, light stability and stability against shaking. ing. However, no studies have been conducted to improve the stability of calcitonins in resin containers.

The present inventors have conducted intensive studies to make a formulation containing a composition containing calcitonin as an active ingredient in a resin container more stable and suitable for storage. Calcitonins were found to be less stable to light than calcitonins filled in glass containers. Since there is no significant difference between glass and resin in light transmission I ", the results of diligent studies on the difference in stability of calcitonins filled in containers of each material showed that the difference in stability to light was as follows: It was speculated that this was caused by the difference in oxygen permeability between the glass and the resin.As a result, even when the container made of resin was filled with calcitonin, it was possible to reduce the contact with oxygen. It has been surprisingly found that the stability of the preparation to light can be improved.

In addition, the inventors of the present invention have studied a container for filling calcitons and a film covering the filled container, and as a result, have found that it is possible to further stabilize calcitons by shielding light.

As a result of such studies, the present invention has been made and led to the present invention in which it is possible to improve the photostability of the protein preparation by shading the protein preparation and reducing the contact with oxygen or oxygen. Things. Hereinafter, the present invention will be described in detail.

In the present invention, the protein preparation may be any preparation containing a protein as an active ingredient, and includes not only a preparation containing only a protein but also a preparation containing a composition containing a protein. In the protein preparation of the present invention, the drug to be filled and stored is not particularly limited as long as it is a protein. Proteins, peptides, such as insulin, secretin, oxycytosine, growth hormone, angiotensin, bradykinin; 3-endorphin, substance P, glucagon, dynorphin, somatostatin, thyroid-stimulating hormone (TSH), enkephalin , Neurotensin, interferon, interleukin, G-CSF, daltathione passoxidase, superoxide dismutase (SOD), soluble thrompomodulin, calcitonins, elcatonin, PTH (parathyroid hormone), erythropoietin, etc. And analogs in which one or more amino acids are substituted while retaining their activities, derivatives or salts thereof, etc. The protein such as calcitonin to be filled may be in the form of an aqueous solution or the like. Be, but is not limited to these.

When the drug is an aqueous solution containing calcitonin as an active ingredient, the aqueous solution is not particularly limited as long as it contains an effective amount of calcitonin. For example, an aqueous solution having an appropriate pH is preferable. As a solvent for ensuring an appropriate pH, a known buffer such as a citrate buffer or an acetate buffer can be used.When calcitonin is elcatonin, the pH is preferably 5 to 7, and the pH ~ 6 is more preferred. These concentrations are, for example, preferably at least 0.05 mmol, more preferably at least 0.1 mmol. The upper limit of the concentration is not particularly limited, but is usually 20 mM or less, preferably 1 mM or less. Specifically, it contains one or more compounds selected from the group consisting of monopotassic acid such as acetic acid, lactic acid and L-histidine and Z or a water-soluble salt thereof, and has a concentration of 0.0. Solvent with 5-20 mmol concentration, pH adjusted to 5.0-6.5, and ionic strength adjusted to μ = 0.01-0.5 (JP-A-2-174726); succinic acid, tartar It contains one or more compounds selected from the group consisting of polycarboxylic acids such as acid and dicarboxylic acid and water or a water-soluble salt thereof, and has a concentration of 0.05 to 20 millimonoles, a pH of 5 0 to 6.5, and solvents whose ionic strength is adjusted to μ = 0.01 to 0.5. In addition, sodium hydroxide, hydrochloric acid, or the like can be used to adjust the pH. In addition, additives can be added as needed, including gelatin in a content of 0.01 to 20 wZv%, isotonicity agent, proforce hydrochloride, xylocaine hydrochloride, and penzyl alcohol. Soothing agents such as phenols and phenols, stabilizers, absorption promoters, surfactants such as P preservatives, polysorbates, polyoxyethylene, glycerin, and macrogol can be added. As the concentration of calcitonin, for example, a concentration of 10 units to 80 units / mL can be used.

In the present invention, the resin container filled with the protein may be any of a syringe, a vial, an ampoule and a soft bag.

