Fexofenadine hydrochloride oral suspension and preparation method thereof

Abstract

The invention relates to the field of medicine, and particularly discloses a fexofenadine hydrochloride oral suspension and a preparation method thereof.The oral suspension comprises an active ingredient and auxiliary materials, the active ingredient is fexofenadine hydrochloride, and the auxiliary materials at least comprise a flavoring agent, a suspending aid, a preservative and a dispersing aid. The suspending aid comprises one or two of sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose; the auxiliary dispersing agent is a mixture of polyvinylpyrrolidone and gelling modified microcrystalline cellulose; the preparation method comprises the following steps: S1, adding water, then adding a buffer solution, stirring for dissolving, then adding a dispersing aid, then adding fexofenadine hydrochloride, and stirring to obtain a raw material A; s2, mixing water with a preservative to prepare a raw material B; s3, adding the suspending aid into the raw material A, then adding the raw material B, mixing and stirring, then adding the flavoring agent, and adding the residual water to a constant volume, thereby obtaining the product. The fexofenadine hydrochloride oral suspension provided by the invention has good redispersion performance.

Description

Technical Field

[0001] The present application relates to the field of medicine, and more specifically, to a fexofenadine hydrochloride oral suspension and a preparation method thereof. Background Art

[0002] The chemical name of fexofenadine hydrochloride is 2,2-dimethyl-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]phenylacetic acid. It is a white or off-white powder. It is the active metabolite of terfenadine in the human body. It is a histamine H1 receptor antagonist and has no anticholinergic or α1-adrenergic receptor blocking effect. Fexofenadine hydrochloride does not have the adverse reaction of prolonging the cardiac QT period of terfenadine, and does not have the rare cardiovascular toxicity that may be caused by similar drugs such as astemizole. It has good clinical therapeutic effects and is a third-generation antihistamine drug without sedative effects. It is used to treat seasonal allergic rhinitis and chronic idiopathic urticaria.

[0003] The raw material of fexofenadine hydrochloride has a distinct bitter taste. Direct oral administration can easily cause discomfort to patients, especially children, and has poor compliance. In the existing preparation process, more flavoring agents, such as artificial sweeteners such as aspartame, are usually added to improve the taste. In addition, fexofenadine hydrochloride is a poorly soluble drug, and the drug dissolution is poor after oral administration, which affects the time it takes for the drug to reach its peak after oral administration.

[0004] For example, a Chinese patent application with publication number CN114681616A discloses a fexofenadine hydrochloride dry suspension and a preparation method thereof. The technical solution is to wet-granulate an ethanol solution of a wetting agent and a flavoring agent with fexofenadine hydrochloride and a filler to obtain the fexofenadine hydrochloride dry suspension, which has good taste, good patient compliance, high stability, and improved drug solubility.

[0005] Although the above technology pays attention to the palatability and adds sodium dioctyl sulfosuccinate as a wetting agent to increase solubility, the dosage form of this solution is a dry suspension, that is, a poorly soluble drug and a suitable auxiliary material are made into a powder or granule, which can be dispersed into a suspension by adding water and shaking when used. It is a liquid preparation for oral administration. It needs to be prepared and used immediately, which is more complicated to use. The suspension is a pre-mixed liquid medicine that can be used directly without additional dissolution, which saves dissolution effort, improves medication efficiency and is more convenient.

[0006] Therefore, it is more convenient to prepare fexofenadine hydrochloride into a suspension dosage form for direct use. In addition, the drug can be quickly administered in an emergency to relieve the condition in time. However, the problem of redispersibility needs to be solved when preparing the suspension dosage form. Redispersibility refers to the dispersion performance of particles in water, that is, the dispersion and stability of drug particles in water. It is an important performance indicator in drug preparations and is usually used to evaluate the quality and stability of drugs. A drug with good redispersibility can be better dissolved in water. Improving the redispersibility of oral suspension drugs can not only improve the quality and stability of the product, but also improve the bioavailability and efficacy of the drug, thereby enhancing the market competitiveness of the product.

[0007] Therefore, it is of great significance to prepare fexofenadine hydrochloride oral suspension with good redispersibility. Summary of the invention

[0008] In order to prepare a fexofenadine hydrochloride oral suspension with good redispersibility, the present application provides a fexofenadine hydrochloride oral suspension and a preparation method thereof.

