WO2023000350A1 - Glycerol phenylbutyrate granules and preparation method therefor and application thereof - Google Patents

Abstract

Glycerol phenylbutyrate granules, comprising the following components in percentage by mass: 5%-15% of glycerol phenylbutyrate, 5%-45% of a solid carrier, 40%-80% of a filler, 1%-5% of an adhesive, 0.5%-3% of a disintegrating agent, 0.1%-1% of a lubricant, and 0.01%-0.5% of a flavoring agent. The present invention further provides a preparation method for the glycerol phenylbutyrate granules and an application of the glycerol phenylbutyrate granules in the preparation of a drug for treating an urea cycle disorder. By screening the type and proportion of the solid carrier and a combination mode of the solid carrier and the glycerol phenylbutyrate, the glycerol phenylbutyrate can be uniformly adsorbed onto the solid carrier, and then granulated together with conventional adjuvants to obtain the granules. The granules have the characteristics of being convenient in carrying, good in stability, high in compliance, capable of mitigating stomach discomfort, etc.

Description

A kind of glyceryl phenylbutyrate granule and its preparation method and application technical field

The invention belongs to the field of medicines, in particular to a glyceryl phenylbutyrate granule and its preparation method and application.

Background technique

Urea cycle disorder (UCD) is a rare genetic disorder that affects approximately 1 in 35,000 infants in the United States. It is caused by a deficiency of an enzyme in the urea cycle, the process that converts excess ammonia from the blood and eventually removes it from the body. As a result, people with UCD experience hyperammonemia, or elevated levels of ammonia in the blood, which can then travel to the brain, causing irreversible brain damage, coma, or death. UCD symptoms may appear at any age, but more severe deficits occur early in life.

In 2013, Ravicti (phenylbutyrate) oral solution, manufactured by Horizon Pharma, was approved by the FDA as a nitrogen-binding agent for long-term use in adult and pediatric patients with UCD who cannot be treated with dietary protein restriction and/or supplementation alone manage. Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free caloric supplements). In 2019, the FDA approved Ravicti to expand the applicable population to include infants under 2 months of age with urea cycle disorder (UCD).

Long-term management of UCD is aimed at preventing hyperammonemia and includes dietary protein restriction; arginine and citrulline supplementation that enhance waste nitrogen excretion in some UCDs; and oral ammonia-scavenging agents that provide an alternative route of waste nitrogen removal therapy ((glyceryl phenylbutyrate, GPB) oral solution or sodium phenylbutyrate (NaPBA; marketed in the United States and marketed in the European Union (EU)).

Glyceryl phenylbutyrate oral solution is an oily liquid with a strength of 1.1 g/ml. In chronically controlled UCD, for children <2 years, it is administered orally in 3 equal doses, each dose is about 0.1 ml , equivalent to 0.11g of glyceryl phenylbutyrate, for children or adults ≥ 2 years old, orally administered in 3 equal doses, each dose is about 0.5ml, equivalent to 0.55g of glyceryl phenylbutyrate. The preparation needs to be administered in divided doses, but the oily liquid has inaccurate dosage, and the stability of the preparation is affected by repeated administration. At the same time, oily formulations are difficult to handle, carry, and distribute. Secondly, oily formulations are rapidly hydrolyzed and released in the stomach, leading to gastric discomfort, gastric retention, and possibly gastrin-related stomach cramps and vomiting. In order to solve the defects of glyceryl phenylbutyrate oral liquid, the oily liquid is prepared into oral solid medicine in the prior art, by mixing or granulating with commonly used fillers, binders, disintegrants, lubricants, etc., but still There are problems such as poor content uniformity and uneven particle size distribution.

Therefore, it is necessary to develop a solid pharmaceutical composition containing glyceryl phenylbutyrate to make up for the poor compliance of liquid dosage forms, poor dosage accuracy, poor stability for repeated use, and prone to stomach cramps or vomiting.

Contents of the invention

The object of the present invention is to provide a glyceryl phenylbutyrate granule and its preparation method and application, which contain a therapeutically effective amount of glyceryl phenylbutyrate. The present invention can evenly adsorb glyceryl phenylbutyrate on the solid carrier by screening the type, ratio and combination mode of the solid carrier; then granulate with conventional auxiliary materials to obtain granules, which have Convenience, good stability, strong compliance, less stomach discomfort and so on. The present invention mainly solves the above-mentioned technical problems through the following technical solutions.

