CN113081958B

CN113081958B - Desloratadine oral solution and preparation method thereof

Info

Publication number: CN113081958B
Application number: CN202110486686.XA
Authority: CN
Inventors: 童亮; 苏俊; 广杰; 丁悦; 杨治旻; 申团结
Original assignee: Anhui New Century Pharmaceutical Co ltd
Current assignee: Anhui New Century Pharmaceutical Co ltd
Priority date: 2021-05-01
Filing date: 2021-05-01
Publication date: 2022-05-03
Anticipated expiration: 2041-05-01
Also published as: CN113081958A

Abstract

The invention discloses a desloratadine oral solution and a preparation method thereof. It is known to those skilled in the art that desloratadine and sorbitol in oral solutions of desloratadine produce compatible impurities upon long term storage, which even in the case of the original research axeris is unavoidable. According to the desloratadine oral solution provided by the invention, on the premise of not changing the types and the proportion of auxiliary materials in the original research, maltitol with the mass ratio of 0.75: 1-1: 0.75 to sorbitol is introduced, so that the generation of the compatible impurities can be effectively inhibited, and the desloratadine oral solution is obviously superior to the original research. The invention can effectively overcome the defects of the original ground product only by slightly changing the original ground formula, and has the advantages of extremely small formula change degree and low process verification workload.

Description

Desloratadine oral solution and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a desloratadine oral solution and a preparation method thereof.

Background

Desloratadine oral solutions undergo slow degradation upon prolonged storage. The generated degradation impurity is different from the recorded known impurity, and is an unknown impurity. Experiments prove that the compound is compatible impurity generated by desloratadine and sorbitol.

In order to improve the stability of desloratadine oral liquid, a metal ion complexing agent such as edetate disodium can be added in the prior art. As the product, axeis, produced by Merck Sharp & Dohme b.v. is marketed in the european union (the netherlands) with adjuvants comprising disodium edetate, sorbitol, sucralose, propylene glycol, hypromellose, anhydrous citric acid, sodium citrate, bubble gum essence, desloratadine and purified water. However, the oral liquid still generates compatible impurities with the sorbitol under the condition of long-term storage.

The invention is especially provided for overcoming the defects.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a desloratadine oral solution and a preparation method thereof.

The above purpose of the invention is realized by the following technical scheme:

a desloratadine oral solution comprises disodium edetate, sorbitol, sucralose, propylene glycol, hydroxypropyl methylcellulose, anhydrous citric acid, sodium citrate, bubble gum essence, desloratadine, purified water and maltitol, wherein the mass ratio of the sorbitol to the maltitol is 0.75: 1-1: 0.75.

Preferably, the mass ratio of the desloratadine to the sorbitol is 1: 300.

A preparation method of the desloratadine oral solution comprises the following steps: heating a proper amount of purified water to 40-60 ℃, adding auxiliary materials except the desloratadine, the sorbitol and the maltitol, dissolving completely, adding the desloratadine, the sorbitol and the maltitol, stirring to dissolve, cooling to normal temperature, supplementing the purified water to the formula amount, filtering, and filling to obtain the desloratadine-sorbitol-maltitol beverage.

Has the advantages that:

as described in the background, desloratadine and sorbitol produce compatible impurities when oral desloratadine solutions are stored for a long period of time, which even in the case of Aeris of the same research could not be avoided. According to the desloratadine oral solution provided by the invention, on the premise of not changing the types and the proportion of auxiliary materials in the original research, maltitol with the mass ratio of 0.75: 1-1: 0.75 to sorbitol is introduced, so that the generation of the compatible impurities can be effectively inhibited, and the desloratadine oral solution is obviously superior to the original research. The invention can effectively overcome the defects of the original ground product only by slightly changing the original ground formula, and has the advantages of extremely small formula change degree and low process verification workload.

Drawings

FIG. 1 is a liquid phase detection diagram of related substances in an accelerated test of desloratadine oral solution of examples 2-4 and 7;

FIG. 2 is a liquid phase detection chart of related substances in the long-term stability test of the desloratadine oral solution of examples 2-4 and 7.

