CN116898825A

CN116898825A - Pancreatin enteric-coated capsule, preparation method and application thereof

Info

Publication number: CN116898825A
Application number: CN202311176201.2A
Authority: CN
Inventors: 李勇; 魏世峰; 汪鹤龄
Original assignee: Innovaco Pharmaceuticals Inc
Current assignee: Innovaco Pharmaceuticals Inc
Priority date: 2023-09-13
Filing date: 2023-09-13
Publication date: 2023-10-20

Abstract

The invention relates to a pancreatin enteric capsule, a preparation method and application thereof. In one aspect, it relates to a pancreatin enteric coated pellet comprising: a pancreatin pellet core comprising pancreatin, polyethylene glycol, and sugar alcohol; an enteric coating film coated on the surface of the pill core; a plasticizer distributed within the enteric coating film, and a detackifier distributed within the enteric coating film. The particle size of the pancreatin enteric-coated pellets is in the range of 0.5mm to 2.0mm, and simethicone is not contained therein. The invention also relates to a method for preparing the pancreatin enteric coated pellets, pancreatin enteric capsules comprising the coated pellets, and the use of the pancreatin enteric coated pellets or pancreatin enteric capsules in the preparation of a medicament for the treatment of pancreatic exocrine insufficiency or pancreatic exocrine insufficiency.

Description

Pancreatin enteric-coated capsule, preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, relates to an enteric preparation of pancreatin, and particularly relates to an enteric capsule of pancreatin. The pancreatin enteric capsule can be used as a digestion promoting agent for treating dyspepsia and dyspepsia caused by pancreatic diseases, and also can be used for substitution treatment of exocrine pancreatic function deficiency caused by various reasons. Furthermore, the invention also relates to a method for preparing the pancreatin enteric capsules of the invention and pharmaceutical uses thereof.

Background

Pancreatin (pancratin) is a mixture of enzymes extracted from porcine, ovine or bovine pancreas, mainly trypsin, pancreatic amylase and pancreatic lipase. The pancreas zymogen material medicine received in the second part of Chinese pharmacopoeia of 2020 edition is provided, wherein the activity of trypsin is not less than 600 units, the activity of pancreatic amylase is not less than 7000 units, and the activity of pancreatic lipase is not less than 4000 units in each 1g calculated according to the dry product. Pancreatin is white to yellowish powder, has slight odor, no mildew odor, hygroscopicity, and no enzyme activity when the water solution is boiled or meets acid.

Pancreatin is a digestion aid and mainly contains trypsin, amylopsin, and pancreatic lipase, etc., wherein trypsin can convert proteins into peptone, amylopsin can convert starch into dextrin and sugar, and pancreatic lipase can decompose fat into glycerol and fatty acid. Has stronger activity under neutral or weak alkaline condition. The starch, protein and fat are digested in the intestinal juice, thereby playing the roles of promoting digestion and stimulating appetite.

The pancreatin is mainly used for clinically replacing and treating dyspepsia caused by dyspepsia and pancreatic diseases and pancreatic exocrine function deficiency caused by various reasons. Pancreatin enteric-coated capsules (150 mg/granule) under the trade name Creon (pancrelipase, available from Abbott corporation) were made from porcine pancreas and were used in patients who were unable to complete pancreatic function due to cystic fibrosis, chronic pancreatitis, type 1 diabetes, or pancreatic resection. Creon capsules sold in China contain 0.15g of pancreatin per capsule (corresponding to the unit of the European pharmacopoeia of pancreatic lipase 10000, the unit of the European pharmacopoeia of pancreatic amylase 8000 and the unit of the European pharmacopoeia of trypsin 600), or 0.3g of pancreatin (corresponding to the unit of the European pharmacopoeia of pancreatic lipase 20000, the unit of the European pharmacopoeia of pancreatic amylase 16000 and the unit of the European pharmacopoeia of trypsin 1200), and the pancreatin has a hydrolytic action on fat, starch and protein. After oral administration, the capsule shell dissolves in the stomach releasing hundreds of pancreatin particles with an enteric coating that avoids inactivation in the stomach and is thoroughly mixed with the food in the stomach and enters the duodenum in synchronization with the food. The particles immediately disintegrate at the proximal end of the duodenum, release more than 80% of activity within 130min, and ensure the digestion and absorption of nutrient substances.

At present, the variety is not published in China as reference preparation information, but according to the national reference preparation selection principle, the obtained Yitong or Creon pancreatin enteric-coated capsule produced by Abbott Laboratories GmbH (Germany) company can be used as a reference preparation for developing imitated products. The basic information of the obtained Yingtong or Creon pancreatic enzyme enteric-coated capsule with registered license number of national drug standard word HJ20171150 is as follows: active ingredients: the capsule is mainly trypsin, pancreatic lipase and pancreatic amylase (PANCRELIPASE (AMYLASE, LIPASE, PROTEASE). The property is brown and colorless transparent bicolor capsule, the content is brown pellets coated with enteric materials, the size of the pellets is 0.71-1.60 mm, the pellets comprise the following components, by weight, 150mg of pancreatic enzyme, 37.5mg of polyethylene glycol (PEG 4000), 52.25mg of isopropyl alcohol (removed in the process of preparing pellets from a solvent), 1.25mg of hydroxypropyl methylcellulose phthalate (HP 55), 2.90mg of triethyl citrate (TEC), 1.10mg of Cetyl Alcohol (CA) and acetone (removed in the process of coating from a solvent).

The specification of the pancreatic enzyme enteric capsule is that: 0.15 g/grain or 0.3 g/grain. The indications are as follows: treating pancreatic exocrine insufficiency in children and adults; exocrine pancreatic insufficiency is common (but not limited to): cystic fibrosis, chronic pancreatitis, post-pancreatectomy, post-gastrectomy, pancreatic cancer, post-gastrointestinal bypass reconstructive surgery (e.g., bi post-gastrectomy), pancreatic duct or common bile duct obstruction (e.g., caused by a tumor), simon-schiff syndrome. The specific dosage will vary from person to person and will depend on the severity of the condition and the dietary structure. It is recommended that 1/2 or 1/3 of the total amount (described in detail below) be taken orally each time a meal begins, the remaining dose being taken during the meal. The pancreatin enteric capsule is preferably swallowed with water without grinding or chewing when eating. If the capsule is difficult to take (such as children or the elderly), the capsule can be opened carefully, and pancreatin particles and fluid (if juice) are mixed and taken together, but the mixed liquid should be taken immediately and cannot be stored. Cystic fibrosis patient: according to the recommendations of the cystic fibrosis consensus, the case control study of the U.S. cystic fibrosis foundation, and the results of the uk case control study, the following doses were recommended in pancreatin replacement therapy: pancreatic lipase is administered 1000 units per kilogram of body weight per meal to children under 4 years old and 500 units per kilogram of body weight per meal to patients over 4 years old. The dosage is adjusted according to the severity of the disease, the control of steatorrhea and the need to maintain good nutritional status. For most patients, the daily dosage should be less than or not more than 10000 units of pancreatic lipase per kg body weight. Other disorders of pancreatic exocrine insufficiency: the specific dosage will vary from person to person and will be determined based on the degree of hypofunction of digestion and the fat content of the diet. Typically, the initial dose is 1-2 pancreatin capsules taken per meal or per meal. The dosage should minimize steatorrhea and maintain good nutritional status. The clinically usual dosages are: at least 2-4 pancreatin capsules are taken per meal, and at least 2 pancreatin capsules are orally taken per meal. In terms of pharmacokinetics, pancreatin exerts its full therapeutic effect in the gastrointestinal tract without absorption. Furthermore, since pancreatin itself is a protein, it is eventually absorbed in the form of peptides and amino acids after being decomposed by proteolytic enzymes. The Creon cubic pancreatin enteric-coated capsule can be stored at a dry place below 30 ℃ in a closed state, and the effective period reaches 24 months; the container is preferably tightly closed to avoid moisture; after unsealing, the product is preserved below 25 ℃ and used within 3 months.

