Levocetirizine Dihydrochloride Oral Solution

Abstract

The present invention relates to an oral solution of levocetirizine hydrochloride. Specifically, the present invention provides a liquid preparation of levocetirizine hydrochloride, and the liquid preparation of levocetirizine hydrochloride includes glycerol monolaurate, propylene glycol, polyethylene glycol 400, a pH regulator, and water. It may also contain one flavoring agent selected from xylitol, sucrose, sucralose, glucose, aspartame, steviol glycoside, or sodium saccharin. The oral solution of levocetirizine hydrochloride of the present invention has excellent taste and stability.

Description

Technical Field

[0001] The present invention relates to an oral pharmaceutical preparation, and more particularly to an oral solution of levocetirizine hydrochloride. Background Art

[0002] Cetirizine Hydrochloride is a second-generation antihistamine, with the chemical name of (±)-2-[2-[4-[(4-chlorophenyl)benzyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, molecular formula: C 21 H 25 ClN 2 O 3 ·2HCl, molecular weight: 461.82. Among them, levocetirizine is the active optical isomer of cetirizine. It has a small dosage and less toxic and side effects than cetirizine. It retains the characteristics of cetirizine such as rapid onset and strong anti-allergic effect. It has a long metabolic time in vivo and is a long-acting and highly selective peripheral H1 receptor antagonist. It can inhibit the release of a variety of inflammatory mediators related to allergic reactions and thus play a wide range of anti-inflammatory effects. It has no cardiotoxicity, no significant adverse effects on liver and kidney functions, no central nervous system sedative effect, high safety, and a long action duration. The structure of levocetirizine hydrochloride is as follows:

[0003]

[0004] Compared with other levocetirizine hydrochloride preparations, the oral solution of levocetirizine hydrochloride preparation has advantages such as convenient administration and rapid onset. Especially for patients with difficulty in swallowing, such as the elderly or children, the oral compliance with the oral solution of levocetirizine hydrochloride preparation is high. Therefore, the oral solution of levocetirizine hydrochloride preparation has excellent clinical application value.

[0005] The existing oral solution of levocetirizine hydrochloride still has many disadvantages:

[0006] First of all, the taste is poor. Levocetirizine hydrochloride has a strong bitter taste, which makes the taste of the oral solution of levocetirizine hydrochloride poor. Although the bitterness of the oral solution can be reduced to a certain extent by increasing sweetness or fragrance, it is still difficult to effectively improve the bitterness, resulting in low oral compliance, especially in children.

[0007] Secondly, poor stability. Levocetirizine shows instability in physical and chemical properties and it is difficult to maintain stability over time. Especially in liquid preparations, levocetirizine is prone to chemical degradation in water, resulting in reduced efficacy, increased toxic and side reactions, and molecular aggregation can occur, making the solution turbid. Existing levocetirizine hydrochloride oral solutions need to be dispensed in brown bottles to avoid degradation of levocetirizine hydrochloride by light, which leads to reduced content and excessive impurities. Moreover, problems such as easy mildew, rancidity, and color change of the oral liquid occur, and a large amount of preservatives need to be added, bringing factors such as unsafe medication to patients.

[0008] Finally, the preservation problem. To solve the problem of excessive microorganisms in the oral liquid during storage and use, a large amount of preservatives are added. In the prior art, most of the preservatives added to the oral liquid composition are aromatic hydrocarbon compounds, and these compounds are somewhat toxic in organisms and difficult to degrade.

[0009] Although prior art CN 115770214 A, CN 115645359 A, CN 115025041 A, CN114601794 A, CN 114404443 A, CN 112641763 A, CN 112006982 A, CN 113712908 A, CN111096949 A, CN 107823647 A, CN 106491522 A, CN 106236697 A, CN 104306331 A, etc. have reported improved technologies for related liquid preparations. However, the improvement in oral taste or stability is limited.

[0010] There is a need in the art to develop a levocetirizine hydrochloride oral solution with excellent taste and stability, and improve the oral availability and safety of the levocetirizine hydrochloride oral solution. Summary of the Invention

[0011] In view of the above problems, the present invention provides a levocetirizine hydrochloride liquid preparation with excellent taste and stability. Its preparation method is simple, raw materials are easily available, and it is suitable for industrial production.

[0012] The specific technical solution of the present invention is as follows:

[0013] A levocetirizine hydrochloride oral solution, the preparation contains levocetirizine hydrochloride, glycerol monolaurate, propylene glycol, polyethylene glycol 400, pH regulator, and water.

