Loxoprofen sodium oral solution and preparation method thereof

Abstract

The invention provides a loxoprofen sodium oral solution, and belongs to the technical field of pharmaceutical preparations. According to the loxoprofen sodium oral solution, chlorogenic acid is used as an additive, degradation of loxoprofen sodium is effectively inhibited by adjusting the pH value of the loxoprofen sodium oral solution in a synergistic manner, and the antibacterial activity and oxidation resistance of chlorogenic acid are utilized to improve the antibacterial activity of the loxoprofen sodium oral solution, so that the long-term storage stability of the loxoprofen sodium oral solution is improved; the viscosity of the loxoprofen sodium oral solution is adjusted by using the inulin, the dispersion stability of each component is improved while the taste of the loxoprofen sodium oral solution is improved, and the loxoprofen sodium oral solution has water-retaining property, so that the storage stability of the loxoprofen sodium oral solution is further improved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a loxoprofen sodium oral solution and a preparation method thereof. Background Art

[0002] Loxoprofen Sodium is the first propionic acid precursor nonsteroidal anti-inflammatory drug (NSAIDs). It was first developed by Sankyo Co., Ltd. of Japan and launched in Japan in July 1986 under the trade name of Loxoprofen. After oral administration, the drug is metabolized into trans-OH active drugs in the body, inhibiting the biosynthesis of prostaglandins, that is, by binding to cyclooxygenase and masking the active center of the enzyme, thereby blocking the enzyme from catalyzing the metabolism of arachidonic acid into PG, exerting analgesic, anti-inflammatory and antipyretic effects. As a new type of NSAIDs, loxoprofen sodium is different from other drugs in that it is a prodrug and has no activity itself. It becomes active only after being rapidly converted into trans-OH metabolites by the liver. Its analgesic effect is 20 times that of indomethacin, and the mouse paw carrageenan edema experiment shows that its anti-inflammatory effect is twice that of indomethacin. The drug takes effect quickly and has strong and lasting analgesic, anti-inflammatory and antipyretic effects. Currently, it is mainly used to treat rheumatoid arthritis, osteoarthritis, low back pain, frozen shoulder, cervical-shoulder-wrist syndrome, pain after surgery and tooth extraction, acute upper respiratory tract inflammation and other diseases.

[0003] Loxoprofen sodium is a prodrug, and its mechanism of action is to be converted into active metabolites after being absorbed by the digestive tract, and competitively binds to cyclooxygenase, and inhibits the biosynthesis of prostaglandins and plays a role. Loxoprofen sodium absorbs rapidly after oral administration, and is distributed in liver, kidney, and blood plasma with higher concentration, and most of them become the glucuronic acid conjugate of original shape or the glucuronic acid conjugate of hydroxylated product thereafter, and mainly excrete rapidly through urine. At present, loxoprofen sodium preparations mainly contain tablets, capsules, granules, dispersible tablets, patches and gel plasters etc. in the domestic market, and there are shortcomings such as slow absorption, low bioavailability, slow onset in above products, and because loxoprofen sodium has poor stability in aqueous solution, being prepared into oral solution can cause impurity growth to be larger. Therefore, providing a kind of loxoprofen sodium oral solution with good long-term stability is a problem that the prior art needs to solve urgently. Summary of the invention

[0004] The invention aims to provide a loxoprofen sodium oral solution and a preparation method thereof. The loxoprofen sodium oral solution provided by the invention has good long-term stability and a long shelf life.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a loxoprofen sodium oral solution, which comprises the following components by weight:

[0007] 0.4-0.8 parts of loxoprofen sodium, 0.5-2 parts of chlorogenic acid, 1-4 parts of inulin, 0.1-0.5 parts of sweetener, 0.06-0.12 parts of cosolvent, 90-99 parts of water;

[0008] The pH value of the loxoprofen sodium oral solution is 6.8-7.8.

[0009] Preferably, the following components are included by weight:

[0010] 0.5-0.7 parts of loxoprofen sodium, 0.75-1.5 parts of chlorogenic acid, 1.3-3.5 parts of inulin, 0.2-0.4 parts of sweetener, 0.08-0.10 parts of cosolvent, 93-97 parts of water;

[0011] The pH value of the loxoprofen sodium oral solution is 7 to 7.5.

[0012] Preferably, the mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:(1.5-2):(2-3).

[0013] Preferably, the sweetener is at least one of maltitol, erythritol, sorbitol, xylitol and mannitol.

[0014] Preferably, the cosolvent is at least one of propylene glycol, glycerol, polyethylene glycol, poloxamer and polyvinyl pyrrolidone.

[0015] Preferably, the co-solvent is at least one of glycerol and polyethylene glycol.

