A cetirizine hydrochloride oral solution composition and its preparation method

Abstract

Cetirizine hydrochloride is an antihistamine drug, which is mainly used clinically to treat seasonal or perennial allergic rhinitis, urticaria and skin pruritus caused by allergens. However, due to the bitter taste of cetirizine hydrochloride, appropriate flavoring agents need to be added to improve the taste. Currently, all the marketed oral solutions of cetirizine hydrochloride are in multi-dose packages, and bacteriostatic agents are added to the prescriptions to control the growth of aerobic bacteria, yeasts, molds and Escherichia coli, but there is no study on the bacteriostatic efficacy against Burkholderia cepacia. The present invention provides an oral solution composition of cetirizine hydrochloride which is safe, effective, has controllable quality and good taste, and a preparation method thereof. The composition includes cetirizine hydrochloride raw material, glycerol, propylene glycol, sweetening agent, flavoring agent, pH regulator, bacteriostatic agent, and purified water.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a cetirizine hydrochloride oral solution composition and a preparation method thereof. Background Art

[0002] Cetirizine hydrochloride is an antihistamine drug, a highly selective H1 receptor antagonist. When taken orally, it quickly binds to the histamine H1 receptor on the target cell membrane, blocking the activation of target cells by histamine. It has no obvious anticholinergic and anti-5-hydroxytryptamine effects, and is not easily permeable through the blood-brain barrier at normal doses. At the same time, it can inhibit the transmission of histamine in the initial stage of allergic reactions, reduce the migratory activity of inflammatory cells and the release of neurotransmitters in the late stage of allergic reactions, so it is also effective against late-stage allergic reactions. Clinically, it is mainly used to treat seasonal or perennial allergic rhinitis, urticaria and skin pruritus caused by allergens.

[0003] Cetirizine hydrochloride (the structure shown in Formula A) is a white or almost white crystalline powder, odorless, bitter in taste, and hygroscopic. It is very soluble in water, soluble in methanol or ethanol, and extremely poorly soluble in acetonitrile or acetone. Its tablets or capsules have a long disintegration time, low dissolution rate and dissolution degree, poor absorption and low bioavailability. As a drug with good water solubility, it can be prepared into an oral solution for easy administration by children, the elderly and patients with difficulty in swallowing. However, due to the bitter taste of cetirizine hydrochloride, an appropriate amount of flavoring agent needs to be added to improve the taste and enhance the compliance of children taking the medicine.

[0004]

[0005] Structural formula of cetirizine hydrochloride of Formula A

[0006] Chinese Patent CN201110059091.2 provides a stable cetirizine oral solution, which contains 1 g of cetirizine hydrochloride, 80 - 100 g of propylene glycol and 360 - 400 g of sorbitol in 1000 mL of solution. The oral solution has a simple formula, few types of excipients and good stability. However, the sweetening agent saccharin sodium used in this invention has a bitter taste, and stevioside has a slight astringent taste, resulting in a poor taste of the oral solution.

[0007] Chinese Patent 02130823.3 provides an anti-allergy drug solution containing levocetirizine. In 1000 mL of the drug composition solution, it includes 0.5 - 20 g of levocetirizine or a pharmaceutically acceptable salt, 20 - 100 g of polyvinylpyrrolidone, 5 - 50 g of poloxamer, and the content of polyethylene glycol 400 is 10 - 250 mL. The defect of this invention is that the prescription contains surfactants, which have certain irritation to the gastrointestinal tract. At the same time, saccharin sodium is used as a flavoring agent in the prescription, resulting in a poor taste.

[0008] Chinese Patent CN 201310375767.8 discloses a cetirizine hydrochloride oral solution, which includes cetirizine hydrochloride, mannitol, hydroxypropyl cellulose, and water. The oral solution of the present invention effectively masks the strong bitter taste of the active ingredient cetirizine, significantly improves the stability of the oral solution, effectively reduces the chemical degradation and side effects of cetirizine, reduces the molecular aggregation phenomenon of the active ingredient, reduces the use risk, and improves the safety of medication. The mannitol used in this invention has a sweetness only 70% that of sucrose; at 25°C, the solubility of mannitol in water is about 18%. In winter, when the temperature is low, it is easy to precipitate crystals during storage and is more difficult to redissolve than sucrose; aspartame used can be decomposed into phenylalanine, aspartic acid, and methanol under the action of human gastrointestinal enzymes, is not suitable for patients with phenylketonuria, and there is no study on its antibacterial efficacy against Burkholderia cepacia.

