Loratadine oral preparation and preparation method thereof

Abstract

The present invention relates to an oral solution containing loratadine, belonging to the field of pharmaceutical preparations. The oral solution of the present invention contains loratadine, a stabilizer, and a fragrance. The oral solution is prepared by stirring loratadine with hot glycerin, heating pure water to dissolve sodium methylparaben, L-tryptophan, and methylparaben, mixing the above solutions, adding sucralose and fragrance, stirring, filtering, and packaging. The oral solution prepared by the present invention has significantly improved loratadine stability, a good mouthfeel, and high medication compliance in children. The preparation process is simple, suitable for industrial production, and has wide market promotion value.

Description

Technical Field

[0001] The present invention relates to a loratadine oral preparation and a preparation method thereof, belonging to the technical field of pharmaceutical preparations and preparations. Background Art

[0002] Loratadine is a second-generation antihistamine drug that is clinically used to improve or treat allergic symptoms. It can be used for allergic rhinitis, chronic urticaria, allergic conjunctivitis, and allergic asthma. It is a commonly used drug for allergic diseases in children.

[0003] Currently, loratadine is available in the domestic market in tablets, syrups, and oral solutions. Because loratadine itself is practically insoluble in water, solid pharmaceutical preparations often suffer from poor dissolution, slow onset of action, and low bioavailability.

[0004] Among liquid preparations, syrups and oral liquids are preparations with higher medication compliance among children due to their high sweetness and the presence of flavors. However, due to the high sucrose content, sucrose inevitably dehydrates at high temperatures during the production process to produce 5-hydroxymethylfurfural. In addition, after being stored at room temperature for a long time, the preparation has poor stability due to light, heat and other factors. Loratadine is easily converted into 2-hydroxymethylloratadine and 4-hydroxymethylloratadine impurities, as well as discoloration, sedimentation, gas generation or other phenomena, resulting in excessive levels of related substances.

[0005] The above problems have a significant impact on the safety of medication for children. Therefore, it is of great significance to seek a loratadine formulation with higher solubility, stronger stability, and more suitable for children.

[0006] CN114788809B provides a light-stable loratadine liquid preparation, wherein the excipients used are sucralose, glycerol, ethanol, tartaric acid, sorbitol, sodium chloride, and hydroxypropyl methylcellulose. The prepared liquid preparation has the advantages that it can be stored and transported in a transparent container without being subpackaged in a brown container for storage and transportation.

[0007] CN114767677B provides a loratadine syrup product, the excipients used are benzoic acid, glycerol, propylene glycol, anhydrous citric acid, sucrose, and flavoring. The impurity growth rate of the product within one month (40°C, 75% RH) is significantly lower than that of the original preparation, and the stability is better.

[0008] CN104856948B provides a loratadine syrup product, which uses γ-cyclodextrin as an inclusion agent, citric acid as a pH regulator, and grapefruit essence or orange essence as a flavoring agent. After an accelerated test at 60°C for 10 days, the product properties, pH value, and impurity content meet the requirements.

[0009] However, given that syrups, oral liquids, etc. are generally packaged in bottles, they need to be stored at room temperature if they are not used up immediately after opening. Therefore, the above methods still need to be further optimized in terms of the degree of stability improvement, the types and amounts of excipients, and the improvement of the preparation process. Summary of the Invention

[0010] In view of the shortcomings of the existing technology, the present invention provides a loratadine oral preparation and a preparation method thereof to overcome the shortcomings of the existing technology. Experiments have confirmed that the degradation of loratadine is significantly improved, the drug stability can be significantly prolonged and the bioavailability can be improved, ensuring that the drug is safer for children. The preparation process is simple and suitable for industrial promotion.

[0011] While attempting to improve product stability, the inventors discovered that adjusting the order of addition effectively improves the active ingredient's environment, contributing to improved drug stability. Furthermore, by adjusting the type and dosage of stabilizers, the inventors discovered that sodium methylparaben, L-tryptophan, and methylparaben synergistically stabilize loratadine, making it less susceptible to decomposition during storage under conventional conditions. Based on this, the inventors conducted extensive experiments to verify the effectiveness of the present invention's technology, ultimately providing a loratadine oral solution with satisfactory stability and taste.

[0012] The loratadine oral solution of the present invention contains loratadine, a solubilizing agent, a stabilizer, a flavoring agent and purified water.