[0016] Preferably, the loxoprofen sodium oral solution further contains a pH adjuster, and the pH adjuster is at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, malic acid, tartaric acid, fumaric acid, maleic acid, sorbic acid, succinic acid, salicylic acid, and oxalic acid.

[0017] Preferably, the pH adjuster is at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, malic acid, tartaric acid, succinic acid, salicylic acid, and oxalic acid.

[0018] The present invention also provides a method for preparing the loxoprofen sodium oral solution described in the above technical scheme, comprising the following steps:

[0019] After mixing loxoprofen sodium, inulin, sweetener, cosolvent and part of water, stirring, heating and cooling are performed in sequence to obtain a mixed solution;

[0020] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0021] Preferably, the partial water accounts for 20% to 40% of the total mass of the water.

[0022] The invention provides a loxoprofen sodium oral solution. Chlorogenic acid is used as an additive to synergistically adjust the pH of the loxoprofen sodium oral solution to effectively inhibit the degradation of loxoprofen sodium. The antibacterial and antioxidant properties of chlorogenic acid are used to improve the antibacterial performance of the loxoprofen sodium oral solution, thereby improving the long-term storage stability. Inulin is used to adjust the viscosity of the loxoprofen sodium oral solution to improve the taste and dispersion stability of each component, and the solution has water retention, thereby further improving the storage stability. The loxoprofen sodium oral solution provided by the invention has low bioavailability and rapid onset of action, and its flowing liquid state meets the needs of different patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 A bar graph showing the total number of aerobic bacteria per 1 mL of loxoprofen sodium oral solutions prepared in Examples 1 to 5 of the present invention and Comparative Examples 1 and 2 after storage for 18 months;

[0024] Figure 2 This is a bar graph showing the detected contents of some related substances in the loxoprofen sodium oral solutions prepared in Examples 1, 3, 5 of the present invention and Comparative Examples 1 and 2 after storage for 18 months. DETAILED DESCRIPTION

[0025] The present invention provides a loxoprofen sodium oral solution, which comprises the following components in parts by mass:

[0026] 0.4-0.8 parts of loxoprofen sodium, 0.5-2 parts of chlorogenic acid, 1-4 parts of inulin, 0.1-0.5 parts of sweetener, 0.06-0.12 parts of cosolvent, 90-99 parts of water;

[0027] The pH value of the loxoprofen sodium oral solution is 6.8-7.8.

[0028] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the art.

[0029] In the present invention, the loxoprofen sodium oral solution preferably comprises the following components in parts by mass:

[0030] 0.5-0.7 parts of loxoprofen sodium, 0.75-1.5 parts of chlorogenic acid, 1.3-3.5 parts of inulin, 0.2-0.4 parts of sweetener, 0.08-0.10 parts of cosolvent, and 93-97 parts of water.

[0031] In the present invention, the pH value of the loxoprofen sodium oral solution is preferably 7 to 7.5.

[0032] In the present invention, the mass ratio of loxoprofen sodium, chlorogenic acid, and inulin is preferably 1: (1.5-2.2): (1.5-5). The present invention controls the mass ratio of loxoprofen sodium, chlorogenic acid, and inulin within the above range, so as to utilize chlorogenic acid to effectively inhibit the degradation of loxoprofen sodium, and utilize the antibacterial and antioxidant properties of chlorogenic acid to improve the antibacterial properties of the loxoprofen sodium oral solution, thereby improving its long-term storage stability; inulin is used to adjust the loxoprofen sodium oral solution to have a suitable viscosity, improve its taste, and improve the dispersion stability of each component, and have water retention, further improving its storage stability.

[0033] In the present invention, the sweetener is preferably at least one of maltitol, erythritol, sorbitol, xylitol and mannitol, more preferably at least one of maltitol and erythritol. The present invention utilizes the sweetener to improve the sweetness and taste of the prepared loxoprofen sodium oral solution.

[0034] In the present invention, the cosolvent is preferably at least one of propylene glycol, glycerol, polyethylene glycol, poloxamer, and polyvinyl pyrrolidone, and more preferably at least one of glycerol and polyethylene glycol.

[0035] In the present invention, the loxoprofen sodium oral solution preferably further contains a pH regulator; the pH regulator is preferably at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, malic acid, tartaric acid, fumaric acid, maleic acid, sorbic acid, succinic acid, salicylic acid, and oxalic acid, and more preferably at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, malic acid, tartaric acid, succinic acid, salicylic acid, and oxalic acid. The present invention utilizes a pH regulator to adjust the pH value of the loxoprofen sodium oral solution, and cooperates with chlorogenic acid as an additive to effectively inhibit the degradation of loxoprofen sodium, thereby improving the storage stability of the loxoprofen sodium oral solution.

