Fexofenadine hydrochloride oral suspension and a method for preparing the same

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a fexofenadine hydrochloride oral suspension and its preparation method. The fexofenadine hydrochloride oral suspension provided by this invention comprises the following components by mass fraction: modified fexofenadine hydrochloride: 0.8-1.4%; composite surfactant: 0.1-0.15%; sodium carboxymethyl cellulose: 0.1-0.4%; flavoring agent: 15-23%; purified water: balance. This invention uses modified fexofenadine hydrochloride, adds a composite surfactant, and simultaneously combines sodium carboxymethyl cellulose and a flavoring agent to prepare a fexofenadine hydrochloride oral suspension with high stability and minimal changes in related substances during long-term storage, which is beneficial for the application and promotion of fexofenadine hydrochloride oral suspension.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an oral suspension of fexofenadine hydrochloride and its preparation method. Background Technology

[0002] Allergic diseases are chronic inflammatory conditions, such as allergic rhinitis and chronic urticaria, characterized by recurrent attacks that severely impact people's quality of life. Fexofenadine hydrochloride, as a second-generation, highly selective H1 antihistamine, significantly reduces the incidence of adverse reactions such as drowsiness and palpitations compared to first-generation antihistamines. It is the first-line antihistamine and is widely used in the treatment of allergic diseases.

[0003] Fexofenadine hydrochloride is available in various formulations, including tablets, capsules, and suspensions. Tablets and capsules present challenges such as difficulty in swallowing and accidental ingestion. Oral suspensions, as dispersible liquid formulations, offer advantages such as convenient administration and adjustable dosage, and are particularly suitable for children, demonstrating significant market potential. However, fexofenadine hydrochloride is a poorly soluble drug. The large surface area of ​​the active pharmaceutical ingredient powder makes it prone to microscopic aggregation, sedimentation, and stratification in suspensions. Furthermore, the unstable content of related substances during long-term storage hinders its practical application and promotion. Summary of the Invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defects of existing fexofenadine hydrochloride oral suspension, such as poor drug stability in suspension and unstable content of related substances during long-term storage, and to provide a fexofenadine hydrochloride oral suspension and its preparation method.

[0005] To solve the above problems, the present invention provides the following solution: A fexofenadine hydrochloride oral suspension, comprising the following components by mass fraction: Modified fexofenadine hydrochloride: 0.8-1.4% Compound surfactant: 0.1-0.15% Sodium carboxymethyl cellulose: 0.1-0.4% Flavoring agent: 15-23% Purified water: Balance.

[0006] In one optional embodiment, the preparation method of the modified fexofenadine hydrochloride includes the following steps: 1) Prepare aqueous solutions of low molecular weight sodium alginate, high molecular weight sodium alginate, and ultra-low molecular weight hyaluronic acid respectively. 2) Fexofenadine hydrochloride was spray-coated sequentially with low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution and ultra-low molecular weight hyaluronic acid aqueous solution, and then dried to obtain modified fexofenadine hydrochloride.

[0007] In one alternative embodiment, the molecular weight (Mn) of low molecular weight sodium alginate is 25-35 kDa, the molecular weight (Mn) of high molecular weight sodium alginate is 120-170 kDa, and the molecular weight (Mn) of ultra-low molecular weight hyaluronic acid is 6-10 kDa.

[0008] In one optional embodiment, the mass concentration of the low molecular weight sodium alginate aqueous solution is 0.20-0.50%, the mass concentration of the high molecular weight sodium alginate aqueous solution is 0.150-0.30%, and the mass concentration of the ultra-low molecular weight hyaluronic acid aqueous solution is 0.20-0.50%.

[0009] In one optional embodiment, the particle size D50 of fexofenadine hydrochloride is 2.5-4.5 μm, and the particle size D50 of modified fexofenadine hydrochloride is 5-7 μm.

[0010] In one optional embodiment, the inlet air temperature is 40-45℃, the outlet air temperature is 30-35℃, the feed rate is 14-18mL / min, and the atomization pressure is 0.2-0.4MPa in the spray coating step. The drying process involves vacuum drying at a temperature of 30-38℃ for 3-6 hours.