[0009] Chinese Patent CN201410562636.5 provides a cetirizine hydrochloride syrup. The preparation contains cetirizine hydrochloride, sodium glutamate, xanthan gum, sucrose, a pH regulator, a flavoring agent, and water. Among them, the weight ratio of cetirizine hydrochloride to xanthan gum is 1:1 to 10, preferably 1:5; the dosage of sodium glutamate accounts for 0.5% to 1.0% of the total weight of the syrup; the pH regulator is a disodium hydrogen phosphate-citric acid buffer; the flavoring agent is aspartame, steviol glycoside, or sodium saccharin. Aspartame has a good taste, but it is easy to decompose and unstable; sodium cyclamate can be decomposed into cyclohexylamine, which may have chronic toxicity, under the action of intestinal bacteria, while sodium saccharin has potential carcinogenic effects. The safety of both has been controversial to a certain extent, and the aftertaste is prone to bitterness.

[0010] The cetirizine levocetirizine oral solution invented in Chinese Patent CN202010921323.X uses propionic acid as a preservative. The volume percentage of propionic acid in the cetirizine levocetirizine oral solution is 0.05% to 0.15%, and it contains 13% to 18% of propylene glycol. Adding propionic acid to the cetirizine levocetirizine oral solution in this invention has the same antiseptic effect as traditional preservatives, but has less toxicity and higher safety. However, this invention contains a relatively high amount of propylene glycol, and sodium saccharin has a bitter taste, which will cause the taste to deteriorate.

[0011] In addition, all the currently marketed cetirizine hydrochloride oral solutions are in multi-dose packages, and bacteriostatic agents are added to the prescriptions to control the growth of aerobic bacteria, yeasts, molds, and Escherichia coli. However, there is no study on the bacteriostatic efficacy against Burkholderia cepacia. Burkholderia cepacia has become one of the more important opportunistic pathogens clinically in recent years. It is an important opportunistic pathogen causing cystic fibrosis and belongs to non-fermenting Gram-negative bacilli, consisting of at least 7 genotypes. It is widely present in soil and water and is closely related to hospital infections. It mainly spreads in hospitals through water, thermometers, nebulizers, intravenous catheters, urinary catheters, infusion tubes, etc. It has a high isolation rate in sputum specimens and intensive care units and can cause various hospital infections, including sepsis, endocarditis, pneumonia, wound infections, abscesses, and conjunctivitis, with a mortality rate as high as 95%. This bacterium is resistant to a variety of antibacterial drugs such as β-lactams, aminoglycosides, and polymyxins, especially with a resistance rate to imipenem as high as 90%. Currently, this bacterium has been included in the microbial control items of the US and Australian Pharmacopoeias, indicating a very high level of attention to this bacterium. The cetirizine hydrochloride oral solution composition of the present invention will screen suitable bacteriostatic agents through bacteriostatic efficacy tests to control Burkholderia cepacia. Summary of the Invention

[0012] Aiming at the deficiencies of the above-mentioned prior art, the present invention provides a cetirizine hydrochloride oral solution composition with good taste, safety, effectiveness, and controllable quality, as well as a preparation method thereof. The preparation process of the cetirizine hydrochloride oral solution is simple, with good stability and excellent taste. Adding appropriate bacteriostatic agents can effectively inhibit the growth of microorganisms such as Burkholderia cepacia.

[0013] To achieve the object of the present invention, a cetirizine hydrochloride oral solution composition provided by the inventor includes cetirizine hydrochloride raw material, glycerol, propylene glycol, sweeteners, flavoring agents, pH regulators, bacteriostatic agents, and purified water.

