Preparation for vitamin c injection

Abstract

To provide a preparation for vitamin C injection having high stability, free of sodium, and not inducing vascular pain.SOLUTION: A preparation for vitamin C injection comprising a freeze-dried powder of an aqueous solution containing 5 mass% or more and 22 mass% or less of L-arginine ascorbate neutral salt.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an injectable vitamin C preparation. [Background technology]

[0002] Ascorbic acid, also known as vitamin C, is a vitamin that has been administered orally or transdermally for a long time due to its expected various effects. High-concentration vitamin C infusion is a method of administering vitamin C into the body at higher concentrations than normal oral intake, and is a treatment performed in a medical facility under the supervision of a doctor. High-concentration vitamin C infusion therapy is considered useful for certain conditions and diseases. Its application in the field of cancer is also progressing, and high-concentration vitamin C infusion is sometimes used as a complementary therapy for some cancer patients. Vitamin C has antioxidant properties, and its effects on cancer cells are being studied based on its antioxidant properties. Vitamin C also has antioxidant properties, helping to protect cells from oxidative stress in the body. Therefore, receiving high-concentration vitamin C intravenous drips is believed to enhance antioxidant activity. Furthermore, it is believed to be useful for immune support, and its use against infections and inflammation is being considered. High-concentration vitamin C intravenous drips are also being used for cosmetic purposes.

[0003] Examples of vitamin C injection solutions that have been reported include an infusion solution containing 2.0% vitamin C (Patent Document 1), a vitamin C injection containing 3-O-glucosyl-L-ascorbic acid as the active ingredient (Patent Document 2), a vitamin C injection containing 6-O-β-D-galactosyl-L-ascorbic acid or a salt thereof as the active ingredient (Patent Document 3), and an injection containing 10% w / v or more ascorbic acid or a salt thereof, 0.015% w / v or less sulfite, and 0.015% w / v or less of a stabilizer selected from L-cysteine ​​or a salt thereof, or thioglycolic acid or a salt thereof (Patent Document 4).

[0004] Currently, high-concentration vitamin C intravenous drips on the market are in liquid form, and because there are concerns about their stability, they are transported and stored under refrigerated conditions. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 57-9712 [Patent Document 2] Japanese Patent Publication No. 59-55833 [Patent Document 3] Japanese Patent Application Publication No. 5-213739 [Patent Document 4] Japanese Patent Application Laid-Open No. 2015-189739 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the vitamin C injections currently available have three problems: they are prone to causing vascular pain, they contain sodium that is unnecessary for the body due to neutralization with sodium bicarbonate and sodium hydroxide, and although they are distributed refrigerated as a 50% concentration liquid, they are prone to discoloration and have low stability. Therefore, an object of the present invention is to provide an injectable vitamin C preparation that does not cause vascular pain, does not contain sodium, and is highly stable. [Means for solving the problem]

[0007] Therefore, after extensive investigations, the present inventors discovered that by neutralizing ascorbic acid with L-arginine to form a salt, preparing an aqueous solution with a specific solids concentration, and freeze-drying this into a powder, it is possible to obtain an injectable vitamin C preparation that is excellent in solubility during use, does not contain sodium, and has excellent storage stability, and thus completed the present invention.

[0008] That is, the present invention provides the following [1] to [4]. [1] A vitamin C injection preparation consisting of a freeze-dried powder of an aqueous solution containing 5% to 22% by weight of L-arginine ascorbate neutral salt. [2] The vitamin C injectable preparation according to [1], wherein the aqueous solution has a pH of 6 to 8. [3] A method for producing an injectable vitamin C preparation, comprising freeze-drying an aqueous solution containing 5% by mass or more and 22% by mass or less of L-arginine ascorbate neutral salt. [4] The method for producing an injectable vitamin C preparation according to [3], wherein the pH of the aqueous solution is 6 to 8. [Effects of the Invention]

[0009] The vitamin C injectable formulation of the present invention has excellent solubility during use, is less likely to cause vascular pain, does not contain sodium unnecessary for the body, and has excellent storage stability. Therefore, the vitamin C injectable formulation of the present invention is useful as a high-concentration vitamin C infusion formulation. DETAILED DESCRIPTION OF THE INVENTION

