Desloratadine oral solution and preparation method thereof

Abstract

The invention provides a desloratadine oral solution preparation and a preparation method thereof, the desloratadine oral solution preparation is a water aqua and is composed of a desloratadine active component, a stabilizer, a sweetening agent, pharmaceutically acceptable auxiliary materials of an antioxidant and a solvent water, the strong bitter taste of desloratadine is obviously reduced, and the desloratadine oral solution preparation has the advantages that the desloratadine oral solution preparation is suitable for oral administration of desloratadine; the stability of the desloratadine oral solution is obviously improved by controlling the quality of auxiliary materials, and the desloratadine oral solution and the preparation method thereof disclosed by the invention are simple in preparation process and good in patient compliance. The pharmaceutical composition is particularly useful for administration to teenagers and infants who are treating allergic rhinitis, urticaria with desloratadine.

Description

1. Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a desloratadine oral solution with good taste and stable quality and a preparation method thereof. 2. Background technology

[0002] Desloratadine, its chemical name: 8-chloro-6,11-dihydro-11-(4-nitrogen cyclohexyl)-5H-phenyl-[5,6]-cyclohepta[1,2-b]pyridine.

[0003] The chemical structure is:

[0004] Desloratadine is a new third-generation antihistamine, a non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H1 receptors, so the substance does not enter the central nervous system.

[0005] Desloratadine is an active metabolite of loratadine. It was first successfully developed by Sepracor, a US research-based pharmaceutical company. In December 1997, Schering Plough (merged with Merck in 2009) signed a global exclusive license with Sepracor for desloratadine-related patents and carried out development. On January 15, 2001, desloratadine was first approved in Europe for the relief of allergic rhinitis symptoms, and on August 6, 2001, the indication was added for chronic idiopathic urticaria. Desloratadine is used to relieve systemic and local symptoms of chronic urticaria and allergic rhinitis. Drugs with desloratadine as the active ingredient have the advantages of rapid onset, strong efficacy, no cardiac toxicity, few drug side effects, and no food taboos.

[0006] Desloratadine is weakly acidic, almost insoluble in water, bitter in taste, has peculiar smell and is not heat resistant. Currently available desloratadine formulations are oral solutions, tablets, capsules, syrups, etc., all of which can achieve therapeutic purposes. The bitter taste of the drug itself causes serious compliance problems in administration (especially for infant patients), especially in liquid preparations that are easy to take. Although there are many methods for suppressing the bitter taste of the current marketed products of desloratadine, the bitter taste compliance problem has not been fully solved.

[0007] The technology of using flavoring agents to improve the taste of drugs is one of the most widely used methods for taste masking, especially in pediatric preparations such as liquid preparations. Flavoring agents include sweeteners, aromatics, and mucilages. However, for highly bitter and water-soluble desloratadine, the marketed preparations and existing technologies do not ideally solve the bitterness problem of desloratadine, and even cause other problems such as stability in solving the bitterness problem.

[0008] In addition, desloratadine is a primary amine compound, which is sensitive to oxygen and temperature and easily oxidized. In order to improve the stability of desloratadine oral solution, the original research company Merck Sharp & Dohme BV's marketed product Aeris added metal ion chelating agents such as disodium edetate, and other excipients include sorbitol, sucralose, propylene glycol, sodium metabisulfite, hydroxypropyl methylcellulose, anhydrous citric acid, sodium citrate, bubble gum flavor and purified water.

[0009] Invention patents such as US6100274A, CN1246794A, and WO2006 / 020534A3 use coating / ion exchange and other methods to improve the stability of tablets, but they are not applicable to liquid preparations. In order to solve the oxidation problem, liquid preparations usually use antioxidants or inert gases during the production process and storage process, but adding antioxidants may cause safety problems, and inert gases will increase production costs. It is also not suitable for repeated use after opening the package many times.

[0010] Therefore, how to completely solve the problem of compliance with the bitter taste of desloratadine and improve the stability of desloratadine oral solution, especially the oxygen stability, is a difficult problem to be solved urgently for those skilled in the art, and is also a hot issue studied by those skilled in the art. 3. Summary of the invention

[0011] The invention solves the technical problems of bitter taste compliance and stability of desloratadine, provides a desloratadine oral solution preparation and a preparation method thereof, and significantly improves the stability of desloratadine while satisfying the requirement of good taste.