[0009] In the first aspect, the present application provides a fexofenadine hydrochloride oral suspension, which adopts the following technical scheme: a fexofenadine hydrochloride oral suspension, comprising an active ingredient and excipients, wherein the active ingredient is fexofenadine hydrochloride, and the excipients at least include a flavoring agent, a suspending agent, a preservative, and a dispersing agent, wherein the suspending agent includes one or two of sodium carboxymethyl cellulose and hydroxypropyl methylcellulose; the dispersing agent is a mixture of polyvinyl pyrrolidone and gel-modified microcrystalline cellulose; The gelled modified microcrystalline cellulose is prepared from nicotinamide, L-hydroxyproline, gum arabic and microcrystalline cellulose.

[0010] By adopting the above technical scheme, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose are added as thixotropic suspending agents in the present application, which can give the suspension thixotropy. When the suspension is stationary, the suspending agent can form a network structure to increase the stability of the suspension. When the suspension is subjected to an external force, the network structure is destroyed and the suspension is easy to flow, which is beneficial to the stability of fexofenadine hydrochloride in a static state and alleviates its sedimentation. In addition, the high fluidity in a dynamic state is more conducive to the redispersion of fexofenadine hydrochloride in water, thereby improving the redispersion performance of the suspension. In addition, the present application adds gelled microcrystalline cellulose made of nicotinamide, L-hydroxyproline and gum arabic modified microcrystalline cellulose. The addition of gum arabic realizes the colloidization of microcrystalline cellulose. The gelled microcrystalline cellulose has better dispersibility, which helps to improve the suspension stability of poorly soluble drugs. The addition of nicotinamide and L-hydroxyproline introduces hydroxyl, amino and carboxyl functional groups, so that hydrogen bonds can be formed with fexofenadine hydrochloride, thereby increasing the interaction between microcrystalline cellulose and fexofenadine hydrochloride molecules, thereby improving its stability in the suspension. The addition of nicotinamide and L-hydroxyproline can improve the stability of the suspension. The gel-modified microcrystalline cellulose of nicotinamide and L-hydroxyproline can form a three-dimensional network structure in water, which can wrap fexofenadine hydrochloride to prevent it from aggregating and settling. Nicotinamide and L-hydroxyproline can improve the hydrophilicity of the surface of fexofenadine hydrochloride particles as dispersants, making it easier to disperse in water. Finally, the addition of suspending agents and dispersants in the present application can improve the stability of the suspension, reduce the sedimentation and agglomeration of fexofenadine hydrochloride particles, and when the suspension settles to a certain extent after standing, the dispersant helps to disperse quickly when shaking, thereby improving the redispersibility of the suspension.

[0011] Optionally, the gelled modified microcrystalline cellulose is prepared by the following method: The microcrystalline cellulose is heated and melted, and then gum arabic is added and mixed, and then homogenized and dried to prepare a primary mixture; After nicotinamide and L-hydroxyproline are dissolved in water, the primary mixture is added, ultrasonically dispersed, and then water is removed by reduced pressure distillation to obtain gelled modified microcrystalline cellulose.

[0012] By adopting the above technical scheme, microcrystalline cellulose and gum arabic are first mixed and dispersed in a molten state, which is more conducive to the dispersion of gum arabic in microcrystalline cellulose. After homogenization, the mixture of the two can exert better suspension stability and redispersion performance, especially the improvement of redispersion performance. Then, the primary mixture is added to a solution dissolved with nicotinamide and L-hydroxyproline, and ultrasonic dispersion is performed. The adsorption performance and partial water solubility of the primary mixture after the microcrystalline cellulose and gum arabic are melt-dispersed are utilized to form a complex with nicotinamide and L-hydroxyproline and microcrystalline cellulose, and a three-dimensional network structure can be formed in water to achieve suspension and redispersion of fexofenadine hydrochloride particles.

[0013] Optionally, when preparing the gelled modified microcrystalline cellulose, raw materials are added according to the following weight portions: 20-30 parts of microcrystalline cellulose, 10-18 parts of gum arabic, 3-6 parts of nicotinamide, 4-10 parts of L-hydroxyproline and 18-25 parts of water.