[0013] Furthermore, in the loratadine oral solution of the present invention, the cosolvent is hot glycerin, the stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the flavoring agent is sucralose.

[0014] By weight, the composition of the loratadine oral solution is:

[0015]

[0016] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben: L-tryptophan: methylparaben = 1: 0.5-1.5: 2-5.

[0017] Preferably, the oral preparation comprises:

[0018]

[0019] Furthermore, the stabilizer is prepared by mixing sodium methylparaben, L-tryptophan, and methylparaben, with the weight ratio of sodium methylparaben: L-tryptophan: methylparaben = 1:1:3.5.

[0020] In addition, the oral preparation further comprises an aroma. Preferably, the aroma is any one or more of blueberry flavor, orange flavor, strawberry flavor, vanilla flavor, cantaloupe flavor, lemon flavor, peach flavor, and raspberry flavor.

[0021] Calculated by weight ratio, loratadine: aromatic agent = 1:5-15.

[0022] Specifically, the oral preparation is composed of:

[0023]

[0024]

[0025] Furthermore, the stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1.5:2.

[0026] A second object of the present invention is to provide a method for preparing a loratadine oral preparation, which specifically comprises the following steps:

[0027] (1) heating glycerol, adding loratadine and stirring to prepare a loratadine-glycerol mixed solution;

[0028] (2) Heat 1 / 2 of pure water, and add sodium methylparaben, L-tryptophan, and methylparaben in order while hot, stirring evenly;

[0029] (3) adding the mixed solution obtained in step (1) to step (2) while hot to obtain a loratadine composite solution;

[0030] (4) When the temperature of the solution in step (3) reaches room temperature, add sucralose and fragrance to the loratadine composite solution in step (3), and add the remaining water at the same time, and stir evenly;

[0031] (5) filtering the solution obtained in step (4), and packaging the solution to obtain a loratadine oral preparation.

[0032] Preferably, in the method for preparing the oral preparation, in step (1), glycerol is heated to 80-100°C.

[0033] Preferably, in the method for preparing the oral preparation, in step (2), water is heated to 60-80°C.

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

[0035] (1) The oral preparation of the present invention can significantly reduce the degradation of loratadine under alkaline and thermal conditions by optimizing the types and weight ratios of excipients, especially when sodium methylparaben, L-tryptophan, and methylparaben are mixed as stabilizers, thereby significantly improving the stability of the preparation;

[0036] (2) The oral preparation of the present invention does not require the pH of the product to be controlled within the strong acid range during the formulation and preparation process, has less gastrointestinal irritation, and is more suitable for children due to the addition of specific flavors;

[0037] (3) The preparation method of the present invention is simple and easy to operate, has low cost, and is suitable for industrial promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is a graph showing the percentage of 2-hydroxymethyl loratadine in each example group;

[0039] Figure 2 The percentage of 4-hydroxymethyl loratadine in each example group;

[0040] Figure 3 The figure is the percentage of total impurities in each embodiment group;

[0041] Figure 4 is a graph showing the percentage of loratadine in each example group;

[0042] Figure 5 This is a taste rating chart for oral solutions. DETAILED DESCRIPTION

[0043] The present invention is further described below by way of specific examples. However, those skilled in the art should be aware that these examples do not limit the present invention in any way.

[0044] Example 1 A loratadine oral preparation

[0045] composition:

[0046]

[0047] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1:3.5.

[0048] Preparation steps:

[0049] (1) heating glycerol to 80-85° C., adding loratadine and stirring to prepare a loratadine-glycerol mixed solution;

[0050] (2) Heat 1 / 2 of pure water to 65-70°C, add sodium methylparaben, L-tryptophan, and methylparaben in sequence while hot, and stir evenly;

[0051] (3) adding the mixed solution obtained in step (1) to step (2) while hot to obtain a loratadine composite solution;

[0052] (4) When the temperature of the solution in step (3) reaches room temperature, add sucralose to the loratadine composite solution in step (3), and add the remaining water at the same time, stirring evenly;

[0053] (5) filtering the solution obtained in step (4), and packaging the solution to obtain a loratadine oral preparation.

[0054] Example 2 A loratadine oral preparation

[0055] composition:

[0056]

[0057] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1:3.5. The fragrance is blueberry essence.

