A dextromethorphan tromethamine oral solution and its preparation method

Abstract

This invention provides a dexketoprofen tromethamine oral solution and its preparation method. The oral solution uses maltitol, acesulfame potassium, and ammonium glycyrrhizate to construct a compound flavoring agent, and controls the dosage of each component to achieve synergistic effects, effectively masking the bitter taste of dexketoprofen tromethamine, significantly improving patient compliance, enhancing the stability of the oral solution, and extending the shelf life of the drug. The method of this invention for preparing the dexketoprofen tromethamine oral solution is simple, and exhibits good flavoring effect and stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a dextrokeprofen tromethamine oral solution and its preparation method. Background Technology

[0002] Dexketoprofen Trometamol, chemical name (+)-( S 2-Amino-2-hydroxymethyl-1,3-propanediol salt of 3'-benzoyl-2-phenylpropionic acid is, with the molecular formula C 16 H 14 O3•C4H 11 NO3, with a molecular weight of 375.42, is a nonsteroidal anti-inflammatory drug (NSAID). It is a white crystalline powder with a characteristic irritating odor and possesses analgesic, anti-inflammatory, and antipyretic pharmacological effects. Clinically, it is mainly used to treat mild to moderate pain, including musculoskeletal pain, toothache, and dysmenorrhea. It is one of the commonly used fast-acting analgesics and anti-inflammatory drugs in clinical practice. Its mechanism of action is to inhibit the COX-2 (cyclooxygenase-2) pathway, thereby reducing the synthesis of prostaglandins.

[0003] Currently, all approved dexketoprofen and tromethamine in China are oral solid dosage forms and injections, which are inflexible in terms of administration, difficult to control in terms of dosage, and difficult for special patients to take. Oral liquid dosage forms can effectively solve the above problems and have the following advantages: (1) flexible dosage, which can be adjusted according to the patient's weight and pain level; (2) convenient to take, especially suitable for patients with difficulty swallowing (such as children and the elderly); (3) rapid onset of action, with rapid absorption of the drug in the gastrointestinal tract.

[0004] The original manufacturer of dexketoprofen tromethamine oral solution is LABORATORIOS MENARINI, SA. It was first launched in Spain in 2009 under the brand name Enantyum, with a strength of 10ml:25mg and a packaging specification of 10ml / sachet.

[0005] Patent CN120617156A discloses a dexketoprofen tromethamine oral solution and its preparation method. The concentration of dexketoprofen tromethamine is 25 mg / ml, which is too different from the concentration of the main drug in the original formulation, posing a risk to its medication safety. The method uses sucralose and ammonium glycyrrhizate as flavoring agents, which are simply combined to mask the strong bitterness of dexketoprofen tromethamine, resulting in poor patient compliance. The preparation process requires nitrogen purging and temperature control at 60-90°C, making the process too complicated and the high temperature also affects the product quality.

[0006] Therefore, there is a need in the field for a dexketoprofen tromethamine oral solution that has a good taste, good patient compliance, simple preparation process, and good quality stability. Summary of the Invention

[0007] The purpose of this invention is to provide a dexketoprofen tromethamine oral solution based on existing technology. The solution uses maltitol, acesulfame potassium, and ammonium glycyrrhizate to construct a compound flavoring agent, and controls the dosage of each component to achieve synergistic effects. This effectively masks the bitter taste of dexketoprofen tromethamine, significantly improves patient compliance, enhances the stability of the oral solution, and extends the shelf life of the drug.

[0008] The second objective of this invention is to provide a method for preparing the above-mentioned dextromethorphan tromethamine oral solution.

