Fexofenadine Hydrochloride Oral Suspension and Its Preparation Method

Abstract

This application relates to the field of medicine, and specifically discloses a fexofenadine hydrochloride oral suspension and a preparation method thereof. The oral suspension includes an active ingredient and excipients. The active ingredient is fexofenadine hydrochloride, and the excipients at least include a flavoring agent, a suspending agent, a preservative, and a dispersing aid. The suspending agent includes one or both of sodium carboxymethylcellulose and hydroxypropyl methylcellulose; the dispersing aid is a mixture of polyvinylpyrrolidone and gelatinized modified microcrystalline cellulose; the preparation method includes the following steps: S1. Add water, then add a buffer solution, stir to dissolve, add the dispersing aid, and then add fexofenadine hydrochloride, and stir to obtain raw material A; S2. Mix water and the preservative to obtain raw material B; S3. Add the suspending agent to raw material A, then add raw material B, mix and stir, add the flavoring agent, and add the remaining water to make up the volume to obtain the product. This application has the advantage that the prepared fexofenadine hydrochloride oral suspension has good redispersibility.

Description

Technical Field

[0001] This application relates to the field of medicine, and more specifically, it relates 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-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]phenylacetic acid, which is a white or off-white powder. It is the active metabolite of terfenadine in the human body and is a histamine H1 receptor antagonist without anticholinergic or α1-adrenergic receptor blocking effects. Fexofenadine hydrochloride has no adverse reaction of prolonging the cardiac QT interval like terfenadine, and no rare cardiovascular toxicity that may be produced by the same kind of drug astemizole. It has good clinical therapeutic effects and belongs to the third-generation antihistamine drug without sedative effects, and is used to treat seasonal allergic rhinitis and chronic idiopathic urticaria.

[0003] The fexofenadine hydrochloride raw material drug has an obvious bitter taste. When taken orally directly, it is likely to cause discomfort to patients, especially children, and has poor compliance. In the existing preparation processes, usually more flavoring agents, such as artificial sweeteners like aspartame, are added to improve the taste. In addition, fexofenadine hydrochloride belongs to poorly soluble drugs, and the dissolution of the drug after oral administration is poor, which affects the peak time of the drug after oral administration.

[0004] For example, Chinese Patent with the publication number CN114681616A discloses a fexofenadine hydrochloride dry suspension and a preparation method thereof. This technical solution is prepared by wet granulation of an ethanol solution of a wetting agent and a flavoring agent with fexofenadine hydrochloride and a filler. The obtained fexofenadine hydrochloride dry suspension has a good taste, good patient compliance, high stability, and also improves the drug dissolution rate.

[0005] Although the above technology pays attention to the palatability and adds dioctyl sodium sulfosuccinate as a wetting agent to provide the dissolution rate, the dosage form of this scheme is a dry suspension, that is, a liquid preparation in which a poorly soluble drug and suitable excipients are made into a powder or granule, and can be dispersed into a suspension for oral administration by shaking with water at the time of use. It needs to be prepared and used immediately, and the use is relatively complicated. While the suspension is a pre-mixed liquid medicine, which can be directly used without additional dissolution, saving the dissolution time, improving the medication efficiency and being more convenient.

[0006] Therefore, it is more convenient to directly use fexofenadine hydrochloride in the form of a suspension. Moreover, in case of emergency, it can be administered quickly to relieve the condition in a timely manner. However, when preparing the suspension dosage form, the problem of redispersibility needs to be solved. Redispersibility refers to the dispersion performance of particles in water, that is, the dispersion degree and stability of drug particles in water. It is an important performance index in pharmaceutical preparations and is usually used to evaluate the quality and stability of drugs. A drug with good redispersibility can dissolve better in water. Improving the redispersibility of oral suspension drugs can not only improve the quality and stability of products, but also enhance the bioavailability and efficacy of drugs, thereby enhancing the market competitiveness of products.

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

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

[0009] In a first aspect, the present application provides an oral suspension of fexofenadine hydrochloride, adopting the following technical solution: An oral suspension of fexofenadine hydrochloride includes an active ingredient and excipients. The active ingredient is fexofenadine hydrochloride, and the excipients at least include a flavoring agent, a suspending agent, a preservative, and a dispersing aid. Among them, the suspending agent includes one or both of sodium carboxymethylcellulose and hydroxypropyl methylcellulose; the dispersing aid is a mixture of polyvinylpyrrolidone and gelatinized modified microcrystalline cellulose;

[0010] Among them, the gelatinized modified microcrystalline cellulose is prepared from nicotinamide, L-hydroxyproline, arabic gum, and microcrystalline cellulose.