[0010] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0011] As used herein, "ascorbic acid" refers to an organic compound designated as (R)-3,4-dihydroxy-5-((S)-1,2-dihydroxyethyl)furan-2(5H)-one in IUPAC nomenclature, which acts as vitamin C in humans and is used as a food additive antioxidant. Furthermore, the excellent antioxidant effect of ascorbic acid inhibits melanin production in the skin, and it is known as an ingredient that prevents pigmentation such as age spots and freckles, and is therefore widely incorporated into cosmetics. As mentioned above, high-concentration vitamin C infusions are being applied in the field of cancer, and are sometimes used as a complementary therapy for some cancer patients. Vitamin C has antioxidant properties, and its effects on cancer cells are being studied based on this antioxidant effect. It is also believed that receiving high-concentration vitamin C infusions enhances antioxidant effects. Furthermore, it is thought to be useful for immune support, and its use against infections and inflammation is being considered. L-arginine, on the other hand, is a basic amino acid. Although it is synthesized within the human body and is therefore not an essential amino acid, it is known as an amino acid that supports energy production within the body and is a source of nutrition and strengthening, and its wide range of functions has been identified. It is significantly involved in vitality, such as muscle building, growth hormone secretion, and improving male sexual function by improving blood flow. It is also known as one of the natural moisturizing factors (NMF) present in the skin, helping to keep the skin fresh and smooth, and is widely used as an ingredient in cosmetics. L-arginine hydrochloride stimulates the pituitary gland to release growth hormone, and an injection containing 30g of L-arginine hydrochloride is used as a pharmaceutical to test pituitary function.

[0012] One aspect of the present invention is a vitamin C injection preparation comprising a freeze-dried powder of an aqueous solution containing 5% by mass or more and 22% by mass or less of an L-arginine neutral salt of ascorbic acid. Another aspect of the present invention is a method for producing an injectable vitamin C formulation, which comprises freeze-drying an aqueous solution containing 5% by mass or more and 22% by mass or less of an L-arginine ascorbate neutral salt.

[0013] The neutralized salt of L-arginine ascorbate can be produced by reacting ascorbic acid with L-arginine in water to form a neutralized salt. In this case, it is important that the concentration of neutralized salt of L-arginine ascorbate in water be 5% by mass or more and 22% by mass or less in order to obtain neutralized salt of L-arginine ascorbate and ensure the stability of the resulting aqueous solution. If the neutralized product concentration is less than 5% by mass, the concentration is low and inefficient. If the neutralized product concentration exceeds 22% by mass, crystals will precipitate after storage of the resulting aqueous solution, causing the aqueous solution to turn yellow. Furthermore, if crystals are precipitated in the aqueous solution, bumping may occur during freeze-drying. The neutralized product concentration is more preferably 5% by mass or more and 20% by mass or less, and even more preferably 5% by mass or more and 18% by mass or less.

[0014] The molar ratio of ascorbic acid to L-arginine is preferably equimolar. The pH of the aqueous solution after adding ascorbic acid and L-arginine is preferably in the range of 6 to 8 from the viewpoint of obtaining a neutralized salt. The reaction is preferably carried out at a temperature in the range of 0°C or higher and 40°C or lower, more preferably in the range of 0°C or higher and 35°C or lower.

[0015] The resulting aqueous solution is freeze-dried to obtain the vitamin C injection formulation of the present invention. The freeze-drying can be carried out using a conventional freeze-drying apparatus. Alternatively, the freeze-drying may be carried out in large quantities and the resulting freeze-dried powder may be filled into vials, or an aqueous solution may be filled into vials and then freeze-dried.

[0016] The freeze-dried powder obtained has good reconstitution with water and suppressed coloration, making it useful as a high-concentration vitamin C infusion injection. [Example]

[0017] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0018] Example 1 10 g of ascorbic acid was completely dissolved in 100 g of ion-exchanged water. While stirring, 9.8 g of L-arginine was gradually added until completely dissolved. The pH was confirmed to be between 6 and 8. The pH of the solution was 6.021 when prepared, and 6.031 after standing for 1 hour, showing little change, indicating that the pH of the solution was stable. The resulting solution was microfiltered through a 0.22-micrometer pore sterilizing filter and then freeze-dried (CDSH100A, Cell Diagnostics) to obtain a powder.

[0019] Example 2 10 g of ascorbic acid was completely dissolved in 100 g of ion-exchanged water. While stirring, 10 g of L-arginine was gradually added until completely dissolved. The pH was confirmed to be between 6 and 8. The pH of the solution was 6.533 when prepared, and 6.489 after standing for 1 hour, showing little change and indicating that the pH of the solution was stable. The resulting solution was microfiltered through a 0.22-micrometer pore sterilizing filter and then freeze-dried (CDSH100A, Cell Diagnostics) to obtain a powder.

