Rupatifen fumarate capsule and preparation method therefor

Abstract

A rupatifen fumarate capsule and a preparation method therefor. The capsule comprises a capsule shell and contents enclosed by the capsule shell. The capsule has excellent formulation performance and good stability. During preparation and long-term storage, there is no reduction in drug substance content and no significant increase in impurity content. The dissolution rate is fast, and the stability is good, thereby ensuring the quality of the final formulation and the safety and effectiveness of clinical use.

Description

A capsule of rupatadine fumarate and a preparation method thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a capsule of rupatadine fumarate and a preparation method thereof. BACKGROUND

[0002] International patent application WO2013000406A1 discloses a multi-channel comprehensive inhibition of allergic drug rupatadine fumarate, the chemical name of which is 4-[1-[(5-methylpyridin-3-yl)methyl]piperidinyl-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one, and the chemical structure is as follows:

[0003] Rupatadine fumarate is a new type of histamine receptor family antagonist. Compared with ketotifen fumarate, the structural modification of rupatadine fumarate has multiple anti-allergic mechanisms, such as anti-histamine effect, stable mast cell effect, anti-platelet activating factor effect and anti-eosinophil effect, and the central sedative side effect of rupatadine fumarate is smaller. The drug realizes multi-target coverage of allergens, has the characteristics of large safety window, strong efficacy and small central side effect, improves the compliance of patients, has a wide range of clinical applications, and has great clinical value. Therefore, it is urgent to study a safe and effective rupatadine fumarate preparation in clinical practice. SUMMARY

[0004] The inventors of the present application first selected to prepare rupatadine fumarate into conventional oral preparations such as tablets and capsules when developing the preparation of rupatadine fumarate. It was found that the content of related substances of rupatadine fumarate tablets increased significantly in high-temperature investigation test, which significantly reduced the stability of the raw material drug and seriously affected the quality of the drug. The increase of impurities of the capsule was significantly lower than that of the tablet. Therefore, the inventors considered preparing rupatadine fumarate into a capsule, but found that the types and ratios of auxiliary materials had an effect on the stability and performance of the preparation when preparing the capsule, especially the material of the capsule shell had a great influence on the dissolution performance of the capsule. The capsule prepared by using traditional gelatin capsule shell cannot be disintegrated in non-enzyme dissolution medium, resulting in incomplete dissolution of the drug.

[0005] Formaldehyde may exist in the raw material of rupatadine fumarate by combining the synthesis process. 1-chloroethyl chloroformate is used in the preparation process of rupatadine fumarate for demethylation reaction. According to the preparation process of 1-chloroethyl chloroformate, a small amount of chloroformic acid methyl ester may exist in 1-chloroethyl chloroformate used in the reaction. The reactivity of chloroformic acid methyl ester is similar to that of 1-chloroethyl chloroformate, and chloroformic acid methyl ester can also react with ketotifen to generate intermediate 2. Intermediate 2 is subjected to alcoholysis to obtain hydrochloric acid desmethyl ketotifen. However, if a small amount of water exists in the methanol used for alcoholysis or the water in the air enters the reaction system during the reaction process, a hydrolysis reaction may occur during the alcoholysis process to generate intermediate 3. Intermediate 3 is unstable and can further decompose to generate carbon dioxide and formaldehyde. The specific reaction mechanism is as follows:

[0006] It is found that a small amount of formaldehyde is detected in the rupatadine fumarate capsules prepared by using gelatin capsules. Formaldehyde and gelatin are cross-linked, which leads to a decrease in the dissolution efficiency of the gelatin capsule shell in the dissolution medium and incomplete dissolution. In addition, the cross-linked capsule shell affects the volatilization of formaldehyde, which further increases the content of formaldehyde in the final preparation and affects the safety of the drug.

[0007] Therefore, based on a large amount of research, the present application provides a rupatadine fumarate capsule, which preferably uses hydroxypropyl methyl cellulose as the raw material of the plant capsule shell. Compared with the gelatin capsule shell, the hydroxypropyl methyl cellulose capsule shell has good air permeability, which is beneficial to the rapid volatilization of the small amount of formaldehyde generated, and no formaldehyde is detected in the final preparation. At the same time, cross-linking does not occur, so the final capsule dissolves rapidly. The rupatadine fumarate capsule prepared by using the hydroxypropyl methyl cellulose capsule shell has excellent preparation performance and good stability. In the accelerated investigation process, there is no decrease in the content of the drug and no significant increase in impurities, and the dissolution speed is fast, which ensures the safety and effectiveness of the clinical medication.