[0012] The present invention discloses a desloratadine oral liquid preparation, and the specific technical scheme is as follows:

[0013] A desloratadine oral solution preparation comprises the following components: a desloratadine active ingredient, a solubilizer, a preservative, a sweetener, sorbitol, hypromellose, a fragrance, a pH buffer, a stabilizer and purified water.

[0014] in,

[0015] The solubilizer is one or more of propylene glycol, glycerol, ethanol, preferably one or more of propylene glycol and ethanol, more preferably propylene glycol.

[0016] Among them, the common usage amount of propylene glycol is 90%-120%, preferably 90%-110%.

[0017] The antioxidant is one or more of sodium pyrosulfite, sodium sulfite, and sodium bisulfite, preferably one or more of sodium pyrosulfite and sodium bisulfite, and more preferably sodium pyrosulfite.

[0018] The pH buffer is citric acid and sodium citrate buffer salt; or disodium hydrogen phosphate and sodium dihydrogen phosphate buffer salt, preferably citric acid and sodium citrate buffer salt;

[0019] The stabilizer is edetate disodium or edetate calcium sodium, preferably edetate disodium;

[0020] Flavoring agents include sweeteners, gums, and aromatics.

[0021] The sweetener is selected from natural sweeteners or synthetic sweeteners. The natural sweetener is selected from one or more of sucrose or monosaccharide syrup, sorbitol, xylitol, etc.; the synthetic sweetener is selected from one or more of stevioside, saccharin sodium, acesulfame potassium, sucralose, and aspartame, etc. Sucralose and aspartame are preferred, and sorbitol and sucralose are most preferred.

[0022] There are hydrophilic and lipophilic types of fragrances, and the hydrophilic type is preferably selected from sweet orange flavor, pineapple flavor, bubble gum flavor, apple flavor, mixed fruit flavor, etc. Fragrances are usually composed of dozens of spices, and different types of flavors have a great influence on masking the bitterness of desloratadine. After research, it was found that bubble gum flavor has the best effect on masking the bitterness of desloratadine.

[0023] The glue agent is selected from one or more of sodium carboxymethylcellulose, hypromellose, gelatin, gum arabic and tragacanth. Preferred are hypromellose and sodium carboxymethylcellulose, more preferred are hypromellose, further preferred are hypromellose 2910E3, hypromellose 2910E4, hypromellose 2910E5, and hypromellose LV E50, and most preferred is hypromellose 2910E4.

[0024] The pH value of the solution ranges from 5.0 to 6.0.

[0025] The present invention also discloses a method for preparing a desloratadine oral liquid preparation, which comprises the following steps:

[0026] ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, disodium edetate, sodium metabisulfite, citric acid, sodium citrate, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1:

[0027] ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2;

[0028] ③Add solution 2 to solution 1 and stir evenly;

[0029] ④Add bubble gum essence and purified water to full volume, stir well.

[0030] ⑤ Remove insoluble impurities through a filter and fill to obtain the final oral liquid preparation.

[0031] The pharmaceutical composition in the form of an oral solution of desloratadine of the present invention significantly reduces the strong bitter taste of desloratadine, significantly improves the stability of the product by controlling the quality of auxiliary materials, reduces the increase of related substances, and improves the stability of the product during storage. The pharmaceutical composition is particularly used for administration to adolescents and infants who are using desloratadine to treat allergic rhinitis and urticaria.

[0032] In order to make the advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0033] Example 1

[0034] The types and amounts of other raw and auxiliary materials of this product except the solubilizer were fixed, and samples containing different amounts of solubilizer were prepared respectively. The preparation methods remained basically the same, and they were prescriptions 1-4 respectively.