[0011] By adopting the above technical solution, in the present application, sodium carboxymethylcellulose and hydroxypropyl methylcellulose are added as thixotropic suspending agents, which can endow the suspension with 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. In this way, it is beneficial to the stability of fexofenadine hydrochloride in the stationary state, alleviating its sedimentation, while having high fluidity during dynamic state, which is more conducive to the redispersion of fexofenadine hydrochloride in water, thereby improving the redispersibility of the suspension;

[0012] In addition, the present application adds gelatinized microcrystalline cellulose prepared from niacinamide, L-hydroxyproline, and gum arabic-modified microcrystalline cellulose. The addition of gum arabic realizes the colloidalization of microcrystalline cellulose. Thus, the gelatinized microcrystalline cellulose has better dispersibility, which helps to improve the suspension stability of poorly soluble drugs. The addition of niacinamide and L-hydroxyproline introduces hydroxyl, amino, and carboxyl functional groups, so that hydrogen bonds can be formed between them and fexofenadine hydrochloride, thereby increasing the intermolecular force between microcrystalline cellulose and fexofenadine hydrochloride molecules, and thus improving its stability in the suspension. Moreover, the gelatinized modified microcrystalline cellulose added with niacinamide and L-hydroxyproline can form a three-dimensional network structure in water. This structure can wrap fexofenadine hydrochloride to prevent its aggregation and sedimentation. Moreover, niacinamide and L-hydroxyproline as co-dispersants can improve the hydrophilicity of the surface of fexofenadine hydrochloride particles, making it easier to disperse in water. Finally, the addition of the suspending agent and co-dispersant in the present application can improve the stability of the suspension, reduce the sedimentation and aggregation of fexofenadine hydrochloride particles. Moreover, when the suspension undergoes a certain degree of sedimentation after standing, the co-dispersant helps to quickly disperse when shaken, improving the redispersibility of the suspension.

[0013] Optionally, the gelatinized modified microcrystalline cellulose is prepared by the following method:

[0014] Heat and melt microcrystalline cellulose, then add gum arabic and mix, and then homogenize and dry to obtain a preliminary mixture;

[0015] Dissolve niacinamide and L-hydroxyproline in water, add the preliminary mixture, disperse ultrasonically, and then remove water by reduced pressure distillation to obtain gelatinized modified microcrystalline cellulose.

[0016] By adopting the above technical solution, first, microcrystalline cellulose and gum arabic are mixed and dispersed in a molten state, which is more conducive to the dispersion of gum arabic in microcrystalline cellulose. After homogenization treatment, the mixture of the two can exhibit better suspension stability and redispersibility performance, especially for the improvement of redispersibility performance. Then, the preliminary mixture is added to the solution dissolved with niacinamide and L-hydroxyproline and dispersed ultrasonically. By using the adsorption performance and partial water solubility of the preliminary mixture after the molten dispersion of microcrystalline cellulose and gum arabic, niacinamide and L-hydroxyproline form a complex with microcrystalline cellulose, and a three-dimensional network structure can be formed in water to realize the suspension and redispersion of fexofenadine hydrochloride particles.

[0017] Optionally, when preparing the gelatinized modified microcrystalline cellulose, the raw materials are added according to the following parts by weight:

[0018] 20-30 parts of microcrystalline cellulose, 10-18 parts of gum arabic, 3-6 parts of niacinamide, 4-10 parts of L-hydroxyproline, and 18-25 parts of water.

[0019] Optionally, the fexofenadine hydrochloride is added after pretreatment, and the pretreatment includes the following steps:

[0020] 1), Dissolve fexofenadine hydrochloride in ethanol, then add polyethylene glycol, and remove ethanol by vacuum distillation to obtain mixture A;

[0021] 2), Mix mixture A with edible oil and hydroxypropyl-β-cyclodextrin to obtain solution A;

[0022] 3), Dissolve hydroxylated lecithin and polyvinylpyrrolidone in sodium chloride solution to obtain solution B;

[0023] 4), Add solution A to solution B, stir and mix at 60-70 °C, then homogenize and spray dry to obtain pretreated fexofenadine hydrochloride.