[0008] In order to achieve the above technical purposes, the technical scheme adopted by the present application is as follows:

[0009] Firstly, the present application provides a rupatadine fumarate capsule, which comprises a capsule shell and contents wrapped in the capsule shell.

[0010] Preferably, the raw material of the capsule shell is selected from one or more of cellulose, gelatin or other materials.

[0011] More preferably, the raw material of the capsule shell is selected from hydroxypropyl methyl cellulose, prussian polysaccharide and gelatin, and is preferably hydroxypropyl methyl cellulose.

[0012] Preferably, the content comprises fumic acid rupatadine in a mass ratio of (0.5-24):(60-98):(0.1-3):(1-20), at least one excipient, at least one lubricant and at least one glidant;

[0013] Preferably, the excipient is selected from one or several of the group consisting of sugars, sugar alcohols, starches or others;

[0014] Preferably, the excipient is selected from one or several of the group consisting of lactose, mannitol and microcrystalline cellulose, preferably lactose.

[0015] Preferably, the lubricant is selected from one or several of the group consisting of esters, stearates or others;

[0016] Preferably, the lubricant is selected from one or several of the group consisting of glyceryl behenate, hydrogenated vegetable oil and sodium lauryl sulfate, preferably glyceryl behenate.

[0017] Preferably, the glidant is selected from one or several of the group consisting of talc or silicon dioxide, preferably talc;

[0018] Preferably, the content comprises lactose as excipient, glyceryl behenate as lubricant and talc as glidant;

[0019] Preferably, the content comprises fumic acid rupatadine in a mass ratio of (0.5-24):(60-98):(0.1-3):(1-20), at least one excipient, at least one lubricant and at least one glidant, more preferably fumic acid rupatadine in a mass ratio of (1-24):(60-85):(0.3-2):(2-15), most preferably fumic acid rupatadine in a mass ratio of (1-5):(70-85):(0.3-2):(2-6).

[0020] In a particular embodiment, the present application provides a rupatadine fumarate capsule comprising a capsule shell and a content enclosed within the capsule shell, the material of the capsule shell being hypromellose, the content comprising rupatadine fumarate, lactose, glyceryl behenate and talc in a mass ratio of (1-5):(70-85):(0.3-2):(2-6).

[0021] In a more specific embodiment, the present application provides a lufufunfun fumarate capsule, which comprises a capsule shell and contents wrapped in the capsule shell, wherein the material of the capsule shell is hypromellose, and the contents comprise lufufunfun fumarate, lactose, glyceryl monostearate and talc in a mass ratio of 1.29:84.4:1.0:4.0.

[0022] Secondly, the present application provides a preparation method of the above-mentioned lufufunfun fumarate capsule, which comprises the following steps:

[0023] (1) weigh lufufunfun fumarate, excipients, lubricant and glidant;

[0024] (2) pass the raw and auxiliary materials weighed in step (1) through a No. 3 standard sieve once, and reserve for use;

[0025] (3) premix lufufunfun fumarate and glidant sieved in step (2) for 3 minutes, take out the sieved powder through a No. 3 standard sieve, and reserve for use;

[0026] (4) add the premixed sieved powder in step (3) into a three-dimensional total mixer, mix well, and reserve for use;

[0027] (5) premix the lubricant sieved in step (2) with 10 times amount of excipients for 3 minutes, take out the sieved powder through a No. 3 standard sieve, and reserve for use;

[0028] (6) mix the remaining sieved excipients in step (2) with the premixed powder in step (4) and step (5) by equal-amount addition method, and reserve for use;

[0029] (7) fill the mixed powder obtained in step (6) into a capsule shell to obtain a lufufunfun fumarate capsule.

