JP2003183167A - Injection solution containing shark-originating iron chondroitin sulfate colloid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an injection solution containing a shark-originating iron chondroitin sulfate colloid which is excellent in pharmaceutical safety, and also is excellent in safety when conducting high calory transfusion, and the like, wherein the injection solution can be used safety and clinically without anxiety about infection with BSE. <P>SOLUTION: This injection solution contains the shark-originating iron chondroitin sulfate colloid, and a method for manufacturing the injection solution containing the shark-originating iron chondroitin sulfate is characterized by adding an aqueous solution of ferric sulfate and an aqueous solution of an alkali metal hydroxide to an aqueous solution of a shark-originating chondroitin sulfate salt so as to control the pH value of the thus obtained mixed solution to an optional value in the range of about pH 5.5 to 7.5. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an iron preparation for treating or preventing iron deficiency anemia in humans and mammals. More specifically, the present invention relates to an injection solution which is excellent in safety and pharmaceutical stability for supplementing chondroitin iron sulfate colloid.

[0002]

2. Description of the Related Art Iron is one of the essential metal nutrients for humans and mammals, and if iron loss occurs orally due to insufficient intake or bleeding, supplementation of iron is essential. When iron is supplemented parenterally, ionic iron compounds are problematic in terms of toxicity due to saturation binding with transferrin and further shock due to binding with plasma proteins. Requires devising such as replenishment. Ferric chloride is generally used as the iron ion to be parenterally supplied to humans, and the ferric chloride is present as ferric hydroxide colloidal particles in an aqueous solution. The colloidal particles are ferric oxide (Fe
₂ O ₃ ) and water, as well as oxychloride (FeOCl), which is a positively charged hydrophobic colloid due to the dissociation of FeO ⁺ and Cl ⁻ , tends to aggregate, and its pH value becomes about 3 or more. Precipitation occurs due to aggregation (for example, see Non-Patent Document 1).

So far, iron hydroxide colloidal solutions using dextran as a protective colloid have been used in the United States, and have been used as iron-poly (sorbitol gluconic acid) complex salts in Europe (for example, see Non-Patent Document 2).
On the other hand, in Japan, an iron colloid solution containing chondroitin sulfate having a high iron utilization rate with few side effects as a protective colloid is used. For example, in Japan, iron chondroitin sulfate colloid is marketed as an intravenous iron deficiency anemia preparation Bultar (trade name, Dainippon Pharmaceutical Co., Ltd.), and also contains chondroitin iron sulfate colloid as an essential trace element supplement for high calorie parenteral nutrition. Formulations are elemental injection, elemate injection (product name, Ajinomoto Pharma Co., Ltd.), minerarin injection, palmyrin injection (product name, Nippon Pharmaceutical Co., Ltd./Takeda Pharmaceutical Co., Ltd.), elemir injection (product name, Sawai Pharmaceutical Co., Ltd.) ) And Volvics Note (trade name, Fuji Yakuhin Co., Ltd./Yakult Co., Ltd.).

All of these chondroitin iron sulfate colloid-containing preparations which have hitherto been marketed in Japan are prepared using bovine-derived sodium chondroitin sulfate as a protective colloid. In 1996, it was announced in the United Kingdom that there was a causal relationship between the development of patients with variant Creutzfeldt-Jakob disease (v CJD) and mad cow disease or bovine spongiform encephalopathy (BSE). The abnormal prion protein, which is the cause of BSE, is stable to heat, and it is considered that high-temperature high-pressure treatment and alkali treatment do not completely inactivate it. In Japan, in view of the trend of bovine BSE outbreaks in Europe, it is necessary to take measures to ensure the quality and safety of manufacturers, etc. for drugs manufactured using raw materials derived from cattle, etc. Ministry of Health, Labor and Welfare, Director General of Pharmaceutical Safety, dated March 12, "Ensuring the quality and safety of pharmaceuticals manufactured from bovine materials as raw materials"
No. 26 was notified, and pharmaceutical manufacturers have been instructed on voluntary inspections and maintenance of approval documents. Although bovine chondroitin sulfate is isolated and purified from cattle trachea, it is required to use chondroitin sulfate which is safer and has higher safety.

[0005]

[Non-Patent Document 1] Translated by B. Jirgensons et al., Bunichi Tamamushi
"Colloid Chemistry" Baifukan Publishing Tokyo 1967

[Non-Patent Document 2] Goodman and Gilman "The Pharma
"Cological Basis of Therapeutics", published by MacMillan,
New York 1980, pp. 1325-1326

[0006]

DISCLOSURE OF THE INVENTION The present invention is a shark-derived chondroitin iron sulfate colloid that does not contain a causative agent of BSE, is safe, has excellent pharmaceutical stability, and is stable even when added to an infusion such as a high-calorie infusion. Provide an injection solution.