The invention provides a glyceryl phenylbutyrate granule, which contains 5% to 15% glyceryl phenylbutyrate, 5% to 45% solid carrier, 40% to 80% filler, 1% to 5% binder, 0.5%-3% disintegrant, 0.1%-1% lubricant, 0.01-0.5% flavoring agent.

Preferably, the ratio of the glyceryl phenylbutyrate to the solid carrier is 1:1˜1:3.

Preferably, the solid carrier is selected from one of silicon dioxide, aluminum oxide, titanium dioxide, calcium silicate, and porous starch.

Preferably, the filler is selected from one or more combinations of starch, sucrose, mannitol, erythritol, lactose monohydrate, spray-dried lactose, and microcrystalline cellulose.

Preferably, the binding agent is selected from pregelatinized starch, carboxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, sodium carboxymethylcellulose one or more combinations.

Preferably, the disintegrant is selected from one or more combinations of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl starch sodium.

Preferably, the lubricant is selected from one or more combinations of magnesium stearate, calcium stearate, stearic acid and colloidal silicon dioxide.

Preferably, the flavoring agent is selected from one or more combinations of sucrose, sucralose, stevioside, sorbitol, mannitol, sodium saccharin, and aspartame.

The present invention also provides the preparation method of glyceryl phenylbutyrate granules, comprising the following steps:

a) Sieving: mixing the solid carrier and glyceryl phenylbutyrate, grinding to obtain a solid mixture, and then sieving through a 40-mesh or 60-mesh sieve, and sieving the rest of the auxiliary materials separately through a 60-mesh sieve for use;

b) Premixing: Mix the mixture containing glyceryl phenylbutyrate, filler, disintegrant and flavoring agent in a) uniformly in a high-shear wet mixing granulator;

c) Wet granulation: Dissolve the binder in water, and slowly add the obtained solution into b) during the high-shear wet granulation process until all the addition is complete, and then pass the wet granules through a 5mm×4mm square hole sieve for wet sizing grain;

d) Drying: move the wet granules into a fluidized bed for drying until the moisture content of the granules is ≤2%;

e) Grain sizing: use 0.6mm round hole sieve for sizing;

f) Total mixing: add the lubricant to the granules in e), and mix evenly;

g) Bagging: Aluminum composite film is used as the inner packaging, with a loading capacity of 1g/bag.

The invention also provides the application of the glyceryl phenylbutyrate granule in the preparation of medicine for treating urea cycle disorder.

Compared with the prior art, the positive progress effect of the present invention is:

(1) A solid composition containing phenylbutyrate provided by the present invention is used for the long-term management of UCD adults, adolescents, children, and infants who cannot be treated with dietary protein restriction and/or supplements alone. The solid composition is in the form of granules, common auxiliary materials and mature technology are selected, and it has the advantages of low production cost and easy commercial production.

(2) The granule provided by the present invention mixes the oily liquid main drug in a certain proportion by adsorbing the oily liquid main ingredient through a solid carrier. Through physical adsorption, the oil can be evenly dispersed in the solid carrier, and the carrier will not affect the release of the oil. Granules with good uniformity can be prepared. Compared with liquid preparations, the single-dose packaging of the granules has the advantages of accurate dosage, convenient carrying, and good stability, and the solid pharmaceutical composition makes up for oily preparations in the stomach. Delayed release, insufficiency for upset stomach, stomach pain, or stomach cramps.

(3) In the granule prescription provided by the present invention, the mouthfeel of oil and fat preparations can be improved by using carbohydrate fillers and flavoring agents as compound flavoring agents, and erythritol does not participate in sugar metabolism and blood sugar changes in the body, so It is suitable for diabetic patients and does not cause dental caries, so it is easy for children to take.

Description of drawings

Fig. 1 is the in vitro dissolution study result of the glyceryl phenylbutyrate granules prepared in Examples 4, 5, and 6.

detailed description

A glyceryl phenylbutyrate granule, containing 5%-15% glyceryl phenylbutyrate, 5%-45% solid carrier, 40%-80% filler, 1%-5% binder agent, 0.5% to 3% disintegrant, 0.1% to 1% lubricant, 0.01 to 0.5% flavoring agent.