[0030] Thirdly, the present application provides a method for preventing and / or treating allergic rhinitis, which comprises administering to a patient in need a therapeutically effective amount of the above fumic acid lupatutifin capsule. During the development process, the applicant found that fumic acid lupatutifin raw material itself is stable in nature, and no obvious increase in related substance content occurs under high temperature, high humidity and strong light, and it is considered suitable for preparing into conventional oral solid preparations. Therefore, the applicant mixes the active ingredient with suitable excipients to prepare tablets and capsules respectively. In the early quality investigation, the fumic acid lupatutifin tablets and capsules were placed in an open container for high temperature stability test, and no obvious impurity increase was found. However, the high temperature stability test results in the closed bottle simulation package showed that the fumic acid lupatutifin tablets and capsules both had impurity increase, but the impurity increase of the capsules was significantly lower than that of the tablets. The applicant further investigated the stability of the active ingredient under pressure, and the results showed that the active ingredient had certain sensitivity to pressure, but it did not affect the preparation of tablets. The applicant found through rigorous comparative tests that it may be due to the formation of a local high temperature and high humidity environment in the closed bottle under high temperature conditions, which is more demanding for drug stability, and the influence of excipients and pressure further aggravates the increase of impurities. The capsule avoids the tabletting process and reduces the risk of instability of the raw material, so the impurity control of the capsule under high temperature and closed conditions is better than that of the tablet. Based on the above findings, the present application finally selects the fumic acid lupatutifin to be prepared into a capsule.

[0031] Further, during the preparation process of the capsule content, excipients with low water content are selected, and the humidity of the preparation environment is strictly controlled, so as to avoid the interference of water to the raw material.

[0032] Further, the present application screens the types and ratios of excipients, including excipients, lubricants and glidants, required for the preparation of the capsule content. Lactose as an excipient is superior to mannitol and microcrystalline cellulose in impurity control, and is significantly superior to pregelatinized starch and corn starch, so lactose is preferably selected as an excipient. Glycerin monostearate is significantly superior to magnesium stearate, hydrogenated vegetable oil and sodium lauryl sulfate in impurity control and properties, and the compatibility of glycerin monostearate and lactose is better, so glycerin monostearate is preferably selected as a lubricant. Talc is superior to silicon dioxide in impurity control, and is easier to sieve, reducing the loss of raw materials, so talc is selected as a lubricant. Through the screening of the ratio of excipients, the content uniformity, flowability and related substances are investigated, so as to obtain a prescription with the best comprehensive evaluation index: the active ingredient is 1.29 mg, lactose is 67.8 mg, glycerin monostearate is 1.5 mg, and talc is 6.0 mg.

[0033] Further, the capsule shell of the present application is selected from hydroxypropyl methyl cellulose. The hydroxypropyl methyl cellulose capsule shell is not affected by trace formaldehyde in the raw drug, and does not undergo crosslinking reaction, so the dissolution is fast, and there is no risk of toxicity caused by formaldehyde in the final preparation. And compared with traditional pharmaceutical capsule shells such as gelatin capsule shells, plant capsule shells are stable in high humidity conditions and are not prone to sticking, can maintain the contents unaffected during long-term storage, especially with low water content, which can reduce the interference of water on the stability of the raw drug. In addition, compared with plant capsule shells made of prussian polysaccharide, the anti-sticking property of hydroxypropyl methyl cellulose is better, and the dissolution efficiency is higher.

[0034] Further, by comparing the composition of different active ingredient dosages of different specifications of the drug, it is shown that in the 1-12 mg specification range, the compatibility of the excipients and the raw drug in the preparation is good, the related substances and the content do not increase significantly, the content uniformity is maintained well, and the dissolution is fast. In summary, the present application provides a fumagillin lupatifin capsule and a preparation method thereof. Compared with tablets, the fumagillin lupatifin capsule does not need to be pressed, thereby avoiding the interference of pressure on the stability of the raw drug; at the same time, the water content is low during the preparation and storage of the capsule, which is conducive to maintaining the stability of the contents, reducing the increase of the related substance content, ensuring the quality of the final preparation, and improving the safety of drug use. The capsule shell of the fumagillin lupatifin capsule is also optimized in the present application, and the capsule shell made of hydroxypropyl methyl cellulose is selected as the raw material, which ensures the preparation performance, dissolution performance and safety of the capsule. The fumagillin lupatifin capsule provided by the present application has excellent preparation performance such as uniform content, fast dissolution speed and good long-term storage stability. And the prescription is also suitable for the preparation of high-specification fumagillin lupatifin capsules, and the process is stable and has strong applicability. BRIEF DESCRIPTION OF DRAWINGS

[0035] FIG. 1 is an image of the fumagillin lupatifin capsule of different prescriptions in Example 8 in a pH = 1.2 phosphate solution dissolution medium after high-temperature storage for 30 days; FIG. 1A is an image of the capsule with a gelatin material as the capsule shell at 30 minutes; FIG. 1B is an image of the capsule with prussian polysaccharide as the capsule shell at 30 minutes; FIG. 1C is an image of the capsule with hydroxypropyl methyl cellulose as the capsule shell at 15 minutes;