[0036] The present invention also provides a method for preparing the loxoprofen sodium oral solution described in the above technical scheme, comprising the following steps:

[0037] After mixing loxoprofen sodium, inulin, sweetener, cosolvent and part of water, stirring, heating and cooling are performed in sequence to obtain a mixed solution;

[0038] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0039] In the present invention, the stirring and heating temperature is preferably 40 to 65°C, more preferably 50 to 65°C; the stirring and heating time is preferably 20 to 90 minutes, more preferably 30 to 60 minutes. In the present invention, the cooling is natural cooling to room temperature.

[0040] In the present invention, the partial water preferably accounts for 20% to 40% of the total mass of water.

[0041] The preparation method of the loxoprofen sodium oral solution provided by the invention has simple operation, mild conditions and is suitable for large-scale production.

[0042] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] Example 1

[0044] A loxoprofen sodium oral solution comprises the following components in parts by mass:

[0045] 0.5 parts of loxoprofen sodium, 0.75 parts of chlorogenic acid, 1.5 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0046] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:1.5:3;

[0047] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0048] The preparation method of the loxoprofen sodium oral solution comprises the following steps:

[0049] Loxoprofen sodium, inulin, sweetener, cosolvent and part of water were mixed, heated with stirring at 60° C. for 60 min, and naturally cooled to room temperature to obtain a mixed solution;

[0050] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0051] Example 2

[0052] A loxoprofen sodium oral solution comprises the following components in parts by mass:

[0053] 0.5 parts of loxoprofen sodium, 1.0 parts of chlorogenic acid, 1.5 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0054] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:2:3;

[0055] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0056] The preparation method of the loxoprofen sodium oral solution comprises the following steps:

[0057] Loxoprofen sodium, inulin, sweetener, cosolvent and part of water were mixed, heated with stirring at 60° C. for 60 min, and naturally cooled to room temperature to obtain a mixed solution;

[0058] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0059] Example 3

[0060] A loxoprofen sodium oral solution comprises the following components in parts by mass:

[0061] 0.5 parts of loxoprofen sodium, 1.0 parts of chlorogenic acid, 2.5 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 93-97 parts of deionized water;

[0062] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:2:5;

[0063] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0064] The preparation method of the loxoprofen sodium oral solution comprises the following steps:

[0065] Loxoprofen sodium, inulin, sweetener, cosolvent and part of water were mixed, heated with stirring at 60° C. for 60 min, and naturally cooled to room temperature to obtain a mixed solution;

[0066] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0067] Example 4

[0068] A loxoprofen sodium oral solution comprises the following components in parts by mass:

[0069] 0.7 parts of loxoprofen sodium, 1.4 parts of chlorogenic acid, 2.1 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0070] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:2:3;

[0071] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0072] The preparation method of the loxoprofen sodium oral solution comprises the following steps:

[0073] Loxoprofen sodium, inulin, sweetener, cosolvent and part of water were mixed, heated with stirring at 60° C. for 60 min, and naturally cooled to room temperature to obtain a mixed solution;

[0074] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0075] Example 5

[0076] A loxoprofen sodium oral solution comprises the following components in parts by mass:

[0077] 0.7 parts of loxoprofen sodium, 1.4 parts of chlorogenic acid, 3.5 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0078] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:2:5;

[0079] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0080] The preparation method of the loxoprofen sodium oral solution comprises the following steps:

[0081] Loxoprofen sodium, inulin, sweetener, cosolvent and part of water were mixed, heated with stirring at 60° C. for 60 min, and naturally cooled to room temperature to obtain a mixed solution;

[0082] The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

[0083] Comparative Example 1

[0084] Loxoprofen sodium oral solution, calculated by weight, comprises the following components:

[0085] 0.7 parts of loxoprofen sodium, 1.4 parts of chlorogenic acid, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0086] The mass ratio of loxoprofen sodium to chlorogenic acid is 1:2;

[0087] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0088] The loxoprofen sodium oral solution in Comparative Example 1 was prepared according to the method of Example 1, except that no inulin was added.

[0089] Comparative Example 2

[0090] Loxoprofen sodium oral solution, calculated by weight, comprises the following components:

[0091] 0.7 parts of loxoprofen sodium, 0.35 parts of chlorogenic acid, 3.5 parts of inulin, 0.2 parts of maltitol as a sweetener, 0.10 parts of glycerol as a cosolvent, and 97 parts of deionized water;

[0092] The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:0.5:5;

[0093] Sodium citrate, a pH regulator, is added to adjust the pH value of the loxoprofen sodium oral solution to 7-7.5.

[0094] The loxoprofen sodium oral solution in Comparative Example 1 was prepared according to the method of Example 1, except that chlorogenic acid was not added.