[0009] The technical solution of the present invention is as follows: A dextromethorphan tromethorphan oral solution comprises the active ingredients dextromethorphan tromethorphan, povidone, polyethylene glycol, an antibacterial agent, a pH adjuster, maltitol, acesulfame potassium, ammonium glycyrrhizate, and a flavoring; wherein the mass concentration of dextromethorphan tromethorphan is 2.5-4.5 mg / mL; the mass concentration of povidone is 30-50 mg / mL; the mass concentration of polyethylene glycol is 10-30 mg / mL; the mass concentration of the antibacterial agent is 1-3 mg / mL; the mass concentration of maltitol is 100-200 mg / mL; the mass concentration of acesulfame potassium is 0.1-0.5 mg / mL; the mass concentration of ammonium glycyrrhizate is 0.1-0.5 mg / mL; and the mass concentration of the flavoring is 0.3-1.8 mg / mL; the pH of the oral solution is adjusted to 5.5-6.5 using a pH adjuster.

[0010] In this invention, the antibacterial agent can be methylparaben; povidone can be povidone K90; polyethylene glycol can be polyethylene glycol 400; and the fragrance can be lemon flavor. The pH adjuster is anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate. During the preparation of the oral solution, the pH value of the oral solution is adjusted to 5.5-6.5, preferably to 5.8-6.2; more preferably, the pH value of the oral solution is adjusted to 6.0.

[0011] This invention uses dexketoprofen tromethamine as the active ingredient and constructs a compound flavoring agent with maltitol, acesulfame potassium, and ammonium glycyrrhizate. By strictly controlling the addition amount of each component, a triple compound flavoring agent of "maltitol (base sweetness) + acesulfame potassium (rapid sweetness) + ammonium glycyrrhizate (bitterness masking)" is constructed to achieve synergistic effects. This results in a dexketoprofen tromethamine oral solution with a better taste, significantly improving patient compliance and increasing solution stability. During the experiment, it was found that even with strict control of the addition amount of each component, using only maltitol, acesulfame potassium, ammonium glycyrrhizate, or any combination of two of them, or replacing them with other similar components, the dexketoprofen tromethamine oral solution could not solve the bitterness problem, resulting in poor patient compliance and poor stability of the oral solution. For the present invention, when the dosage and ratio of each component in maltitol, acesulfame potassium and ammonium glycyrrhizate are too high or too low, a good flavoring effect cannot be obtained, and the stability of the resulting oral solution also decreases.

[0012] In a preferred embodiment, the dexketoprofen tromethamine oral solution provided by the present invention contains the following concentrations: dexketoprofen tromethamine at a concentration of 3.2-4.2 mg / mL; povidone K90 at a concentration of 35-45 mg / mL; polyethylene glycol 400 at a concentration of 15-25 mg / mL; methylparaben at a concentration of 1.5-2.5 mg / mL; anhydrous disodium hydrogen phosphate at a concentration of 2-4 mg / mL; sodium dihydrogen phosphate dihydrate at a concentration of 0.5-1.8 mg / mL; maltitol at a concentration of 110-180 mg / mL; acesulfame at a concentration of 0.2-0.4 mg / mL; ammonium glycyrrhizate at a concentration of 0.1-0.3 mg / mL; and flavoring at a concentration of 0.5-1.5 mg / mL.

[0013] In a more preferred embodiment, the dexketoprofen tromethamine oral solution provided by the present invention contains the following concentrations: dexketoprofen tromethamine at a concentration of 3.5-3.7 mg / mL; povidone K90 at a concentration of 38-42 mg / mL; polyethylene glycol 400 at a concentration of 18-22 mg / mL; methylparaben at a concentration of 1.8-2.2 mg / mL; anhydrous disodium hydrogen phosphate at a concentration of 2.5-3.5 mg / mL; sodium dihydrogen phosphate dihydrate at a concentration of 0.8-1.5 mg / mL; maltitol at a concentration of 125-175 mg / mL; acesulfame K at a concentration of 0.26-0.34 mg / mL; ammonium glycyrrhizate at a concentration of 0.16-0.24 mg / mL; and lemon flavor at a concentration of 0.8-1.2 mg / mL.