Examples of the material of the container include polypropylene, polyethylene, cyclic polyolefin, a copolymer of cyclic polyolefin and α-olefin, polyethylene terephthalate, polystyrene, ABS resin, polyester, polyvinyl chloride, nylon, polytetrafluoroethylene, polymethylpentene, 6 Plastics such as fluororesin, polymethyl methacrylate, and polycarbonate can be selected from, but are not limited to.

The protein-filled container is further packaged, if necessary, in a package such as a pillow bag, prister pack, wrap, or box.

The present invention has found that a protein preparation filled in a resin container lacks stability against light, and by shielding the protein preparation from light and reducing contact with oxygen, And a method for stabilizing the protein preparation of the present invention. Any means may be used for light shielding. For example, a container filled with protein (an ampoule, a vial, a syringe, a soft bag, etc.) or a package wrapped around a container filled with protein from outside (a pillow bag, Prister packs, wraps, boxes, etc.) may be made of a material having a light shielding effect.

Any material may be used as long as it has a light-shielding effect.Metal materials, for example, those containing aluminum, a material having a light-shielding effect by coloring, or a material having a light-shielding effect by being thicker Or a combination thereof. Further, the present inventors, when shielding the protein preparation, at least 70% or less, preferably 60% or less, more preferably 50% or less of the transmittance of light having a wavelength of 332ηπι to 400 nm. It has been found that a more stable effluent effect can be obtained by blocking as follows.

Figure 1 shows the absorbance of the packaging material covering the resin container with respect to wavelength. The horizontal axis is wavelength, The vertical axis is the transmittance. All transmittances were measured using a spectrophotometer UV-2500 PC manufactured by Shimadzu Corporation. Figure 1 shows the transmittance for the wavelength of light for each of the five types of packaging materials (1) to (4). Light stability was obtained with all of the packaging materials (1) to (4) when not packed. The stabilizing effects were in the order of (1), (2) and (3). In (1), the transmittance at 332 nm is about 52%, the transmittance at 403 nm is about 70%, and in (2), the transmittance at 332 nm is about 5%, and the transmittance at 403 nm is about 65%. is there. Therefore, in order for the preparation of the present invention to obtain the desired photostability, 332 ηπ! It was found that the transmittance of the light of ~ 403 was required to be 70% or less. -At least wavelength 332 ηπ! Materials that block the light of ~ 403 from 70% or less are, specifically, materials containing aluminum / aluminum (aluminum-deposited film, alumina-deposited film, aluminum foil, etc.), red colored PVC film thickness 500; ζπι, blocking light wavelength 590 nm or less. Sumitomo Becrite; UV 3 red 1-391), orange colored PVC film (thickness 250 111, blocking light wavelength 545 nm or less. Sumitomo Beta Light; VSS-1202 colored), red coloring on cellophane film A light-shielding pillow bag with a PE40 film bonded to a material coated (blocking light wavelengths of 570 nm or less, Hosokawa Yoko Co., Ltd.), a vermilion colorant applied between PET films and nylon And a colored pillow bag with a polyethylene film attached thereto (blocking light at a wavelength of 545 nm or less, Okada Paper Industries Co., Ltd.). Light shielding can be performed by manufacturing a container or a package filled with calcitonin with such a material. Aluminum has the effect of blocking light over all wavelengths. A colored film is more preferable in that the contents can be checked from the outside.

These wavelengths were measured using a spectrophotometer UV-2500PC manufactured by Shimadzu Corporation.

Methods for packaging with these films include, but are not limited to, a method of sealing with heat, a method of sealing with pressure, and a method of sealing with an adhesive.

The present inventors have found that in order to increase the photostability of a protein preparation in a resin container, as described above, in addition to directly blocking the causal light, It has been found that the light stability is improved by reducing the contact with oxygen. For ampoule preparations, when transferring chemicals to injections, etc., the possibility of contamination of microscopic glass fragments and bacterial contamination generated during ampule cutting was pointed out, and the transfer of chemicals to syringes was complicated. Prefilled syringes have been developed due to the possibility of medication errors. The syringe material of the prefilled syringe is preferably made of resin because it is lightweight and hard to break. However, the resin has a light blocking property equivalent to that of glass in blocking light having a wavelength of about 260 nm or less. However, the present inventors have found that when the protein is a calcitonin, the resin formulation is less stable to light than the glass formulation. Therefore, as a result of diligent studies on a method for improving the stability of a resin pre-injected syringe against light, we surprisingly found that it can improve the stability against light by reducing the contact with oxygen. Was found.