[0036] FIG. 2 is a dissolution curve of the fumagillin lupatifin capsule of different batches in Example 12 in different dissolution media; FIG. 2A is a dissolution medium of pH = 1.2 phosphate solution; FIG. 2B is a dissolution medium of pH = 4.5 phosphate solution; FIG. 2C is a dissolution medium of water for injection; FIG. 2D is a dissolution medium of pH = 6.8 phosphate solution containing 0.5% SDS;

[0037] FIG. 3 is a dissolution curve of the fumagillin lupatifin capsule of different specifications in Example 13 in a pH = 1.2 phosphate solution. Detailed Implementation

[0038] To better understand the above technical solutions, exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that the present invention can be understood more clearly and thoroughly, and that the scope of the present invention can be fully conveyed to those skilled in the art.

[0039] Example 1: Stability of active ingredients under high temperature, high humidity and strong light

[0040] This embodiment examines the stability of the active ingredient under high temperature, high humidity and strong light conditions as a reference for selecting formulations.

[0041] The specific method is as follows: Weigh an appropriate amount of the active ingredient of this invention, rupatifine fumarate, and place it loosely in an open container (such as a weighing bottle or petri dish), spreading it evenly with a thickness not exceeding 3 mm. Place the active ingredient under high temperature (60°C), high humidity (25°C, RH 90% ± 5%), and strong light (total illuminance 1.2 × 10⁻⁶). 6 Lux / hr, near-ultraviolet energy 200w·hr / m 2 Under certain conditions, samples were taken at specific time points to observe the appearance and properties of the active ingredients and to determine the content of related substances.

[0042] The results are shown in Table 1. No changes in appearance or significant increase in impurities were observed in the active ingredient when stored under high temperature, high humidity, and light conditions, indicating good stability and suitability for development into oral formulations such as tablets and capsules.

[0043] Table 1 Results of the investigation into factors affecting active ingredients

[0044] Example 2: Preparation of Rupatifine Fumarate Tablets

[0045] This embodiment provides a rupatifine fumarate tablet, and the raw materials used are shown in Table 2. The preparation method is as follows:

[0046] (1) Weigh out rupatifine fumarate, microcrystalline cellulose, magnesium stearate, and talc according to Table 2;

[0047] (2) Pass the raw and auxiliary materials from step (1) through a No. 3 standard sieve once and set aside;

[0048] (3) Premix the lumatafen fumarate that was sieved in step (2) with the glidant for 3 minutes, take it out and pass it through a No. 3 standard sieve for later use.

[0049] (4) The premixed powder of step (3) is added into the three-dimensional total mixer and mixed evenly, ready for use;

[0050] (5) The sieved lubricant of step (2) is premixed with 10 times the amount of excipients for 3 minutes, and then taken out through a No. 3 standard sieve, ready for use;

[0051] (6) The remaining sieved excipients of step (2) are mixed evenly with the premixed powder of step (4) and step (5) using the equal increment method, ready for use;

[0052] (7) The mixed powder obtained in step (6) is filled into the capsule shell to obtain the rupatadine fumarate capsule.

[0053] Table 2 Formulation table of rupatadine fumarate tablets

[0054] Example 3: Preparation of rupatadine fumarate capsules

[0055] This example provides a rupatadine fumarate capsule, and the raw materials used are shown in Table 3. The preparation method is as follows:

[0056] (1) Rupatadine fumarate, excipients, lubricant, and glidant are weighed;

[0057] (2) The raw and auxiliary materials weighed in step (1) are sieved through a No. 3 standard sieve once, ready for use;

[0058] (3) The sieved rupatadine fumarate of step (2) is premixed with the glidant for 3 minutes, and then taken out through a No. 3 standard sieve, ready for use;

[0059] (4) The premixed powder of step (3) is added into the three-dimensional total mixer and mixed evenly, ready for use;

[0060] (5) The sieved lubricant of step (2) is premixed with 10 times the amount of excipients for 3 minutes, and then taken out through a No. 3 standard sieve, ready for use;

[0061] (6) The remaining sieved excipients of step (2) are mixed evenly with the premixed powder of step (4) and step (5) using the equal increment method, ready for use;

[0062] (7) The mixed powder obtained in step (6) is filled into the capsule shell to obtain the rupatadine fumarate capsule.

[0063] Table 3 Formulation table of rupatadine fumarate capsules

[0064] Example 4: Stability test of tablets and capsules

[0065] This example compares the stability of the active ingredient of the lufufenine fumarate tablets prepared in Example 2 and the lufufenine fumarate capsules prepared in Example 3 under high temperature conditions.