[0014] In a particularly preferred embodiment, the dexketoprofen tromethamine oral solution provided by the present invention contains the following concentrations: dexketoprofen tromethamine at a concentration of 3.69 mg / mL; povidone K90 at a concentration of 39-41 mg / mL; polyethylene glycol 400 at a concentration of 19-21 mg / mL; methylparaben at a concentration of 1.9-2.1 mg / mL; anhydrous disodium hydrogen phosphate at a concentration of 2.8-3.2 mg / mL; sodium dihydrogen phosphate dihydrate at a concentration of 1.1-1.3 mg / mL; maltitol at a concentration of 130-180 mg / mL; acesulfame K at a concentration of 0.28-0.32 mg / mL; ammonium glycyrrhizate at a concentration of 0.18-0.22 mg / mL; and lemon flavor at a concentration of 0.9-1.1 mg / mL.

[0015] For example, the dexketoprofen tromethamine oral solution provided by this invention has the following mass concentrations: dexketoprofen tromethamine 3.69 mg / mL; povidone K90 40 mg / mL; polyethylene glycol 400 20 mg / mL; methylparaben 2 mg / mL; anhydrous disodium hydrogen phosphate 3 mg / mL; sodium dihydrogen phosphate dihydrate 1.2 mg / mL; maltitol 130 mg / mL; acesulfame K 0.28 mg / mL; ammonium glycyrrhizate 0.18 mg / mL; and lemon flavor 1 mg / mL.

[0016] For example, the dexketoprofen tromethamine oral solution provided by this invention has the following mass concentrations: dexketoprofen tromethamine 3.69 mg / mL; povidone K90 40 mg / mL; polyethylene glycol 400 20 mg / mL; methylparaben 2 mg / mL; anhydrous disodium hydrogen phosphate 3 mg / mL; sodium dihydrogen phosphate dihydrate 1.2 mg / mL; maltitol 150 mg / mL; acesulfame K 0.3 mg / mL; ammonium glycyrrhizate 0.2 mg / mL; and lemon flavor 1 mg / mL.

[0017] For example, the dexketoprofen tromethamine oral solution provided by this invention has the following mass concentrations: dexketoprofen tromethamine 3.69 mg / mL; povidone K90 40 mg / mL; polyethylene glycol 400 20 mg / mL; methylparaben 2 mg / mL; anhydrous disodium hydrogen phosphate 3 mg / mL; sodium dihydrogen phosphate dihydrate 1.2 mg / mL; maltitol 170 mg / mL; acesulfame K 0.32 mg / mL; ammonium glycyrrhizate 0.22 mg / mL; and lemon flavor 1 mg / mL.

[0018] The present invention also provides a method for preparing the above-mentioned dextromethorphan tromethamine oral solution, comprising the following steps: (1) Heat 60-80% of the total amount of purified water to 40-60℃, add pH adjuster and antibacterial agent, and stir until dissolved; add polyethylene glycol and povidone, and stir again until dissolved; (2) Cool the mixed solution obtained in step (1) to 20-30℃, add the active ingredient dextromethorphan tromethamine, and stir until dissolved; add maltitol, acesulfame potassium, ammonium glycyrrhizate and flavoring in sequence, and stir until dissolved; add the remaining purified water to make up to 1 mL, filter, and fill into a container to obtain the product.

[0019] In this invention, the antibacterial agent can be methylparaben; povidone can be povidone K90; polyethylene glycol can be polyethylene glycol 400; and the fragrance can be lemon flavor. The pH adjuster is anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate. During the preparation of the oral solution, the pH value of the oral solution is adjusted to 5.5-6.5, preferably to 5.8-6.2; more preferably, the pH value of the oral solution is adjusted to 6.0.

[0020] In this invention, in step (1), the amount of purified water added is 60-80% of the total amount, which may be but is not limited to 60%, 65%, 70%, 75% or 80%, preferably 65-75% of the total amount; more preferably, the amount of purified water added is 70% of the total amount.

[0021] In this invention, in step (1), the purified water is heated to 40-60°C, which may be but is not limited to 40°C, 45°C, 50°C, 55°C or 60°C. Preferably, the purified water is heated to 45-65°C; more preferably, the purified water is heated to 50°C.