[0024] By adopting the above technical solution, first dissolve fexofenadine hydrochloride in ethanol, then add polyethylene glycol, and both dissolve in ethanol. After realizing the mixing and dispersion of the two, then remove ethanol by vacuum distillation, so that fexofenadine hydrochloride is wrapped in the helical structure of polyethylene glycol crystals, which is beneficial to slowing down the sedimentation rate of drug particles by increasing the viscosity, thereby improving the suspension stability. Moreover, when shaking well after sedimentation, it is more conducive to redispersibility in water under the drive of polyethylene glycol; then mix it with edible oil and hydroxypropyl-β-cyclodextrin to obtain solution A;

[0025] The addition of edible oil helps dissolve fexofenadine hydrochloride. Hydroxypropyl-β-cyclodextrin has a lipophilic cavity and a hydrophilic surface, which can initially encapsulate fexofenadine hydrochloride. Then it is added to a sodium chloride solution. Sodium chloride has a certain osmotic pressure regulating effect. After hydroxypropyl-β-cyclodextrin initially encapsulates the active pharmaceutical ingredient, phosphatidylcholine, which has both hydrophilic and lipophilic properties, can adsorb on the surface of fexofenadine hydrochloride particles to form a protective film, reducing the direct contact between particles, lowering the interaction force between particles, preventing particle aggregation and sedimentation. Moreover, the long-chain molecular structure of phosphatidylcholine forms a steric hindrance around the particles, further preventing the particles from approaching and aggregating each other. This steric hindrance effect helps maintain the uniform dispersion state of the particles in the suspension. In addition, phosphatidylcholine has good wettability, which can improve the wetting performance of the surface of fexofenadine hydrochloride particles. The improvement of wettability helps the particles to be uniformly dispersed and stably suspended in the dispersion medium, thereby improving redispersibility. Finally, the mixed dispersion of fexofenadine hydrochloride and polyethylene glycol in the present application is initially included 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 phosphatidylcholine and with a certain steric hindrance effect, the above particles are separated from each other, which is beneficial to improving their suspension stability. The partial lipophilic properties of the above substances are beneficial to the stable suspension of the included fexofenadine hydrochloride in the suspension. When shaken under force, the above hydrophilic substances are beneficial to improving their redispersion performance. Finally, the obtained suspension has excellent redispersion performance and better dissolution rate.

[0026] Optionally, during the pretreatment of fexofenadine hydrochloride, in step 1), fexofenadine hydrochloride is dissolved in ethanol with a mass multiple of 2 - 3, and the addition amount of polyethylene glycol is 6 - 10 wt% of the addition amount of fexofenadine hydrochloride;

[0027] In step 2), the mass ratio of the mixture A, edible oil, and hydroxypropyl-β-cyclodextrin added is 1:(0.8 - 1.2):(0.2 - 0.3);

[0028] In step 3), the mass ratio of phosphatidylcholine, polyvinylpyrrolidone, and sodium chloride solution added is 1:(0.2 - 0.3):(2 - 3), and the mass concentration of the sodium chloride solution is 20 - 30 wt%;

[0029] In step 4), the mass ratio of solution A and solution B added is 1:(0.3 - 0.4).

[0030] Optionally, the co-dispersant is selected as polyvinylpyrrolidone and gelatinized modified microcrystalline cellulose with a mass ratio of 1:(1.2 - 1.5).

[0031] Optionally, the preservative is selected as sorbic acid.

[0032] By adopting the above technical solution, compared with traditional nipagin esters preservatives, sorbic acid is a preservative with relatively high safety. Sorbic acid can be rapidly metabolized into carbon dioxide and water in the body, so it will not accumulate in the body to produce toxicity.

[0033] Optionally, the flavoring agent is selected from one or more of sucrose, mannitol, xylitol and essence.

[0034] By adopting the above technical solution, the addition of an appropriate flavoring agent can increase the sweetness of the drug and improve the palatability of the drug.

[0035] Optionally, every 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, 0.3 - 0.5 g of dispersing aid and the balance of water.

[0036] In a second aspect, the present application provides a preparation method of fexofenadine hydrochloride oral suspension, adopting the following technical solution:

[0037] A preparation method of fexofenadine hydrochloride oral suspension, comprising the following steps:

[0038] S1. Add the first portion of water, add the dispersing aid, and then add fexofenadine hydrochloride, and stir to obtain raw material A;

[0039] S2. Mix the second portion of water with the preservative to obtain raw material B;

[0040] S3. Add the suspending agent to raw material A, then add raw material B, mix and stir, add the flavoring agent, and add the remaining water to make up the volume to obtain fexofenadine hydrochloride oral suspension.