[0011] In one optional embodiment, the composite surfactant is poloxamer 407, Tween 80 and Tween 20, and the mass ratio of poloxamer 407, Tween 80 and Tween 20 is (2.5-3.5):(1.5-2.2):(0.7-1.5).

[0012] In one alternative embodiment, the flavoring agent is selected from at least one of sucrose, lactose, and xylitol.

[0013] The present invention also provides a method for preparing the above-mentioned fexofenadine hydrochloride oral suspension, comprising the following steps: 1) Dissolve the composite surfactant in a portion of water to obtain a premixed solution; 2) Add flavoring agent and sodium carboxymethyl cellulose to the premixed solution, stir, and obtain the base solution; 3) Add the modified fexofenadine hydrochloride to the base solution, stir to homogenize, make up to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

[0014] In one optional embodiment, the stirring and homogenization step includes stirring at a temperature of 20-30°C and a rotation speed of 3000-3500 r / min for 3-10 min, then stirring at a low speed of 1200-1800 r / min at 20-30°C for 10-20 min, followed by homogenization at 20-30°C and a rotation speed of 5500-6000 r / min for 3-8 min.

[0015] The technical solution of this invention has the following advantages: This invention first modifies fexofenadine hydrochloride by adding a composite surfactant, along with sodium carboxymethyl cellulose and a flavoring agent. The resulting oral suspension of fexofenadine hydrochloride exhibits high stability and minimal changes in related substances during long-term storage, which is beneficial for the application and promotion of oral suspension of fexofenadine hydrochloride. Detailed Implementation

[0016] The following embodiments are provided to further understand the present invention and are not limited to the preferred embodiments described herein, nor do they limit the scope of protection of the present invention.

[0017] Experimental steps or conditions not specified in the following embodiments of this invention can be implemented according to conventional experimental steps and conditions used in existing literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagents or instruments.

[0018] A fexofenadine hydrochloride oral suspension, comprising the following components by mass fraction: Modified fexofenadine hydrochloride: 0.8-1.4% Compound surfactant: 0.1-0.15% Sodium carboxymethyl cellulose: 0.1-0.4% Flavoring agent: 15-23% Purified water: Balance.

[0019] This invention first modifies fexofenadine hydrochloride by adding a composite surfactant, along with sodium carboxymethyl cellulose and a flavoring agent. The resulting oral suspension of fexofenadine hydrochloride exhibits high stability and minimal changes in related substances during long-term storage, which is beneficial for the application and promotion of oral suspension of fexofenadine hydrochloride.

[0020] In one optional embodiment, the preparation method of the modified fexofenadine hydrochloride includes the following steps: 1) Prepare aqueous solutions of low molecular weight sodium alginate, high molecular weight sodium alginate, and ultra-low molecular weight hyaluronic acid respectively. 2) Fexofenadine hydrochloride was spray-coated sequentially with low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution and ultra-low molecular weight hyaluronic acid aqueous solution, and then dried to obtain modified fexofenadine hydrochloride.

[0021] In one optional embodiment, the molecular weight (Mn) of low molecular weight sodium alginate is 25-35 kDa, the molecular weight (Mn) of high molecular weight sodium alginate is 120-170 kDa, and the molecular weight (Mn) of ultra-low molecular weight hyaluronic acid is 6-10 kDa. This invention sequentially uses aqueous solutions of low molecular weight sodium alginate, high molecular weight sodium alginate, and ultra-low molecular weight hyaluronic acid to spray-coat fexofenadine hydrochloride. Low molecular weight sodium alginate has short chains and dense packing, forming a relatively dense coating layer on the surface of fexofenadine hydrochloride powder, isolating it from water and dissolved oxygen. However, the film formed by low molecular weight sodium alginate is brittle and prone to cracking. This invention further uses specific high molecular weight sodium alginate for spray coating. Specific high molecular weight sodium alginate provides a long-chain elastic framework, which is then used to spray-coat the specific molecular weight hyaluronic acid. Hyaluronic acid, with its abundant hydrophilic groups, can form a hydrophilic layer on the outer surface of drugs, significantly reducing interfacial tension and improving the wettability of powder in aqueous phase. In this invention, fexofenadine hydrochloride is spray-coated sequentially with a low molecular weight sodium alginate aqueous solution, a high molecular weight sodium alginate aqueous solution, and an ultra-low molecular weight hyaluronic acid aqueous solution, forming a specific three-layer coating on the surface of fexofenadine hydrochloride. The modified fexofenadine hydrochloride can significantly improve the stability and dispersibility of suspensions when preparing them in subsequent processes, and its related substances do not differ much during long-term storage.