[0014] Among them, the sweeteners include one or more of mannitol, sorbitol, xylitol, sucrose, sucralose, sodium saccharin, steviol glycoside, and aspartame; more preferably, the sweeteners are sorbitol and sucralose. The sweet taste of sucralose is very close to that of sucrose, and it is very stable to heat, acids, and alkalis, with high safety. At the same time, sucralose is not utilized by cariogenic bacteria, can reduce the amount of acid produced by bacteria in the oral cavity, and the adhesion of Streptococcus cells on the tooth surface, effectively playing an anti-caries role, which is particularly beneficial to the dental health of children; sucralose has good stability, can be stored for a long time, and will not be damaged during the freeze-drying process; the sweet taste is pure, similar to the sweet taste of sucrose, and will not produce a bitter aftertaste or strange smell like some other high-intensity sweeteners; the price is cheap, cheaper than sucrose at the same sweetness, and the sweetness is 500-600 times that of sucrose, suitable for industrial applications.

[0015] Among them, the fragrance includes one or a combination of strawberry essence, banana essence, raspberry essence, white peach essence, orange essence, cherry essence, vanilla essence; more preferably, the essence is white peach essence.

[0016] Among them, the pH regulator includes one or more of citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, sodium acetate; more preferably, the pH regulator is acetic acid and sodium acetate; the pH value is 4.5 - 5.5.

[0017] Furthermore, the cetirizine hydrochloride oral solution composition includes cetirizine hydrochloride raw material medicine, glycerol, propylene glycol, sweeteners: sucralose and sorbitol, fragrance: white peach essence, pH regulator: glacial acetic acid and sodium acetate, and the pH value is 4.5 - 5.5; wherein the content of sucralose is 0.8 - 1.2 g / L, the content of sorbitol is 230 - 270 g / L, and the content of white peach essence is 4 - 6 g / L.

[0018] To inhibit the growth of Burkholderia cepacia, aerobic bacteria, yeasts, molds and Escherichia coli in the cetirizine hydrochloride oral solution, the present invention adds an antibacterial agent to the oral solution.

[0019] Among them, the antibacterial agent includes one or more of propionic acid, benzoic acid, sodium benzoate, methylparaben, sodium methylparaben, ethylparaben, sodium ethylparaben, propylparaben, sodium propylparaben, butylparaben, sodium butylparaben, sorbic acid, potassium sorbate; more preferably, the antibacterial agent is a combination of methylparaben and potassium sorbate. For example, in Examples 22 - 24, in the antibacterial efficacy evaluation experiment of oral preparations, when methylparaben and potassium sorbate are combined, the reduction in lg values of bacteria and fungi both meet the antibacterial efficacy evaluation criteria.

[0020] Among them, when the ratio of methylparaben to potassium sorbate is 6:5 and the total dosage of the two is between 1.1 g / L and 3.3 g / L, it can have a good effect of inhibiting the growth of microorganisms such as Burkholderia cepacia.

[0021] Furthermore, the cetirizine hydrochloride oral solution composition includes cetirizine hydrochloride raw material medicine, glycerol, propylene glycol, sweeteners: sucralose and sorbitol, fragrance: white peach essence, pH regulator: glacial acetic acid and sodium acetate (pH value is 4.5 - 5.5), wherein the content of sucralose is 0.8 - 1.2 g / L, the content of sorbitol is 230 - 270 g / L, and the content of white peach essence is 4 - 6 g / L; antibacterial agent: methylparaben and potassium sorbate.

[0022] Meanwhile, adding more than 4% (mass ratio to volume) of propylene glycol to the formulation can significantly enhance the antibacterial efficacy of the bacteriostat against other bacteria and fungi except Burkholderia cepacia in this product. Further, it is found that adding more than 6% of propylene glycol to the formulation can significantly increase the antibacterial efficacy against Burkholderia cepacia. However, when the dosage of propylene glycol reaches more than 10%, it will significantly affect the taste and increase the bitter aftertaste. Therefore, further determination shows that adding 6% - 10% of propylene glycol to the formulation can significantly enhance the antibacterial efficacy against Burkholderia cepacia and maintain relatively good palatability. To ensure the stable and controllable quality of the present invention, the prescription dosages are as follows:

[0023]

[0024]

[0025] Furthermore, the prescription of the cetirizine hydrochloride oral solution composition is as follows:

[0026] The prescription of the cetirizine hydrochloride oral solution composition can also be:

[0027] The prescription of the cetirizine hydrochloride oral solution composition is:

[0028]

[0029]

[0030] Furthermore, the present invention also provides a bacteriostat composition, the active ingredients of which include methylparaben, potassium sorbate and propylene glycol, and this bacteriostat can be used to inhibit the growth of Burkholderia cepacia.