[0041] By adopting the above technical solution, the method provided by the present application is simple and convenient and is easy to realize industrialization.

[0042] In summary, the present application has the following beneficial effects:

[0043] 1. In the present application, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose are added as thixotropic suspending agents, which can endow the suspension with 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 under external force, the network structure is destroyed and the suspension is easy to flow. Thus, it is beneficial to the stability of fexofenadine hydrochloride in the stationary state, alleviates its sedimentation, and has high fluidity during dynamic state, which is more beneficial to the redispersion of fexofenadine hydrochloride in water, thereby improving the redispersion performance of the suspension;

[0044] 2. The gelatinized microcrystalline cellulose prepared from nicotinamide, L-hydroxyproline and gum arabic-modified microcrystalline cellulose is added in this application. The addition of gum arabic realizes the colloidization of microcrystalline cellulose. Thus, the gelatinized 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 between them and fexofenadine hydrochloride, thereby increasing the intermolecular force between microcrystalline cellulose and fexofenadine hydrochloride molecules, and thus improving its stability in the suspension. Moreover, the gelatinized modified microcrystalline cellulose added with nicotinamide and L-hydroxyproline can form a three-dimensional network structure in water. This structure can wrap fexofenadine hydrochloride to prevent its aggregation and sedimentation. Moreover, nicotinamide and L-hydroxyproline as co-dispersants can improve the hydrophilicity of the surface of fexofenadine hydrochloride particles, making it easier to disperse in water. Finally, the addition of the suspending agent and co-dispersant in this application can improve the stability of the suspension, reduce the sedimentation and aggregation of fexofenadine hydrochloride particles. And when a certain degree of sedimentation occurs after the suspension stands, the co-dispersant helps to disperse quickly when shaken, improving the redispersibility of the suspension. Detailed Description of the Invention

[0045] The following examples are used to further illustrate this application in detail. It should be specifically noted that: for those not indicating specific conditions in the following examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. Except for special instructions, the raw materials used in the following examples can all be obtained from ordinary commercial sources.

[0046] In the following examples, the colloidal microcrystalline cellulose is the colloidal microcrystalline cellulose of Shanghai Shenmei Pharmaceutical Development Technology Co., Ltd., which is prepared from microcrystalline cellulose and sodium carboxymethylcellulose;

[0047] The following preparation examples are for the preparation of gelatinized modified microcrystalline cellulose

[0048] Preparation Example 1

[0049] A preparation method of gelatinized modified microcrystalline cellulose includes the following steps:

[0050] 1). Heat and melt 25 parts of microcrystalline cellulose, add 15 parts of gum arabic and mix, then homogenize and cool and dry to obtain a preliminary mixture;

[0051] 2). Dissolve 5 parts of nicotinamide and 6 parts of L-hydroxyproline in 20 parts of water, add the obtained preliminary mixture, ultrasonically disperse for 15 min, and then remove water by reduced pressure distillation to obtain gelatinized modified microcrystalline cellulose.

[0052] Preparation Example 2

[0053] A preparation method of gelatinized modified microcrystalline cellulose includes the following steps:

[0054] 1), Heat 20 parts of microcrystalline cellulose until molten, add 10 parts of gum arabic and mix. Then homogenize and cool to dryness to obtain a preliminary mixture.

[0055] 2), Dissolve 3 parts of nicotinamide and 4 parts of L-hydroxyproline in 18 parts of water. Then add the obtained preliminary mixture, ultrasonically disperse for 10 min, and then remove water by vacuum distillation to obtain gelatinized modified microcrystalline cellulose.

[0056] Preparation Example 3

[0057] A method for preparing gelatinized modified microcrystalline cellulose, comprising the following steps:

[0058] 1), Heat 30 parts of microcrystalline cellulose until molten, add 18 parts of gum arabic and mix. Then homogenize and cool to dryness to obtain a preliminary mixture.

[0059] 2), Dissolve 6 parts of nicotinamide and 10 parts of L-hydroxyproline in 25 parts of water. Then add the obtained preliminary mixture, ultrasonically disperse for 20 min, and then remove water by vacuum distillation to obtain gelatinized modified microcrystalline cellulose.