[0014] Preferably, in 1000 ml of the levocetirizine hydrochloride oral solution, it contains 0.2 - 0.6 g of levocetirizine hydrochloride, 2 - 10 g of glycerol monolaurate, 60 - 130 g of propylene glycol, and 10 - 30 g of polyethylene glycol 400.

[0015] Further preferably, 1000 ml of levocetirizine hydrochloride oral solution contains 0.5 g of levocetirizine hydrochloride, 8 g of monoglyceride laurate, 80 g of propylene glycol, and 25 g of polyethylene glycol 400.

[0016] Preferably, the pH regulator is disodium hydrogen phosphate - citric acid buffer or citric acid - sodium citrate buffer, and preferably citric acid - sodium citrate buffer.

[0017] Preferably, the pH is 5.5 - 6.5.

[0018] Preferably, the levocetirizine hydrochloride oral solution further contains one flavoring agent selected from xylitol, sucrose, sucralose, glucose, aspartame, steviol glycoside or sodium saccharin. Preferably xylitol, and its dosage is 15 - 20 g in 1000 ml of levocetirizine hydrochloride oral solution.

[0019] In a preferred embodiment, 1000 ml of levocetirizine hydrochloride oral solution contains:

[0020] 0.2 - 0.6 g of levocetirizine hydrochloride,

[0021] 2 - 10 g of monoglyceride laurate,

[0022] 60 - 130 g of propylene glycol,

[0023] 10 - 30 g of polyethylene glycol 400,

[0024] An appropriate amount of citric acid - sodium citrate buffer is added to adjust the pH to 5.5 - 6.5.

[0025] In another preferred embodiment, 1000 ml of levocetirizine hydrochloride oral solution contains:

[0026] 0.2 - 0.6 g of levocetirizine hydrochloride,

[0027] 2 - 10 g of monoglyceride laurate,

[0028] 60 - 130 g of propylene glycol,

[0029] 10 - 30 g of polyethylene glycol 400,

[0030] 15 - 20 g of xylitol,

[0031] An appropriate amount of citric acid - sodium citrate buffer is added to adjust the pH to 5.5 - 6.5.

[0032] The present invention also provides a preparation method of the above - mentioned levocetirizine hydrochloride oral solution, which includes the following operation steps:

[0033] After stirring and mixing 70 - 80% of the total oral liquid volume of water, propylene glycol, and polyethylene glycol 400 for dissolution at 40 - 50°C, add monoglyceride laurate and stir and mix for dissolution at 40 - 50°C. Then add levocetirizine hydrochloride and continue to stir and mix for dissolution at 40 - 50°C, or add flavoring agent for dissolution to obtain the medicinal liquid. After adjusting the pH of the medicinal liquid to 5.5 - 6.5 by adding pH - adjusting buffer solution, add water to make up to the dispensing volume, stir and mix evenly, filter through a microporous membrane, package, and sterilize to obtain the levocetirizine hydrochloride oral solution.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] In the present invention, adding monoglyceride laurate has the effect of antibacterial and antiseptic, and also improves the taste of the oral liquid. Unexpectedly, the interaction between monoglyceride laurate and citric acid buffer increases the stability of the oral liquid. Detailed implementation manners

[0036] The following further illustrates the present invention through examples. It should be correctly understood that the examples and other contents of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope protected by the present invention.

[0037] Example 1

[0038] Preparation of levocetirizine hydrochloride oral solution:

[0039] 1. Prescription

[0040]

[0041]

[0042] 2. Preparation process:

[0043] After stirring and mixing 70 - 80% of the total oral liquid volume of water, propylene glycol, and polyethylene glycol 400 for dissolution at 40 - 50°C, add monoglyceride laurate and stir and mix for dissolution at 40 - 50°C. Then add levocetirizine hydrochloride and continue to stir and mix for dissolution at 40 - 50°C to obtain the medicinal liquid. After adjusting the pH of the medicinal liquid to 5.5 - 6.5 by adding pH - adjusting buffer solution, add water to make up to the dispensing volume, stir and mix evenly, filter through a 0.22 - μm microporous membrane, package, and sterilize at 115°C to obtain the levocetirizine hydrochloride oral solution.

[0044] Example 2

[0045] Preparation of levocetirizine hydrochloride oral solution:

[0046] 1. Prescription

[0047]

[0048] 2. Preparation process: same as Example 1.

[0049] Example 3

[0050] Preparation of Levocetirizine Hydrochloride Oral Solution:

[0051] 1. Prescription

[0052]

[0053]

[0054] 2. Preparation process: same as Example 1.