[0066] Specific method: Take an equal amount of lufufenine fumarate tablets (prepared according to the method of Example 2) and lufufenine fumarate capsules (prepared according to the method of Example 3), and place them in open containers and closed containers, respectively, wherein the closed state is used to simulate the storage environment after packaging. Place the tablets and capsules in an incubator set to 60°C. Take samples on days 0, 10, and 30, and determine the impurity content by liquid chromatography.

[0067] The results are shown in Table 4. The results show that under high temperature (60°C) and naked conditions, the related substance content of lufufenine fumarate tablets and capsules does not increase significantly with the extension of storage time; while under high temperature (60°C) and sealed conditions, the related substance content of tablets and capsules increases, which may be due to the formation of a local high temperature and high humidity environment in the closed container under high temperature. This investigation condition is more demanding and magnifies the instability of the active ingredient. The applicant believes that this condition is more conducive to the stability evaluation of the preparation, and therefore the subsequent stability test is carried out in a closed container. In addition, the impurity increase of the tablets is significantly more than that of the capsules, indicating that the capsule dosage form is more conducive to the impurity control of lufufenine fumarate preparations.

[0068] Table 4: Related substance content of tablets and capsules under different conditions (unit: %)

[0069] Example 5: Stability of the active ingredient under pressure

[0070] The results of Example 1 show that the active ingredient is stable under high temperature, high humidity, and strong light conditions, while the results of Example 4 show that the impurity of tablets and capsules increases under high temperature and sealed conditions, and the impurity increase of the capsules is significantly lower than that of the tablets, which is presumably due to the sensitivity of the active ingredient to pressure. Therefore, the stability of the active ingredient under pressure is further explored.

[0071] Specific method: Take an appropriate amount of the active ingredient of the application and place it on a tablet press to press it into a tablet shape using a force of 3 kg. Place the tablet-shaped active ingredient and loose active ingredient into closed containers, respectively, and place them in an incubator set to 60°C. Take samples on days 0, 10, and 30, and determine the impurity content by liquid chromatography.

[0072] The results are shown in Table 5. The results show that the content of related substances of the active ingredient after tabletting is slightly higher than that of the loose active ingredient; with the increase of the test time, the impurities of the tabletted active ingredient slightly increase, and the total impurity change amount is 0.30% on the 30th day, while the loose active ingredient has almost no change in impurity content, indicating that although the active ingredient has a certain sensitivity to pressure, it does not affect the preparation of tablets. In combination with the test results of Example 4, under the same conditions, the total impurity change amount of fumagillin lupatifin tablets is 1.86% on the 30th day, which is significantly higher than that of the active ingredient alone, and the influence of the excipient may exacerbate the sensitivity of the active ingredient to pressure. Compared with tablets, the impurities of capsules are better controlled, indicating that the active ingredient of the application is more suitable for preparation into capsules.

[0073] Table 5: Content of related substances of active ingredient under pressure for 30 days (%)

[0074] Example 6: Dissolution performance of capsules

[0075] In this example, the dissolution performance of fumagillin lupatifin capsules is investigated. The specific method is as follows: fumagillin lupatifin capsules prepared according to Example 3 are placed in a closed container and put into a thermostat, and the temperature is set to 60℃. On the 0th day, the 10th day and the 30th day, samples are taken, the appearance of the capsules is observed and the dissolution is measured.

[0076] Dissolution determination method: the test sample is placed in a sinker, and the dissolution is determined by the slurry method. The dissolution medium is pH = 1.2 phosphate solution with a volume of 900mL, and the rotation speed is set to 75r / min. The sample is taken at 30 minutes, the content of the compound in the sample solution is determined, and the dissolution content (%) is calculated.

[0077] The results are shown in Table 6. In Example 3, fumagillin lupatifin capsules are prepared using gelatin capsules, and when stored in a closed container at high temperature (60℃) for 10 days, the capsules are obviously adhered, and the adhesion is more serious on the 30th day. During the dissolution determination, it is found that the gelatin capsule shell has crosslinking phenomenon, and the capsule shell does not disintegrate in water at 30 minutes, which leads to the failure of drug dissolution, and the dissolution further decreases after storage at high temperature.