[0035] Table 1 Desloratadine oral solution solubilizer dosage prescription composition

[0036] Table 1 composition Prescription 1 Prescription 2 Prescription 3 Prescription 4 Desloratadine 1g 1g 1g 1g Propylene glycol 180g 200g 220g 240g Sodium metabisulfite 2g 2g 2g 2g Sorbitol 300g 300g 300g 300g Hydroxypropyl methylcellulose 7.0g 7.0g 7.0g 7.0g Sucralose 2g 2g 2g 2g Edetate Disodium 2g 2g 2g 2g Citric acid 0.5g 0.5g 0.5g 0.5g Sodium Citrate 1.0g 1.0g 1.0g 1.0g Bubble Gum Fragrance 3g 3g 3g 3g Add purified water to 2L 2L 2L 2L

[0037] Prescriptions 1 to 4 all adopt the following preparation process:

[0038] ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, disodium edetate, sodium metabisulfite, citric acid, sodium citrate, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1:

[0039] ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2;

[0040] ③Add solution 2 to solution 1 and stir evenly;

[0041] ④Add bubble gum essence and purified water to full volume, stir well.

[0042] ⑤ Remove insoluble impurities through a filter and fill to obtain the final oral liquid preparation.

[0043] Example 2 Antioxidant Test of Desloratadine Oral Solution

[0044] The above-mentioned prescription 2 was used to prepare the sample, and the antioxidants were sodium metabisulfite, sodium sulfite, and sodium bisulfite, respectively, which were prescriptions 4, 5, and 6. The preparation process is shown in Example 1. According to the four guiding principles of the 2020 edition of the "Chinese Pharmacopoeia" 9001 Guidelines for the stability of raw materials and pharmaceutical preparations, Example 2 was tested for influencing factors, and the quality results after being placed at high temperature 60°C for 30 days are shown in Table 2.

[0045] Table 2

[0046] Example 3 Taste and smell evaluation test of desloratadine oral solution

[0047] The sample was prepared using the above prescription 2, and the taste and smell were compared with the control example (trade name: Aerius, manufacturer: Merck Sharp & Dohme Limited). The basic taste is the taste that is initially felt when entering the mouth, the aftertaste is the taste that remains after oral administration, and the smell is the feeling after the nose smells. Hydrophilic sweet orange flavor, pineapple flavor, bubble gum flavor, apple flavor, mixed fruit flavor, etc. are preferred, and the prescriptions are 7, 8, 9, 10, and 11, respectively. The judgment of taste and smell is relatively important. The scoring basis is shown in Table 3, and the scoring results of 5 tasters for taste and smell are shown in Table 4.

[0048] Prescriptions 7 to 11 all adopt the following preparation process:

[0049] ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, disodium edetate, sodium metabisulfite, citric acid, sodium citrate, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1:

[0050] ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2;

[0051] ③Add solution 2 to solution 1 and stir evenly;

[0052] ④Add essence and purified water to full volume and stir evenly.

[0053] ⑤ Remove insoluble impurities through a filter, fill into a 100 ml brown glass bottle and seal it completely to obtain the final oral liquid preparation.

[0054] Table 3 Scoring basis

[0055] The smaller the taste score, the less bitter it is; the smaller the olfactory suitability score, the weaker the taste is. A score over 9 is too irritating, and a score below 1 means that it is basically unscented and has no effect.

[0056] Table 4 Scoring results of prescriptions 7 to 11

[0057] The taste comparison results of prescriptions 7 to 11 and the control examples in Table 4 show that the taste and olfactory sensitivity of flavors with different flavors are significantly different.

[0058] The taste and olfactory applicability of prescriptions 7 to 11 and the control example can achieve satisfactory results, indicating that the use of sweeteners is reasonable. However, there are large differences in bitterness and olfactory perception, and the differences between different prescriptions are large. Bitterness is the taste of desloratadine itself, and we aim to select the most suitable flavor to cover up the bitterness.

[0059] According to the above prescriptions 7 to 11, it was found that different types of flavors have a great effect on masking the bitterness of desloratadine, and the olfactory perception is also very different. Among them, the bubble gum flavor in prescription 9 has the best flavor correction effect, masks the bitterness most obviously, and is also suitable for the sense of smell. It is most easily accepted when added to the desloratadine liquid preparation.

[0060] Example 4 Screening of Hydroxypropyl Methylcellulose Types of Desloratadine Oral Solution

[0061] The prescription slurry agents respectively use hypromellose 2910E3, hypromellose 2910E4, hypromellose 2910E5, and hypromellose LV E50. The preparation process is shown in Example 1 to prepare desloratadine oral solution. The prescriptions are respectively prescription 12, prescription 13, prescription 14, and prescription 15. The prescription dosage is shown in Table 5. The results are shown in Table 6.