[0031] Furthermore, in the above bacteriostat composition, the mass ratio of methylparaben, potassium sorbate and propylene glycol is 0.1 - 1.8:0.5 - 1.5:60 - 80.

[0032] The present invention also provides a preparation method of the cetirizine hydrochloride oral solution, which specifically includes the following contents:

[0033] 1. Preparation: Take an appropriate amount of purified water, heat it to 50 - 60 °C, weigh and add methylparaben and stir to dissolve, then cool to room temperature;

[0034] 2. Add the prescribed amounts of sorbitol, sucralose, sodium acetate, potassium sorbate and stir to dissolve, then add glycerol and propylene glycol and stir to disperse;

[0035] 3. After adding and dissolving cetirizine hydrochloride, add white peach essence and disperse evenly;

[0036] 4. Adjust the pH to 4.5 - 5.5 with glacial acetic acid, and then make up the volume to 1 L with purified water. After uniform dispersion, it is obtained.

[0037] The beneficial effects of the present invention are as follows:

[0038] (1) For the cetirizine hydrochloride oral solution composition of the present invention, the sweeteners are a combination of sorbitol and sucralose, and by adding white peach essence, the bitterness of cetirizine hydrochloride is excellently masked, and the taste of the oral liquid is greatly improved.

[0039] (2) It is found in the present invention that when using a combination of antibacterial agents of methylparaben and potassium sorbate, with the control ratio at 6:5 and the total dosage of the two between 1.1 g / L and 3.3 g / L, it can have a good effect on inhibiting the growth of microorganisms such as Burkholderia cepacia. At the same time, adding more than 4% of propylene glycol to the formula can significantly enhance the antibacterial efficacy of the antibacterial agent in this product. Further discovery shows that adding 6% - 10% of propylene glycol to the formula can significantly enhance the antibacterial efficacy against Burkholderia cepacia and has good palatability.

[0040] (3) The preparation process of the present invention is simple, with high repeatability, good stability after accelerating for 6 months at 40°C, no growth of microorganisms is seen in the 3 - month study after opening the bottle, and the antibacterial effect is good. Detailed implementation manners

[0041] The content of the present invention includes but is not limited to the following examples. Those skilled in the art who make non - essential improvements and adjustments to the implementation schemes based on the above - mentioned invention content still fall within the protection scope of the present invention.

[0042] Samples for taste screening of cetirizine hydrochloride oral solution compositions in Examples 1 - 16

[0043] Table 1 Screening prescriptions for the influence of sweeteners on taste

[0044] Ingredients Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Cetirizine Hydrochloride 1g 1g 1g 1g 1g 1g 1g Glycerol 200g 200g 200g 200g 200g 200g 200g Mannitol 300g / / / / / / Sucrose / 300g / / / / / Sorbitol / / 150g 250g 300g 250g 250g Sodium Saccharin / / / / / 0.1g / Steviosin / / / / / / 0.1g Sucralose 1g 1g 1g 1g 0.5g / / White Peach Flavor 4g 4g 4g 4g 4g 4g 4g Methylparaben 1.2g 1.2g 1.2g 1.2g 1.2g 1.2g 1.2g Propylparaben 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g Sodium Acetate 4.5g 4.5g 4.5g 4.5g 4.5g 4.5g 4.5g Glacial Acetic Acid 0.7g 0.7g 0.7g 0.7g 0.7g 0.7g 0.7g Purified Water Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L

[0045] Table 2 Screening prescriptions for the influence of flavoring agents on taste