[0022] In one optional embodiment, the mass concentration of the low molecular weight sodium alginate aqueous solution is 0.20-0.50%, the mass concentration of the high molecular weight sodium alginate aqueous solution is 0.150-0.30%, and the mass concentration of the ultra-low molecular weight hyaluronic acid aqueous solution is 0.20-0.50%.

[0023] In one optional embodiment, the particle size D50 of fexofenadine hydrochloride is 2.5-4.5 μm, and the particle size D50 of modified fexofenadine hydrochloride is 5-7 μm.

[0024] In one optional embodiment, the inlet air temperature is 40-45℃, the outlet air temperature is 30-35℃, the feed rate is 14-18mL / min, and the atomization pressure is 0.2-0.4MPa in the spray coating step. The drying process involves vacuum drying at a temperature of 30-38℃ for 3-6 hours.

[0025] In one optional embodiment, the composite surfactant is poloxamer 407, Tween 80, and Tween 20, with a mass ratio of (2.5-3.5):(1.5-2.2):(0.7-1.5). This invention uses specific poloxamer 407, Tween 80, and Tween 20 as composite surfactants. The low HLB value of poloxamer 407 can anchor microscopic hydrophobic defects in the drug, preventing local particle aggregation and sedimentation. The medium HLB value of Tween 80 can fill interfacial adsorption gaps, bridging the hydrophilic and hydrophobic interfaces. The high HLB value of Tween 20 helps reduce solid-liquid interfacial tension. The synergistic effect of these three specific surfactants effectively improves the stability of the suspension.

[0026] In one alternative embodiment, the flavoring agent is selected from at least one of sucrose, lactose, and xylitol.

[0027] This invention can also add preservatives and flavorings as needed, and the amount of preservatives and flavorings added can be the same as the conventional amount.

[0028] The present invention also provides a method for preparing the above-mentioned fexofenadine hydrochloride oral suspension, comprising the following steps: 1) Dissolve the composite surfactant in a portion of water to obtain a premixed solution; 2) Add flavoring agent and sodium carboxymethyl cellulose to the premixed solution, stir, and obtain the base solution; 3) Add the modified fexofenadine hydrochloride to the base solution, stir to homogenize, make up to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

[0029] In one optional embodiment, the stirring and homogenization step includes stirring at a temperature of 20-25°C and a rotation speed of 3000-3500 r / min for 3-10 min, then stirring at a low speed of 25-30°C and a rotation speed of 1200-1800 r / min for 10-20 min, followed by homogenization at a temperature of 20-25°C and a rotation speed of 5500-6000 r / min for 3-8 min. The stirring and homogenization process of this invention involves three stages: a low-speed stirring stage at 1200-1800 rpm for 10-20 minutes, where the stirring temperature is higher than that of the stirring stage at 3000-3500 rpm and the homogenization stage at 5500-6000 rpm. Conventional stirring and homogenization can easily lead to excessively high local temperatures, causing thermal degradation of fexofenadine hydrochloride and uneven distribution of drug powder. In this invention, stirring is first performed at a lower temperature using a speed of 3000-3500 rpm to achieve initial dispersion of the drug powder. Then, the temperature is increased and stirring is performed at a lower speed for a longer period of time to ensure sufficient swelling of sodium carboxymethyl cellulose and other components. Finally, high-speed homogenization is performed at a lower temperature using a speed of 5500-6000 rpm. The three stages work together to achieve better stability of the suspension.