[0022] The advantages of using the technical solution of this invention are as follows: This invention provides a dexketoprofen tromethamine oral solution, which uses maltitol, acesulfame potassium, and ammonium glycyrrhizate to construct a compound flavoring agent. By controlling the dosage of each component, a synergistic effect is achieved, effectively masking the bitterness of dexketoprofen tromethamine, significantly improving patient compliance, enhancing the stability of the oral solution, and extending the shelf life of the drug. The method of this invention for preparing the dexketoprofen tromethamine oral solution is simple and exhibits good flavoring effect and stability. Detailed Implementation

[0023] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0024] Examples 1-3 The formulation of the dextromethorphan tromethamine oral solution provided by the present invention is shown in Table 1.

[0025]

[0026] The preparation method of the dexketoprofen tromethamine oral solution in Examples 1-3 includes the following steps: (1) Heat 70% of the total purified water to 50°C, add anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate and methylparaben, and stir until dissolved; add polyethylene glycol 400 and povidone K90, and stir again until dissolved; (2) Cool the mixed solution obtained in step (1) to 20-30℃, add the active ingredient dextromethorphan tromethamine, and stir until dissolved; add maltitol, acesulfame potassium, ammonium glycyrrhizate and lemon flavoring in sequence, and stir until dissolved; add the remaining purified water to make up to 1 mL, filter, and fill into a container to obtain the product.

[0027] Comparative Examples 1-6 To investigate the effects of each component on the oral solution, a comparative example was set up, and its formulation is shown in Table 2.

[0028]

[0029] The preparation method of the dexketoprofen tromethamine oral solution in Comparative Example 1 includes the following steps: (1) Heat 70% of the total purified water to 50°C, add anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate and methylparaben, and stir until dissolved; add polyethylene glycol 400 and povidone K90, and stir again until dissolved; (2) Cool the mixed solution obtained in step (1) to 20-30℃, add the active ingredient dextromethorphan tromethorphan, and stir until dissolved; add maltitol, sucralose, ammonium glycyrrhizate and lemon flavoring in sequence, and stir until dissolved; add the remaining purified water to make up to 1 mL, filter, fill into a container, and obtain the product.

[0030] Compared with the preparation method of the oral solution in Example 1, the difference is that "sodium saccharin" is replaced with "acesulfame potassium" in Comparative Example 2, and "maltitol" is replaced with "sucrose" in Comparative Example 6. The preparation methods of the oral solutions in Comparative Examples 3, 4, and 5 are the same as those in Example 1.

[0031] Comparative Example 7 Dextromethorphan tromethamine oral solution prepared according to the formulation and preparation method in Example 1 of patent CN 120617156 A.

[0032] The effect data of the examples and comparative examples are as follows: The taste of the oral solutions in the examples and comparative examples was investigated, and the results are shown in Tables 3 and 4 below.

[0033]

[0034]

[0035] The evaluation criteria involved having 10 tasters compare and rate the bitterness of each sample. The taste score ranged from 1 to 10, with the following scores: very poor (0 points), poor (1-3 points), acceptable (4-6 points), good (7-9 points), and excellent (10 points).

[0036] As shown in Tables 3 and 4, the tasters rated the samples of Examples 1-3 as having a good or very good taste, indicating that the oral solution prepared by constructing a compound flavoring agent using maltitol, acesulfame potassium, and ammonium glycyrrhizate achieves synergistic effects, effectively masks the bitterness of dexketoprofen tromethamine, significantly improves patient compliance, and has a good flavoring effect. In contrast, the tasters rated the samples of Comparative Examples 1-7 as acceptable or having a good taste, indicating that replacing maltitol, acesulfame potassium, and ammonium glycyrrhizate in the compound flavoring agent with other flavoring agents, or adjusting the proportion of maltitol, acesulfame potassium, and ammonium glycyrrhizate in the compound flavoring agent, would not result in a taste that is inferior to that of the samples of Examples 1-3.