[0046] Ingredients Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Cetirizine Hydrochloride 1g 1g 1g 1g 1g 1g Glycerol 200g 200g 200g 200g 200g 200g Sorbitol 250g 250g 250g 250g 250g 250g Sucralose 1g 1g 1g 1g 1g 1g Strawberry Flavor 4g / / / / / Raspberry Flavor / 4g / / / / Orange Flavor / / 4g / / / Vanilla Flavor / / / 4g / / White Peach Flavor / / / / 2g 6g Methylparaben 1.2g 1.2g 1.2g 1.2g 1.2g 1.2g Propylparaben 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g Sodium Acetate 4.5g 4.5g 4.5g 4.5g 4.5g 4.5g Glacial Acetic Acid 0.7g 0.7g 0.7g 0.7g 0.7g 0.7g Purified Water Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L

[0047] Table 3 Screening prescriptions for the influence of propylene glycol on taste

[0048] Ingredients Example 4 Example 14 Example 15 Example 16 Cetirizine Hydrochloride 1g 1g 1g 1g Glycerol 200g 200g 200g 200g Propylene Glycol / 40g 60g 100g Sorbitol 250g 250g 250g 250g Sucralose 1g 1g 1g 1g White Peach Flavor 4g 4g 4g 4g Methylparaben 1.2g 1.2g 1.2g 1.2g Propylparaben 0.8g 0.8g 0.8g 0.8g Sodium Acetate 4.5g 4.5g 4.5g 4.5g Glacial Acetic Acid 0.7g 0.7g 0.7g 0.7g Purified Water Add up to 1 L Add up to 1 L Add up to 1 L Add up to 1 L

[0049] Preparation of Examples 1 - 16: Take an appropriate amount of purified water, heat it and control the temperature at 70°C - 80°C. After adding methylparaben and propylparaben and stirring to dissolve, cool it to room temperature. Add the prescribed amounts of sorbitol, sodium saccharin / sucralose, and sodium acetate and stir to dissolve. Then add glycerol and / or propylene glycol and stir to disperse. After adding cetirizine hydrochloride and dissolving it completely, add strawberry essence / blueberry essence / white peach essence and disperse evenly. Adjust the pH to 4.5 - 5.5 with glacial acetic acid, and then make up the volume to 1 L with purified water. After dispersing evenly, it is obtained.

[0050] Use the electronic tongue taste analysis system SA402B to detect the taste indexes of sour, sweet, bitter, astringent and various aftertastes for Examples 1 - 14, and the results are shown in Table 2.

[0051] Table 4 Results of the taste test

[0052]

[0053]

[0054] Note: All data are absolute output values based on artificial saliva (reference solution). The state of the electronic tongue testing artificial saliva simulates the state when there is only saliva in the human mouth. Among them, Tasteless is the tasteless point, that is, the output of the reference solution. When the taste value of the example is lower than Tasteless, it means there is no such taste, otherwise there is.

[0055] From the above taste test results, it can be seen that in the screening prescriptions of sweeteners for Examples 1 - 7, no sour taste was detected. Among them, the bitter and astringent aftertastes of Examples 1, 2, 6, and 7 are more obvious than those of Examples 3, 4, and 5. The sweetness of Example 4 is greater than that of Examples 3 and 5, and at the same time, the bitter and astringent tastes and their aftertastes are more subtle. Therefore, sorbitol and sucralose are selected as sweeteners, and it is clear that the dosages of sorbitol and sucralose need to reach 250 mg / ml and 1 mg / ml respectively to have a better taste.

[0056] In the screening prescriptions of flavoring agents for Examples 8 - 13, sour taste was detected in Examples 9 - 11. The aftertaste of Example 8 is more bitter and astringent than those of Examples 12 and 13. Therefore, white peach essence is selected as the flavoring agent. In the screening of the dosage of white peach essence in Examples 4, 12, and 13, the bitter and astringent aftertaste value of Example 12 is greater than those of Examples 4 and 13. Therefore, it is clear that a dosage of white peach essence of 4 - 6 mg / ml can have a good taste.

[0057] Comparing Examples 4, 14, 15, and 16, the bitterness, astringency and their bitter and astringent aftertastes in Example 16 increased significantly, indicating that the addition of propylene glycol has a certain impact on the taste, and when its dosage reaches 10%, the taste will deteriorate significantly.