The glyceryl phenylbutyrate granule of the present invention contains a therapeutically effective amount of glyceryl phenylbutyrate. Phenylbutyrate, a triglyceride comprising three phenylbutyric acid molecules attached to a glycerol backbone, is a prodrug of phenylbutyric acid and a prodrug precursor of the active compound phenylacetate, which has been Approved in the United States for use as a nitrogen-binding agent for the chronic management of adults and patients older than 2 months with UCD who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Based on the percentage of the glyceryl phenylbutyrate granule as 100%, the added amount of the glyceryl phenylbutyrate is 5% to 15%, preferably 11%. The source of glyceryl phenylbutyrate is not particularly limited in the present invention, and commercially available products can be used.

The glyceryl phenylbutyrate granule of the present invention includes a solid carrier, which includes but is not limited to silicon dioxide, aluminum oxide, titanium dioxide, calcium silicate, porous starch, etc., preferably silicon dioxide. The granule provided by the invention absorbs the oily liquid main drug through the solid carrier, so that the granule with good uniformity can be prepared. Based on the percentage of glyceryl phenylbutyrate granules as 100%, the amount of solid carrier added is 5% to 45%, preferably 11% to 33%. The ratio of it to the main drug phenylbutyric acid glyceride is preferably in the range of 1:1 to 3:1. The source of glyceryl phenylbutyrate is not particularly limited in the present invention, and commercially available products can be used.

The glyceryl phenylbutyrate granules of the present invention include fillers. The function of the filler is mainly to increase the weight and volume of the granule preparation, and to absorb the liquid in the prescription. In the present invention, the filler includes, but is not limited to, one or more compositions such as starch, sucrose, mannitol, erythritol, lactose monohydrate, spray-dried lactose, microcrystalline cellulose, etc., preferably erythritol Fresh sugar alcohol, and erythritol does not participate in sugar metabolism and blood sugar changes in the body, so it is suitable for diabetics to take, and it does not have dental caries, so it is easy for children to take. Based on the percentage of glyceryl phenylbutyrate granules as 100%, the proportion of the filler is in the range of 40% to 80%, preferably 50% to 70%, more preferably 60%. The present invention does not have special limitation to the source of filler, adopts commercially available product to get final product.

The glyceryl phenylbutyrate granule of the present invention includes a binder. Adhesive is a class of solid or liquid substances that are viscous in themselves, and its effect is to increase the viscosity of the material. In the present invention, the adhesive includes but is not limited to pregelatinized starch, carboxypropyl methylcellulose, formazan Base cellulose, ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, sodium carboxymethyl cellulose, etc. Based on the percentage of glyceryl phenylbutyrate granules as 100%, the proportion of the binder is in the range of 1% to 5%, preferably 2% to 4%, more preferably 3%. In the present invention, there is no special limitation on the source of the adhesive, and commercially available products can be used.

The glyceryl phenylbutyrate granules of the present invention include a disintegrant, which refers to a substance that eliminates the binding force produced by the binder or high compression, and makes the drug rapidly break into fine particles in the gastrointestinal fluid , so that the functional ingredients can be quickly dissolved and absorbed to play a role. Most of these substances have good water absorption and swelling properties, so as to realize disintegration. In the present invention, the disintegrating agent includes but is not limited to such as cross-linked carmellose sodium, cross-linked povidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, etc. The percentage of disintegrating agent is calculated as 100%, and the proportion of disintegrant is in the range of 0.5% to 3%, preferably 1% to 2%, more preferably 1.5%. In the present invention, there is no special limitation on the source of the disintegrant, and commercially available products can be used.

In the phenylbutyrate granules of the present invention, lubricants are included, which can improve the powder properties of medicines, and the production of solid preparations is carried out smoothly. In the present invention, the lubricants include but are not limited to magnesium stearate , calcium stearate, stearic acid, colloidal silicon dioxide, based on 100% of the glyceryl phenylbutyrate granule, the lubricant ratio is in the range of 0.1% to 1%, preferably 0.5%. In the present invention, the source of the lubricant is not particularly limited, and commercially available products can be used.