[0014] Optionally, the fexofenadine hydrochloride is added after pretreatment, and the pretreatment comprises the following steps: 1) Dissolving fexofenadine hydrochloride in ethanol, then adding polyethylene glycol, and removing the ethanol by vacuum distillation to obtain a mixture A; 2) Mixing mixture A with edible oil and hydroxypropyl β-cyclodextrin to prepare solution A; 3) Dissolve hydroxylated lecithin and polyvinyl pyrrolidone in sodium chloride solution to prepare solution B; 4) Add solution A to solution B, stir and mix at 60-70° C., then homogenize and spray-dry to obtain pretreated fexofenadine hydrochloride.

[0015] By adopting the above technical scheme, fexofenadine hydrochloride is firstly dissolved in ethanol, and then polyethylene glycol is added, and both are dissolved in ethanol, and after the two are mixed and dispersed, the ethanol is removed by reduced pressure distillation, so that the fexofenadine hydrochloride is wrapped in the spiral structure of the polyethylene glycol crystal, which is beneficial to slow down the sedimentation speed of the drug particles by increasing the viscosity, thereby improving the suspension stability, and when it is shaken after sedimentation, it is more conducive to redispersibility in water under the drive of polyethylene glycol; then it is mixed with edible oil and hydroxypropyl β-cyclodextrin to obtain solution A; The addition of edible oil helps dissolve fexofenadine hydrochloride, and hydroxypropyl β-cyclodextrin has a lipophilic cavity and a hydrophilic surface, which can achieve the initial encapsulation of fexofenadine hydrochloride. Then it is added to the sodium chloride solution. Sodium chloride has a certain osmotic pressure regulating effect. After the initial encapsulation of the active ingredient of the drug by hydroxypropyl β-cyclodextrin, it is combined with hydroxylated lecithin, which has both hydrophilic and lipophilic properties and can be adsorbed on the surface of fexofenadine hydrochloride particles to form a protective film, reduce direct contact between particles, reduce the interaction force between particles, and prevent particle agglomeration and sedimentation. In addition, the long-chain molecular structure of hydroxylated lecithin forms a steric hindrance around the particles, further preventing the particles from approaching and agglomerating each other. This steric hindrance effect helps to maintain the uniform dispersion of the particles in the suspension, and hydroxylated lecithin has good Wettability can improve the wettability of the surface of the fexofenadine hydrochloride particles. The improvement of wettability is conducive to the uniform dispersion and stable suspension of the particles in the dispersion medium, thereby improving the redispersibility. Finally, the mixed dispersion of fexofenadine hydrochloride and polyethylene glycol in the present application is initially encapsulated by hydroxypropyl β-cyclodextrin, and the increased hydrophilicity is beneficial to improving the stability and redispersibility in the suspension. Then, under the re-coating effect of hydroxylated lecithin, it has a certain steric hindrance effect, so that the above particles are separated from each other, which is beneficial to improving its suspension stability. In addition, the partial lipophilicity of the above substances is beneficial to the stable suspension of the encapsulated fexofenadine hydrochloride in the suspension. When shaken by force, the above hydrophilic substances are beneficial to improving its redispersibility. The final suspension has excellent redispersibility and better solubility.

[0016] Optionally, during the pretreatment of fexofenadine hydrochloride, the fexofenadine hydrochloride in step 1) is dissolved in 2-3 times the mass of ethanol, and the amount of polyethylene glycol added is 6-10wt% of the amount of fexofenadine hydrochloride added; In step 2), the mass ratio of mixture A to edible oil and hydroxypropyl β-cyclodextrin is 1:(0.8-1.2):(0.2-0.3); In step 3), the mass ratio of hydroxylated lecithin to polyvinyl pyrrolidone and sodium chloride solution is 1:(0.2-0.3):(2-3), and the mass concentration of the sodium chloride solution is 20-30wt%; In step 4), the mass ratio of solution A to solution B is 1:(0.3-0.4).

[0017] Optionally, the dispersing aid is polyvinyl pyrrolidone and gelled modified microcrystalline cellulose in a mass ratio of 1:(1.2-1.5).

[0018] Optionally, the preservative is sorbic acid.

[0019] By adopting the above technical solution, compared with traditional paraben preservatives, sorbic acid is a safer preservative. Sorbic acid can be rapidly metabolized into carbon dioxide and water in the body, so it will not accumulate in the body and produce toxicity.