[0058] Samples for Screening the Bacteriostatic Efficacy of Cetirizine Hydrochloride Oral Solution Compositions in Examples 17 to 23

[0059] Table 5 Prescriptions for Screening the Bacteriostatic Efficacy of Cetirizine Hydrochloride Oral Solution Compositions

[0060]

[0061]

[0062] Preparation of Examples 17 to 18: Take an appropriate amount of purified water, add the corresponding preservative and stir to dissolve, then add the prescribed amounts of sorbitol, sucralose, and sodium acetate and stir to dissolve. Then add glycerol and propylene glycol and stir to disperse. After adding cetirizine hydrochloride and dissolving completely, add white peach essence and disperse evenly. Adjust the pH to 4.5 - 5.5 with glacial acetic acid, and then make up the volume to 1 L with purified water. After dispersing evenly, it is obtained.

[0063] Preparation of Examples 19 to 24: Take an appropriate amount of purified water, heat and control the temperature at 50°C - 60°C, add methylparaben and stir to dissolve. After cooling to room temperature, add the prescribed amounts of sorbitol, sucralose, sodium acetate, propionic acid / potassium sorbate and stir to dissolve. Then add glycerol and propylene glycol and stir to disperse. After adding cetirizine hydrochloride and dissolving completely, add white peach essence and disperse evenly. Adjust the pH to 4.5 - 5.5 with glacial acetic acid, and then make up the volume to 1 L with purified water. After dispersing evenly, it is obtained.

[0064] For Examples 4, 14 - 15, and 17 - 24, referring to the Bacteriostatic Efficacy Test Method in General Chapter 1121 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition), in addition to detecting the bacteriostatic efficacy against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger, the bacteriostatic efficacy against Burkholderia cepacia complex is added, and the test method is as follows:

[0065] Take the agar cultures of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans, add 0.9% sterile sodium chloride solution to elute the cultures on the agar surface, and transfer the bacterial suspension to a sterile test tube. Dilute with 0.9% sterile sodium chloride solution and prepare a bacterial suspension containing approximately 10 8 cfu per 1 ml for standby.

[0066] Take the agar cultures of Burkholderia cepacia (ATCC25416), Burkholderia cepacia (ATCC BAA - 245), and Burkholderia cepacia (ATCC BAA - 247), add pH7.0 sterile sodium chloride - peptone buffer to elute the cultures on the agar surface, and transfer the bacterial suspension to a sterile test tube. Dilute with pH7.0 sterile sodium chloride - peptone buffer and prepare a bacterial suspension containing approximately 10 8Prepare a bacterial suspension with a concentration of

[0067] Take a fresh culture of Aspergillus niger and add an appropriate amount of 0.9% sterile sodium chloride solution containing 0.05% (ml / ml) polysorbate 80 to elute the spores. Then aspirate the spore suspension into a sterile test tube and add an appropriate amount of 0.9% sterile sodium chloride solution containing 0.05% (ml / ml) polysorbate 80 to prepare a spore suspension with approximately 8 cfu per 1 ml for standby.

[0068] Take the test sample and add Burkholderia cepacia (ATCC25416), Burkholderia cepacia (ATCC BAA - 245), Burkholderia cepacia (ATCC BAA - 247), Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger at 1% of the filling volume of this product ( 7 ~ 8 cfu / ml) and mix well to evenly distribute the test bacterial solution in the test sample. Store in the dark at 20 - 25°C. Determine the number of viable bacteria on the 14th day and the 28th day respectively. The evaluation criteria are shown in Table 6, and the results are shown in Table 7.

[0069] Table 6 Evaluation Criteria for Bacteriostatic Efficacy of Oral Preparations

[0070]

[0071] Note: NI: No increase, which means that the increase in the number of test bacteria does not exceed 0.5 lg compared to the previous detection time.