[0058] Preparation steps:

[0059] (1) Loratadine is micronized to 150 nm and sieved. Glycerol is heated to 80-85°C, and loratadine is added and stirred to prepare a loratadine-glycerol mixed solution.

[0060] (2) Heat 1 / 2 of pure water to 65-70°C, add sodium methylparaben, L-tryptophan, and methylparaben in sequence while hot, and stir evenly;

[0061] (3) adding the mixed solution obtained in step (1) to step (2) while hot to obtain a loratadine composite solution;

[0062] (4) When the temperature of the solution in step (3) reaches room temperature, add sucralose and fragrance to the loratadine composite solution in step (3), and add the remaining water at the same time, and stir evenly;

[0063] (5) filtering the solution obtained in step (4), and packaging the solution to obtain a loratadine oral preparation.

[0064] Example 3 A loratadine oral preparation

[0065] composition:

[0066]

[0067] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:0.5:2. The fragrance is orange essence.

[0068] The preparation method is the same as Example 2.

[0069] Example 4 A loratadine oral preparation

[0070] composition:

[0071]

[0072] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1.5:2. The fragrance is cantaloupe essence.

[0073] The preparation method is the same as Example 2.

[0074] Example 5 A loratadine oral preparation

[0075] composition:

[0076]

[0077]

[0078] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1.5:5. The fragrance is strawberry essence.

[0079] The preparation method is the same as Example 2.

[0080] Example 6 A loratadine oral preparation

[0081] composition:

[0082]

[0083] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1.5:2. The fragrance is vanilla essence.

[0084] The preparation method is the same as Example 2.

[0085] Comparative Example 1 A loratadine oral preparation

[0086] composition:

[0087]

[0088] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1.5:2. The fragrance is blueberry essence.

[0089] The preparation method is the same as Example 2.

[0090] Comparative Example 2 A loratadine oral preparation

[0091] composition:

[0092]

[0093]

[0094] The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:5:10. The fragrance is blueberry essence.

[0095] The preparation method is the same as Example 2.

[0096] Comparative Example 3: a loratadine oral preparation

[0097] composition:

[0098]

[0099] The stabilizer is sodium methylparaben and methylparaben, and the weight ratio is sodium methylparaben:methylparaben=1:1. The fragrance is blueberry essence.

[0100] The preparation method is the same as Example 2.

[0101] Comparative Example 4: a loratadine oral preparation

[0102] composition:

[0103]

[0104] The preparation method is the same as that of Example 2, and the fragrance is blueberry essence.

[0105] Comparative Example 5: a loratadine oral preparation

[0106] composition:

[0107]

[0108]

[0109] Preparation method:

[0110] Glycerol and ethanol were mixed and heated to 45°C, loratadine was added and stirred, and then 80% of the prescribed amount of purified water heated to 45°C was added and mixed, sucralose, tartaric acid, sorbitol, sodium chloride and hydroxypropyl methylcellulose were added and stirred, and the remaining purified water was added to make up to volume. The mixture was filtered through a 0.22 μm microporous membrane to obtain a loratadine oral solution, which was packaged separately.

[0111] Comparative Example 6: a loratadine oral preparation

[0112] composition:

[0113]

[0114] Preparation method:

[0115] (1) Methylparaben and propylparaben were added to boiled purified water, stirred for 20 minutes, and cooled to room temperature;

[0116] (2) Add loratadine, sorbitol, sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium edetate, and blueberry essence to the solution of step (1), stir until dissolved, add purified water to make up to volume, and dispense.

[0117] Verification Example 1: Stability Investigation

[0118] (1) Effect of light on the stability of oral preparations

[0119] Referring to the "Guidelines for Stability Testing of Raw Materials and Preparations" 9001 of the "Chinese Pharmacopoeia" (2020 edition), the inspection was carried out under light conditions (4500±500lux, 25℃).

[0120] The loratadine oral solutions prepared in Examples 1-4 and Comparative Examples 1-4 were packaged in transparent PET bottles, and the stability of the preparations was measured by HPLC on the 0th day, 30th day and 60th day after preparation, respectively, to determine the percentage of loratadine and impurities.

[0121] The test results are shown in the following table:

[0122] Table 1 Solution clarity and impurity content in each example

[0123]

[0124]

[0125] As can be seen from the table, the loratadine oral solutions prepared in each group of the examples of the present invention have good light stability.