The phenylbutyrate granule of the present invention includes a flavoring agent. The flavoring agent can cover the bitter taste, peculiar smell, smell and stimulation of the medicine, improve the taste and increase the bioavailability. In the present invention, the flavoring agent includes, but is not limited to, sucrose, sucralose, stevioside, sorbitol, mannitol, sodium saccharin, aspartame, etc., preferably aspartame. Based on the percentage of the glyceryl phenylbutyrate granule as 100%, the proportion of the flavoring agent is in the range of 0.01-0.5%, preferably 0.2%-0.4%. More preferably, it is 0.3%. The source of the flavoring agent is not particularly limited in the present invention, and commercially available products can be used. In the present invention, the mouthfeel of the oil preparation can be improved by using the carbohydrate filler and the flavoring agent as the compound flavoring agent.

The present invention also provides the preparation method of glyceryl phenylbutyrate granules, comprising the following steps:

a) Sieving: Mix the solid carrier with glyceryl phenylbutyrate, grind to obtain a solid mixture, then sieve through a 40-mesh or 60-mesh sieve, and sieve the remaining auxiliary materials separately through a 60-mesh sieve for subsequent use;

b) Premixing: Mix the mixture containing glyceryl phenylbutyrate, filler, disintegrant and flavoring agent in a) uniformly in a high-shear wet mixing granulator;

c) Wet granulation: Dissolve the binder in water, and slowly add the obtained solution into b) during the high-shear wet granulation process until all the addition is complete, and then pass the wet granules through a 5mm×4mm square hole sieve for wet sizing grain;

d) Drying: move the wet granules into a fluidized bed for drying until the moisture content of the granules is ≤2%;

e) Grain sizing: use 0.6mm round hole sieve for sizing;

f) Total mixing: add the lubricant to the granules in e), and mix evenly;

g) Bagging: Aluminum composite film is used as the inner packaging, with a loading capacity of 1g/bag.

In the preparation method of glyceryl phenylbutyrate granules of the present invention, glyceryl phenylbutyrate is a solid mixture obtained by combining with a solid carrier by soaking, ultrasonication, shaking, drying under reduced pressure, and grinding. The method of carrier adsorption can produce granules with good uniformity, and then granulate with other auxiliary materials to obtain granules. The granules have the characteristics of easy portability, good stability, strong compliance, and less stomach discomfort.

In the preparation method of glyceryl phenylbutyrate granules of the present invention, the solid mixture and auxiliary materials are sieved, preferably through a 60-mesh sieve.

In the preparation method of the glyceryl phenylbutyrate granule of the present invention, there is no special limitation on the granulation process, and the drug granulation process well known in the art can be used. For example, a fluidized bed granulation process or a wet granulation process is used to prepare granules, preferably a wet granulation process. The actual additives added to the formulation and their purpose can be readily understood by those skilled in the art. It should also be understood that certain compounds may exert two or more properties.

The invention also provides the application of the glyceryl phenylbutyrate granule in the preparation of medicine for treating urea cycle disorder.

In order to make the object, technical scheme and advantages of the present invention clearer, the present invention will be described in detail below in conjunction with the examples, but they should not be interpreted as limiting the protection scope of the present invention.

Example 1

The present embodiment provides a kind of glyceryl phenylbutyrate granules, and the prescription is composed as follows:

prescription composition Proportion%

Glyceryl phenylbutyrate 11% silica 11% sucrose 73% Sodium carboxymethyl cellulose 3% Crospovidone 1.5% aspartame 0.1% Magnesium stearate 0.4%

Preparation Process:

a) Silicon dioxide is added to glyceryl phenylbutyrate in equal increments, ground to obtain a solid mixture, and then sieved through a 60-mesh sieve, and the remaining auxiliary materials are sieved separately through a 60-mesh sieve, and set aside;

b) Premixing: Mix sucrose, the mixture containing glyceryl phenylbutyrate in a), crospovidone, and aspartame uniformly in high-shear wet mixing granulation, and set the parameters to the speed of the stirring paddle: 200rpm, cutter closed, stirring time: 5min, torque 33%;

c) Wet granulation: Dissolve sodium carboxymethyl cellulose in water, and slowly add the obtained solution into b) during the high-shear wet granulation process until all the addition is complete, and then pass the wet granules through a 5mm×4mm square hole sieve. Wet granulation, wet granulation parameters are as follows:

d) Drying: move the wet granules into a fluidized bed for drying until the moisture content of the granules is ≤2%;

e) Grain sizing: use 0.6mm round hole sieve for sizing;

f) Blending: adding magnesium stearate to the granules in e), and mixing evenly;

g) Bagging: Aluminum composite film is used as the inner packaging, with a loading capacity of 1g/bag.