[0072] Table 7 Detection Results of Bacteriostatic Efficacy

[0073]

[0074]

[0075] According to the test results in Table 7, it can be seen that potassium sorbate and propionic acid were separately added as bacteriostatic agents in Examples 17 and 18, and the inhibitory effect on microorganisms such as Burkholderia cepacia was poor. The combination of methyl paraben and propyl paraben in Example 15 and the combination of methyl paraben and propionic acid in Example 19 had better control effects on Burkholderia cepacia than single bacteriostatic agents. However, the optimal choice was the combination of methyl paraben and potassium sorbate. When the ratio was 6:5 and the total dosage of the two was less than 0.88 g / L, the inhibitory effect on microorganisms such as Burkholderia cepacia was not ideal. When it reached between 1.1 g / L and 3.3 g / L, it could have a good inhibitory effect on the growth of microorganisms such as Burkholderia cepacia. At the same time, the comparison of the bacteriostatic efficacy results of Examples 4, 14, and 15 showed that adding more than 4% of propylene glycol to the formula could significantly enhance the bacteriostatic efficacy of the bacteriostatic agent against other bacteria and fungi except Burkholderia cepacia in this product. Further, it was found that adding more than 6% of propylene glycol to the formula could significantly increase the bacteriostatic efficacy against Burkholderia cepacia. However, as shown in Table 4, when the dosage of propylene glycol reached more than 10%, it would significantly affect the taste and increase the bitter aftertaste. Therefore, it was further determined that adding 6% - 10% of propylene glycol to the formula could significantly enhance the bacteriostatic efficacy against Burkholderia cepacia and maintain relatively good palatability.

[0076] Stability of Example 25

[0077] Three batches of samples were prepared according to the prescription with the best taste and bacteriostatic efficacy, namely Example 22, and accelerated (40°C ± 2°C, 75% ± 5% RH) and open-bottle stability investigations were carried out. All indicators such as related substances and microbial limits of the three batches of products met the requirements, and the specific results are shown in Table 8 and Table 9.

[0078] Table 8 Results of accelerated investigation

[0079]

[0080]

[0081] Table 9 Results of open-bottle investigation

[0082]

[0083] The results of the accelerated test in Table 8 and the open-bottle stability test in Table 9 prove that the cetirizine hydrochloride oral solution composition of the present invention has controllable quality and good stability. The bacteriostatic agent combination of methyl paraben and potassium sorbate added to the formula can effectively control the growth of Burkholderia cepacia during the storage and use of this product.

Claims

1. An oral solution composition of cetirizine hydrochloride, comprising cetirizine hydrochloride raw material, glycerol, propylene glycol, sweeteners: sucralose and sorbitol, flavoring agent: white peach essence, pH regulator, purified water; the pH regulator is glacial acetic acid and sodium acetate, and the pH value is 4.5 - 5.5; wherein the content of sucralose is 0.8 - 1.2 g / L, the content of sorbitol is 230 - 270 g / L, and the content of white peach essence is 4 - 6 g / L; The bacteriostatic agent is a mixture of methylparaben and potassium sorbate, and the weight ratio of methylparaben to potassium sorbate is 6:5, and the total dosage of the two is 1.1 g / L - 3.3 g / L; The content of propylene glycol is 6% - 10%.

2. The composition according to claim 1, characterized in that, The prescription of the composition is:

3. The composition according to claim 2, wherein The prescription of the composition is:

4. The composition according to claim 2, characterized in that, The prescription of the composition is:

5. The composition according to claim 2, wherein The prescription of the composition is:

6. A method for preparing the cetirizine hydrochloride oral solution composition according to any one of claims 1 to 5, characterized in that, Comprising: (1) Take an appropriate amount of purified water, heat it to 50 - 60 °C, weigh methylparaben and add it and stir to dissolve, and cool to room temperature; (2) Add the prescribed amount of sorbitol, sucralose, sodium acetate, potassium sorbate and stir to dissolve, then add glycerol and propylene glycol and stir to disperse; (3) After adding and dissolving cetirizine hydrochloride, add white peach essence and disperse evenly; (4) Adjust the pH to 4.5 - 5.5 with glacial acetic acid, then make up the volume to 1 L with purified water, and obtain the product after dispersing evenly.

7. Use of an oral solution composition of cetirizine hydrochloride according to any one of claims 1 - 5 in the preparation of a product for inhibiting the growth of Burkholderia cepacia.

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