[0078] Table 6: Appearance and dissolution performance of capsules of Example 3 stored at high temperature for 30 days

[0079] Example 7: Formaldehyde content determination

[0080] In combination with the preparation process of fumagillin lupatifin, formaldehyde may exist in fumagillin lupatifin raw material. Formaldehyde reacts with gelatin to cause crosslinking, which leads to the decrease of the dissolution performance of the capsules. In this example, the formaldehyde content of fumagillin lupatifin raw material and capsules is determined.

[0081] Specific method is: according to the preparation of fumarate lupatifin capsule of example 3, the active ingredient raw material and capsule are respectively placed in the closed container, and put into the thermostat, and the temperature is set to 60 DEG C. On the 0th day, the 10th day and the 30th day, sample is taken, and the free formaldehyde content in the raw material and capsule is determined.

[0082] The results are shown in table 7. Trace amounts of formaldehyde are detected in the active ingredient raw material and fumarate lupatifin capsule made of gelatin capsule shell. After 30 days of storage under high temperature and closed conditions, the formaldehyde content in the raw material does not change significantly; while the formaldehyde content in the capsule increases with the prolongation of storage time. This may be due to the crosslinking of formaldehyde in the raw material with the gelatin capsule shell, resulting in the formaldehyde being unable to volatilize in the capsule.

[0083] Table 7 formaldehyde content of raw material and capsule stored for 30 days under high temperature conditions

[0084] Example 8: screening of capsule shell materials

[0085] Although gelatin is a commonly used traditional pharmaceutical capsule shell material, it can react with the formaldehyde in the active ingredient raw material of the application, affecting the preparation performance of the final capsule, and there is also the risk of toxicity caused by formaldehyde. In order to obtain a capsule shell material suitable for the active ingredient of the application, the materials of the capsule shell are screened in this example, and different excipients are weighed according to table 8, and fumarate lupatifin capsules are prepared by the preparation method described in example 3, and the preparation performance of the capsules prepared by different prescriptions under high temperature conditions is investigated, including capsule appearance, impurity control, dissolution performance, and the formaldehyde content in the capsule is determined.

[0086] The results are shown in table 9 and figure 1. The capsules made of gelatin capsule shell and prussian polysaccharide capsule shell are obviously adhered after 10 days of storage under high temperature, and the adhesion is more serious after 30 days. The preparation stability of fumarate lupatifin capsule made of hydroxypropyl methyl cellulose capsule shell is better, and the capsule shell does not adhere within 30 days, which is more beneficial to long-term storage; and the total impurity content of the active ingredient does not change significantly within 30 days, which can maintain the stability of the drug.

[0087] Figure 1 is the dissolution of the capsules prepared by different prescriptions in the dissolution medium (pH = 1.2 phosphate solution) after 30 days of storage under high temperature and closed conditions. The fumarate lupatifin capsule with gelatin material as the capsule shell forms a film during dissolution, and the capsule shell still cannot be disintegrated after 30 minutes, resulting in the drug being unable to dissolve. The capsule with prussian polysaccharide as the capsule shell is seriously adhered under high temperature storage, the capsule shell is difficult to break, and the drug dissolution rate is reduced. The fumarate lupatifin capsule prepared by using hydroxypropyl methyl cellulose capsule shell dissolves rapidly, and is completely dissolved at 15 minutes.

[0088] In addition, the determination of the formaldehyde content of the capsules found that only a trace amount of formaldehyde was detected in the capsules prepared using gelatin capsule shells, while no formaldehyde was detected in the capsules prepared using Prussian polysaccharide and hydroxypropyl methyl cellulose as the material of the plant capsule shell. This can be because Prussian polysaccharide and hydroxypropyl methyl cellulose do not crosslink with formaldehyde, and the capsule shell itself has good air permeability, and the formaldehyde in the drug substance can be naturally volatilized. Based on the above results, Prussian polysaccharide and hydroxypropyl methyl cellulose are selected as the material of the capsule shell, and hydroxypropyl methyl cellulose is preferably selected as the material of the capsule shell for the preparation of the capsule.

[0089] Table 8 Raw material table of the lupatiquin fumarate capsule of Example 8 (unit: mg)

[0090] Table 9 Formulation performance of the capsules stored under high temperature conditions for 30 days

[0091] Example 9: Screening of the types of excipients

[0092] In order to obtain a suitable excipient combination of the active ingredient of the present application, the types of excipients in the capsule excipients were screened in this example, different excipients were weighed according to Table 10, and the lufatiquin fumarate capsules were prepared by the preparation method described in Example 3, and the stability of the capsules prepared by different formulations under high temperature conditions was investigated.