Example 2

The present embodiment provides a kind of glyceryl phenylbutyrate granules, and the prescription is composed as follows:

prescription composition Proportion%

Glyceryl phenylbutyrate 11% silica 11% Mannitol 73% Sodium carboxymethyl cellulose 3% Crospovidone 1.5% aspartame 0.1% Magnesium stearate 0.4%

Preparation Process:

Consistent with embodiment 1.

Example 3

The present embodiment provides a kind of glyceryl phenylbutyrate granules, and the prescription is composed as follows:

prescription composition Proportion% Glyceryl phenylbutyrate 11% silica 11% Erythritol 73% Sodium carboxymethyl cellulose 3% Crospovidone 1.5% aspartame 0.1% Magnesium stearate 0.4%

Preparation Process:

Consistent with embodiment 1.

Example 4

This embodiment provides a kind of glyceryl phenylbutyrate granule, and the prescription composition is consistent with embodiment 3.

Preparation Process:

a) Dissolve glyceryl phenylbutyrate in an appropriate amount of ethanol, then add silicon dioxide, ultrasonicate for 10 minutes, stir on a magnetic stirrer for 2 hours, remove ethanol by drying under reduced pressure, and grind the obtained solid mixture so that it can pass through 60 Mesh sieve; Erythritol, sodium carboxymethyl cellulose, crospovidone, aspartame, magnesium stearate are sieved through 60 mesh sieve respectively, for subsequent use;

b) Premixing: Mix erythritol, the mixture containing glycerol phenylbutyrate in a), crospovidone, and aspartame evenly in high-shear wet mixing granulation, and set the parameters as stirring paddle Speed: 200rpm, cutter closed, stirring time: 5min, torque 33%;

c) Wet granulation: Dissolve sodium carboxymethyl cellulose in water, and slowly add the obtained solution into b) during the high-shear wet granulation process until all the addition is complete, and then pass the wet granules through a 5mm×4mm square hole sieve. Wet granulation, wet granulation parameters are consistent with embodiment 1;

d) Drying: move the wet granules into a fluidized bed for drying until the moisture content of the granules is ≤2%;

e Grain granulation: use 0.6mm round hole sieve for granulation;

f) Blending: adding magnesium stearate to the granules in e), and mixing evenly;

g) Bagging: Aluminum composite film is used as the inner packaging, with a loading capacity of 1g/bag.

Example 5

The present embodiment provides a kind of glyceryl phenylbutyrate granules, and the prescription is composed as follows:

prescription composition Proportion% Glyceryl phenylbutyrate 11% silica twenty two% Erythritol 62% Sodium carboxymethyl cellulose 3% Crospovidone 1.5% aspartame 0.1% Magnesium stearate 0.4%

Preparation Process:

Consistent with embodiment 4.

Example 6

The present embodiment provides a kind of glyceryl phenylbutyrate granules, and the prescription is composed as follows:

prescription composition Proportion% Glyceryl phenylbutyrate 11% silica 33% Erythritol 51% Sodium carboxymethyl cellulose 3% Crospovidone 1.5%

aspartame 0.1% Magnesium stearate 0.4%

Preparation Process:

Consistent with embodiment 4.