[0007]

Means for Solving the Problems To obtain an injectable solution which does not contain a causative agent of BSE, is excellent in pharmaceutical stability, and is stable even when blended with an infusion solution such as a high-calorie infusion solution. Various studies were repeated. As a result, the shark-derived chondroitin iron sulfate colloidal solution using shark-derived sodium chondroitin sulfate as a protective colloid was found to have good stability after heating, and continued diligent research based on these findings to complete the present invention. Came to. That is, the present invention provides (1) an injectable solution containing a shark-derived chondroitin iron sulfate colloid, and (2) an injectable solution according to 1 above, wherein the shark-derived chondroitin iron sulfate colloid is produced from a shark-derived chondroitin sulfate salt. , (3) The injection solution according to 2 above, wherein the shark-derived chondroitin sulfate salt is a shark-derived chondroitin sulfate alkali metal salt, (4) The injection solution according to 2 above, wherein the shark-derived chondroitin sulfate salt is a shark-derived chondroitin sulfate salt, ( 5) The injection solution according to 4 above, wherein the shark-derived sodium chondroitin sulfate has an average molecular weight of about 10,000 to 25,000, an intrinsic viscosity of about 0.27 to 0.65 dL / g, and a sulfur content of about 6.4 to 7.0 W / W%, (6) to iron Injectable solution according to the above 5, wherein the weight ratio of sodium chondroitin sulfate is 7 times or more, and (7) a shark-derived chondroitin sulfate aqueous solution,
The ferric iron salt aqueous solution and the alkali metal hydroxide aqueous solution, the pH value of the mixed solution is controlled at any pH value in the range of about 5.5 ~ 7.5, the shark-derived chondroitin iron sulfate colloid produced by adding the above Injectable solution according to 1, and (8) Shark-derived chondroitin sulfate aqueous solution, ferric salt aqueous solution and alkali metal hydroxide aqueous solution, the pH value of the mixture is controlled at any pH value in the range of about 5.5 ~ 7.5 And a method for producing a shark-derived chondroitin iron sulfate colloidal solution, and (9) a shark-derived sodium chondroitin sulfate aqueous solution, a ferric salt aqueous solution and a sodium hydroxide aqueous solution, and a pH value of the mixed solution. Is controlled at an arbitrary pH value in the range of about 5.5 to 7.5 and added, to a method for producing a shark-derived chondroitin iron sulfate colloidal solution.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION An injection solution containing a shark-derived chondroitin iron sulfate colloid of the present invention has a pH value of a mixture solution of a shark-derived chondroitin sulfate aqueous solution, a ferric salt aqueous solution and an alkali metal hydroxide aqueous solution. Can be produced by adding under controlled conditions such that the pH value is in the range of about 5.5 to 7.5. Examples of the shark-derived chondroitin sulfate include alkali metal salts such as sodium salt and potassium salt of shark-derived chondroitin sulfate, and preferably shark-derived sodium chondroitin sulfate. Shark-derived sodium chondroitin sulfate has, for example, an average molecular weight of about 10,000 to 25,000 derived from shark cartilage and an intrinsic viscosity of about 0.27 to 0.65 dL.
/ g (measured by capillary viscometer method), sulfur content of about 6.4 ~
An example is one having a physical property of 7.0 W / W%. The shark-derived sodium chondroitin sulfate preferably has a composition ratio of chondroitin 4-sulfate (chondroitin sulfate A): chondroitin 6-sulfate (chondroitin sulfate C) of about 1: 3.

[0009] Chondroitin sulfate is a linear polymeric polysaccharide composed of a repeating structure of a disaccharide unit of [→ 4 glucuronic acid β1 → 3 N-acetyl-D-galactosamine β1 →],
It is a polyanion with a high negative charge in which isomers exist depending on the number of sulfate groups bonded to this disaccharide unit and the bonding position. Table 1 shows the composition ratio of each isomer of sodium chondroitin sulfate (average molecular weight 20,000 to 25,000) derived from shark cartilage and bovine trachea.