[0030] In one alternative implementation, the amount of purified water added in step 1) is 75-90% of the prescription amount.

[0031] In one optional implementation, the stirring time in step 2) is 10-30 min.

[0032] Example 1

[0033] This embodiment provides a fexofenadine hydrochloride oral suspension, the components of which, by mass fraction, are as follows: Modified fexofenadine hydrochloride: 1.0%; Composite surfactant: 0.12%; Sodium carboxymethyl cellulose: 0.2%; Sucrose: 18%; Purified water: Balance.

[0034] Its preparation method includes the following steps: 1) Prepare 0.40% aqueous solution of low molecular weight sodium alginate (Mn=30kDa), 0.20% aqueous solution of high molecular weight sodium alginate (Mn=150 kDa), and 0.25% aqueous solution of ultra-low molecular weight hyaluronic acid (Mn=8 kDa); 2) Fexofenadine hydrochloride (D50=4.0μm) was sequentially spray-coated in a fluidized bed using low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution, and ultra-low molecular weight hyaluronic acid aqueous solution. The inlet air temperature was 45℃, the outlet air temperature was 35℃, the feed rate was 15 mL / min, and the atomization pressure was 0.3MPa. After the hyaluronic acid coating was completed, the material was placed in a low-temperature vacuum dryer at 35℃ for 4 h to obtain modified fexofenadine hydrochloride (the particle size of modified fexofenadine hydrochloride was D50=5.8μm). 3) Weigh poloxamer 407, Tween 80, and Tween 20 in a mass ratio of 3:2:1, and dissolve them in purified water (80% of the prescribed amount) to obtain a premixed solution; 4) Add sucrose and sodium carboxymethyl cellulose to the premixed solution and stir for 20 min to obtain the base solution; 5) Add the modified fexofenadine hydrochloride to the base solution, stir at 20℃ and 3000 r / min for 5 min, then stir at 25℃ and 1500 r / min for 15 min, then homogenize at 20℃ and 6000 r / min for 5 min, finally bring to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

[0035] Example 2

[0036] This embodiment provides a fexofenadine hydrochloride oral suspension, the components of which, by mass fraction, are as follows: Modified fexofenadine hydrochloride: 1.0%; Composite surfactant: 0.14%; Sodium carboxymethyl cellulose: 0.19%; Sucrose: 18%; Purified water: Balance.

[0037] Its preparation method includes the following steps: 1) Prepare 0.45% aqueous solution of low molecular weight sodium alginate (Mn=30kDa), 0.20% aqueous solution of high molecular weight sodium alginate (Mn=150 kDa), and 0.30% aqueous solution of ultra-low molecular weight hyaluronic acid (Mn=8 kDa) respectively; 2) Fexofenadine hydrochloride (D50=4.0μm) was sequentially spray-coated in a fluidized bed using low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution, and ultra-low molecular weight hyaluronic acid aqueous solution. The inlet air temperature was 45℃, the outlet air temperature was 30℃, the feed rate was 15mL / min, and the atomization pressure was 0.35MPa. After the hyaluronic acid coating was completed, the material was placed in a low-temperature vacuum dryer at 35℃ for 4 h to obtain modified fexofenadine hydrochloride (the particle size of modified fexofenadine hydrochloride was D50=6.1μm). 3) Weigh poloxamer 407, Tween 80, and Tween 20 in a mass ratio of 3:2:1.5, and dissolve them in purified water (80% of the prescribed amount) to obtain a premixed solution; 4) Add sucrose and sodium carboxymethyl cellulose to the premixed solution and stir for 20 min to obtain the base solution; 5) Add the modified fexofenadine hydrochloride to the base solution, stir at 20℃ and 3000 r / min for 5 min, then stir at 25℃ and 1500 r / min for 12 min, then homogenize at 20℃ and 6000 r / min for 4 min, finally bring to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

[0038] Example 3

[0039] This embodiment provides a fexofenadine hydrochloride oral suspension, the components of which, by mass fraction, are as follows: Modified fexofenadine hydrochloride: 1.0%; Composite surfactant: 0.15%; Sodium carboxymethyl cellulose: 0.21%; Sucrose: 18%; Purified water: Balance.