[0095] 1. Stability test

[0096] The antibacterial performance test was performed on the loxoprofen sodium oral solutions prepared in Examples 1 to 5 and Comparative Examples 1 and 2, and the microbial limits and changes in related substances were tested after the products were stored for 18 months. The results are shown in Tables 1 and 2.

[0097] Table 1 Antibacterial properties of loxoprofen sodium oral solutions prepared in Examples 1 to 5 and Comparative Examples 1 and 2

[0098]

[0099]

[0100] After the loxoprofen sodium oral solutions prepared in Examples 1 to 5 and Comparative Examples 1 and 2 were stored for 18 months, the histogram of the total number of aerobic bacteria per 1 mL was as follows: Figure 1 shown.

[0101] From Table 1 and Figure 1 It can be seen that the antibacterial efficacy of the loxoprofen sodium oral solution prepared in Examples 1 to 5 meets the requirements, and the microbial growth is small after storage for 18 months, and the microbial limit meets the requirements; while the amount of chlorogenic acid added in Comparative Example 2 is small, and the antibacterial efficacy of the loxoprofen sodium oral solution prepared therefrom does not meet the requirements, and the microbial growth is large after storage for 18 months, and aerobic bacteria, molds and yeasts all exceed the limit requirements, indicating that the loxoprofen sodium oral solution prepared by the present invention has excellent antibacterial performance, reducing the risk of microbial contamination during storage.

[0102] Table 2 Comparison results of related substances in loxoprofen sodium oral solution prepared in Examples 1, 3 and 5 and Comparative Examples 1 and 2

[0103]

[0104] After the loxoprofen sodium oral solutions prepared in Examples 1, 3, 5 and Comparative Examples 1 and 2 were stored for 18 months, the bar graph of the detected contents of some related substances was as follows: Figure 2 shown.

[0105] From Table 2 and Figure 2 It can be seen that the related substances in the loxoprofen sodium oral solutions prepared in Examples 1, 3 and 5 of the present invention increased less after storage for 18 months; the impurities in the loxoprofen sodium oral solution in Comparative Example 2 increased significantly after storage for 18 months, indicating that the present invention can effectively inhibit the degradation of loxoprofen sodium and improve product stability by adding a certain amount of chlorogenic acid.

[0106] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A loxoprofen sodium oral solution, characterized in that By mass, it includes the following components: 0.4-0.8 parts of loxoprofen sodium, 0.5-2 parts of chlorogenic acid, 1-4 parts of inulin, 0.1-0.5 parts of sweetener, 0.06-0.12 parts of cosolvent, 90-99 parts of water; The pH value of the loxoprofen sodium oral solution is 6.8-7.

8.

2. The loxoprofen sodium oral solution according to claim 1, characterized in that By mass, it includes the following components: 0.5-0.7 parts of loxoprofen sodium, 0.75-1.5 parts of chlorogenic acid, 1.3-3.5 parts of inulin, 0.2-0.4 parts of sweetener, 0.08-0.10 parts of cosolvent, 93-97 parts of water; The pH value of the loxoprofen sodium oral solution is 7 to 7.

5.

3. The loxoprofen sodium oral solution according to claim 1, characterized in that The mass ratio of loxoprofen sodium, chlorogenic acid and inulin is 1:(1.5-2):(2-3).

4. The loxoprofen sodium oral solution according to claim 3, characterized in that The sweetener is at least one of maltitol, erythritol, sorbitol, xylitol and mannitol.

5. The loxoprofen sodium oral solution according to claim 1, characterized in that The cosolvent is at least one of propylene glycol, glycerol, polyethylene glycol, poloxamer and polyvinyl pyrrolidone.

6. The loxoprofen sodium oral solution according to claim 5, characterized in that The cosolvent is at least one of glycerol and polyethylene glycol.

7. The loxoprofen sodium oral solution according to claim 1, characterized in that The loxoprofen sodium oral solution also contains a pH regulator, which is at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, malic acid, tartaric acid, fumaric acid, maleic acid, sorbic acid, succinic acid, salicylic acid, and oxalic acid.

8. The loxoprofen sodium oral solution according to claim 7, characterized in that The pH adjuster is at least one of acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide, malic acid, tartaric acid, succinic acid, salicylic acid, and oxalic acid.

9. The method for preparing the loxoprofen sodium oral solution according to any one of claims 1 to 8, characterized in that: The following steps are involved: After mixing loxoprofen sodium, inulin, sweetener, cosolvent and part of water, stirring, heating and cooling are performed in sequence to obtain a mixed solution; The mixed solution is mixed with chlorogenic acid and the remaining water, and the pH is adjusted with a pH adjuster to obtain a loxoprofen sodium oral solution.

10. The preparation method according to claim 6, characterized in that: The partial water accounts for 20% to 40% of the total mass of the water.

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