[0010]

[Table 1]

Note) Chs: sodium chondroitin sulfate ΔDi-0S: no binding of sulfate group ΔDi-4S: C-4 of N-acetyl-D-galactosamine
Sulfate group is bound to position C-6 of ΔDi-6S: N-acetyl-D-galactosamine
Position sulfate group is bonded ΔDi-diS _D: the N- acetyl -D- galactosamine C
-6-position and D-C-2 position on the sulfate group glucuronic acid bound ΔDi-diS _E: the N- acetyl -D- galactosamine C
-Sulfate group is bonded to 4-position and C-6 position

[0012] ferric salt is a compound containing ferric available in the body, for example, ferric chloride hexahydrate (FeCl ₃ · 6
H ₂ O), iron citrate (FeC ₆ H ₅ O ₇ ), iron oxide hydroxide (F
eO (OH)), iron nitrate _{(Fe (NO 3) 3 ·} 9H 2 O), iron oxide (Fe
₂ O ₃ ), iron sulfate (Fe ₂ (SO ₄ ) ₃・ nH ₂ O) and iron phosphate (FePO
₄ · nH ₂ O) and the like. The ferric salt becomes ferric hydroxide in an aqueous solution, and shark-derived chondroitin sulfate is used as a protective colloid for the hydrophobic colloidal solution of ferric hydroxide. Of these, ferric chloride such as ferric chloride hexahydrate (FeCl ₃ .6H ₂ O) is preferable. The weight ratio of shark-derived sodium chondroitin sulfate to iron is 7 times or more (that is, the weight ratio of iron: shark-derived sodium chondroitin sulfate is 1: 7 or more). Examples of the alkali metal hydroxide include sodium hydroxide and potassium hydroxide, and preferably sodium hydroxide. In the present production method, a solution of a ferric salt (for example, ferric chloride hexahydrate) dissolved in water for injection and an appropriate amount of an aqueous solution of an alkali metal hydroxide (for example, sodium hydroxide) are added to the above for iron. Shark-derived chondroitin sulphate corresponding to the weight ratio (for example, sodium chondroitin sulphate) is added to a solution prepared by dissolving in water for injection with stirring, and the pH value of the reaction mixture is about 5.5 to 7.5. It is preferable to control the pH value.

The concentration of the ferric salt (for example, ferric chloride hexahydrate) aqueous solution for injection to be added is usually about 3 to 62 W / V%,
Preferably about 13-32 W / V% is used. The alkali metal hydroxide (eg, sodium hydroxide) aqueous solution to be added is usually used in an amount of about 1-28 W / V%, preferably about 2-7 W / V%. A chondroitin sulfate aqueous solution is usually about 3
~ 30 W / V% is used, preferably about 4-20 W / V%.
The reaction mixture of ferric salt, alkali metal hydroxide and chondroitin sulfate is thoroughly stirred so that the pH value of the mixture is maintained at a constant value. The reaction time can be appropriately set by those skilled in the art, but is usually about 1 to 6 hours. The reaction temperature can be appropriately selected by those skilled in the art, and is preferably about 5 ° C to 25 ° C. The shark-derived chondroitin iron sulfate colloid-containing liquid thus obtained may be used as an injection after sterilization, if necessary, or in small amounts (for example, 1, 2 or 4 mL each) filled in a container, It may be sealed and sterilized (for example, high-pressure steam sterilization) and used. The injection solution of the present invention preferably has a pH value of about 5.0 to 7.5. As the container for enclosing the injection solution of the present invention, for example, a glass container (ampoule or the like) or a plastic container such as polypropylene containing a prefilled syringe type can be used.

The injection of the present invention has almost no side effects, is safe, and can be administered to humans and mammals according to a method known per se. The iron contained in the injectable solution of the present invention to be administered is about 0.9 as a daily dose per adult.
˜720 μmol, preferably about 9 to 720 μmol, desirably about 2 to 20 mL of aqueous solution. If necessary, the injection solution of the present invention may further contain copper, zinc, manganese, selenium, iodine and chromium. In this case, the injection solution of the present invention to be administered is
The daily dose per adult is about 0.9-55 μmol of copper,
Zinc about 3.85 to 210 μmol, manganese about 0 to 51 μmol, selenium about 0.025 to 5.0 μmol and iodine about 0 to 11 μmol,
Preferably about 9.1 to 27.3 μm copper, about 38.5 to 61.5 μm zinc
ol, manganese about 0 to 14.5 μmol, selenium about 0.25 to 2.5 μm
It is desirable to contain about 0.6 to 1.1 μmol of ol and iodine.