[0037] The stability of the dexketoprofen tromethamine oral solutions prepared in the examples and comparative examples was investigated under conditions following the guidelines of the 2025 edition of the Chinese Pharmacopoeia 9001 and ICH Q1. The solutions were packaged in weighing bottles and placed at high temperatures of 40±2℃ and 60±2℃ for 30 days, respectively; and in commercially available packaging and placed at 40±2℃ and 75±5% relative humidity for 3 months. Changes in sample mass were observed, and the results are shown in Tables 5 and 6 below.

[0038]

[0039]

[0040] As shown in Tables 5 and 6, among the oral solutions prepared in Examples 1-3 of this invention, Example 1 is the best. By strictly controlling the dosage and ratio of maltitol, acesulfame potassium, and ammonium glycyrrhizate, a compound flavoring agent is constructed to achieve synergistic effects. Under high temperature (40°C), high temperature (60°C), and accelerated aging (3 months), the content of related substances is low, which improves the stability of the oral solution and extends the shelf life of the drug.

[0041] The oral solutions prepared in Comparative Examples 1-7 showed higher growth trends of related substances under high temperature (40°C), high temperature (60°C), and accelerated conditions (3 months) than those in Examples 1-3, indicating that replacing the amount and ratio of maltitol, acesulfame potassium, and ammonium glycyrrhizate resulted in poor sample stability.

[0042] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A dextroketoprofen tromethamine oral solution, characterized in that, The oral solution comprises the active ingredients dexketoprofen tromethamine, povidone, polyethylene glycol, an antibacterial agent, a pH adjuster, maltitol, acesulfame potassium, ammonium glycyrrhizate, and a flavoring. The concentrations of the dexketoprofen tromethamine are: 2.5-4.5 mg / mL; the povidone concentration is 30-50 mg / mL; the polyethylene glycol concentration is 10-30 mg / mL; the antibacterial agent concentration is 1-3 mg / mL; the maltitol concentration is 100-200 mg / mL; the acesulfame potassium concentration is 0.1-0.5 mg / mL; the ammonium glycyrrhizate concentration is 0.1-0.5 mg / mL; and the flavoring concentration is 0.3-1.8 mg / mL. The pH of the oral solution is adjusted to 5.5-6.5 using a pH adjuster.

2. The oral solution according to claim 1, characterized in that, The antibacterial agent is methylparaben; the pH adjuster is anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate; the povidone is povidone K90; the polyethylene glycol is polyethylene glycol 400; and the fragrance is lemon flavoring.

3. The oral solution according to claim 2, characterized in that, The oral solution contains the following concentrations: dextromethorphan tromethamine 3.2-4.2 mg / mL; povidone K90 35-45 mg / mL; polyethylene glycol 400 15-25 mg / mL; methylparaben 1.5-2.5 mg / mL; anhydrous disodium hydrogen phosphate 2-4 mg / mL; sodium dihydrogen phosphate dihydrate 0.5-1.8 mg / mL; maltitol 110-180 mg / mL; acesulfame K 0.2-0.4 mg / mL; ammonium glycyrrhizate 0.1-0.3 mg / mL; and lemon flavoring 0.5-1.5 mg / mL.

4. The oral solution according to claim 3, characterized in that, The oral solution contains the following concentrations: dextromethorphan tromethamine 3.5-3.7 mg / mL; povidone K90 38-42 mg / mL; polyethylene glycol 400 18-22 mg / mL; methylparaben 1.8-2.2 mg / mL; anhydrous disodium hydrogen phosphate 2.5-3.5 mg / mL; sodium dihydrogen phosphate dihydrate 0.8-1.5 mg / mL; maltitol 125-175 mg / mL; acesulfame K 0.26-0.34 mg / mL; ammonium glycyrrhizate 0.16-0.24 mg / mL; and lemon flavoring 0.8-1.2 mg / mL.