Detailed Description

The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.

Examples 1-7 desloratadine oral solutions were formulated as shown in table 1.

TABLE 1 formulation composition of desloratadine oral solution

Examples 1-7 the preparation of desloratadine oral solutions is the same, specifically: heating a proper amount of purified water to 40-60 ℃, adding the rest auxiliary materials, completely dissolving, adding the desloratadine, the sorbitol and the maltitol with the contents of the formula in examples 1-6, only adding the desloratadine and the sorbitol with the contents of the formula in example 7, stirring, dissolving, and cooling to normal temperature. Purified water was added to 1000 ml. Filtering with microporous membrane of less than 10 μm, and packaging to obtain desloratadine oral solution.

According to the requirements of ICH Q1A stability test of new drugs and preparations, the stability of the desloratadine oral solution of the examples 1-7 is examined, and related substances and contents are subjected to high-phase liquid chromatography, and chromatographic parameters are as follows.

A chromatographic column using octadecylsilane chemically bonded silica as a filler takes phosphate buffer solution (0.865 g of sodium dodecyl sulfate and 3.1202g of sodium dihydrogen phosphate are taken and put in 1000ml of water, 0.5ml of trifluoroacetic acid is added) as a mobile phase A, acetonitrile as a mobile phase B, the detection wavelength is 280nm, the flow rate is 1.0ml/min, and the column temperature is 35 ℃. Precisely measuring 100 μ l of the system applicability solution, injecting into a liquid chromatograph, and performing gradient elution according to the following table.

The detection results are shown in tables 2-4, wherein the largest unknown single impurity is a compatible impurity generated by desloratadine and sorbitol.

TABLE 2 Desloratadine oral solution test results on day 0

TABLE 3 Desloratadine oral solution accelerated test results

(simulate original grinding package, temperature 40 ℃ +/-2 ℃, relative humidity 75% +/-5%, standing for 6 months)

TABLE 4 Long-term stability test results for desloratadine oral solutions

(simulate the commercial package, temperature 25 ℃. + -. 2 ℃, relative humidity 60%. + -. 10%, standing for 12 months)

As can be seen from table 3, in the accelerated test, the maximum detectable amount of unknown single impurities in examples 2 to 4 is only less than 0.08%, which is significantly better than 0.35% of the original research, and the chromatogram pair is shown in fig. 1; as can be seen from table 4, in the accelerated test, the maximum detectable amount of unknown impurities in examples 2 to 4 is only less than 0.05%, which is significantly better than 0.29% of the original research, and the chromatogram pair is shown in fig. 2.

The embodiment shows that the desloratadine oral solution provided by the invention can effectively inhibit the generation of the compatible impurities by introducing maltitol with the mass ratio of 0.75: 1-1: 0.75 to sorbitol on the premise of not changing the types and the proportion of auxiliary materials in the original research, and is obviously superior to the original research. The invention can effectively overcome the defects of the original ground product only by slightly changing the original ground formula, and has the advantages of extremely small formula change degree and low process verification workload.

The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims

1. A desloratadine oral solution contains disodium edetate, sorbitol, sucralose, propylene glycol, hydroxypropyl methylcellulose, anhydrous citric acid, sodium citrate, bubble gum essence, desloratadine and purified water, and is characterized in that: and further contains maltitol, wherein the mass ratio of sorbitol to maltitol is 0.75: 1-1: 0.75.

2. The desloratadine oral solution of claim 1 wherein: the mass ratio of desloratadine to sorbitol is 1: 300.

3. A method for preparing the desloratadine oral solution of claim 1 or 2, comprising:

heating a proper amount of purified water to 40-60 ℃, adding auxiliary materials except the desloratadine, the sorbitol and the maltitol, dissolving completely, adding the desloratadine, the sorbitol and the maltitol, stirring to dissolve, cooling to normal temperature, supplementing the purified water to the formula amount, filtering, and filling to obtain the desloratadine-sorbitol-maltitol beverage.