The reason why photostability can be obtained by reducing contact with oxygen without blocking light is that the mechanism of photodegradation is as follows. It is presumed that one of the possibilities is that it is going forward.

Usually, proteins are shipped in containers such as ampoules, pierces, syringes, and soft bags. The protein-filled container is further packaged, if necessary, in a package such as a pillow bag, blister pack, wrap (film sticking, etc.), box, or the like.

As a method for reducing the contact between protein and oxygen, there is a method in which the material of the protein-filled container and z or the package for packaging the container is made of a material having a low oxygen permeability.

The material of the package may be any material as long as the oxygen permeability is sufficiently low. For example, aluminum (hereinafter referred to as A1), aluminum alloy, stainless steel, copper, gold, platinum, silver, lead, titanium, etc. Metals and glass, plastics such as polychlorinated vinyl (hereinafter abbreviated as PVC), polyethylene terephthalate (hereinafter abbreviated as PET), polytetrafluoroethylene, hexafluororesin, etc., or silica-deposited on them, or Metal

'Composite materials. Preferably, a material obtained by laminating a PET film on which silica is vapor-deposited and a polyethylene (hereinafter referred to as PE) film, or a composite material obtained by laminating PET, PE, or aluminum foil is used. These forms include, but are not limited to, pillow bags, prestar packs, and wraps.

More specifically, PET12 / zm, PE15 / zm, Al9m, PE40 / xm pillow bags (Kanaye), 重ね 12μπι silica-deposited two-layer films and linear low-density polyethylene (LLDPE) 60 μπι Transparent plastic bag with laminated film and transparent film with UV cut treatment (Okada Paper Industries).

In particular, when the protein is calcitonin, the amount of oxygen permeation is preferably 0.1 cc / m ² -24 h-atm or less. The oxygen permeation was measured by the JIS K7126A method.

Further, as a method for reducing contact with oxygen, the present invention also provides a method of reducing the oxygen permeation of the container itself for filling the protein, in addition to using the packaging material with such a low oxygen permeation material. Included. A method of appropriately selecting the material of the container itself, or a method of bonding the above-mentioned film or the like to the outer surface of the container by an appropriate method may be used.

Further, as a method of reducing the contact with oxygen, there is a method of replacing the inside of the protein preparation container, and the inside of Z or the package with an inert gas. Examples of the inert gas include nitrogen, argon and the like. More preferably, after replacing the inside of the container with an inert gas, it is preferable to use the above-mentioned film having low oxygen permeability as a package in order to prevent re-mixing of oxygen.

Further, instead of replacing the inside of the package with an inert gas, removing the gas inside the package and vacuum-packing it to remove oxygen is also included in the present invention.

Further, as a method of reducing the contact between protein and oxygen, a method of putting an oxygen scavenger in the package is exemplified. The oxygen scavenger to be put into the package is not particularly limited as long as it has an action of absorbing oxygen. For example, a mixture of iron and natural zeolite (Ageless (registered trademark) “Mitsubishi Gas Chemical Co., Ltd.”) or ascorbin Acids and the like.

If the protein is in the form of an aqueous solution, it may affect the photostability in advance in a container filled with the protein, such as a syringe, ampoule, vial, or soft bag. Filling with an aqueous protein solution to the extent that there is no room for oxygen to be mixed is also exemplified as one of the methods for maintaining the state of the contact between the protein and oxygen at a sufficiently small 1 /. Specifically, when the volume of the aqueous protein solution in the container is 1, the volume of the void is 0.2 or less, more preferably 0.1 or less, and further preferably 0. In the present invention, the “void” refers to a void other than the liquid portion remaining in a container body such as a syringe.