5. The oral solution according to claim 4, characterized in that, The oral solution contains the following concentrations: dextromethorphan tromethamine 3.69 mg / mL; povidone K90 39-41 mg / mL; polyethylene glycol 400 19-21 mg / mL; methylparaben 1.9-2.1 mg / mL; anhydrous disodium hydrogen phosphate 2.8-3.2 mg / mL; sodium dihydrogen phosphate dihydrate 1.1-1.3 mg / mL; maltitol 130-180 mg / mL; acesulfame K 0.28-0.32 mg / mL; ammonium glycyrrhizate 0.18-0.22 mg / mL; and lemon flavoring 0.9-1.1 mg / mL.

6. The oral solution according to claim 5, characterized in that, In this oral solution: The mass concentration of dextromethorphan tromethamine is 3.69 mg / mL; the mass concentration of povidone K90 is 40 mg / mL; the mass concentration of polyethylene glycol 400 is 20 mg / mL; the mass concentration of methylparaben is 2 mg / mL; the mass concentration of anhydrous disodium hydrogen phosphate is 3 mg / mL; the mass concentration of sodium dihydrogen phosphate dihydrate is 1.2 mg / mL; the mass concentration of maltitol is 130 mg / mL; the mass concentration of acesulfame potassium is 0.28 mg / mL; the mass concentration of ammonium glycyrrhizate is 0.18 mg / mL; and the mass concentration of lemon flavor is 1 mg / mL. The mass concentration of dextromethorphan tromethamine is 3.69 mg / mL; the mass concentration of povidone K90 is 40 mg / mL; the mass concentration of polyethylene glycol 400 is 20 mg / mL; the mass concentration of methylparaben is 2 mg / mL; the mass concentration of anhydrous disodium hydrogen phosphate is 3 mg / mL; the mass concentration of sodium dihydrogen phosphate dihydrate is 1.2 mg / mL; the mass concentration of maltitol is 150 mg / mL; the mass concentration of acesulfame potassium is 0.3 mg / mL; the mass concentration of ammonium glycyrrhizate is 0.2 mg / mL; and the mass concentration of lemon flavor is 1 mg / mL. The mass concentration of dextromethorphan tromethamine is 3.69 mg / mL; the mass concentration of povidone K90 is 40 mg / mL; the mass concentration of polyethylene glycol 400 is 20 mg / mL; the mass concentration of methylparaben is 2 mg / mL; the mass concentration of anhydrous disodium hydrogen phosphate is 3 mg / mL; the mass concentration of sodium dihydrogen phosphate dihydrate is 1.2 mg / mL; the mass concentration of maltitol is 170 mg / mL; the mass concentration of acesulfame potassium is 0.32 mg / mL; the mass concentration of ammonium glycyrrhizate is 0.22 mg / mL; and the mass concentration of lemon flavor is 1 mg / mL.

7. The method for preparing the dexketoprofen tromethamine oral solution according to claim 1, characterized in that, Includes the following steps: (1) Heat 60-80% of the total amount of purified water to 40-60℃, add pH adjuster and antibacterial agent, and stir until dissolved; add polyethylene glycol and povidone, and stir again until dissolved; (2) Cool the mixed solution obtained in step (1) to 20-30℃, add the active ingredient dextromethorphan tromethamine, and stir until dissolved; add maltitol, acesulfame potassium, ammonium glycyrrhizate and flavoring in sequence, and stir until dissolved; add the remaining purified water to make up to 1 mL, filter, and fill into a container to obtain the product.

8. The preparation method according to claim 7, characterized in that, The antibacterial agent is methylparaben; the pH adjuster is anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate; the povidone is povidone K90; the polyethylene glycol is polyethylene glycol 400; and the fragrance is lemon flavoring.

9. The preparation method according to claim 8, characterized in that, In step (1), the amount of purified water added is 65-75% of the total amount, preferably 70% of the total amount.

10. The preparation method according to claim 8, characterized in that, In step (1), the purified water is heated to 45-65°C, preferably to 50°C.

Images