[0060] Comparative Preparation Example 1

[0061] A method for preparing gelatinized modified microcrystalline cellulose, carried out according to the method in Preparation Example 1. The difference is that the preliminary mixture obtained by heating microcrystalline cellulose until molten, mixing with gum arabic, homogenizing and then cooling to dryness in step 1) is the gelatinized modified microcrystalline cellulose, and step 2) operation of compounding with nicotinamide and L-hydroxyproline is not carried out.

[0062] Comparative Preparation Example 2

[0063] A method for preparing gelatinized modified microcrystalline cellulose, carried out according to the method in Preparation Example 1. The difference is that in step 2), nicotinamide is replaced with L-hydroxyproline in equal amount.

[0064] Comparative Preparation Example 3

[0065] A method for preparing gelatinized modified microcrystalline cellulose, carried out according to the method in Preparation Example 1. The difference is that in step 2), L-hydroxyproline is replaced with nicotinamide in equal amount.

[0066] Example 1

[0067] A method for preparing fexofenadine hydrochloride oral suspension, comprising the following steps:

[0068] S1. Add 15 ml of water, then add 2 g of buffer solution. After stirring and dissolving, add 0.4 g of co-dispersant, and then add 0.6 g of fexofenadine hydrochloride. Stir to prepare raw material A. The buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate with a mass ratio of 6:4, and the co-dispersant is a combination of polyvinylpyrrolidone and the gelatinized modified microcrystalline cellulose prepared in Preparation Example 1 with a mass ratio of 1:1.3;

[0069] S2. Mix 10 ml of water with 0.02 g of preservative to prepare raw material B. The preservative is sorbic acid;

[0070] S3. Add 0.5 g of suspending agent to raw material A, then add raw material B. After mixing and stirring, add 5 g of flavoring agent, and add the remaining water to make up to 100 ml to prepare the fexofenadine hydrochloride oral suspension.

[0071] Among them, the flavoring agent is a combination of xylitol and apple essence with a mass ratio of 1:1, and the suspending agent is a mixture of sodium carboxymethylcellulose and hydroxypropyl methylcellulose with a mass ratio of 1:1.

[0072] Example 2

[0073] A preparation method of fexofenadine hydrochloride oral suspension, comprising the following steps:

[0074] S1. Add 15 ml of water, then add 1 g of buffer solution. After stirring and dissolving, add 0.3 g of co-dispersant, and then add 0.5 g of fexofenadine hydrochloride. Stir to prepare raw material A. The buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate with a mass ratio of 6:4, and the co-dispersant is a combination of polyvinylpyrrolidone and the gelatinized modified microcrystalline cellulose prepared in Preparation Example 2 with a mass ratio of 1:1.2;

[0075] S2. Mix 10 ml of water with 0.01 g of preservative to prepare raw material B. The preservative is sorbic acid;

[0076] S3. Add 0.3 g of suspending agent to raw material A, then add raw material B. After mixing and stirring, add 3 g of flavoring agent, and add the remaining water to make up to 100 ml to prepare the fexofenadine hydrochloride oral suspension.

[0077] Among them, the flavoring agent is a combination of xylitol and apple essence with a mass ratio of 1:1, and the suspending agent is sodium carboxymethylcellulose.

[0078] Example 3

[0079] A preparation method of fexofenadine hydrochloride oral suspension, comprising the following steps:

[0080] S1. Add 15 ml of water, then add 3 g of buffer solution. After stirring and dissolving, add 0.5 g of dispersant aid, and then add 0.8 g of fexofenadine hydrochloride. Stir to obtain raw material A. The buffer solution is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate with a mass ratio of 6:4, and the dispersant aid is a combination of polyvinylpyrrolidone and the gelatinized modified microcrystalline cellulose prepared in Preparation Example 1 with a mass ratio of 1:1.5;

[0081] S2. Mix 10 ml of water with 0.03 g of preservative to obtain raw material B. The preservative is sorbic acid;

[0082] S3. Add 0.8 g of suspending agent to raw material A, then add raw material B. After mixing and stirring, add 8 g of flavoring agent, and add the remaining water to make up to 100 ml to obtain fexofenadine hydrochloride oral suspension.

[0083] Among them, the flavoring agent is a combination of xylitol and apple essence with a mass ratio of 1:1, and the suspending agent is hydroxypropyl methylcellulose.