[0040] Its preparation method includes the following steps: 1) Prepare 0.48% aqueous solution of low molecular weight sodium alginate (Mn=30kDa), 0.25% aqueous solution of high molecular weight sodium alginate (Mn=150 kDa), and 0.25% aqueous solution of ultra-low molecular weight hyaluronic acid (Mn=8 kDa) respectively; 2) Fexofenadine hydrochloride (D50=4.0μm) was sequentially spray-coated in a fluidized bed using low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution, and ultra-low molecular weight hyaluronic acid aqueous solution. The inlet air temperature was 45℃, the outlet air temperature was 35℃, the feed rate was 14mL / min, and the atomization pressure was 0.37MPa. After the hyaluronic acid coating was completed, the material was placed in a low-temperature vacuum dryer at 35℃ for 6h to obtain modified fexofenadine hydrochloride (the particle size of modified fexofenadine hydrochloride was D50=6.4μm). 3) Weigh poloxamer 407, Tween 80, and Tween 20 in a mass ratio of 3:1.8:1.5, and dissolve them in purified water (80% of the prescribed amount) to obtain a premixed solution; 4) Add sucrose and sodium carboxymethyl cellulose to the premixed solution and stir for 20 min to obtain the base solution; 5) Add the modified fexofenadine hydrochloride to the base solution, stir at 20℃ and 3000 r / min for 5 min, then stir at 25℃ and 1400 r / min for 15 min, then homogenize at 20℃ and 6000 r / min for 6 min, finally bring to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

[0041] Example 4

[0042] This embodiment provides a fexofenadine hydrochloride oral suspension, which differs from Example 1 in that: in step 3), poloxamer 124, Tween 80, and Tween 20 are weighed in a mass ratio of 3:2:1 and dissolved in purified water (80% of the prescription amount of water) to obtain a premixed solution.

[0043] Example 5

[0044] This embodiment provides a fexofenadine hydrochloride oral suspension, which differs from Example 1 in that: in step 3), poloxamer 407, Tween 65, and Tween 20 are weighed in a mass ratio of 3:2:1 and dissolved in purified water (80% of the prescription amount of water) to obtain a premixed solution.

[0045] Example 6

[0046] This embodiment provides an oral suspension of fexofenadine hydrochloride, which differs from Example 1 in that: in step 5), modified fexofenadine hydrochloride is added to the base solution, stirred at 20°C and 3000 r / min for 20 min, then homogenized at 20°C and 6000 r / min for 5 min, and finally diluted to volume, degassed, and aseptically filled to obtain the oral suspension of fexofenadine hydrochloride.

[0047] Comparative Example 1 This comparative example provides an oral suspension of fexofenadine hydrochloride, which differs from Example 1 in that the modified fexofenadine hydrochloride is replaced with an equal mass of fexofenadine hydrochloride.

[0048] Comparative Example 2 This comparative example provides an oral suspension of fexofenadine hydrochloride, which differs from Example 1 in that: in step 2), the spray coating order of ultra-low molecular weight hyaluronic acid aqueous solution, low molecular weight sodium alginate aqueous solution and high molecular weight sodium alginate aqueous solution is changed. Ultra-low molecular weight hyaluronic acid aqueous solution, low molecular weight sodium alginate aqueous solution and high molecular weight sodium alginate aqueous solution are used in sequence to spray and coat fexofenadine hydrochloride (D50=4.0μm) in a fluidized bed, while other conditions remain unchanged.

[0049] Comparative Example 3 This comparative example provides an oral suspension of fexofenadine hydrochloride, which differs from Example 1 in that: in step 2), low molecular weight sodium alginate is not used for spray coating, and the concentration of high molecular weight sodium alginate (Mn=150 kDa) aqueous solution is adjusted to 0.60%. Specifically, high molecular weight sodium alginate aqueous solution and ultra-low molecular weight hyaluronic acid aqueous solution are used sequentially to spray coating fexofenadine hydrochloride (D50=4.0μm) in a fluidized bed, while other conditions remain unchanged.