[0126] (2) Effect of accelerated testing on the stability of oral preparations

[0127] Referring to the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" 9001 of the "Chinese Pharmacopoeia" (2020 edition), the inspection was carried out at a temperature of 40±2°C and a relative humidity of 75±5%.

[0128] The loratadine oral solutions prepared in Examples 2, 3, and 5 and Comparative Examples 2, 3, and 5 were tested, and samples were taken at 0, 1, 3, and 6, respectively. The sample detection method was the same as the illumination test, and the contents of 2-hydroxymethyl loratadine and 4-hydroxymethyl loratadine were recorded.

[0129] The test results are as follows Figures 1 to 4 shown. Figure 1 The content of 2-hydroxymethyl loratadine in each example group is shown in the figure. Figure 2 is the content of 4-hydroxymethyl loratadine in each embodiment group, Figure 3 is the content diagram of total impurities in each embodiment group, Figure 4 The graph shows the loratadine content in each example group. As can be seen from the graph, the loratadine oral solutions prepared in Examples 2, 3, and 5 have good stability during the test and are significantly better than those in the comparative example group.

[0130] Verification Example 2: Taste Investigation

[0131] After tasting, testers will score according to Table 2. Testers are selected between 22 and 50 years old, with half male and half female. Before testing, testers should rinse their mouths and then taste each solution in turn, ensuring that the test solution is held in their mouth for 10 seconds.

[0132] The preparations tested were Example 2 to 6 and Comparative Example 2 to 6.

[0133] The scoring results were statistically analyzed using SPSS22.0.

[0134] Table 2 Reference table for oral solution taste rating

[0135] level standard score 1 Poor experience, obvious bitterness or strange smell 1-2 2 Average experience, slight bitterness or odor 3-4 3 Average experience, no bitterness or slight odor 5-6 4 The experience is good, with little bitterness or odor 7-8 5 Good experience, no bitterness or odor 9-10

[0136] The experimental results are as follows Figure 5 As shown in the results, after adding the aromatics, the taste of the present invention is better than that of the comparative example.

[0137] The above examples demonstrate that the loratadine oral preparation prepared by the present invention has good stability, is superior to conventional commercially available positive control agents, has a simple preparation process, has a good taste, is suitable for children, and has high industrial promotion value.

Claims

1. A loratadine oral preparation, characterized in that The oral preparation of loratadine is composed of: The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1:3.

5.

2. A loratadine oral preparation, characterized in that: The oral preparation of loratadine is composed of: The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1:3.

5. The fragrance is any one or more of blueberry flavor, orange flavor or strawberry flavor, vanilla flavor, cantaloupe flavor, lemon flavor, peach flavor, and raspberry flavor.

3. The loratadine oral preparation according to claim 2, wherein The oral preparation is composed of: The stabilizer is sodium methylparaben, L-tryptophan, and methylparaben, and the weight ratio is sodium methylparaben:L-tryptophan:methylparaben=1:1:3.

5.

4. The loratadine oral preparation according to claim 2 or 3, wherein The preparation method of the oral preparation is: (1) heating glycerol, adding loratadine and stirring to prepare a loratadine-glycerol mixed solution; (2) heating pure water, adding sodium methylparaben, L-tryptophan, and methylparaben while hot, and stirring evenly to obtain a mixed stabilizer solution; (3) slowly adding the loratadine-glycerol mixed solution obtained in step (1) to the mixed stabilizer solution in step (2) while hot, stirring evenly to obtain a loratadine composite solution; (4) After the temperature of the loratadine composite solution in step (3) drops to room temperature, sucralose and fragrance are added to the loratadine composite solution in step (3), and an appropriate amount of pure water is added and stirred evenly; (5) filtering the solution obtained in step (4), and packaging the solution to obtain a loratadine oral preparation.

5. The loratadine oral preparation according to claim 4, wherein In the method for preparing the oral preparation, in step (1), loratadine is crushed into 120 to 180 nm.

6. The loratadine oral preparation according to claim 4, wherein In the method for preparing the oral preparation, in step (1), glycerol is heated to 80-100°C.

7. The loratadine oral preparation according to claim 4, wherein In the method for preparing the oral preparation, in step (2), water is heated to 60-80°C.

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