[0055] Example 4

[0056] Preparation of Levocetirizine Hydrochloride Oral Solution:

[0057] 1. Prescription

[0058]

[0059] 2. Preparation process: same as Example 1.

[0060] Example 5

[0061] Preparation of Levocetirizine Hydrochloride Oral Solution:

[0062] 1. Prescription

[0063]

[0064] 2. Preparation process: same as Example 1.

[0065] Example 6

[0066] Preparation of Levocetirizine Hydrochloride Oral Solution:

[0067] 1. Prescription

[0068]

[0069] 2. Preparation process:

[0070] After mixing and dissolving water, propylene glycol, and polyethylene glycol 400, which account for 70-80% of the total oral liquid volume, at 40-50°C, add monoglyceride laurate and stir to dissolve at 40-50°C. Then add levocetirizine hydrochloride and continue to stir and dissolve at 40-50°C. Next, add xylitol to dissolve to obtain the medicinal liquid. After adjusting the pH of the medicinal liquid to 5.5-6.5 by adding a pH-adjusting buffer, add water to make up the volume to the dispensing volume, stir and mix evenly, filter through a 0.22μm microporous filter membrane, package, and sterilize at 115°C to obtain the levocetirizine hydrochloride oral solution.

[0071] Comparative Example 1

[0072] Preparation of levocetirizine hydrochloride oral solution:

[0073] 1. Prescription

[0074]

[0075] 2. Preparation process: The same as in Example 1.

[0076] Comparative Example 2

[0077] Preparation of levocetirizine hydrochloride oral solution:

[0078] 1. Prescription

[0079]

[0080] 2. Preparation process: The same as in Example 1.

[0081] Comparative Example 3

[0082] Preparation of levocetirizine hydrochloride oral solution:

[0083] 1. Prescription

[0084]

[0085] 2. Preparation process: The same as in Example 1.

[0086] Comparative Example 4

[0087] Preparation of levocetirizine hydrochloride oral solution:

[0088] 1. Prescription

[0089]

[0090]

[0091] 2. Preparation process:

[0092] 1) Dissolve the above-mentioned prescribed amount of sorbitol in an aqueous medium, heat it to 45°C - 50°C and stir for 25 - 35 minutes. After the sorbitol is completely dissolved, cool it to obtain a sorbitol solution;

[0093] 2) Add the above-mentioned prescribed amounts of sodium saccharin, sodium acetate, propylene glycol, glycerol and propionic acid to the sorbitol solution prepared in step 1), mix them evenly, and then add the above-mentioned prescribed amount of glacial acetic acid to adjust the pH value to 5.0 - 5.6 to obtain a matrix solution;

[0094] 3) Add an aqueous medium to the matrix solution in step 2), and then add the above-mentioned prescribed amount of levocetirizine hydrochloride, and stir until the main drug is completely dissolved;

[0095] 4) After stirring until the main drug is completely dissolved, add an aqueous medium to make up to 1000 ml, continue to stir for 20 - 25 minutes, filter through a 0.22 μm microporous membrane, package, and sterilize at 115°C to obtain an oral solution of levocetirizine hydrochloride.

[0096] Examine the taste and stability of the oral solution of levocetirizine hydrochloride prepared in the examples and comparative examples 1 - 4 of the present invention.

[0097] 1. Taste evaluation

[0098] To evaluate the taste and bitterness degree of the oral solution of levocetirizine hydrochloride, 30 healthy adult men and women aged 20 - 40 were selected for taste testing this time. The bitterness was graded according to the following criteria, and the bitterness evaluation results were expressed as the average value. The bitterness grading and evaluation results are as follows:

[0099] Bitterness grading:

[0100] Level 0 Level 1 Level 2 Level 3 Level 4 Level 5 Level 6 Not bitter at all Not bitter Feeling bitter Slightly bitter Bitter Very bitter Extremely bitter

[0101] Table 1 Evaluation results

[0102] Example 1 0.6 Levocetirizine Hydrochloride 5.4 Example 2 0.9 Comparative Example 1 0.7 Example 3 0.5 Comparative Example 2 0.8 Example 4 1.1 Comparative Example 3 2.3 Example 5 0.5 Comparative Example 4 2.2 Example 6 0.4

[0103] From the taste evaluation results, it can be seen that the addition of monoglyceryl laurate in the examples and comparative examples 1 and 2 greatly improved the taste and effectively masked the bitterness of levocetirizine hydrochloride. Especially the addition of xylitol in Example 6 made the oral liquid have a sweet taste and is suitable for patients who like sweets and diabetes patients.