[0084] Example 4

[0085] A preparation method of 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. The pretreatment includes the following steps:

[0086] 1). Dissolve fexofenadine hydrochloride in 2 mass times of ethanol, then add polyethylene glycol. The addition amount of polyethylene glycol is 8 wt% of the addition amount of fexofenadine hydrochloride. Remove ethanol by vacuum distillation to obtain mixture A;

[0087] 2). Mix mixture A with edible oil soybean oil and hydroxypropyl-β-cyclodextrin in a mass ratio of 1:1:0.25 to obtain solution A;

[0088] 3). Dissolve hydroxylated lecithin and polyvinylpyrrolidone in sodium chloride solution with a mass concentration of 25 wt%. The addition mass ratio of hydroxylated lecithin, polyvinylpyrrolidone and sodium chloride solution is 1:0.25:2.5 to obtain solution B;

[0089] 4). Add solution A to solution B. The addition mass ratio of solution A to solution B is 1:0.35, and stir and mix at 65 °C, then homogenize and spray dry to obtain pretreated fexofenadine hydrochloride.

[0090] Example 5

[0091] A preparation method of 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. The pretreatment includes the following steps:

[0092] 1), Dissolve fexofenadine hydrochloride in 2 times the mass of ethanol, then add polyethylene glycol, and the addition amount of polyethylene glycol is 6 wt% of the addition amount of fexofenadine hydrochloride. Remove ethanol by vacuum distillation to obtain mixture A;

[0093] 2), Mix mixture A with edible oil soybean oil and hydroxypropyl-β-cyclodextrin according to a mass ratio of 1:0.8:0.2 to obtain solution A;

[0094] 3), Dissolve hydroxylated lecithin and polyvinylpyrrolidone in sodium chloride solution, the mass concentration of the sodium chloride solution is 20 wt%, and the addition mass ratio of hydroxylated lecithin to polyvinylpyrrolidone and sodium chloride solution is 1:0.2:2 to obtain solution B;

[0095] 4), Add solution A to solution B, the addition mass ratio of solution A to solution B is 1:0.3, stir and mix at 60 °C, then homogenize and spray dry to obtain pretreated fexofenadine hydrochloride.

[0096] Example 6

[0097] A preparation method of an oral suspension of fexofenadine hydrochloride is carried out according to the method in Example 1, the difference is that fexofenadine hydrochloride in step S1 is added after pretreatment, and the pretreatment includes the following steps:

[0098] 1), Dissolve fexofenadine hydrochloride in 3 times the mass of ethanol, then add polyethylene glycol, and the addition amount of polyethylene glycol is 10 wt% of the addition amount of fexofenadine hydrochloride. Remove ethanol by vacuum distillation to obtain mixture A;

[0099] 2), Mix mixture A with edible oil soybean oil and hydroxypropyl-β-cyclodextrin according to a mass ratio of 1:1.2:0.3 to obtain solution A;

[0100] 3), Dissolve hydroxylated lecithin and polyvinylpyrrolidone in sodium chloride solution, the mass concentration of the sodium chloride solution is 30 wt%, and the addition mass ratio of hydroxylated lecithin to polyvinylpyrrolidone and sodium chloride solution is 1:0.3:3 to obtain solution B;

[0101] 4), Add solution A to solution B, the addition mass ratio of solution A to solution B is 1:0.4, stir and mix at 70 °C, then homogenize and spray dry to obtain pretreated fexofenadine hydrochloride.

[0102] Example 7

[0103] A preparation method of an oral suspension of fexofenadine hydrochloride is carried out according to the method in Example 4, the difference is that hydroxypropyl-β-cyclodextrin is not added in step 2).

[0104] Example 8

[0105] A preparation method of fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that hydroxylated lecithin is not added in step 3).

[0106] Example 9

[0107] A preparation method of fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that hydroxylated lecithin is replaced with lecithin in equal amount in step 3).

[0108] Example 10

[0109] A preparation method of fexofenadine hydrochloride oral suspension is carried out according to the method in Example 4, except that step 1) is not carried out, and fexofenadine hydrochloride is directly mixed with edible oil in step 2).

[0110] Comparative Examples 1-3

[0111] A preparation method of 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 respectively selected from the aminated modified microcrystalline cellulose prepared in Comparative Preparation Examples 1-3).

[0112] Comparative Example 4

[0113] A preparation method of 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 replaced with colloidal microcrystalline cellulose in equal amount).