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[Example of chemical solution adjustment]

As an example of a preparation example of a calcitonin preparation, an L-potency medicinal solution was prepared as follows. Take about 900 ml of water for injection into a 1 L graduated cylinder that has been cleaned and sterilized, weigh 9 g of reagent grade NaCl, add, and dissolve in the graduated cylinder. -Add 5'ml of 20mM sodium acetate (reagent grade) solution previously dissolved in water for injection, and dissolve and stir. Add about 1 ml of 0.01N-HC1 to the solution and stir to adjust the pH to 5.4-5.6. After adjusting the pH, add water for injection to make the total volume 1 L, and prepare an O.lm sodium acetate buffer.

To the buffer solution, weigh and add the L-tonin park to a concentration of 3.2 μg / ml. After addition, the mixture is stirred and dissolved for 10 minutes to give a 3.2 μg / ml drug solution used in the following Examples and Comparative Examples.

[Example 1]

(1) The chemical solution prepared according to [Example of chemical solution adjustment] is used to make a syringe made of cyclic polyolefin (capacity: 1 ml, light with a wavelength of 260 nm or less, thickness: 1.8 nm, oxygen permeability: 37.5 cc / m ² · 24 h · atm) The syringe was filled with a syringe filling and filling machine so that the volume of the cavity became 0.1 ml, to produce a L-tonin prefilled syringe.

(2) Package: Large enough for a syringe to hold a red-colored PVC film sheet with a thickness of 500 μπι (Sumitomo Beclite UV 3 Red 1-391: a sheet that blocks light with a wavelength of 590 nm or less). Then press-mold it into a blister pack Was. As the lid material, a Tyvek sheet, which is a high-density polyethylene sheet having a high gas-permeability Pacteria Paria property, was used. (Tyvek sheet of lid material does not have oxygen (gas) barrier properties.)

(3) An elcatonin prefilled syringe was placed in a blister pack, covered with a Tyvek sheet and sealed to obtain an elcatonin prefilled syringe packaged in a package.

[Example 2]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Packaging: Orange colored PVC film 500μπι thick sheet (Sumitomo Beta Light; VSS-1202 colored, sheet that blocks light of 545 nm or less) is press-molded into a size that can accommodate a syringe. This was used as a prestar pack. As the lid material, a Tyvek sheet, a high-density polyethylene sheet with high gas permeability and pacteria barrier properties, was used. (The Tyvek sheet for the lid material has no oxygen (gas) noria.)

(3) According to Example 1 (3), an elcatonin prefilled syringe packaged in a package was obtained. -

[Example 3]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Package: A transparent film (a film that blocks light with a wavelength of 400 nm or less by applying UV cutting to a multilayer film consisting of two layers of silica vapor-deposited on ΡΕΤ12μπι and an LLDPE 60 m film laminated with an adhesive). The oxygen permeation rate was 0.1 cc / m ² · 24h · atm (Okada Paper Industries).) Which was shaped into a size that could accommodate a syringe. Tyvek sheet, a high-density polyethylene sheet with high gas permeability and bacterial barrier properties, was used as the cover material.

(The Tyvek sheet for the lid does not have oxygen (gas) barrier properties.)

(3) According to Example 1 (3), an elcatonin prefilled syringe packaged in a package was obtained.

[Example 4] (1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) package: a 2-ply and silica-deposited on a transparent film (PET 12 zm film, LLDPE60; a multilayer film laminated with an adhesive zni film, the oxygen permeation amount 0.1cc / m ² - 24 h · Atm film, which cuts off light with a wavelength of 300nm or less (Okada Paper Industries). (Size: 180mm X 45)

(3) The prefilled syringe was placed in the bag and sealed, to obtain an L-tonin prefilled syringe packaged in a package.

[Example 5]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Package: Colored film (Silver vapor-deposited on ΡΕΤ12 / 、 πι and coated with vermilion ink, UV cut on multilayer film laminated with nylon and LLDPE60m film) A film with an oxygen transmission rate of O.lcc / m ² -24.atm, which blocks light with a wavelength of 545 nm or less (Okada Paper). (Size: 180mm X 45)

(3) The prefilled syringe was placed in the bag and sealed, to obtain an L-forced prefinoledo syringe packaged in a package.

[Example 6]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) An aluminum film (aluminum 9μπα and ΡΡ20μπι, ΡΕ15μιη, PE40 / m laminated film) that does not have oxygen permeability and blocks light was molded into a piro bag.