[0015]

EXAMPLES In the present specification, W / W% is weight%, W / V% is weight /
Shows% by volume. Hereinafter, the present invention will be described more specifically by way of examples. Example 1 Each solution of shark cartilage-derived sodium chondroitin sulfate in a weight ratio of 5, 10, and 12 times that of iron (Fe) (6.4 W / V%)
And an aqueous solution of ferric chloride (20.8
W / V%) and sodium hydroxide aqueous solution (4.3 W / V%) were fed and stirred (at 5 to 25 ° C. for about 60 minutes). Each obtained chondroitin iron sulfate colloidal solution is diluted with water for injection,
Each chondroitin iron sulfate colloidal solution having a target iron concentration of 4 mg / mL was produced. 2 mL of glass ampoule was filled with each of the produced solutions and sealed, and the temperature was 105 ° C / 20 minutes, 110 ° C / 20 minutes, 11 ° C.
High-pressure steam sterilization was performed under the conditions of 5 ° C / 20 minutes and 121 ° C / 20 minutes to produce 50 samples of each. The properties of each sample were observed, and a membrane filter (pore size 0.2 μm) was prepared for each 10 mL sample containing 5 glass ampoules of 2 mL.
The filtration test according to m) was carried out. The results are shown in Table 2.
Two types of sodium chondroitin sulfate (Chs) derived from shark cartilage having molecular weights of about 20,000 to 25,000 and about 10,000 were examined.

[0016]

[Table 2] Note) Chs: Content of sodium chondroitin sulphate Evaluation Properties: Filtration test: A Dark red brown clear. ○ Pass the filter. B Dark reddish brown with slight turbidity. × It does not pass through the filter C It is dark reddish-brown and clearly turbid.

As shown in Table 2, the stability of the chondroitin iron sulfate colloidal solutions prepared at iron: sodium chondroitin sulfate weight ratios of 1:10 and 1:12 under the respective heating conditions was determined by the properties and filtration tests. It was confirmed to be stable.

Example 2 Each solution * of sodium chondroitin sulfate derived from shark cartilage in a weight ratio of 7, 9, 11, 13, 20 times to iron (Fe) * (concentration of the solution is shown below) has a pH value of about 6.5. The ferric chloride aqueous solution (20.8 W / V%) and the sodium hydroxide aqueous solution (4.3 W / V%) were fed and stirred (about 5 to 25 ° C for about 60 minutes) while maintaining the above temperature. * Concentration of sodium chondroitin sulfate Iron: Sodium chondroitin sulphate Weight ratio concentration of sodium chondroitin sulphate W / V% 1: 7 and 1: 9 6.4 1:11 7.8 1:13 9.1 1:20 13.7 Each obtained chondroitin iron sulfate colloidal solution was diluted with water for injection to prepare each chondroitin iron sulfate colloidal solution having a target iron concentration of 4 mg / mL. 2 mL of glass ampoule was filled with each of the produced solutions and sealed, and autoclaved under the conditions of 110 ℃ / 20 minutes and 121 ℃ / 20 minutes.
0 pieces were manufactured. With respect to each sample, a property and a filtration test were performed under the same evaluation conditions as in Example 1. The results are shown in Table 3. The molecular weight of shark cartilage-derived sodium chondroitin sulfate (Chs) was examined to be about 10,000.

[0019]

[Table 3]

As shown in Table 3, the stability of the chondroitin iron sulfate colloidal solution prepared at an iron: sodium chondroitin sulfate weight ratio of 1: 7 to 20 was stable in the properties and filtration tests. Was confirmed.

Example 3 Each solution of sodium chondroitin sulfate derived from shark cartilage in a weight ratio of 5, 7, 9, 11, 13, 20 times to iron (Fe) **
(The concentration of the solution is shown below), while maintaining the pH value at about 6.5, ferric chloride aqueous solution (20.8 W / V%) and sodium hydroxide aqueous solution (4.3 W / V%) are fed and stirred (5 to About 60 at 25 ℃
Minutes). Each obtained chondroitin iron sulfate colloidal solution was diluted with water for injection to prepare each chondroitin iron sulfate colloidal solution having a target iron concentration of 4 mg / mL. ** Concentration of sodium chondroitin sulfate Iron: Sodium chondroitin sulphate Weight ratio concentration of sodium chondroitin sulphate W / V% 1: 5, 1: 7, and 1: 9 6.4 1:11 7.8 1:13 9.1 1:20 13.7 2 mL of this chondroitin iron sulfate colloidal solution derived from shark cartilage
A glass ampoule (2 mL) was filled and sealed, and high-pressure steam sterilization was performed at 110 ° C. for 20 minutes to produce 40 samples of each. The stability of each sample was stored at 70 ° C. The results are shown in Table 4.