Example 7

Glyceryl phenylbutyrate granule quality research that above-mentioned embodiment 1-6 prepares

According to the Chinese Pharmacopoeia 2020 Edition, the quality inspection of the granules of the above-mentioned Examples 1-6 is carried out in the four general rules of preparations, and the results are shown in Table 1. Each embodiment can meet the conventional requirements of granules. Wherein the filling agent is the mouthfeel of the embodiment of erythritol the best, i.e. embodiment 3,4,5,6, and erythritol has advantages such as no dental caries, good stability; Both are immersed in the organic solvent, and ultrasonic vibration is used to make the two fully contact, and then the organic solvent is removed. The content uniformity of the particles prepared by the wet granulation process is better, that is, Examples 4, 5, and 6. The reason may be that only through The grinding method failed to disperse the main ingredient evenly in the pores of silica, which affected its content uniformity; as the carrier ratio increased, the content of glyceryl phenylbutyrate showed a downward trend, but the content was all > 95%, that is, Example 4 , 5, 6, the reason may be that the proportion of the carrier is large, and the main drug is more distributed in the shallow pores of the silica, which is more likely to cause the outflow of the main drug during the granulation process, causing loss.

The quality inspection result of table 1 embodiment 1-6

Example 8

The in vitro dissolution study of the glyceryl phenylbutyrate granules prepared in the above-mentioned examples 4, 5, and 6

According to the fourth general rule of the Chinese Pharmacopoeia 2020 edition <0931 Dissolution and Release Determination Method>, the in vitro dissolution behavior of the granules prepared in Examples 4, 5, and 6 in a pH 1.0 medium was investigated. The dissolution condition was paddle method 50rpm, and the dissolution The medium volume is 900ml, and the dissolution behavior results are shown in Figure 1. The higher the carrier ratio, the faster the dissolution and release.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

A glyceryl phenylbutyrate granule is characterized in that, by mass percentage, it contains 5% to 15% glyceryl phenylbutyrate, 5% to 45% solid carrier, 40% to 80% filler, 1% to 5% binder, 0.5%-3% disintegrant, 0.1%-1% lubricant, 0.01-0.5% flavoring agent. The glyceryl phenylbutyrate granule according to claim 1, wherein the ratio of the glyceryl phenylbutyrate to the solid carrier is 1:1-1:3. The glyceryl phenylbutyrate granule according to claim 1, wherein the solid carrier is selected from the group consisting of silicon dioxide, aluminum oxide, titanium dioxide, calcium silicate, and porous starch. The glyceryl phenylbutyrate granule according to claim 1, wherein the filler is selected from the group consisting of starch, sucrose, mannitol, erythritol, lactose monohydrate, spray-dried lactose, microcrystalline cellulose One or more combinations of them. Glyceryl phenylbutyrate granule according to claim 1, is characterized in that, described binding agent is selected from pregelatinized starch, carboxypropyl methylcellulose, methylcellulose, ethylcellulose, polyester One or more combinations of vinylpyrrolidone, polyethylene glycol, and sodium carboxymethylcellulose. The glyceryl phenylbutyrate granule according to claim 1, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxylated One or several combinations of sodium starch glycolate. The glyceryl phenylbutyrate granule according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and colloidal silicon dioxide. kind of composition. Glyceryl phenylbutyrate granule according to claim 1, is characterized in that, described flavoring agent is selected from among sucrose, sucralose, stevioside, sorbitol, mannitol, sodium saccharin, aspartame one or more combinations. A preparation method of the glyceryl phenylbutyrate granule as described in any one of claims 1-8, is characterized in that, comprises the following steps: a) Sieving: mixing the solid carrier with glyceryl phenylbutyrate, grinding to obtain a solid mixture, and then sieving through a 40-mesh or 60-mesh sieve, and sieving the rest of the auxiliary materials separately through a 60-mesh sieve for subsequent use; b) Premixing: Mix the mixture containing glyceryl phenylbutyrate, filler, disintegrant and flavoring agent in a) uniformly in a high-shear wet mixing granulator; c) Wet granulation: Dissolve the binder in water, and slowly add the obtained solution into b) during the high-shear wet granulation process until all the addition is complete, and then pass the wet granules through a 5mm×4mm square hole sieve for wet sizing grain; d) Drying: move the wet granules into a fluidized bed for drying until the moisture content of the granules is ≤2%; e) Grain sizing: use 0.6mm round hole sieve for sizing; f) Total mixing: add the lubricant to the granules in e), and mix evenly; g) Bagging: Aluminum composite film is used as the inner packaging, with a loading capacity of 1g/bag. Application of the glyceryl phenylbutyrate granule described in any one of claims 1-8 in the preparation of a medicament for treating urea cycle disorder.

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