[0062] Table 5

[0063] Table 6 Test items Reference Prescription 12 Prescription 13 Prescription 14 Prescription 15 Viscosity (cp) 20.2 10.3 18.7 25.9 89.4

[0064] From Table 6, it can be seen that the viscosity of Hydroxypropyl Methylcellulose E4 is basically the same as that of the reference substance.

[0065] Example 5 Stability Study of Desloratadine Oral Solution

[0066] The prescription is shown in Table 7.

[0067] Table 7 composition Prescription 16 Desloratadine 1g Propylene glycol 200g Sodium metabisulfite 4g Sorbitol 300g Hydroxypropyl methylcellulose 7.0g Sucralose 2g Edetate Disodium 2g Citric acid 0.5g Sodium Citrate 1.0g Bubble Gum Fragrance 3g Add purified water to 2L

[0068] Prescription 16 adopts the following preparation process:

[0069] ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, disodium edetate, sodium metabisulfite, citric acid, sodium citrate, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1:

[0070] ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2;

[0071] ③Add solution 2 to solution 1 and stir evenly;

[0072] ④Add bubble gum essence and purified water to full volume, stir well.

[0073] ⑤ Remove insoluble impurities through a filter and fill to obtain the final oral liquid preparation.

[0074] According to the 2020 edition of the "Chinese Pharmacopoeia" four guidelines 9001 API and drug preparation stability guidelines, Example 5 was tested for influencing factors, and the product performance results are shown in Table 8.

[0075] Table 8

[0076] Example 6 Stability Study of Desloratadine Oral Solution

[0077] The prescription is shown in Table 9.

[0078] Table 9

[0079] Prescription 17 adopts the following preparation process:

[0080] ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, disodium edetate, sodium metabisulfite, citric acid, sodium citrate, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1:

[0081] ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2;

[0082] ③Add solution 2 to solution 1 and stir evenly;

[0083] ④Add bubble gum essence and purified water to full volume, stir well.

[0084] ⑤ Remove insoluble impurities through a filter and fill to obtain the final oral liquid preparation.

[0085] According to the 2020 edition of the "Chinese Pharmacopoeia" four guidelines 9001 API and drug preparation stability guidelines, Example 5 and Prescription 2 were tested for influencing factors, and the product performance results are shown in Table 8.

[0086] Table 10

Claims

1. A desloratadine oral solution, characterized in that: The invention comprises the following components: desloratadine active ingredient, solubilizer, antioxidant, sweetener, sorbitol, hydroxypropyl methylcellulose, bubble gum flavor, pH buffer, stabilizer and purified water.

2. The desloratadine oral solution according to claim 1, characterized in that The type of sorbitol is sorbitol solution. The mass ratio of sorbitol to purified water is 1.1:1 to 1.7:1, preferably 1.5:

1.

3. The desloratadine oral solution according to claim 1, characterized in that The type of the solubilizer is propylene glycol.

4. The desloratadine oral solution according to claim 1, characterized in that The antioxidant is sodium pyrosulfite.

5. The desloratadine oral solution according to claim 1, characterized in that The model of the hypromellose is hypromellose 2910.

6. The desloratadine oral solution according to claim 1, characterized in that The pH buffer salt is citric acid and sodium citrate, and the pH value ranges from 5.0 to 6.

0.

7. The desloratadine oral solution according to claim 1, characterized in that: The desloratadine oral solution according to claim 1, characterized in that the total impurity content of the desloratadine oral solution is 0.4% after being placed at 60°C for 1 month.

8. A method for preparing a desloratadine oral liquid preparation, the method comprising the following steps: ① When preparing and filling, first add 60% to 70% purified water, then add hydroxypropyl methylcellulose, stabilizer, antioxidant, pH buffer, sorbitol, and sucralose in sequence and stir to dissolve, as solution 1: ② Take the remaining propylene glycol, add desloratadine, and stir evenly to obtain solution 2; ③Add solution 2 to solution 1 and stir evenly; ④Add bubble gum essence and purified water to full volume, stir well. ⑤ Remove insoluble impurities through a filter and fill to obtain the final oral liquid preparation.

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