[0050] Stability test 1. The sedimentation volume ratio of fexofenadine hydrochloride oral suspension was tested according to the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 1.

[0051] Table 1

[0052] 2. After the sample was placed at 60℃ for 30 days, the relevant substances were tested. The test results are shown in Table 2.

[0053] Table 2

[0054] Obviously, those skilled in the art can make other modifications based on the above embodiments, and the obvious modifications therefrom are still within the protection scope of this invention.

Claims

1. A fexofenadine hydrochloride oral suspension, characterized in that, By mass fraction, it includes the following components: Modified fexofenadine hydrochloride: 0.8-1.4% Compound surfactant: 0.1-0.15% Sodium carboxymethyl cellulose: 0.1-0.4% Flavoring agent: 15-23% Purified water: Balance.

2. The fexofenadine hydrochloride oral suspension according to claim 1, characterized in that, The preparation method of the modified fexofenadine hydrochloride includes the following steps: 1) Prepare aqueous solutions of low molecular weight sodium alginate, high molecular weight sodium alginate, and ultra-low molecular weight hyaluronic acid respectively. 2) Fexofenadine hydrochloride was spray-coated sequentially with low molecular weight sodium alginate aqueous solution, high molecular weight sodium alginate aqueous solution and ultra-low molecular weight hyaluronic acid aqueous solution, and then dried to obtain modified fexofenadine hydrochloride.

3. The fexofenadine hydrochloride oral suspension according to claim 2, characterized in that, The molecular weight (Mn) of low molecular weight sodium alginate is 25-35 kDa, that of high molecular weight sodium alginate is 120-170 kDa, and that of ultra-low molecular weight hyaluronic acid is 6-10 kDa.

4. The fexofenadine hydrochloride oral suspension according to claim 2, characterized in that, The mass concentration of the low molecular weight sodium alginate aqueous solution is 0.20-0.50%, the mass concentration of the high molecular weight sodium alginate aqueous solution is 0.150-0.30%, and the mass concentration of the ultra-low molecular weight hyaluronic acid aqueous solution is 0.20-0.50%.

5. The fexofenadine hydrochloride oral suspension according to claim 2 or 3, characterized in that, The particle size D50 of fexofenadine hydrochloride is 2.5-4.5 μm, and the particle size D50 of modified fexofenadine hydrochloride is 5-7 μm.

6. The fexofenadine hydrochloride oral suspension according to claim 2 or 3, characterized in that, In the spray coating step, the inlet air temperature is 40-45℃, the outlet air temperature is 30-35℃, the feed rate is 14-18mL / min, and the atomization pressure is 0.2-0.4MPa. The drying process involves vacuum drying at a temperature of 30-38℃ for 3-6 hours.

7. The fexofenadine hydrochloride oral suspension according to claim 1, characterized in that, The composite surfactant is poloxamer 407, Tween 80 and Tween 20, and the mass ratio of poloxamer 407, Tween 80 and Tween 20 is (2.5-3.5):(1.5-2.2):(0.7-1.5).

8. The fexofenadine hydrochloride oral suspension according to claim 1, characterized in that, The flavoring agent is selected from at least one of sucrose, lactose, and xylitol.

9. A method for preparing the fexofenadine hydrochloride oral suspension according to any one of claims 1-8, characterized in that, Includes the following steps: 1) Dissolve the composite surfactant in a portion of water to obtain a premixed solution; 2) Add flavoring agent and sodium carboxymethyl cellulose to the premixed solution, stir, and obtain the base solution; 3) Add the modified fexofenadine hydrochloride to the base solution, stir to homogenize, make up to volume, degas, and aseptically fill to obtain fexofenadine hydrochloride oral suspension.

10. The method for preparing fexofenadine hydrochloride oral suspension according to claim 9, characterized in that, The mixing and homogenization steps include mixing at 20-30℃ and 3000-3500 r / min for 3-10 min, then mixing at 20-30℃ and 1200-1800 r / min for 10-20 min, and then homogenizing at 20-30℃ and 5500-6000 r / min for 3-8 min.

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