[0093] The results are shown in Table 11. As can be seen from the table, lactose as an excipient is superior to mannitol and microcrystalline cellulose in impurity control, and is significantly superior to pregelatinized starch and corn starch. Therefore, lactose is preferably used as an excipient.

[0094] Table 10 Raw material table of the lufatiquin fumarate capsule of Example 9 (unit: mg)

[0095] Table 11 Content of related substances under high temperature conditions for 30 days (unit: %)

[0096] Example 10: Screening of the types of lubricants and glidants

[0097] In order to obtain a suitable excipient combination of the active ingredient of the present application, the types of lubricants and glidants in the excipients were screened in this example, different excipients were weighed according to Table 12, and the lufatiquin fumarate capsules were prepared by the preparation method described in Example 3, and the stability of the capsules prepared by different formulations under high temperature conditions was investigated.

[0098] Since the active ingredient is obviously electrostatic, easy to form a cluster, difficult to sieve dispersion, this embodiment further investigates the influence of different lubricants and flow agents on the sieving step. The specific steps are to mix the drug substance with the same amount of lubricant and flow agent according to Table 12, sieve, and observe and record whether the sieving process is smooth.

[0099] The results are shown in Tables 13 and 14. The high temperature stability test results show that glyceryl behenate as a lubricant is significantly better than magnesium stearate, hydrogenated vegetable oil and sodium dodecyl sulfate in impurity control and properties. Talc as a lubricant is better than silicon dioxide in impurity control. And glyceryl behenate as a lubricant, the capsule content is stable in the accelerated investigation test, no discoloration phenomenon, indicating that glyceryl behenate and lactose have better compatibility, which will not cause lactose discoloration.

[0100] The sieving test results show that the drug substance is easier to sieve after adding talc, while it is difficult to pass through when adding silicon dioxide, and the material adheres to the screen, causing loss of the material. This is mainly due to the fact that talc is more effective in eliminating the static electricity of the active ingredient, so talc is preferred as a flow agent.

[0101] Table 12 Raw material table of fumaric acid rupatadine capsules of Example 10 (unit: mg)

[0102] Table 13 Content of related substances under high temperature storage for 30 days (unit: %)

[0103] Table 14 Changes in the properties of the capsule content under high temperature storage for 30 days

[0104] Example 11: Screening of excipient ratio

[0105] Through the screening of excipients, lubricants, flow agents and capsule shells, the present application finally determines to use lactose as an excipient, glyceryl behenate as a lubricant, talc as a flow agent, and hydroxypropyl methyl cellulose capsules as a capsule shell. This embodiment further screens the ratio of each excipient, and prepares fumaric acid rupatadine capsules according to the preparation method described in Example 3 by weighing different excipients according to Table 15, and investigates the preparation performance of the capsules prepared by different formulations.

[0106] The results are shown in Tables 16-17. The results show that the content uniformity and powder flowability in Example 11-1 are worse than those in Examples 11-2 and 11-3; at the same time, the related substance control in Example 11-3 is worse than that in Examples 11-1 and 11-2. Considering comprehensively, the preferred formulation composition is Example 11-2.

[0107] Table 15 Raw material table of the fumarate lupatiquine capsules of Example 11 (unit: mg)

[0108] Table 16 Formulation performance of the fumarate lupatiquine capsules of Example 11

[0109] Table 17 Compound related substance content under high temperature storage for 30 days (unit: %)

[0110] Example 12: Performance and stability investigation of fumarate lupatiquine capsules of different batches

[0111] According to the procedure of Example 3 and the prescription of Example 11-2, fumarate lupatiquine capsules of different batches were prepared. The fumarate lupatiquine capsules of different batches were subjected to formulation performance evaluation and stability investigation (accelerated test, condition: 40℃±2℃, 75%RH±5%RH, time: 6 months).

[0112] Dissolution determination: The test sample was put into a sinker basket, and the dissolution was determined by slurry method. Different dissolution media were selected (see Figure 2), the volume of the dissolution medium was 900 mL, and the rotation speed was set to 75 rpm. The sample was taken at a specific time point, the compound content in the sample solution was determined, and the dissolution content-time curve was calculated and plotted.

[0113] The results are shown in Tables 18-19 and Figure 2. The fumarate lupatiquine capsules of the application have good reproducibility, and the fumarate lupatiquine capsules prepared in different batches all exhibit good formulation performance in terms of appearance, identification, inspection (content uniformity, dissolution, related substance, microbial limit), content, etc. The in vitro dissolution performance of the three batches is consistent, indicating that the method is stable and reliable, and the quality is controllable. In the 6-month accelerated experiment, the fumarate lupatiquine capsules of the application are stable in nature, indicating that they have good long-term storage stability.