(3) The elcatonin prefilled syringe obtained in (1) was put in the bag of the pillow and sealed, and an ertotonin prefilled syringe packaged in a package was obtained.

[Example 7]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Example 4 In accordance with (2), one pillow bag was molded.

(3) When putting a pre-filled syringe in a bag of Piro, use AGELESS (registered trademark).

"Mitsubishi Gas Chemical Co., Ltd.)) was carried out in the same manner as in [Example 4] except that the bag was placed in a pillow bag to obtain an erutotonin prefilled syringe packaged in a package. Was.

[Example 8]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Example 4 In accordance with (2), one pillow bag was molded.

(3) The procedure was performed in the same manner as in Example 4 except that nitrogen gas was sealed and the air in one pillow bag was replaced with nitrogen and sealed, to obtain an L-tonin prefilled syringe packaged in a package. ,

[Example 9].

(1) According to Example 1 (1) ′, an elcatonin pre-filled syringe was manufactured in the same manner as in Example 1 (1), except that the volume of the cavity was set to 0 when filling the syringe with the drug solution. .

(2) Example 4 In accordance with (2), one pillow bag was molded.

[Example 10].

(1) Elcatonin prefilled syringe was manufactured according to Example 9 (1).

(2) Package: The same package as that used in Example 1 (2) was used.

(3) According to Example 1 (3), an elcatonin-prefilled syringe packaged in a package was obtained.

[Example 11] '

(1) Put a thin tube into the chemical solution prepared according to [Example of chemical solution adjustment], flow nitrogen gas through the thin tube, and blow out nitrogen bubbles from the tip of the thin tube to reduce dissolved oxygen in the solution (nitrogen bubbling). Of dissolved oxygen was reduced to 1PPM or less. The solution was filtered through a closed pressure filtration device to obtain a drug solution in which the dissolved oxygen was kept at 1 PPM or less. This drug solution was filled into the same syringe as that used in Example 1 (1) with a syringe filling and stoppering machine so that the volume of the void portion became 0, and an L-force tonin prefilled syringe was manufactured.

(2) Example 4 In accordance with (2), one pillow bag was molded. The syringe was stopped and a prefilled syringe was obtained.

[Example 1 2] '

(1) According to Example 1 (1), an elcatonin pre-filled syringe was manufactured in the same manner as in Example 1 (1) except that the volume of the cavity was set to 0.4 ml when filling the syringe with the drug solution.

(2) Package: The same package as that used in Example 1 (2) was used.

[Example 13]

(1) in accordance with Example 1 2 (1), to produce a El Kato pregnant refill syringe _¾

(2) According to Example 4 '(2), a bag of Piro was molded.

(3) The L-tonin prefilled syringe obtained in (1) was placed in the bag and sealed, to obtain an L-tonin prefilled syringe packaged in a package.

[Example 14]

(1) According to Example 1 (1), a L-tonin prefilled syringe was manufactured.

(2) Package: Transparent film (Silver vapor-deposited on 12μπι, double-layered film, LLDPE60m film is laminated with adhesive, UV cut treatment is applied, and transmittance of light with wavelength of 400nm is 60% or less. Oxygen permeation was 0.1 lcc / nf · h'atm (Okada Paper Industries). (Size: 180 images X45)

(3) The prefilled syringe was put in this bag of pillows and sealed to obtain a L-tonin prefilled syringe packaged by a package.

[Example 15]

(1) According to Example 1 (1), a L-tonin prefilled syringe was produced.

(2) Packaging: Transparent film (a double layer of PET12 / zm silica vapor-deposited film and an LLDPE60 μτη film laminated with an adhesive are subjected to power treatment to block light with a wavelength of 400 nm or less. Oxygen permeation is 0.1 lcc / m ² · 24 h-atm (Okada Paper Industries).) And blue transparent cellophane film are superimposed, with a wavelength of 470 nm. A film with a close-up of 55% or less was obtained, and a bag with one mouth was formed.

(3) The prefilled syringe was placed in the bag and sealed, and an L-forced tonin prefilled syringe packaged in a package was obtained.