[0104] 2. Investigation on the stability under the influence of light

[0105] According to the guiding principles for the stability test of preparations in the Chinese Pharmacopoeia, the levocetirizine hydrochloride oral solutions prepared in the examples and comparative examples of the present invention were dispensed into transparent PET bottles, and then the transparent PET bottles filled with levocetirizine hydrochloride oral solution were placed under light conditions (4500 lx, 25 °C) for 0 days (after preparation), 10 days, 20 days and 30 days, and samples were taken for content and total impurity detection. The results are shown in Table 2.

[0106] Table 2 Results of light stability investigation

[0107]

[0108] 3. Accelerated stability investigation

[0109] According to the guiding principles for the stability test of preparations in the Chinese Pharmacopoeia, the levocetirizine hydrochloride oral solutions prepared in the examples and comparative examples of the present invention were dispensed into transparent PET bottles and packaged with the marketed cartons, and then placed under the conditions of a temperature of 40 ± 2 °C and a relative humidity of RH75 ± 5% for 0 days (after preparation) and 6 months, and samples were taken for detection. The results are shown in Table 3.

[0110] Table 3 Results of accelerated investigation

[0111]

[0112] Judging from the stability investigation data, the addition of monoglyceryl laurate and citrate buffer salt, especially in the light test, has greatly improved the stability of the present invention. From the results of the antibacterial efficacy determination, for the products obtained in the examples of the present invention, after 6 months of accelerated investigation, the antibacterial efficacy is still qualified. In Comparative Examples 1 and 2, compared with Example 1, only the citrate buffer salt was replaced with acetate-sodium acetate buffer salt and citric acid, but the antibacterial efficacy was unqualified after accelerated investigation. In Comparative Example 3, monoglyceryl laurate was not added, and in the absence of other preservatives, the antibacterial efficacy was unqualified. In Comparative Example 4, although preservatives such as sorbitol and propionic acid were added, after 6 months of acceleration, the antibacterial efficacy was unqualified, and there was a risk of microbial over-standard during storage and use. Moreover, after the accelerated investigation of Comparative Example 4, the oral liquid had a putrid smell. It can be seen that the interaction between monoglyceryl laurate and citrate buffer salt is beneficial to improving the antibacterial efficacy of the preparation.

Claims

1. Levocetirizine Hydrochloride Oral Solution, characterized in that, the oral solution is composed of levocetirizine hydrochloride, glycerol monolaurate, propylene glycol, polyethylene glycol 400, citric acid - sodium citrate buffer solution, and water; wherein, in 1000 ml of levocetirizine hydrochloride oral solution, there are 0.2 - 0.6 g of levocetirizine hydrochloride, 2 - 10 g of glycerol monolaurate, 60 - 130 g of propylene glycol, and 10 - 30 g of polyethylene glycol 400; the citric acid - sodium citrate buffer solution is appropriate and adjusts the pH to 5.5 - 6.

5.

2. Levocetirizine Hydrochloride Oral Solution, characterized in that, the oral solution is composed of levocetirizine hydrochloride, glycerol monolaurate, propylene glycol, polyethylene glycol 400, xylitol, citric acid - sodium citrate buffer solution, and water; in 1000 ml of levocetirizine hydrochloride oral solution, there are: 0.2 - 0.6 g of levocetirizine hydrochloride, 2 - 10 g of glycerol monolaurate, 60 - 130 g of propylene glycol, 10 - 30 g of polyethylene glycol 400, 15 - 20 g of xylitol, the citric acid - sodium citrate buffer solution is appropriate and adjusts the pH to 5.5 - 6.

5.

3. Preparation method of the levocetirizine hydrochloride oral solution according to any one of claims 1 - 2, characterized in that, it includes the following steps: After stirring and mixing 70 - 80% of the total oral solution volume of water, propylene glycol, and polyethylene glycol 400 at 40 - 50 °C for dissolution, add glycerol monolaurate and stir and mix for dissolution at 40 - 50 °C, then add levocetirizine hydrochloride and continue to stir and mix for dissolution at 40 - 50 °C, or add xylitol for dissolution to obtain the medicinal liquid; After adjusting the pH of the medicinal liquid to 5.5 - 6.5 by adding a pH - adjusting buffer solution to the medicinal liquid, add water to make up the volume to the dispensing volume, stir and mix evenly, filter through a microporous membrane, package, and sterilize to obtain the levocetirizine hydrochloride oral solution.

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