[0114] Table 18 Formulation performance evaluation of the fumarate lupatiquine capsules of the application

[0115] Table 19 Accelerated stability investigation of the fumarate lupatiquine capsules of the application

[0116] Example 13: Performance and stability investigation of fumarate lupatiquine capsules of different specifications

[0117] In view of different requirements of clinical application, other formulations of different specifications were provided in this example, and the amounts of the auxiliary materials were shown in Table 20. The preparation method was the same as that in Example 3. The formulations of the fumarate lupatiquine capsules of different specifications were evaluated for their performances. The dissolution was determined in the same manner as in Example 6.

[0118] The results are shown in Table 21 and Figure 3. The selected auxiliary materials were compatible with the drug substance. Even if the proportion of the drug substance was increased, the content of the related substances (total impurities) in the final formulation did not increase significantly. The fumarate lupatiquine capsules of high specifications also had good performances, such as good content uniformity, dissolution higher than 85% within 15 minutes, and fast dissolution.

[0119] Table 20 Raw material table of the fumarate lupatiquine capsules of Example 13 (unit: mg)

[0120] Table 21 Evaluation of the performances of the fumarate lupatiquine capsules of different specifications

Claims

1. A lufuberol fumarate capsule comprising a capsule shell and a content wrapped in the capsule shell.

2. The capsule according to claim 1, wherein, The raw material of the capsule shell is selected from one or more of cellulose, gelatin or other materials; More preferably, the raw material of the capsule shell is selected from one or more of hypromellose, prussin, gelatin, preferably hypromellose.

3. The capsule according to claim 1 or 2, wherein, The content comprises lufuberol fumarate, at least one excipient, at least one lubricant and at least one glidant in a mass ratio of (0.5-24):(60-98):(0.1-3):(1-20).

4. The capsule according to any one of claims 1 to 3, wherein, The excipient is selected from one or more of sugar, sugar alcohol, starch or other types; Preferably, the excipient is selected from one or more of lactose, mannitol and microcrystalline cellulose, preferably lactose.

5. The capsule according to any one of claims 1 to 4, wherein, The lubricant is selected from one or more of esters, stearate or other types; Preferably, the lubricant is selected from one or more of glyceryl behenate, hydrogenated vegetable oil and sodium lauryl sulfate, preferably glyceryl behenate.

6. The capsule according to any one of claims 1 to 5, wherein, The glidant is selected from one or more of talc or silicon dioxide, preferably talc.

7. The capsule according to any one of claims 1 to 6, wherein, The content uses lactose as the excipient, glyceryl behenate as the lubricant and talc as the glidant.

8. The capsule according to any one of claims 1 to 7, wherein, The mass ratio of lufuberol fumarate, at least one excipient, at least one lubricant and at least one glidant in the content is (1-24):(60-95):(0.3-3):(2-15), more preferably the mass ratio of lufuberol fumarate, at least one excipient, at least one lubricant and at least one glidant in the content is (1-24):(60-85):(0.3-2):(2-15), most preferably the mass ratio of lufuberol fumarate, at least one excipient, at least one lubricant and at least one glidant in the content is (1-5):(70-85):(0.3-2):(2-6).

9. A preparation method of the lufuberol fumarate capsule of any one of claims 1-8, comprising the following steps: (1) weighing lufuberol fumarate, excipient, lubricant and glidant; (2) sieving the excipient, lubricant and glidant of step (1) through a No. 3 standard sieve once, and reserving; (3) premixing lufuberol fumarate and glidant of step (2) for 3 minutes, taking out the sieved powder through a No. 3 standard sieve, and reserving; (4) adding the premixed powder of step (3) into a three-dimensional total mixer, mixing uniformly, and reserving; (5) premixing the lubricant of step (2) with 10 times the amount of excipient for 3 minutes, taking out the sieved powder through a No. 3 standard sieve, and reserving; (6) mixing the remaining sieved excipient of step (2) with the premixed powder of step (4) and step (5) uniformly by equal-amount addition method, and reserving; (7) filling the mixed powder obtained in step (6) into a capsule shell to obtain a lufuberol fumarate capsule.

10. A method for preventing and / or treating allergic rhinitis, comprising administering a therapeutically effective amount of the lufuberol fumarate capsule of any one of claims 1-8 to a patient in need thereof.

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