[0020] Example 3 The amount of L-arginine added was changed to 10.5 g in the same manner as in Example 1. In this case, the end point pH was 7.721. Simple bacterial testing did not detect any common live bacteria or fungi.

[0021] Comparative Examples 1 and 2 The amount of L-arginine added was changed to 15.0 g and 20.5 g in the same manner as in Example 1. The end point pH values ​​in these cases were 6.708 and 6.824, respectively.

[0022] The aqueous solutions (before freeze-drying) obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were stored for two weeks at 4°C, room temperature (25°C), and 40°C, and the state of the aqueous solutions was observed with the naked eye. The results are shown in Table 1.

[0023] [Table 1]

[0024] The pH should be in the neutral range of 6-8, preferably 6.5-7.5. The pH in the body is about 7.3, which is in the neutral range, so a pH closer to this is thought to be less likely to cause a potential difference and less likely to cause irritation. Of the solutions tested, the lower the pH, the less yellow the coloration. As the amount of L-arginine added increased, the pH rose sharply once it exceeded pH 6. When equal amounts of ascorbic acid and L-arginine were mixed, the pH remained within a range centered around 6.5, so mixing equal amounts is considered desirable from the standpoint of control during manufacturing. Accelerated testing at elevated storage temperatures revealed that the product was not very stable and showed significant yellowing. While refrigerated storage is an option, considering transportation costs and convenience, it would be preferable to store the product at room temperature.

[0025] The freeze-drying results of Examples 1 to 3 and Comparative Examples 1 and 2 are shown in Table 2.

[0026] [Table 2]

[0027] In Comparative Example 2, traces of bubbles thought to be caused by bumping remained, but in the other examples, freeze-drying was carried out normally.

[0028] Test Example 1 Next, we investigated a method in which the prepared solution was filled into a glass vial and freeze-dried. Each solution was dispensed into a commercially available glass vial and freeze-dried using the standard method. The 20% solution was filled into 30 mL glass vials (inner diameter 30 mm) with varying volumes and freeze-dried. The freeze-dried powders were observed and their reconstitution was investigated. The results are shown in Table 3.

[0029] [Table 3]

[0030] The freeze-dried powder was formed without any excipients and contained no other components other than ascorbic acid and L-arginine, and had a good shape. The lyophilized powder had good reconstitution in water, and when the same amount of water was added to replace the removed water, the solubility was very good, with no turbidity or residual dissolution, and the degree of coloring was almost the same as in the solution before lyophilization.In addition to injecting the reconstituted solution directly into the body in a sterilized state, it can also be administered by mixing it with saline or intravenous fluids and infusing it at an appropriate speed. Furthermore, it was considered more desirable to perform the sealing under vacuum.

[0031] Test Example 2 (Activity as Vitamin C) When one packet of DPD reagent (free residual chlorine measurement reagent "DPD Plus" (manufactured by Oyalax Co., Ltd.) was added to 200 mL of tap water, residual chlorine was detected and the liquid turned pink. When 1 mL each of a 20% aqueous ascorbic acid solution (Comparative Example 3, pH 2.011) or a 20% aqueous sodium ascorbate solution (Comparative Example 4, pH 7.744, Brix 21.1%) was added to the tap water beforehand, the water did not turn pink even after the addition of the DPD reagent. This is thought to be because the ascorbic acid reduced the chlorine contained in the tap water. 1 mL of the solution of Example 1 (pH 6.021, Brix 19.80%) was added to the tap water beforehand. Even when the DPD reagent was then added, the water did not turn pink. This suggests that the formulation of the present invention preserves its vitamin C function.

Claims

1. A vitamin C injection preparation comprising a freeze-dried powder of an aqueous solution containing 5% by mass or more and 22% by mass or less of a neutral salt of L-arginine ascorbate.

2. 2. The vitamin C injectable preparation according to claim 1, wherein the aqueous solution has a pH of 6 to 8.

3. A method for producing an injectable vitamin C preparation, comprising freeze-drying an aqueous solution containing 5% by mass or more and 22% by mass or less of a neutralized salt of L-arginine ascorbate.

4. The method for producing an injectable vitamin C preparation according to claim 3, wherein the pH of the aqueous solution is 6 to 8.

Images