[Example 16]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Package: A transparent film (a double layer of silica-deposited film with a thickness of 12μηι) and a multi-layer film consisting of an LLDPE 60μm film laminated with an adhesive, which is subjected to UV cutting to block light with a wavelength of 400nm or less. Oxygen permeation amount (0.1 lcc / m · 24h. Atm '(Okada Paper Industries)) and a transparent yellow cellophane film were superimposed to obtain a film with a wavelength of 470 nm or less, and a pillow bag was formed.

[Example 17]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) Package: Transparent film (ΡΕΠ2μπι, silica laminated on two layers and LLDPE60; um film laminated with an adhesive, UV protection is applied to the multilayer film to block light with a wavelength of 400nm or less. Oxygen permeation rate is 0. Ice / m-24h-atm (Okada Paper Industries).) And brown transparent cellophane film are superimposed to suppress the wavelength around 545nm to 15% or less, and to increase the wavelength from 545nm to 900nm by 60%. The following film was obtained and a pillow bag was molded.

(3) The prefilled syringe was placed in the bag and sealed, and an L-L-tonin prefilled syringe packaged in a package was obtained.

[Comparative Example 1]

(1) Elcatonin prefilled syringe was produced according to Example 1 (1).

(2) No package was used.

(3) L-tonin prefilled syringe not packaged by the package was obtained.

[Comparative Example 2]

(1) According to Example 8 (1), a L-tonin prefilled syringe was produced. (2) No package was used. .

(3) L-tonin prefilled syringe not packaged by the package was obtained.

[Experimental example 1]

The preparations prepared in Examples 1 to 12 and Comparative Examples 1 and 2 were placed in a light irradiation tester and irradiated with an integrated light amount of 600,000 lux · hr and 1.2 million lux · hr. The stability was measured by high-performance liquid mouth chromatography, and the residual ratio of L-tonin in the L-tonin solution in the aqueous solution of L-tonin taken out of the syringe immediately after manufacture was determined as 100%.

The results are shown in Table 1.

(Irradiation conditions)

Illuminance: fluorescent lamp 39001ux / hr

(Wavelength of fluorescent lamp: 300-700 nm)

Testing machine used: Nagano Scientific Machinery Works (Model LT-120)

Temperature: 25. C

Total time: 307.7 hours (1.2 million lux · hr)

[table 1 ]

[Possibility of industrial use]

According to the present invention, at least the wavelength 3 3 2 η π! By blocking light of 4403 nm and / or reducing the contact between the protein preparation and oxygen, the stability of the protein preparation filled in the resin container to light can be improved.

Claims

The scope of the claims

1. At least wavelength 332 ηπ! A protein preparation filled in a resin container, which is shielded from light so that the transmittance of light of 403 nm is 70% or less.

2. Filled in resin containers, characterized by having means to reduce contact with oxygen

3. A protein preparation filled in a resin container, which is shielded from light so that the transmittance of light having a wavelength of at least 332 nm to 403 nm is 70% or less, and has means for reducing contact with oxygen. .

4. The preparation according to claim 1 or 3, characterized in that light is blocked by coloring a container filled with protein or a package covering the container.

5. The preparation according to any one of claims 1 to 3, wherein the container filled with the protein is covered with a package containing aluminum.

A formulation according to any one of claims 2-5 which 6. protein and wherein the oxygen permeability of the package which covers the containers or container filling is less than ^{0. 1 cc / m 2 · 24h} · atm .

7. The preparation according to any one of claims 2 to 6, wherein the inside of the container filled with the protein is replaced with an inert gas.

8. The preparation according to any one of claims 2 to 7, wherein an oxygen scavenger is enclosed in a package covering the container.

9. The formulation according to any one of claims 1 to 8, wherein the volume of the void portion of the container filled with the protein is reduced.

10. A method for improving the stability of a protein preparation filled in a resin container, wherein the light is shielded so that the transmittance of light having a wavelength of at least 332 nm to 403 nm is 70% or less. .

1 1. A method for improving the stability of protein preparations filled in resin containers, characterized by reducing contact with oxygen.

1 2. At least wavelength 332 ηπ! A method for improving the stability of a protein formulation filled in a resin container, which is characterized by shading light so that the transmittance of light at 403 nm to 70% or less is reduced and reducing contact with oxygen. .