CN103397013a (201310288017.7, public welfare) discloses a pancreatin and its enteric capsule, the amino acid sequence of pancreatin is as shown in seq id no:2, etc.; the pancreatin enteric capsule consists of a capsule shell and particles filled in the capsule shell, wherein the particles consist of a pill core and a coating wrapped outside the pill core, the pill core consists of pancreatin, sucrose, dextrin and hydroxypropyl methylcellulose, the coating consists of polyacrylic resin, triethyl citrate and talcum powder, and the weight ratio of the pancreatin, the sucrose, the dextrin and the hydroxypropyl methylcellulose is 23-35:3-12:2-7:0.3-1, wherein the weight ratio of the polyacrylic resin to the triethyl citrate to the talcum powder is 23-35:1-5:5-12, and the weight ratio of the pill core to the coating is 2-8:1-3. The preparation method of the capsule comprises the following steps: dissolving hydroxypropyl methylcellulose in a mixed solution of ethanol and water to prepare an ethanol aqueous solution of the hydroxypropyl methylcellulose; mixing pancreatin, sucrose and dextrin, and centrifuging with ethanol water solution of hydroxypropyl methylcellulose to obtain pill core; mixing triethyl citrate with water, adding into polyacrylic resin latex, adding talcum powder, and mixing to obtain enteric coating solution; coating the enteric coating liquid outside the pill core by a boiling coating machine to obtain particles; the granules are filled into capsule shells.

CN107823174a (application No. 201711256994.3, jinsheng) discloses a preparation method of pancreatin enteric capsule, comprising the following steps: (1) Dissolving 2-3 parts by weight of chitosan in 200-250 parts by weight of sodium acetate buffer solution with the concentration of 0.1-0.2mol/L completely, and then adding 70-80 parts by weight of pancreatin powder, mixing and dispersing uniformly under the low temperature condition to obtain pancreatin-chitosan blend solution; (2) Adding 5-10 parts by weight of mannose into the pancreatin-chitosan blend solution obtained in the step (1) to dissolve completely, then performing vacuum freeze drying, and crushing to obtain pancreatin-chitosan composite powder; (3) Adding the pancreatin-chitosan composite powder obtained in the step (2) with 35-40 parts by weight of lactose and 35-40 parts by weight of sucrose powder into a three-dimensional motion mixer, mixing for 30-40min, finishing granules by using a stainless steel screen, filling into an enteric capsule shell, and packaging to obtain the pancreatin enteric capsule.

It can be seen that CN103397013a is prepared by centrifugally granulating the material into pellet cores and then coating the pellet cores with enteric coating to prepare enteric pellets, and then filling the enteric pellets into a common capsule shell, while CN107823174a is prepared by granulating the material into common granules and then filling the common granules into an enteric capsule shell, and the important defects of the centrifugal granulation into pellet cores are that the yield of the finished product is low, a large number of pellets with unqualified particle sizes are formed, and the scheme of filling the common granules into the enteric capsule shell is easy to cause the capsule to be unable to release in the intestines due to leakage of the capsule shell, and the process is completely different from the commercially available per-pass or Creon pancreatic enzyme enteric capsules with the content of brown small granules coated with enteric materials.

Accordingly, it would be highly desirable to provide pancreatin enteric-coated capsules and methods for their preparation by those skilled in the art.

Disclosure of Invention

The invention aims to provide a pancreatin enteric capsule, and another aim of the invention is to provide a preparation method of the pancreatin enteric capsule and pharmaceutical application thereof. It has been found that pancreatin enteric-coated capsules prepared by the method of the present invention exhibit the advantageous effects of one or more aspects as described in the specification, and the present invention has been completed based on such findings.

To this end, a first aspect of the present invention provides a pancreatin enteric-coated pellet, comprising:

a. a pancreatin pellet core comprising pancreatin, polyethylene glycol, povidone, and sugar alcohol;

b. the enteric coating film is coated on the surface of the pill core, and the film material of the enteric coating film is selected from the following materials: hydroxypropyl cellulose, hydroxypropyl methyl succinate acetate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, methacrylic acid-ethyl acrylate copolymers, in particular methacrylic acid-ethyl acrylate copolymers;

c. a plasticizer distributed within the enteric coating film selected from the group consisting of: cetyl alcohol or triethyl citrate; and

d. A detackifier distributed within the enteric coating film.

The pancreatin enteric coated pellets according to the first aspect of the invention have a particle size in the range of 0.5mm to 2.0mm, for example in the range of 0.6mm to 1.8mm, for example in the range of 0.7mm to 1.6 mm.

The pancreatin enteric coated pellets according to the first aspect of the invention do not contain simethicone (also known as dimethicone). Simethicone is generally considered to be an excellent anti-sticking agent, however, the inventors have found that it is beneficial to not include simethicone in the pancreatin enteric coated pellets of the present invention in the case of using the coating material of the present invention.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the polyethylene glycol is selected from: polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000 and polyethylene glycol 10000, in particular polyethylene glycol 4000.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the polyethylene glycol is used in an amount of 20 to 50 parts by weight, such as 25 to 40 parts by weight, such as 25 to 35 parts by weight, such as 27 to 33 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the povidone is povidone K30.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein povidone is used in an amount of 1 to 4 parts by weight, such as 1.5 to 3 parts by weight, such as 2 to 2.5 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the sugar alcohol is selected from lactose, mannitol, sorbitol, fructose and combinations thereof.

The pancreatin enteric coated pellets according to the first aspect of the invention, in which the sugar alcohol is used in an amount of 20 to 60 parts by weight, for example 30 to 50 parts by weight, for example 35 to 45 parts by weight, for example 37 to 43 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer, for example in the form of a commercial product provided as a 30% methacrylic acid-ethyl acrylate copolymer (1:1) solution, for example as a product under the brand name Kollicoat MAE 30 DP.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the amount of methacrylic acid-ethyl acrylate copolymer is 20 to 40 parts by weight, such as 25 to 35 parts by weight, such as 27 to 33 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the plasticizer is triethyl citrate.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the amount of triethyl citrate is 3 to 6 parts by weight, such as 3.5 to 5.5 parts by weight, such as 4.1 to 4.9 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the detackifier is talc.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein talc is used in an amount of 10 to 20 parts by weight, for example 12 to 18 parts by weight, for example 13.5 to 16.5 parts by weight, per 150 parts by weight of pancreatin.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the pellet core is prepared according to the following steps:

(1) Mixing pancreatin with polyethylene glycol, sugar alcohol and povidone, and then adding ethanol water solution with wetting amount to continuously mix until uniform;

(2) Extruding the obtained mixture through an extrusion spheronizer, extruding the material from the holes, and cutting the extruded material into extruded strips;

(3) Transferring the extrusion strip to a rounding part of an extrusion rounding machine for rounding until a nearly spherical wet pill core is obtained;

(4) And (3) drying the obtained wet pill core in a vacuum drying oven, and screening particles with the particle size ranging from 0.7mm to 3.2mm by using a medicine sieve with a proper pore diameter to obtain the dried pill core.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein in step (1) of preparing the pellet core, polyethylene glycol is pre-pulverized before use, sugar alcohol is pre-pulverized to pass 200 mesh fine powder before use, the materials are mixed in a high shear mixer, and/or the aqueous ethanol solution is 40 to 60% such as 50% aqueous ethanol solution.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein in step (2) of preparing the pellet core, the resulting mixture is extruded through an extrusion spheronizer at a temperature of 40 to 60 ℃, e.g. 40 to 55 ℃, e.g. 45 to 50 ℃, e.g. 45 to 48 ℃ and/or the material is cut into extruded strands of about 5mm after extrusion from 0.8mm holes.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein in step (3) of preparing the pellet cores, the extruded strands are transferred to the spheronization section of an extrusion spheronization machine for spheronization until approximately spherical wet pellet cores are obtained, and 40 to 60% of a wetting amount of, for example, 50% aqueous ethanol solution is slowly injected during the spheronization.

The pancreatin enteric coated pellets according to the first aspect of the invention, in which in step (4) of preparing the pellet cores, the resulting wet pellet cores are dried in a vacuum drying oven at 35±2 ℃ for 5 hours, 40±4 ℃ for 4 hours, and 45±2 ℃ for 3 hours.

(1) Mixing pancreatin with 600g polyethylene glycol (pre-pulverized before use), sugar alcohol (pre-pulverized to 200 mesh fine powder before use), povidone in high shear mixer, and adding 50% ethanol water solution with wetting amount, and mixing until uniform;

(2) Extruding the obtained mixture through an extrusion spheronizer at the temperature of 45-48 ℃, extruding the material from 0.8mm holes, and cutting the extruded material into extruded strips with the thickness of about 5 mm;

(3) Transferring 4000g of extrusion strips to a rounding part of an extrusion rounding machine for rounding until approximately spherical wet pill cores are obtained, and slowly spraying 50% ethanol water solution with a wetting amount in the rounding process;

(4) And (3) drying the obtained wet pill core in a vacuum drying oven (a procedure of drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening particles with the particle size in the range of 0.7-3.2 mm by using a medicine sieve with a proper pore diameter to obtain the dried pill core.

In the present invention, the term "moisture amount" means an amount added to make a material into a soft material according to practical situations and experience in preparing the soft material, which is easily grasped by a person skilled in the art, especially a person skilled in the art of solid preparations, according to experience.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the pellet core is further made into an enteric coated pellet according to the following steps:

(5) Slowly adding a proper amount of water, triethyl citrate and talcum powder into the methacrylic acid-ethyl acrylate copolymer in sequence at room temperature under stirring to dissolve/suspend the materials uniformly, thus obtaining coating liquid;

(6) Placing the pill-containing cores in the step (4) into a coating machine, and coating the pill cores with coating liquid at a temperature lower than 50 ℃ such as 40-45 ℃ until the required coating film thickness is reached;

(7) And (3) drying the obtained coated pellets in a vacuum dryer, and screening coated pellets with the particle size of 0.7-1.6 mm by using a medicine screen with a proper pore diameter to obtain enteric coated pellets.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the concentration of solids in the coating liquid obtained in step (5) is 10 to 25%, such as 10 to 20%, such as 14 to 18%.

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein step (6) places the pellet-containing cores in a fluid bed coater, and spray coats the cores with coating liquid at a temperature of 40±2 ℃ until the desired coating film thickness is reached (e.g., coating the surface of each 222.3mg of the cores with an amount of coating liquid equivalent to 30mg of methacrylic acid-ethyl acrylate copolymer (1: 1)).

The pancreatin enteric coated pellets according to the first aspect of the invention, wherein the obtained coated pellets in step (7) are dried in a vacuum dryer (for example, dried in a mode of drying at 35±2 ℃ for 5 hours, 40±4 ℃ for 4 hours, and 45±2 ℃ for 3 hours in sequence), and coated pellets having a particle diameter in the range of 0.7mm to 1.6mm are screened using a drug sieve having a suitable pore diameter, to obtain enteric coated pellets.

(5) Slowly adding water, triethyl citrate and talcum powder into methacrylic acid-ethyl acrylate copolymer (1:1) in sequence at room temperature under stirring to uniformly dissolve/suspend the materials, thereby obtaining coating liquid, wherein the concentration of solids in the coating liquid is 10-25%, for example 10-20%, for example 14-18%;

(6) Placing the pill-containing cores of step (4) in a fluidized bed coating machine, controlling the temperature of the pill cores to spray coat with a coating liquid at 40+/-2 ℃ until the required coating film thickness is reached (for example, coating the surface of each 222.3mg of pill cores with a coating liquid in an amount corresponding to 30mg of methacrylic acid-ethyl acrylate copolymer (1:1));

(7) And (3) drying the obtained coated pellets in a vacuum dryer (a procedure of drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening the coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine screen with a proper pore diameter to obtain the enteric coated pellets.

Further, a second aspect of the present invention provides a process for preparing a pancreatin enteric-coated pellet as described in any of the first aspects of the present invention, comprising the steps of:

(4) Drying the obtained wet pill core in a vacuum drying oven, and screening particles with the particle size in the range of 0.7 mm-3.2 mm by using a medicine screen with a proper pore diameter to obtain a dried pill-containing core;

The method according to the second aspect of the invention further has the features as set forth in any of the first aspects.

Further, a third aspect of the present invention provides a pancreatin enteric-coated capsule comprising a hollow hard capsule shell and a pancreatin enteric-coated pellet of any of the first aspects of the present invention enclosed therein.

The pancreatin enteric capsule according to the third aspect of the present invention, in which the amount of pancreatin enteric coated pellets per granule is 50 to 500mg, for example 100 to 400mg, for example 150mg to 300mg, for example 150mg or 300mg, in terms of pancreatin.

Further, the fourth aspect of the present invention provides the use of the pancreatin enteric-capsules according to the third aspect of the present invention for the preparation of a medicament for the treatment of:

pancreatic exocrine insufficiency in children and adults; pancreatic exocrine insufficiency, which is common in, but not limited to, the following conditions: cystic fibrosis, chronic pancreatitis, post-pancreatectomy, post-gastrectomy, pancreatic cancer, post-gastrointestinal bypass reconstructive surgery (e.g., bi post-gastrectomy), pancreatic duct or common bile duct obstruction (e.g., caused by a tumor), simon-schiff syndrome.

The pancreatin enteric-coated capsules provided by the invention exhibit excellent effects as described herein.

Description of the embodiments

The various aspects of the invention and the effects that they exhibit are illustrated by the following specific examples, which are not intended to limit the invention. In the following formulation of the composition, the total amount of each ingredient is not less than 1kg unless otherwise specifically indicated. In the following specific examples, the amounts of materials may be expressed as either specific amounts or ratios, for example, when a product obtained in a step is insufficient for the next step, the amounts of materials sufficient for the next step may be obtained by repeating or amplifying the steps. The pancreatic raw material medicine used in the invention is purchased from Sichuan fritillary biological pharmacy Co., ltd, and is tested to meet the standards under the pancreatic enzyme item carried by the two parts of Chinese pharmacopoeia of 2020 edition, and the same batch of raw material medicine is used unless otherwise stated.

Example 1: preparation of pancreatin enteric capsule

The preparation of the embodiment is basically carried out by referring to the prescription process of the commercially available imported medicines to obtain each-pass or Creon-type pancreatin enteric-coated capsules (national drug standard HJ 20171150).

The enteric pellets in the pancreatin enteric capsule have the following material proportions:

pancreatic enzyme 150mg,

Polyethylene glycol (PEG 4000) 37.5mg,

Proper amount of isopropanol (proper amount of material is formed into soft material with proper hardness, and is removed in the process of making pills),

52.25mg of hydroxypropyl methylcellulose phthalate (HP 55),

1.25mg of simethicone,

2.90mg of triethyl citrate (TEC),

Cetyl Alcohol (CA) 1.10mg,

Proper amount of acetone (about 452mg, coating solution solvent, removed during coating process).

1. Preparation of the core containing the pill

(1) 3000g of pancreatin are mixed with 750g of polyethylene glycol (PEG 4000 type, pre-crushed before use) in a high shear mixer (the device designed according to China patent No. 201320500343.5 is used in this example, other similar devices are also used in the market), and then 750g of isopropanol is added to continue mixing until homogeneous;

(2) Extruding the obtained mixture at a temperature of 45-48 ℃ through an extrusion spheronizer (JCD-100, force is healthy), extruding the material from 0.8mm holes and cutting the extruded material into extruded strips with the thickness of about 5 mm;

(3) Transferring 4000g of extrusion strips to a rounding part of an extrusion rounding machine for rounding until a nearly spherical wet pill core is obtained, and slowly spraying 150g of isopropanol in the rounding process;

(4) Drying the obtained wet pill core in a vacuum drying oven (DZF-L type, proplin) (drying at 35+ -2 ℃ for 5 hours, drying at 40+ -4 ℃ for 4 hours and drying at 45+ -2 ℃ for 3 hours), and screening particles with the particle diameter of 0.7 mm-3.2 mm by using a medicine sieve with a proper aperture to obtain a dry pill-containing core;

2. Preparation of enteric coated pellets and enteric capsules

(5) 522.5g of hydroxypropyl methylcellulose phthalate (HP 55), 12.5g of simethicone, 29.0g of triethyl citrate and 11g of cetyl alcohol are sequentially and slowly added into 4520g of acetone at room temperature under stirring, so that the materials are uniformly dissolved/suspended to obtain a coating liquid;

(6) Placing 1875g of the pellet-containing cores of step (4) in a fluidized bed coating machine (YC-1000 model, yacheng), controlling the temperature of the cores at 40±2 ℃ and spraying the cores with a coating liquid at a speed of about 85g/min until the required coating film thickness is reached (coating liquid in an amount corresponding to 52.25mg of hypromellose phthalate per 187.5mg of the surface of the cores);

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (1836 g, coating yield 74.9%); optionally, the composition may be in the form of a gel,

(8) Filling the obtained enteric coated pellets into hard capsule shells, wherein the amount of each filled pellet is 150mg calculated by pancreatin, and the pancreatin enteric capsule is obtained.

In some of the examples provided below, reference was made to the preparation process of example 1, but the recipe was slightly changed to prepare several pancreatin enteric capsules.

Example 11: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

30mg of polyethylene glycol (PEG 4000),

Lactose 40mg,

K30 type povidone 2.3mg,

A proper amount of 50% ethanol water solution (proper amount of materials form soft materials with proper hardness, and the wet liquid for making pills is removed in the process of making pills),

methacrylic acid-ethyl acrylate copolymer (1:1 gauge, kollicoat (r) MAE 30DP product of BASF SE) provided as a 30% solution of methacrylic acid-ethyl acrylate copolymer (1:1) in an amount of 30mg on a solids basis),

4.5mg of triethyl citrate (TEC),

15mg of talcum powder,

Proper amount of water (about 200mg of coating solution solvent, removed during coating process).

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 600g of polyethylene glycol (PEG 4000, pre-crushed before use), 800g of lactose (pre-crushed to a fine powder of 200 meshes before use), 46g of povidone K30 in a high shear mixer (the device designed according to Chinese patent No. 201320500343.5 is used in this example, other similar devices on the market can also be used), and then 1000g of 50% aqueous ethanol solution is added to continue mixing until uniform;

(3) Transferring 4000g of extrusion strips to a rounding part of an extrusion rounding machine for rounding until approximately spherical wet pill cores are obtained, and slowly spraying 100g of 50% ethanol water solution in the rounding process;

2. preparation of enteric coated pellets and enteric capsules

(5) Sequentially and slowly adding 2000g of water, 45g of triethyl citrate (TEC) and 150g of talcum powder into 300g of methacrylic acid-ethyl acrylate copolymer (1:1, 30% solution, the dosage is calculated by solid matter) at room temperature under stirring to dissolve/suspend the materials uniformly to obtain coating liquid;

(6) Placing 2223g of the pellet-containing cores of step (4) in a fluid bed coater (YC-1000 model, yacheng), controlling the temperature of the cores at 40±2 ℃ and spraying the cores with a coating liquid at a speed of about 75g/min until the required coating film thickness is reached (coating the surface of each 222.3mg of the cores with a coating liquid in an amount equivalent to 30mg of methacrylic acid-ethyl acrylate copolymer (1:1));

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2432 g, coating yield is 89.5%); optionally, the composition may be in the form of a gel,

Example 12: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

30mg of polyethylene glycol (PEG 4000),

40mg of mannitol,

K30 type povidone 2.3mg,

4.5mg of triethyl citrate (TEC),

15mg of talcum powder,

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 600g of polyethylene glycol (PEG 4000, pre-crushed before use), 800g of mannitol (pre-crushed to a fine powder of 200 meshes before use), 46g of povidone K30 in a high shear mixer (the device designed according to Chinese patent No. 201320500343.5 is used in this example, other similar devices on the market can also be used), and then 1000g of 50% ethanol aqueous solution is added and mixed until uniform;

2. preparation of enteric coated pellets and enteric capsules

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2397 g, coating yield 88.2%); optionally, the composition may be in the form of a gel,

Example 13: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

30mg of polyethylene glycol (PEG 4000),

40mg of sorbitol,

K30 type povidone 2.3mg,

4.5mg of triethyl citrate (TEC),

15mg of talcum powder,

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 600g of polyethylene glycol (PEG 4000, pre-crushed before use), 800g of sorbitol (pre-crushed to a fine powder which can pass through 200 meshes before use), 46g of povidone K30 in a high shear mixer (the device designed according to Chinese patent No. 201320500343.5 is used in the example, and other similar devices on the market can also be used), and then 1000g of 50% ethanol aqueous solution is added and mixed until uniform;

2. preparation of enteric coated pellets and enteric capsules

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2462 g, coating yield 90.6%); optionally, the composition may be in the form of a gel,

Example 14: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

30mg of polyethylene glycol (PEG 4000),

40mg of fructose,

K30 type povidone 2.3mg,

4.5mg of triethyl citrate (TEC),

15mg of talcum powder,

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 600g of polyethylene glycol (PEG 4000, pre-crushed before use), 800g of fructose (pre-crushed to a fine powder of 200 meshes before use), 46g of povidone K30 in a high shear mixer (the device designed according to Chinese patent No. 201320500343.5 is used in this example, other similar devices on the market can also be used), and then 1000g of 50% ethanol aqueous solution is added to continue mixing until uniform;

2. Preparation of enteric coated pellets and enteric capsules

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2404 g, coating yield 88.4%); optionally, the composition may be in the form of a gel,

Example 15: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

Polyethylene glycol (PEG 4000) 27mg,

Lactose 43mg,

K30 type povidone 2.5mg,

methacrylic acid-ethyl acrylate copolymer (1:1 gauge, kollicoat (r) MAE 30DP product of BASF SE) provided as a 30% solution of methacrylic acid-ethyl acrylate copolymer (1:1) in an amount of 33mg, calculated as solids),

4.1mg of triethyl citrate (TEC),

13.5mg of talcum powder,

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 540g of polyethylene glycol (PEG 4000, pre-crushed before use), 860g of lactose (pre-crushed to a fine powder which can pass through 200 meshes before use), 50g of povidone K30 in a high shear mixer (the equipment designed according to Chinese patent No. 201320500343.5 is used in the example, and other similar equipment on the market can also be used), and then 1000g of 50% ethanol aqueous solution is added to continue mixing until uniform;

2. preparation of enteric coated pellets and enteric capsules

(5) Slowly adding 2000g of water, 41g of triethyl citrate (TEC) and 135g of talcum powder into 330g of methacrylic acid-ethyl acrylate copolymer (1:1, 30% solution, the dosage is calculated by solid matter) in sequence at room temperature under stirring to dissolve/suspend the materials uniformly to obtain coating liquid;

(6) Placing 2225g of the pellet-containing cores of step (4) in a fluid bed coater (YC-1000 model, yacheng), controlling the temperature of the cores at 40±2 ℃ and spraying the cores with a coating liquid at a speed of about 75g/min until the required coating film thickness is reached (coating the surface of each 222.5mg of the cores with a coating liquid in an amount equivalent to 30mg of methacrylic acid-ethyl acrylate copolymer (1:1));

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size ranging from 0.7mm to 1.6mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2441 g, coating yield 89.4%); optionally, the composition may be in the form of a gel,

Example 16: preparation of pancreatin enteric capsule

pancreatic enzyme 150mg,

33mg of polyethylene glycol (PEG 4000),

Lactose 37mg,

K30 type povidone 2.1mg,

methacrylic acid-ethyl acrylate copolymer (1:1 gauge, kollicoat (r) MAE 30DP product of BASF SE) provided as a 30% solution of methacrylic acid-ethyl acrylate copolymer (1:1) in an amount of 27mg on a solids basis),

4.9mg of triethyl citrate (TEC),

16.5mg of talcum powder,

1. Preparation of the core containing the pill

(1) 3000g of pancreatin is mixed with 660g of polyethylene glycol (PEG 4000, pre-crushed before use), 740g of lactose (pre-crushed to a fine powder which can pass through 200 meshes before use), 42g of povidone K30 in a high shear mixer (the device designed according to Chinese patent No. 201320500343.5 is used in the example, and other similar devices on the market can also be used), and then 1000g of 50% ethanol aqueous solution is added to continue mixing until uniform;

2. preparation of enteric coated pellets and enteric capsules

(5) Slowly adding 2000g of water, 49g of triethyl citrate (TEC) and 165g of talcum powder into 270g of methacrylic acid-ethyl acrylate copolymer (1:1, 30% solution, the dosage is calculated by solid matter) in sequence at room temperature under stirring to dissolve/suspend the materials uniformly to obtain coating liquid;

(6) Placing 2221g of the pellet-containing cores of step (4) in a fluid bed coater (YC-1000 model, elegance), controlling the temperature of the cores at 40±2 ℃ and spraying the cores with a coating liquid at a speed of about 75g/min until the desired film thickness is reached (coating the surface of each 222.1mg of the cores with a coating liquid in an amount equivalent to 30mg of methacrylic acid-ethyl acrylate copolymer (1:1));

(7) Drying the obtained coated pellets in a vacuum dryer (drying at 35+/-2 ℃ for 5 hours, drying at 40+/-4 ℃ for 4 hours and drying at 45+/-2 ℃ for 3 hours), and screening coated pellets with the particle size in the range of 0.7-1.6 mm by using a medicine sieve with a proper pore diameter to obtain enteric coated pellets (2422 g, coating yield 89.5%); optionally, the composition may be in the form of a gel,

Test example 1: quality detection of pancreatin enteric capsule

1. General procedure

According to the two parts of the Chinese pharmacopoeia of 2020 edition,

the trypsin activity in each 1g of the pancreatic enzyme feed is not less than 600 units, the pancreatic enzyme activity is not less than 7000 units and the pancreatic lipase activity is not less than 4000 units;

the trypsin activity in each 1g of the pancreatin enteric-coated capsule/tablet is not less than 540 units, the amylopsin activity is not less than 6300 units, and the pancreatic lipase activity is not less than 3400 units.

The test examples were carried out according to the methods under the section of pancreatin enteric-coated capsules carried by the chinese pharmacopoeia of the 2020 edition, and some pancreatin enteric-coated capsules or pancreatin bulk drugs prepared herein were tested, the methods (all according to the methods described in pharmacopoeia if not specified) and the results were as follows.

2. Quality detection of pancreatin bulk drug

The pancreatic proenzyme drug used herein was measured with reference to the pancreatic proenzyme drug carried by the two parts of the chinese pharmacopoeia of the 2020 edition, and the results were as follows:

traits: white powder, slight odor, no mildew odor, moisture permeability and compliance with pharmacopoeia regulations;

fat: according to the method, 5.7mg of residual fat is measured, and the method meets the regulations;

drying weight loss: according to the measurement of the method, the weight loss is reduced by 3.4 percent, and the method meets the regulations;

microbial limit: 1g of the test sample contains 700cfu of total aerobic bacteria, 20cfu of total mold and yeast, no escherichia coli is detected, and 10g of the test sample contains no salmonella, which meets the regulations;

trypsin potency: according to the method, each 1g of the trypsin-containing activity 925u accords with the specification of more than 600 u;

amylopsin potency: according to the measurement of the method, each 1g of the trypsin-containing activity 16537u accords with the regulation of more than 7000 u;

pancrelipase potency: per 1g trypsin-containing activity 6324u, as determined by the method, meets the regulations of more than 4000 u.

3. Quality detection of pancreatin enteric capsule

The total of 7 batches of pancreatin enteric capsules of example 1 and examples 11 to 16 were measured with reference to each item of pancreatin enteric capsules carried by the second part of the chinese pharmacopoeia of 2020 edition, and the results were as follows:

Traits: the content of 7 batches of capsules is white to pale yellow pellets, and the size of the pellets is 0.7 mm-1.6 mm;

drying weight loss: taking 5g of capsule content, drying at 105 ℃ for 4 hours, determining according to a law, precisely and stably calculating the weight loss before and after drying, wherein the weight loss of 7 batches of capsule pellets is 2-4% of the weight loss of the capsule of the example 11, and the weight loss of the capsule meets the general regulations;

microbial limit: taking the content of the capsules to measure according to the corresponding method of the bulk drug, and as a result, for all 7 batches of capsules, the total number of aerobic bacteria in 1g of the test products is smaller than 1000cfu, the total number of mold and the total number of saccharomycetes are smaller than 40cfu, no escherichia coli is detected, and no salmonella is detected in 10g of the test products, so that the requirements are met; for example, in the capsule of example 11, the total number of aerobic bacteria in 1g of the test sample was 640cfu, the total number of mold and yeast in 22cfu, and Escherichia coli was not detected, and in 10g of the test sample, salmonella was not detected;

trypsin potency: the activity of 7 batches of pancreatin enteric capsules is in the range of 135-142 u per capsule (corresponding to 150mg containing pancreatin) measured according to the method of the pharmacopoeia pancreatin enteric capsule standard (each batch of samples is calculated according to the average value of the results obtained by 5 times), for example, the activity of each of the capsules of example 11 containing trypsin is 136.6u (corresponding to 98.5% of theoretical amount calculated according to the actual measured titer of the raw materials);

Amylopsin potency: the activity of pancreatic amylase contained in 7 batches of pancreatic enzyme enteric-coated capsules is in the range of 2432-2513 u per granule (equivalent to 150mg containing pancreatic enzyme drug per granule) measured according to the method of the standard of the pancreatic enzyme enteric-coated capsule of pharmacopeia (the average value of the results obtained by measuring 5 times per batch of samples), for example, the activity of pancreatic enzyme contained in each granule of the capsule of example 11 is 2503.2u (equivalent to 100.9% of theoretical amount calculated according to actual measurement titer of raw materials);

pancrelipase potency: the activity of pancreatic lipase contained in 7 batches of pancreatic enzyme enteric capsules (calculated by the average value of the results obtained by measuring 5 times for each batch of samples) is in the range of 933-964 u per granule (equivalent to 150mg containing pancreatic enzyme as a raw material) measured by the method of the standard of the pancreatic enzyme enteric capsule of pharmacopoeia, for example, the activity of pancreatic lipase contained in each granule of the capsule of example 11 is 943.4u (equivalent to 99.5% of theoretical amount calculated by actual measurement of raw material).

The trypsin, the pancreatic amylase and the pancreatic lipase should be not less than 81u, 945u and 510u, respectively, per 150mg of pancreatin enteric capsule carried in Chinese pharmacopoeia of 2020 edition.

According to the results, the pancreatin enteric-coated capsules prepared by the method disclosed by the invention with the commercial pancreatin raw materials have excellent performance, for example, the titer of active substances is basically in the range of 97-103% of the theoretical dosage.

However, example 1 and the obtained per pass or Creon pancreatic enzyme enteric capsules (HJ 20171150) prepared by the method and entering China use isopropanol and acetone which are significantly more toxic than ethanol and water according to the invention, so that when the quality of imported medicines is detected in China, the residue of isopropanol and acetone needs to be detected by gas chromatography, while the enteric pellets prepared by the method of examples 11-16 by using ethanol and water are obviously much safer, and the residual quantity of solvent does not need to be checked. It is well known that isopropanol has a large pungent taste, is not only harmful to human, but also is unfavorable for worker production; isopropanol belongs to an organic solvent, and more strict conditions are required to control the isopropanol within a safe limit range; in addition, acetone is easy to prepare and needs to be controlled, has explosive property and has great potential safety hazard.

Test example 2: test of gastric acid resistance (pH 1.0 and pH 5.0) of pancreatin enteric capsules

The method comprises the steps of placing the content of 1-grain pancreatin enteric capsule into a rotary basket by using a first method (basket method) of a dissolution and release measurement method of four parts of the Chinese pharmacopoeia 2020, taking out the rotary basket carefully after the rotary basket is started for 2 hours at a temperature of 37 ℃ and a rotation speed of 50rpm by taking 900ml of hydrochloric acid as a medium, draining, quantitatively transferring the content into a mortar by using a proper amount of a tris buffer (taking 606mg of tris (hydroxymethyl) and adding 45.7ml of 0.1mol/L hydrochloric acid solution, adding 100ml of water, shaking uniformly, regulating the pH value to 7.1), quantitatively diluting the solution with the buffer to prepare a solution with about 8-16 units of pancreatic lipase in each 1m1, and measuring the pancreatic lipase titer according to a method under two parts of the Chinese pharmacopoeia 2020.

The measurement was carried out on 7 batches of pancreatin enteric-coated capsules of examples 1 and 11 to 16, wherein the pancrelipase titer of the capsule measured in test example 1 was 0h titer for a certain batch of capsules, the total of the pancrelipase residues (%) of the batch of pancrelipase enteric-coated capsules after 2 hours treatment with 0.1mol/l hydrochloric acid was calculated as the average of the results obtained by measuring 5 times, with the titer measured by 2 hours treatment with 0.1mol/l hydrochloric acid as the pH 1 and the titer obtained by dividing the 2h titer by the 0h titer and multiplying 100%.

In addition, referring to the above method, the trypsin residual rate (%) of the pancreatin enteric capsule after 2 hours of treatment with 0.1mol/l hydrochloric acid and the pancreatic amylase residual rate (%) of the pancreatin enteric capsule after 2 hours of treatment with 0.1mol/l hydrochloric acid were measured.

In addition, the above method was used, but the test medium was changed to pH5.0 phosphate buffer (2.0 g of sodium chloride and 9.2g of sodium dihydrogen phosphate monohydrate were dissolved to 1L with water and adjusted to pH5.0 with phosphoric acid or sodium hydroxide), and the pancreatic lipase residual rate (%) after the pancreatin enteric capsule was treated with pH5.0 phosphate buffer for 2 hours, the trypsin residual rate (%) after the pancreatin enteric capsule was treated with pH5.0 phosphate buffer for 2 hours, and the pancreatic amylase residual rate (%) after the pancreatin enteric capsule was treated with pH5.0 phosphate buffer for 2 hours were measured as described above. The results of the tests at both pH conditions are shown in Table 1 below.

Table 1: examination of acid resistance of pancreatin enteric capsules to different pH conditions

From the above results, it can be seen that pancreatin enteric-coated capsules prepared according to some embodiments of the present invention have excellent acid resistance.

Test example 3: examination of storage stability of pancreatin enteric capsules

The pancreatin enteric capsules (hard capsule shell filled enteric pellets) prepared according to the present invention were filled into simulated commercial aluminum plastic blister packages, which were then placed in a closed environment at a temperature of 40 ℃ and a relative humidity of 75% (which may be referred to herein as T40RH75 treatment) for 6 months, and the titers of pancreatic lipase, trypsin, pancreatic amylase, and pancreatic amylase of the capsules at 0 month, 3 month, and 6 month, respectively, were determined using the method of test example 1 herein, and the titers of the individual batches of capsules were calculated at their 0 month titers of 100%, and the titers residual for 3 month, 6 month (each data is an average of n=6), and the results are shown in table 2.

Table 2: residual rate of active ingredient of pancreatin enteric-coated capsule after 6 months of treatment by T40RH75

From the above results, it can be seen that the stability of the enteric capsules of examples 11 to 16 is significantly better than that of the capsules of example 1, especially trypsin and pancreatic amylase, after 6 months of treatment with T40RH75 under simulated commercial packaging conditions. Although it is not clear by the inventors why such stability improvement is due in particular, it is believed that prescription changes are one of the possible reasons.

The results of the above capsules treated with T40RH75 for 6 months only indicate the stability of the active substance inside the pellets, however, how stable the enteric coating film is after 6 months of treatment with T40RH75 still necessitates investigation. For this purpose, referring to the methods of test example 1 and test example 2, the residual rate of the active ingredient after 2 hours of treatment at ph1.0 and 2 hours of treatment at ph5.0 (residual rate compared with the result of 0 hour of treatment of the capsule at T40RH75 for 6 months) was examined for 7 kinds of enteric capsules treated at T40RH75 for 6 months, and the results are shown in table 3.

Table 3: examination of acid resistance of pancreatin enteric capsules treated with T40RH75 for 6 months for different pH conditions

From the above results, it can be seen that the enteric capsules of examples 11 to 16 were slightly inferior in acid resistance to treatment for 6 months after undergoing treatment for T40RH75, but still at a good level, while the capsule of example 1 was slightly inferior to the other capsules.

Test example 4: dissolution investigation of pancreatin enteric-coated capsules

The pancreatin enteric-capsules of the invention are not soluble in the stomach, but rather should dissolve and release the active substance in the intestine. In this test example, dissolution rates of pancreatin enteric capsules of example 1 and examples 11 to 16 were examined.

For each batch of samples, taking 3 particles of pancreatin enteric capsules, placing the samples in a rotary basket according to a dissolution rate measurement method (four parts of Chinese pharmacopoeia 2020, "0931 dissolution rate and release rate measurement method," first method (basket method) "), taking simulated gastric fluid 800m1 as a dissolution medium, operating at 100 rpm according to law, and taking out the rotary basket after 120 minutes;

Then, according to a dissolution rate measurement method (four parts of Chinese pharmacopoeia 2020, "0931 dissolution rate and release rate measurement method," second method (Paddle method) "), the contents of the rotating basket are completely transferred to a phosphate buffer solution (pH 6.8) at 37 ℃, 250ml of 0.2mol/L potassium dihydrogen phosphate solution is taken, 118ml of 0.2mol/L sodium hydroxide solution is added, diluted to 1000ml with water, and shaking is carried out, thus obtaining a dissolution solution after 30 minutes and 45 minutes at a rotation speed of 50 rpm in a solvent of 500m 1;

the trypsin titer in the dissolution liquid is measured by a method under the two-part pancreatin item of the Chinese pharmacopoeia 2020 edition, and when necessary, the dissolution liquid is quantitatively diluted by borate buffer solution cooled to below 5 ℃ to prepare a solution containing about 0.1-0.15 units of trypsin in each 1ml, the trypsin titer in each batch of capsules measured in test example 1 is taken as the theoretical trypsin amount, and the dissolution percentage, namely the dissolution rate, of the enteric-coated capsules characterized by trypsin at two time points of 30 minutes and 45 minutes is measured and calculated, and the result is shown in Table 4.

In addition, referring to the above method, except that 500m1 phosphate buffer was replaced with equal volume of McIlvain buffer (pH 6.0; solution A:7.098 g anhydrous Na2HPO4 and 4 g bile acid salt were dissolved in 1000ml water, solution B: C6H8O7.H2O of 5.25 g and 4 g bile acid salt were dissolved in 100 ml water, and the two were mixed to obtain), the dissolution percentages of the enteric capsules as characterized by trypsin at two time points of 30 minutes and 45 minutes were measured and calculated, as the results are shown in Table 4.

Table 4: dissolution investigation of pancreatin enteric capsules in phosphate buffer and McIlvain buffer (trypsin)

According to the results, the dissolution rate of the enteric capsules prepared by the invention can reach more than 80% after the enteric capsules are subjected to phosphate buffer solution with pH of 6.8 and McIlvain buffer solution with pH of 6.0 for 45min, which shows that the enteric capsules have excellent enteric dissolution performance. The results also show that the capsules of example 1 have lower dissolution than the other capsules. Since trypsin is an index component of the pancreatin enteric capsules of the present invention, it is significant to examine the dissolution of the capsules using it as an index.

Test example 5: formulation investigation of enteric capsules

The formulations of the pancreatin enteric capsules of examples 11 to 16, which exhibit excellent properties, were obtained through a large number of experiments, and particularly in some research formulation investigation experiments, it was found that the combination of sugar alcohols such as lactose in the formulation with the enteric coating material methacrylic acid-ethyl acrylate copolymer (1:1) was essential for obtaining excellent stability and other properties, and some specific experiments were as follows.

Supplementary example a: referring to the formulations and the preparation methods of examples 11 to 14, except that sugar alcohol such as lactose was changed to 10mg of PEG4000, that is, sugar alcohol such as lactose was not used, 4 parts of enteric capsules were obtained and were respectively designated as examples 11a to 14a; supplementary example b: referring to the formulations and the preparation methods of examples 11 to 14, except that the sugar alcohol such as lactose was changed to microcrystalline cellulose in the same amount, that is, the sugar alcohol was changed to microcrystalline cellulose, 4 parts of enteric capsules were obtained and were respectively recorded as examples 11b to 14b; supplementary example c: referring to the formulations and the preparation methods of examples 11 to 14, except that sugar alcohols such as lactose and the like are changed into starch of the same amount, namely that the sugar alcohols are changed into starch, and 4 parts of enteric capsules are respectively recorded as examples 11c to 14c; supplementary example d: referring to the formulations and the preparation methods of examples 11 to 14, except that the methacrylic acid-ethyl acrylate copolymer (1:1) was changed to hydroxypropylmethyl cellulose phthalate (HP 55) with equal amount of solids and the solvent was changed to acetone, the weight ratio of acetone to HP55 was 8.65:1, and equal amounts of triethyl citrate and talc were dissolved/suspended in the obtained coating liquid, i.e., the coating material was changed to HP55 of example 1, and 4 parts of enteric capsules were respectively recorded as examples 11d to 14d; supplementary example e: referring to the formulations and the preparation methods of examples 11 to 14, except that the coating material methacrylic acid-ethyl acrylate copolymer (1:1) was changed to a methacrylic acid-ethyl methacrylate copolymer (1:1, rohm) of similar performance of the same amount of solids, 4 parts of enteric capsules were obtained and were respectively recorded as examples 11e to 14e; supplementary example f: referring to the formulations and preparation methods of examples 11-14, except that the coating material methacrylic acid-ethyl acrylate copolymer (1:1) was changed to a similar performance methacrylic acid-methyl methacrylate copolymer (1:1, rohm) of equivalent solids, 4 parts of enteric capsules were obtained and were respectively designated as examples 11 f-14 f.

Next, referring to the method of test example 3, the residual rate of the active ingredient after the pancreatin enteric capsules obtained in the above supplementary examples were treated with T40RH75 for 6 months, i.e., the results were provided at the residual rate of 6 months similarly to those shown in table 2, concretely as follows: the pancreatic lipase 6 month residue rates of the four capsules of examples 11a to 14a are all in the range of 71 to 73%, the trypsin 6 month residue rates are all in the range of 65 to 69%, and the pancreatic amylase 6 month residue rates are all in the range of 62 to 66%, for example, the pancreatic lipase, trypsin, pancreatic amylase 6 month residue rates of the capsule of example 11a are 72.4%, 66.3%, 64.6%, respectively; the pancreatic lipase 6 month residue rates of the four capsules of examples 11b to 14b are all 72 to 75%, the trypsin 6 month residue rates are all 65 to 68%, and the pancreatic amylase 6 month residue rates are all 64 to 67%, for example, the pancreatic lipase, trypsin, and pancreatic amylase 6 month residue rates of the capsule of example 11b are 74.3%, 66.7%, and 66.4%, respectively; the pancreatic lipase 6 month residue rates of the four capsules of examples 11c to 14c are all in the range of 71 to 73%, the trypsin 6 month residue rates are all in the range of 66 to 69%, and the pancreatic amylase 6 month residue rates are all in the range of 63 to 67%, for example, the pancreatic lipase, trypsin, pancreatic amylase 6 month residue rates of the capsule of example 11c are 72.1%, 66.5%, 64.7%, respectively; the pancreatic lipase 6 month residual rate of the four capsules of examples 11d to 14d is in the range of 67 to 70%, the trypsin 6 month residual rate is in the range of 63 to 65%, and the pancreatic amylase 6 month residual rate is in the range of 60 to 64%, for example, the pancreatic lipase, trypsin, pancreatic amylase 6 month residual rate of the capsule of example 11d are 68.3%, 64.1%, 62.2%, respectively; the pancreatic lipase 6 month residue rates of the four capsules of examples 11e to 14e are all 69 to 71%, the trypsin 6 month residue rates are all 62 to 65%, and the pancreatic amylase 6 month residue rates are all 57 to 61%, for example, the pancreatic lipase, trypsin, pancreatic amylase 6 month residue rates of the capsules of example 11e are respectively 70.1%, 63.3%, 59.4%; the pancreatic lipase 6 month residue rates of the four capsules of examples 11f to 14f are all 68 to 72%, the trypsin 6 month residue rates are all 60 to 63%, and the pancreatic amylase 6 month residue rates are all 59 to 62%, for example, the pancreatic lipase, trypsin, and pancreatic amylase 6 month residue rates of the capsules of example 11f are 71.1%, 61.4%, and 60.6%, respectively.

From the above results, it was unexpectedly found that the stability of the enteric capsule thus produced was significantly inferior to that of the capsules of examples 11 to 16, i.e., the combination of sugar alcohol and methacrylic acid-ethyl acrylate copolymer was necessary to obtain a capsule of excellent stability, without using sugar alcohol, or changing sugar alcohol to cellulose or starch, or changing HP55 or methacrylic acid-ethyl methacrylate copolymer or the like as a coating material when sugar alcohol was used. The inventors have also found in some other examples that the use of other conventional coating materials is less effective than the use of methacrylic acid-ethyl acrylate copolymer of examples 11-16, similar to HP 55.

In addition, although starch, microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, sorbitol, etc. are thought to be useful as fillers for the pellet cores, in the present invention, the technical effect of the sugar alcohol used is not limited to the filling function, but is more important in imparting more excellent stability to the pancreatin as an active ingredient in the pellets; in addition, this stability is not achieved separately from the use of specific coating materials.

In the art, simethicone was used as a precedent for the anti-sticking agent in the coating materials, however, the inventors found that if talc was not used in the coating materials of examples 11 to 16, the acid resistance of the obtained enteric coated pellets could not be satisfied by changing to simethicone or adding simethicone, and some experiments were as follows. Supplementary example g: referring to the formulations and the preparation methods of examples 11-14, except that 15mg of talcum powder was changed to 1.5mg of simethicone, and the talcum powder was uniformly suspended in the coating liquid by strong stirring, namely, the anti-sticking agent was replaced by simethicone without talcum powder, and 4 parts of enteric capsules were respectively recorded as examples 11-14 g; next, referring to the examination method of test example 2 above with respect to the results of table 1, the acid resistance of 4 batches of pancreatin enteric capsules to different pH conditions was tested, and the results showed that the residual rate of three enzymes after 2 hours of treatment of pH5.0 for 4 batches of enteric capsules was 95% or more; however, the residual rate of the three enzymes after 2 hours of treatment at pH1.0 was less than 70%, specifically: examples 11g to 14g of the four capsules had pancreatic lipase residual rates of 63 to 67%, trypsin residual rates of 60 to 65% and pancreatic amylase residual rates of 56 to 60% after 2 hours of treatment at pH1.0, and examples 11g of the capsules had pancreatic lipase, trypsin and pancreatic amylase residual rates of 64.4%, 61.8% and 57.3%, respectively. Supplementary example h: referring to the formulations and the preparation methods of examples 11-14, except that the amount of talcum powder in the formulation was changed from 15mg to 10mg and 0.75mg of simethicone was added, and the formulation was uniformly suspended in the coating liquid by strong stirring, i.e., the anti-sticking agent used both talcum powder and simethicone, and 4 parts of enteric capsules were recorded as examples 11 h-14 h, respectively; next, referring to the examination method of test example 2 above with respect to the results of table 1, the acid resistance of 4 batches of pancreatin enteric capsules to different pH conditions was tested, and the results showed that the residual rate of three enzymes after 2 hours of treatment of pH5.0 for 4 batches of enteric capsules was 95% or more; however, the residual rate of the three enzymes was less than 75% after 2 hours of treatment at pH1.0, specifically: the pancreatic lipase residual rate of the four capsules of examples 11h to 14h after 2 hours of treatment at pH1.0 is 68 to 72%, the trypsin residual rate is 65 to 68%, and the pancreatic amylase residual rate is 62 to 67%, for example, the pancreatic lipase, trypsin, and pancreatic amylase residual rates of the capsules of example 11h are 71.8%, 66.2%, and 64.8%, respectively. This indicates that the use of simethicone is not feasible with the formulation of examples 11-16 of the present invention, and that the resulting enteric capsules have insufficient acid resistance.

Although embodiments of the invention have been described using specific terms and methods, such description is for illustrative purposes only. The words used are words of description rather than limitation. It should be understood that variations and changes may be made by those of ordinary skill in the art without departing from the spirit and scope of the present disclosure as set forth in the following claims. Additionally, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. The spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.

Claims

1. A pancreatin enteric coated pellet comprising:

b. the enteric coating film is coated on the surface of the pill core, and the film material of the enteric coating film is selected from the following materials: hydroxypropyl cellulose, hydroxypropyl methyl succinate acetate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, methacrylic acid-ethyl acrylate copolymer;

d. a detackifier distributed within the enteric coating film.

2. The pancreatin enteric coated pellet according to claim 1, having a particle size in the range of 0.5mm to 2.0 mm.

3. The pancreatin enteric-coated pellet according to claim 1, wherein simethicone is not included.

4. The pancreatin enteric coated pellet according to claim 1, wherein:

the polyethylene glycol is selected from the group consisting of: polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000 and polyethylene glycol 10000, wherein the dosage of the polyethylene glycol is 25-40 parts by weight per 150 parts by weight of pancreatin;

the povidone is povidone K30, and the dosage of povidone is 1-4 parts by weight based on 150 parts by weight of pancreatin;

the sugar alcohol is selected from lactose, mannitol, sorbitol, fructose and a combination thereof, and the dosage of the sugar alcohol is 30-50 parts by weight based on 150 parts by weight of pancreatin;

the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer, and the dosage of the methacrylic acid-ethyl acrylate copolymer is 20-40 parts by weight based on 150 parts by weight of pancreatin;

the plasticizer is triethyl citrate, and the dosage of the triethyl citrate is 3-6 parts by weight based on 150 parts by weight of pancreatin; or alternatively, the process may be performed,

the anti-sticking agent is talcum powder, and the dosage of the talcum powder is 10-20 parts by weight based on 150 parts by weight of pancreatin.

5. The pancreatin enteric coated pellet according to claim 1, which is prepared according to the following steps:

(6) Placing the pill-containing core in the step (4) into a coating machine, and coating the pill core with coating liquid at the temperature of less than 50 ℃ until the required coating film thickness is reached;

6. The pancreatin enteric-coated pellets according to claim 5, wherein,

in the step (1), polyethylene glycol is crushed in advance before use, sugar alcohol is crushed in advance before use until fine powder of 200 meshes can pass through, materials are mixed in a high-shear mixer, and/or ethanol aqueous solution with 40-60% of ethanol aqueous solution;

in the step (2), the obtained mixture is extruded by an extrusion spheronizer at the temperature of 40-60 ℃ and/or the material is cut into extrusion strips with the thickness of about 5mm after being extruded from 0.8mm holes;

in the step (3), the extruded strips are transferred to a rounding part of an extrusion rounding machine for rounding until approximately spherical wet pill cores are obtained, and 40-60% ethanol water solution with a wetting amount is slowly sprayed in the rounding process;

in the step (4), the obtained wet pill core is placed in a vacuum drying oven to be dried for 5 hours at 35+/-2 ℃, dried for 4 hours at 40+/-4 ℃ and dried for 3 hours at 45+/-2 ℃;

the concentration of solids in the coating liquid obtained in the step (5) is 10-20%;

step (6) putting the pill-containing cores into a fluidized bed coating machine, and controlling the temperature of the pill cores to be 40+/-2 ℃ and spraying and coating the pill cores with coating liquid until the required film thickness is reached; and/or the number of the groups of groups,

and (7) placing the obtained coated pellets into a vacuum dryer, sequentially drying for 5 hours at 35+/-2 ℃, drying for 4 hours at 40+/-4 ℃ and drying for 3 hours at 45+/-2 ℃, and screening the coated pellets with the particle size in the range of 0.7-1.6 mm by using a medicine screen with a proper aperture to obtain the enteric coated pellets.

7. The pancreatin enteric coated pellets according to claim 5, which are prepared according to the following steps:

(1) Mixing pancreatin with polyethylene glycol which is crushed in advance before use, sugar alcohol which is crushed in advance to pass through 200 meshes of fine powder before use and povidone in a high-shear mixer, and then adding 50% ethanol water solution with wetting amount for continuous mixing until uniform;

(4) Placing the obtained wet pill core into a vacuum drying oven, drying for 5 hours at 35+/-2 ℃, drying for 4 hours at 40+/-4 ℃, drying for 3 hours at 45+/-2 ℃, and screening particles with the particle diameter in the range of 0.7 mm-3.2 mm by using a medicine sieve with a proper aperture to obtain a dried pill-containing core;

(5) Slowly adding water, triethyl citrate and talcum powder into methacrylic acid-ethyl acrylate copolymer (1:1) in sequence at room temperature under stirring to enable materials to be dissolved/suspended uniformly, so as to obtain coating liquid, wherein the concentration of solids in the coating liquid is 10-20%;

(6) Placing the pill-containing cores in the step (4) into a fluidized bed coating machine, and controlling the temperature of the pill cores to be 40+/-2 ℃ and spraying and coating the pill cores with coating liquid until the required film thickness is reached;

(7) And (3) placing the obtained coated pellets in a vacuum dryer, drying for 5 hours at 35+/-2 ℃, drying for 4 hours at 40+/-4 ℃, drying for 3 hours at 45+/-2 ℃, and screening the coated pellets with the particle size in the range of 0.7-1.6 mm by using a medicine screen with a proper pore diameter to obtain the enteric coated pellets.

8. A method for preparing the pancreatin enteric-coated pellets of any of claims 1 to 7, comprising the steps of:

9. A pancreatin enteric capsule comprising a hollow hard capsule shell and a pancreatin enteric coated pellet as defined in any one of claims 1 to 7 enclosed therein, wherein the amount of pancreatin enteric coated pellets in each capsule is 100 to 400mg by pancreatin.

10. Use of a pancreatin enteric-coated pellet according to claims 1 to 7 or a pancreatin enteric-capsule according to claim 9 for the preparation of a medicament for the treatment of: pancreatic exocrine insufficiency in children and adults; pancreatic exocrine insufficiency selected from the group consisting of: cystic fibrosis, chronic pancreatitis, post-pancreatectomy, post-gastrectomy, pancreatic cancer, post-gastrointestinal bypass reconstructive surgery, pancreatic duct or common bile duct obstruction, simon-schiff syndrome.