[0020] Optionally, the flavoring agent is one or more of sucrose, mannitol, xylitol and essence.

[0021] By adopting the above technical solution, the addition of appropriate flavoring agents can increase the sweetness of the medicine and improve the palatability of the medicine.

[0022] Optionally, each 100 mL of fexofenadine hydrochloride oral suspension comprises the following raw materials: 0.5-0.8 g of fexofenadine hydrochloride, 3-8 g of flavoring agent, 1-3 g of buffer solution, 0.3-0.8 g of suspending agent, 0.01-0.03 g of preservative and 0.3-0.5 g of dispersing agent and the balance of water.

[0023] In a second aspect, the present application provides a method for preparing fexofenadine hydrochloride oral suspension, using the following technical solution: A method for preparing fexofenadine hydrochloride oral suspension comprises the following steps: S1, adding the first part of water, adding a dispersant, and then adding fexofenadine hydrochloride, stirring to obtain raw material A; S2, mixing the second portion of water with a preservative to obtain raw material B; S3. After adding a suspending agent to raw material A, add raw material B, mix and stir, add a flavoring agent, and add the remaining water to make up to volume to prepare fexofenadine hydrochloride oral suspension.

[0024] By adopting the above technical solution, the method provided by the present application is simple, convenient and easy to realize industrialization.

[0025] In summary, this application has the following beneficial effects: 1. In the present application, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose are added as thixotropic suspending agents, which can give the suspension thixotropy. When the suspension is stationary, the suspending agent can form a network structure to increase the stability of the suspension. When the suspension is subjected to external force, the network structure is destroyed and the suspension is easy to flow, which is beneficial to the stability of fexofenadine hydrochloride in a static state and alleviates its sedimentation. The high fluidity in the dynamic state is more conducive to the redispersion of fexofenadine hydrochloride in water, thereby improving the redispersion performance of the suspension; 2. The present application adds gelled microcrystalline cellulose made of nicotinamide, L-hydroxyproline and gum arabic modified microcrystalline cellulose. The addition of gum arabic realizes the colloidization of microcrystalline cellulose. The gelled microcrystalline cellulose has better dispersibility, which helps to improve the suspension stability of poorly soluble drugs. The addition of nicotinamide and L-hydroxyproline introduces hydroxyl, amino and carboxyl functional groups, which can form hydrogen bonds with fexofenadine hydrochloride, thereby increasing the interaction between microcrystalline cellulose and fexofenadine hydrochloride molecules, thereby improving its stability in the suspension. The addition of nicotinamide and L-hydroxyproline can improve the stability of the suspension. The gel-modified microcrystalline cellulose of nicotinamide and L-hydroxyproline can form a three-dimensional network structure in water, which can wrap fexofenadine hydrochloride to prevent it from aggregating and settling. Nicotinamide and L-hydroxyproline can improve the hydrophilicity of the surface of fexofenadine hydrochloride particles as dispersants, making it easier to disperse in water. Finally, the addition of suspending agents and dispersants in the present application can improve the stability of the suspension, reduce the sedimentation and agglomeration of fexofenadine hydrochloride particles, and when the suspension settles to a certain extent after standing, the dispersant helps to disperse quickly when shaking, thereby improving the redispersibility of the suspension. DETAILED DESCRIPTION

[0026] The present application is further described in detail below in conjunction with the examples. It is particularly noted that if no specific conditions are specified in the following examples, the experiments are carried out according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0027] The colloidal microcrystalline cellulose in the following examples is colloidal microcrystalline cellulose from Shanghai Shenmei Pharmaceutical Development Technology Co., Ltd., which is prepared from microcrystalline cellulose and sodium carboxymethyl cellulose; The following preparation example is a preparation example of gelatinized modified microcrystalline cellulose. Preparation Example 1 A method for preparing gelatinized modified microcrystalline cellulose comprises the following steps: 1) Heat and melt 25 parts of microcrystalline cellulose, add 15 parts of gum arabic and mix, then homogenize and cool and dry to prepare a primary mixture; 2) After dissolving 5 parts of nicotinamide and 6 parts of L-hydroxyproline in 20 parts of water, add the prepared primary mixture, disperse by ultrasonic for 15 minutes, and then remove water by vacuum distillation to obtain gelled modified microcrystalline cellulose.

[0028] Preparation Example 2 A method for preparing gelatinized modified microcrystalline cellulose comprises the following steps: 1) Heat and melt 20 parts of microcrystalline cellulose, add 10 parts of gum arabic and mix, then homogenize and cool and dry to prepare a primary mixture; 2) After dissolving 3 parts of nicotinamide and 4 parts of L-hydroxyproline in 18 parts of water, add the prepared primary mixture, disperse by ultrasonic for 10 minutes, and then remove water by vacuum distillation to obtain gelled modified microcrystalline cellulose.

[0029] Preparation Example 3 A method for preparing gelatinized modified microcrystalline cellulose comprises the following steps: 1) Heat and melt 30 parts of microcrystalline cellulose, add 18 parts of gum arabic and mix, then homogenize and cool and dry to prepare a primary mixture; 2) After dissolving 6 parts of nicotinamide and 10 parts of L-hydroxyproline in 25 parts of water, add the prepared primary mixture, disperse by ultrasonic for 20 minutes, and then remove water by vacuum distillation to obtain gelled modified microcrystalline cellulose.

[0030] Comparative Preparation Example 1 A method for preparing gelatinized modified microcrystalline cellulose is carried out according to the method in Preparation Example 1, except that only the initial mixture obtained by heating and melting the microcrystalline cellulose and mixing it with gum arabic, homogenizing it, and then cooling and drying it in step 1) is carried out, and the operation of compounding with nicotinamide and L-hydroxyproline in step 2) is not carried out.

[0031] Comparative Preparation Example 2 A method for preparing gelled modified microcrystalline cellulose is carried out according to the method in Preparation Example 1, except that in step 2), nicotinamide is replaced by L-hydroxyproline in an equal amount.

[0032] Comparative Preparation Example 3 A method for preparing gelled modified microcrystalline cellulose is carried out according to the method in Preparation Example 1, except that in step 2), an equal amount of L-hydroxyproline is replaced by nicotinamide.

[0033] Example 1 A method for preparing fexofenadine hydrochloride oral suspension comprises the following steps: S1, add 15ml of water, then add 2g of buffer solution, stir to dissolve, add 0.4g of dispersant, then add 0.6g of fexofenadine hydrochloride, stir to prepare raw material A, wherein the buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate in a mass ratio of 6:4, and the dispersant is a combination of polyvinyl pyrrolidone in a mass ratio of 1:1.3 and the gelled modified microcrystalline cellulose prepared in Preparation Example 1; S2, 10 ml of water and 0.02 g of preservative are mixed to obtain raw material B, wherein the preservative is sorbic acid; S3. Add 0.5 g of suspending agent to raw material A and then add raw material B. After mixing and stirring, add 5 g of flavoring agent and add the remaining water to make the volume to 100 ml to prepare fexofenadine hydrochloride oral suspension.

[0034] Among them, the flavor corrector is xylitol and apple flavor in a mass ratio of 1:1, and the suspending agent is a mixture of sodium carboxymethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 1:1.

[0035] Example 2 A method for preparing fexofenadine hydrochloride oral suspension comprises the following steps: S1, add 15ml of water, then add 1g of buffer solution, stir to dissolve, add 0.3g of dispersant, then add 0.5g of fexofenadine hydrochloride, stir to prepare raw material A, wherein the buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate in a mass ratio of 6:4, and the dispersant is a combination of polyvinyl pyrrolidone in a mass ratio of 1:1.2 and the gelled modified microcrystalline cellulose prepared in Preparation Example 2; S2, 10 ml of water and 0.01 g of preservative are mixed to obtain raw material B, wherein the preservative is sorbic acid; S3. Add 0.3 g of suspending agent to raw material A and then add raw material B. After mixing and stirring, add 3 g of flavoring agent and add the remaining water to make the volume to 100 ml to prepare fexofenadine hydrochloride oral suspension.

[0036] Among them, the flavoring agent is xylitol and apple flavor with a mass ratio of 1:1, and the suspending agent is sodium carboxymethyl cellulose.

[0037] Example 3 A method for preparing fexofenadine hydrochloride oral suspension comprises the following steps: S1, add 15ml of water, then add 3g of buffer solution, stir to dissolve, add 0.5g of dispersant, then add 0.8g of fexofenadine hydrochloride, stir to prepare raw material A, wherein the buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate in a mass ratio of 6:4, and the dispersant is a combination of polyvinyl pyrrolidone in a mass ratio of 1:1.5 and the gelled modified microcrystalline cellulose prepared in Preparation Example 1; S2, 10 ml of water and 0.03 g of preservative are mixed to prepare raw material B, wherein the preservative is sorbic acid; S3. Add 0.8 g of suspending agent to raw material A and then add raw material B, add 8 g of flavoring agent after mixing and stirring, and add the remaining water to make the volume to 100 ml to prepare fexofenadine hydrochloride oral suspension.

[0038] Among them, the flavoring agent is xylitol and apple essence with a mass ratio of 1:1, and the suspending agent is hydroxypropyl methylcellulose.

[0039] Example 4 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that the fexofenadine hydrochloride in step S1 is added after pretreatment, and the pretreatment comprises the following steps: 1) Dissolve fexofenadine hydrochloride in 2 weight times of ethanol, then add polyethylene glycol, the amount of polyethylene glycol added is 8wt% of the amount of fexofenadine hydrochloride added, and remove the ethanol by vacuum distillation to obtain a mixture A; 2) Mixing mixture A with edible oil soybean oil and hydroxypropyl β-cyclodextrin in a mass ratio of 1:1:0.25 to prepare solution A; 3) dissolving hydroxylated lecithin and polyvinyl pyrrolidone in a sodium chloride solution, wherein the mass concentration of the sodium chloride solution is 25 wt %, and the added mass ratio of hydroxylated lecithin to polyvinyl pyrrolidone to the sodium chloride solution is 1:0.25:2.5, to obtain solution B; 4) adding solution A to solution B in a mass ratio of solution A to solution B of 1:0.35, stirring and mixing at 65° C., homogenizing, and spray drying to obtain pretreated fexofenadine hydrochloride.

[0040] Example 5 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that the fexofenadine hydrochloride in step S1 is added after pretreatment, and the pretreatment comprises the following steps: 1) Dissolve fexofenadine hydrochloride in 2 weight times of ethanol, then add polyethylene glycol, the amount of polyethylene glycol added is 6wt% of the amount of fexofenadine hydrochloride added, and remove the ethanol by vacuum distillation to obtain a mixture A; 2) Mixing mixture A with edible oil soybean oil and hydroxypropyl β-cyclodextrin in a mass ratio of 1:0.8:0.2 to prepare solution A; 3) dissolving hydroxylated lecithin and polyvinyl pyrrolidone in a sodium chloride solution, wherein the mass concentration of the sodium chloride solution is 20 wt %, and the mass ratio of hydroxylated lecithin to polyvinyl pyrrolidone to the sodium chloride solution is 1:0.2:2, to obtain a solution B; 4) adding solution A to solution B in a mass ratio of solution A to solution B of 1:0.3, stirring and mixing at 60° C., homogenizing, and spray drying to obtain pretreated fexofenadine hydrochloride.

[0041] Example 6 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that the fexofenadine hydrochloride in step S1 is added after pretreatment, and the pretreatment comprises the following steps: 1) Dissolve fexofenadine hydrochloride in 3 times the mass of ethanol, then add polyethylene glycol, the amount of polyethylene glycol added is 10wt% of the amount of fexofenadine hydrochloride added, and remove the ethanol by vacuum distillation to obtain a mixture A; 2) Mixing mixture A with edible oil soybean oil and hydroxypropyl β-cyclodextrin in a mass ratio of 1:1.2:0.3 to prepare solution A; 3) dissolving hydroxylated lecithin and polyvinyl pyrrolidone in a sodium chloride solution, wherein the mass concentration of the sodium chloride solution is 30 wt %, and the added mass ratio of hydroxylated lecithin to polyvinyl pyrrolidone to the sodium chloride solution is 1:0.3:3, to obtain a solution B; 4) adding solution A to solution B in a mass ratio of solution A to solution B of 1:0.4, stirring and mixing at 70° C., homogenizing, and spray drying to obtain pretreated fexofenadine hydrochloride.

[0042] Example 7 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that hydroxypropyl β-cyclodextrin is not added in step 2).

[0043] Example 8 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that hydroxylated lecithin is not added in step 3).

[0044] Example 9 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that in step 3), an equal amount of hydroxylated lecithin is replaced by lecithin.

[0045] Example 10 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that the treatment in step 1) is not carried out, and fexofenadine hydrochloride is directly mixed with edible oil in step 2).

[0046] Comparative Examples 1-3 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that the aminated modified microcrystalline cellulose in step S1 is the aminated modified microcrystalline cellulose prepared in Comparative Preparation Examples 1-3.

[0047] Comparative Example 4 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that an equal amount of the aminated modified microcrystalline cellulose in step S1 is replaced by colloidal microcrystalline cellulose.

[0048] Comparative Example 5 A method for preparing fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that the aminated modified microcrystalline cellulose in step S1 is directly replaced by a mixture of microcrystalline cellulose and gum arabic in a mass ratio of 5:3.

[0049] Comparative Example 6 A method for preparing a fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that polyethylene glycol is also added when fexofenadine hydrochloride is added in step S1, and the amount of polyethylene glycol added is 8wt% of the amount of fexofenadine hydrochloride added.

[0050] Performance Testing 1. In combination with the sedimentation volume ratio test method for oral suspensions in the 2020 edition of the Chinese Pharmacopoeia, the sedimentation volume ratios of the fexofenadine hydrochloride oral suspensions prepared in the examples and comparative examples were measured, and the results are shown in Table 1 below.

[0051] In addition, the oral suspension after precipitation was rotated at a speed of 20 rpm, and the time required for the precipitation to be redispersed evenly in the system was observed to measure the redispersibility of the obtained fexofenadine hydrochloride oral suspension. The results are shown in Table 1 below.

[0052] Table 1: Combined with the test results in Table 1 above, the fexofenadine hydrochloride oral suspension prepared in the embodiment of the present application has good suspension properties. Combined with the test results of Example 1 and Examples 4-6, in Example 4, fexofenadine hydrochloride is added after pretreatment to further improve its suspension stability and redispersibility. Combined with the test results of Example 7 and Example 8, when hydroxylated lecithin or hydroxypropyl β-cyclodextrin is not added in Examples 7 and 8, the suspension property is reduced, and its redispersibility is significantly reduced. Combined with the test results in Example 9, when hydroxylated lecithin is replaced with lecithin in Example 9, the performance of the two is completely different, and its suspension stability and redispersibility are reduced. Combined with the test results in Example 10, when fexofenadine hydrochloride is not added after direct inclusion with polyethylene glycol in Example 10, its suspension stability and redispersibility are significantly reduced.

[0053] Combining the test results of Example 1 with those of Comparative Examples 1-3, it can be seen that when microcrystalline cellulose is directly compounded with gum arabic in Comparative Example 1 without nicotinamide and L-hydroxyproline, its suspension stability is significantly reduced and its redispersibility is also reduced. When nicotinamide or L-hydroxyproline is not added in Comparative Example 2, its suspension stability and redispersibility are improved compared with Comparative Example 1, but are still far weaker than Example 1. Combining the test results of Comparative Example 4, when microcrystalline cellulose in Comparative Example 4 is replaced with commercially available colloidal microcrystalline cellulose prepared from microcrystalline cellulose and sodium carboxymethyl cellulose, its suspension stability and redispersibility are also significantly reduced compared with Example 1. Referring to the test results of Comparative Example 5, when microcrystalline cellulose is directly added with gum arabic, the suspension stability and redispersibility of the final suspension are poor. Combining the test results of Comparative Example 6, when fexofenadine hydrochloride is directly added and polyethylene glycol is also added, the final suspension stability and redispersibility are weak.

[0054] In addition, the viscosity, yield stress and solubility of the suspensions prepared in Examples 1-4 of the present application were tested, and the test results are shown in Table 2 below.

[0055] Table 2: Detection indicators Example 1 Example 2 Example 3 Example 4 <![CDATA[Viscosity (mPa.s / 50s -1 )]]> 106.46 100.99 105.89 110.39 Yield stress / MPa 2.37 2.12 2.26 2.52 Dissolution value / % 97.2 96.5 97.8 99.87 50s of the suspension prepared in the present application example -1 The viscosity is above 100 mPa·s, and the dissolution amount in 30 minutes is not less than 85% of the labeled amount, which meets the requirements and has good redispersibility.

[0056] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A fexofenadine hydrochloride oral suspension, characterized in that, The invention comprises an active ingredient and excipients, wherein the active ingredient is fexofenadine hydrochloride, and the excipients at least include a flavoring agent, a suspending agent, a preservative, and a dispersing agent, wherein the suspending agent comprises one or two of sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose; and the dispersing agent is a mixture of polyvinyl pyrrolidone and gel-modified microcrystalline cellulose; The gelled modified microcrystalline cellulose is prepared from nicotinamide, L-hydroxyproline, gum arabic and microcrystalline cellulose.

2. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: The gelled modified microcrystalline cellulose is prepared by the following method: The microcrystalline cellulose is heated and melted, and then gum arabic is added and mixed, and then homogenized and dried to prepare a primary mixture; After nicotinamide and L-hydroxyproline are dissolved in water, the primary mixture is added, ultrasonically dispersed, and then water is removed by reduced pressure distillation to obtain gelled modified microcrystalline cellulose.

3. A fexofenadine hydrochloride oral suspension according to claim 2, characterized in that: When preparing the gelatinized modified microcrystalline cellulose, the raw materials are added according to the following weight parts: 20-30 parts of microcrystalline cellulose, 10-18 parts of gum arabic, 3-6 parts of nicotinamide, 4-10 parts of L-hydroxyproline and 18-25 parts of water.

4. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: The fexofenadine hydrochloride is added after pretreatment, and the pretreatment comprises the following steps: 1) Dissolve fexofenadine hydrochloride in ethanol, then add polyethylene glycol, and remove the ethanol by vacuum distillation to obtain a mixture A; 2) Mixing mixture A with edible oil and hydroxypropyl β-cyclodextrin to prepare solution A; 3) Dissolve hydroxylated lecithin and polyvinyl pyrrolidone in sodium chloride solution to prepare solution B; 4) Add solution A to solution B, stir and mix at 60-70° C., homogenize and spray-dry to obtain pretreated fexofenadine hydrochloride.

5. A fexofenadine hydrochloride oral suspension according to claim 4, characterized in that: In the pretreatment process of fexofenadine hydrochloride, in step 1), fexofenadine hydrochloride is dissolved in 2-3 times the mass of ethanol, and the amount of polyethylene glycol added is 6-10wt% of the amount of fexofenadine hydrochloride added; In step 2), the mass ratio of mixture A to edible oil and hydroxypropyl β-cyclodextrin is 1:(0.8-1.2):(0.2-0.3); In step 3), the mass ratio of hydroxylated lecithin to polyvinyl pyrrolidone and sodium chloride solution is 1: (0.2-0.3): (2-3), and the mass concentration of the sodium chloride solution is 20-30wt%; In step 4), the mass ratio of solution A to solution B is 1:(0.3-0.4).

6. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: The dispersing aid is selected from polyvinyl pyrrolidone and gelled modified microcrystalline cellulose in a mass ratio of 1: (1.2-1.5).

7. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: The preservative is selected from sorbic acid.

8. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: The flavor corrector is selected from one or more of sucrose, mannitol, xylitol and essence.

9. A fexofenadine hydrochloride oral suspension according to claim 1, characterized in that: Each 100 mL of fexofenadine hydrochloride oral suspension contains the following ingredients: 5-0.8g of fexofenadine hydrochloride, 3-8g of flavoring agent, 1-3g of buffer solution, 0.3-0.8g of suspending agent, 0.01-0.03g of preservative and 0.3-0.5g of dispersing agent and the balance of water.

10. A method for preparing a fexofenadine hydrochloride oral suspension according to any one of claims 1 to 9, characterized in that: The following steps are involved: S1, adding the first part of water, adding a dispersant, and then adding fexofenadine hydrochloride, stirring to obtain raw material A; S2, mixing the second portion of water with a preservative to obtain raw material B; S3. After adding a suspending agent to raw material A, add raw material B, mix and stir, add a flavoring agent, and add the remaining water to make up to volume to prepare fexofenadine hydrochloride oral suspension.

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