[0114] Comparative Example 5

[0115] A preparation method of 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 with a mixture of microcrystalline cellulose and arabic gum according to a mass ratio of 5:3).

[0116] Comparative Example 6

[0117] A preparation method of fexofenadine hydrochloride oral suspension is carried out according to the method in Example 1, except that polyethylene glycol is added when fexofenadine hydrochloride is added in step S1, and the addition amount of polyethylene glycol is 8wt% of the addition amount of fexofenadine hydrochloride).

[0118] Performance detection

[0119] 1. In combination with the sedimentation volume ratio test method for oral suspensions in the Chinese Pharmacopoeia (2020 Edition), the sedimentation volume ratios of the fexofenadine hydrochloride oral suspensions prepared in the examples and comparative examples were measured, and the measurement results are shown in Table 1 below.

[0120] In addition, the above-mentioned sedimented oral suspension was rotated at a speed of 20 revolutions per minute, and the time required for the sediment to be evenly redispersed into the system was observed to measure the redispersibility of the prepared fexofenadine hydrochloride oral suspension. The results are shown in Table 1 below.

[0121] Table 1:

[0122]

[0123] Combined with the test results in Table 1 above, the fexofenadine hydrochloride oral suspension prepared in the examples of this application has good suspension properties. Combining the test results of Example 1 and Examples 4-6, after the fexofenadine hydrochloride in Example 4 was pretreated and then added, its suspension stability and redispersibility were further improved. Combining the test results of Example 7 and Example 8, when hydroxylated lecithin or hydroxypropyl-β-cyclodextrin was not added in Examples 7 and 8, the suspension property decreased, and its redispersibility decreased significantly. Combining the test results in Example 9, when hydroxylated lecithin was replaced by lecithin in Example 9, the properties of the two were completely different, and both its suspension stability and redispersibility decreased. Combining the test results in Example 10, when fexofenadine hydrochloride was directly included without being compounded with polyethylene glycol and then added in Example 10, its suspension stability and redispersibility decreased significantly.

[0124] Combined with the test results of Example 1 and Comparative Examples 1-3, it can be seen that in Comparative Example 1, when microcrystalline cellulose was directly compounded with gum arabic without compounding with niacinamide and L-hydroxyproline, its suspension stability decreased significantly, and its redispersibility also decreased. In Comparative Example 2, when niacinamide or L-hydroxyproline was not added, although its suspension stability and redispersibility were improved compared with Comparative Example 1, they were still much weaker than those in Example 1. Combining the test results of Comparative Example 4, when microcrystalline cellulose was replaced with commercially available colloidal microcrystalline cellulose prepared from microcrystalline cellulose and sodium carboxymethylcellulose in Comparative Example 4, its suspension stability and redispersibility were also significantly reduced compared with Example 1. Referring to the test results of Comparative Example 5, when microcrystalline cellulose was directly added to gum arabic, the suspension stability and redispersibility of the final suspension were poor. Combining the test results of Comparative Example 6, when fexofenadine hydrochloride was directly added and polyethylene glycol was also added, the final suspension stability and redispersibility were weak.

[0125] In addition, the viscosities, yield stresses, and dissolution degrees of the suspensions prepared in Examples 1-4 of this application were detected, and the detection results are shown in Table 2 below.

[0126] Table 2:

[0127] Detection index 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

[0128] The viscosity of the suspension prepared in the embodiment of the present application at 50 s -1 is 100 mPa·s or more, and the dissolution amount in 30 minutes is not less than 85% of the labeled amount, meeting the requirements and having good redispersibility.

[0129] This specific embodiment is only an explanation of the present application and is not a limitation thereof. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A fexofenadine hydrochloride oral suspension, characterized in that, The invention comprises active ingredients and excipients, wherein the active ingredient is fexofenadine hydrochloride, and the excipients at least include flavoring agents, suspending agents, preservatives, and dispersing agents. Each 100 mL of fexofenadine hydrochloride oral suspension comprises the following raw materials: 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; The suspending agent includes one or two of sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose; the dispersing agent includes polyvinyl pyrrolidone and gelled modified microcrystalline cellulose in a mass ratio of 1: (1.2-1.5); 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 preservative is sorbic acid.

7. 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.

8. A method for preparing a fexofenadine hydrochloride oral suspension as claimed in any one of claims 1 to 7, 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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