[0022]

[Table 4] Note) The iron content is indicated by the average value of n = 3 and the minimum value in ().
Indicates the maximum value.

As shown in Table 4, all the chondroitin iron sulfate colloidal solutions prepared with the iron: sodium chondroitin sulfate weight ratio of 1: 5 to 20 are stable in the insoluble foreign matter test and the iron content. Was confirmed.

From the test results of Examples 1 to 3, it was confirmed that the chondroitin iron sulfate colloidal solutions prepared with the iron: sodium chondroitin sulfate weight ratio of 1: 7 or more are excellent in stability.

Example 4 Shark cartilage-derived chondroitin iron sulfate colloidal solution containing 12 times the weight ratio of sodium chondroitin sulfate to iron (Fe) produced in Example 1 was filled in a glass ampoule (2 mL) and melted. For a sample that had been subjected to high-pressure steam sterilization under the condition of 20 ° C for 20 minutes, 1 mL of the solution was co-injected into the following commercial infusion solution, and a composition change test was performed. Sodium chondroitin sulfate derived from shark cartilage has a molecular weight of about 10,000 and about 20,000 to 25,000.
The species was also examined. That is, the properties, pH value and insoluble foreign matter were observed before mixed injection, immediately after mixed injection and after 24 hours. The results are shown in Table 5. Commercially available infusion solutions used were "Aminotripa No. 2" (trade name, Otsuka Pharmaceutical Co., Ltd.) and "PIN Twin-3" (trade name, Ajinomoto Pharma Co., Ltd.).

[0026]

[Table 5]

As shown in Table 5, none of the injectable solution of the present invention (Example 4) was observed in the properties until 24 hours after being mixed with a commercially available infusion solution, and precipitates such as insoluble foreign matters were also observed. I couldn't do it.

[0028]

INDUSTRIAL APPLICABILITY The injectable solution of the present invention can be safely used clinically without fear of BSE infection, has excellent pharmaceutical stability, and has excellent stability even during infusion such as high calorie infusion.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Makoto Sato             3-9-3 Honjo-nishi, Kita-ku, Osaka Nipro             Within the corporation F term (reference) 4C076 AA12 BB11 CC14 CC46 EE37                       FF12 FF36 FF63                 4C086 AA01 AA02 EA26 HA11 HA20                       MA01 MA02 MA04 MA05 MA17                       MA66 NA03 ZA55                 4C087 AA01 AA02 BB29 MA17 MA66                       NA03 ZA55

Claims (9)

[Claims] 1. An injection solution comprising a shark-derived chondroitin iron sulfate colloid. 2. The injectable solution according to claim 1, wherein the shark-derived chondroitin iron sulfate colloid is produced from shark-derived chondroitin sulfate. 3. The injection solution according to claim 2, wherein the shark-derived chondroitin sulfate is a shark-derived chondroitin sulfate alkali metal salt. 4. The injectable solution according to claim 2, wherein the shark-derived chondroitin sulfate is shark-derived sodium chondroitin sulfate. 5. A shark-derived sodium chondroitin sulfate having an average molecular weight of about 10,000 to 25,000 and an intrinsic viscosity of about 0.27 to 0.
The injection solution according to claim 4, which has a content of 65 dL / g and a sulfur content of about 6.4 to 7.0 W / W%. 6. The injection solution according to claim 5, wherein the weight ratio of sodium chondroitin sulfate to iron is 7 times or more. 7. A shark-derived chondroitin sulfate aqueous solution,
A shark-derived chondroitin iron sulfate colloid produced by adding an aqueous solution of ferric salt and an aqueous solution of alkali metal hydroxide at a pH value of the mixed solution controlled at an arbitrary pH value in the range of about 5.5 to 7.5, and containing the same. The injection solution according to item 1. 8. A shark-derived chondroitin sulfate aqueous solution,
A ferric salt aqueous solution and an alkali metal hydroxide aqueous solution, the pH value of the mixed solution is controlled at any pH value in the range of about 5.5 to 7.5, and is added to the shark-derived chondroitin iron sulfate colloidal solution. Production method. 9. A ferric salt aqueous solution and a sodium hydroxide aqueous solution are added to a shark-derived sodium chondroitin sulfate aqueous solution while controlling the pH value of the mixed solution at an arbitrary pH value in the range of about 5.5 to 7.5. A method for producing a shark-derived chondroitin iron sulfate colloidal solution, which comprises: