CN116251075A

CN116251075A - Lansoprazole enteric capsule and preparation method thereof

Info

Publication number: CN116251075A
Application number: CN202310334612.3A
Authority: CN
Inventors: 邹平; 齐宜广; 陈勇; 郑泽华; 刘文光
Original assignee: Jiangsu Huiju Pharmaceutical Co ltd Guangzhou Branch; Jiangsu Huiju Pharmaceutical Co ltd
Current assignee: Jiangsu Huiju Pharmaceutical Co ltd Guangzhou Branch; Jiangsu Huiju Pharmaceutical Co ltd
Priority date: 2023-03-31
Filing date: 2023-03-31
Publication date: 2023-06-13

Abstract

The invention belongs to the technical field of medicinal preparations, and discloses a lansoprazole enteric capsule and a preparation method thereof. Lansoprazole enteric-coated capsules comprise a pill, a capsule shell and an enteric coating; the capsule shell is filled with the medicine-containing pills to form capsule grains; the enteric coating is coated on the surface of the capsule; the capsule shell is hydroxypropyl methyl cellulose capsule shell, and the enteric coating comprises the following raw material components in parts by weight: 24.13-43.37 parts of enteric coating material, 1.45-6.50 parts of plasticizer and 2.41-4.34 parts of titanium dioxide; the plasticizer accounts for 6-15% of the mass of the enteric coating material. According to the invention, the raw material components and the preparation process of the lansoprazole enteric capsule are optimized and improved, so that an enteric capsule preparation with strong acid resistance, high release speed, high dissolution and good stability is obtained; compared with the conventional preparation process, the method has the advantages of fewer auxiliary materials and working procedure steps, better reproducibility, low production cost, simplicity and easiness in operation.

Description

Lansoprazole enteric capsule and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to a lansoprazole enteric capsule and a preparation method thereof.

Background

Currently, a class of active substances widely used in proton pump inhibitor drugs for treating peptic ulcers are absorbed in the upper segment of the small intestine and are unstable in acid. If prepared into a conventional preparation, the active substance enters the stomach after oral administration, and the active substance is rapidly degraded and can not be absorbed by human body because gastric juice is a strong acid environment. In addition, some active substances have strong stimulation to the stomach and cannot be taken directly.

Aiming at the active substances which are sensitive to acid or irritate the stomach, the conventional solution is to make the medicine into an enteric preparation, so that the medicine is not released in the stomach, and after the medicine enters the small intestine, the enteric layer is dissolved, and the medicine is released, so that the release of the medicine in the stomach is effectively avoided. Lansoprazole enteric-coated capsules which are currently marketed are typical proton pump inhibiting drugs.

Lansoprazole, chemical name: (±) -2[ [ [ 3-methyl-4- (2, 2-trifluoroethoxy) -2-pyridyl ]]Methyl group]Sulfinyl group]Benzimidazole. Molecular formula C ₁₆ H ₁₄ F ₃ N ₃ O ₂ S, molecular weight 369.37, which is a brown white crystalline powder. Melting point 166 ℃, is easy to be dissolved in dimethylformamide, is soluble in methanol, is difficult to be dissolved in absolute ethyl alcohol and diethyl ether, and is almost insoluble in water. Lansoprazole is a novel proton pump inhibitor, is a benzimidazole substituent developed after omeprazole, is a proton pump inhibitor, and specifically inhibits H ⁺ -K ⁺ -atpase activity, which is a key enzyme in gastric acid production, with an inhibitory effect on basal gastric acid and on the stimulated gastric acid secretion. Lansoprazole is suitable for gastric ulcer, duodenal ulcer, erosive gastroesophageal reflux disease, helicobacter pylori and Zollimger-ellison syndrome. The lansoprazole tablet and lansoprazole enteric-coated capsule are clinically applied at present.

Lansoprazole is sensitive to acid, oxygen, moisture and heat, is unstable particularly under acidic conditions, is easily damaged in gastric acid, and can be prepared into enteric-coated capsules for oral administration to improve bioavailability.

The conventional preparation method of lansoprazole enteric-coated capsules published by the prior original research (CN 100562317C) comprises the following steps:

(1) The preparation method of the pill-containing core comprises the steps of preparing a main medicine lansoprazole, a filling agent, a disintegrating agent, an alkalizing agent, an adhesive, a blank pill core and the like;

(2) Coating a release coating layer, wherein the release coating layer consists of a filler, an adhesive and the like;

(3) An enteric coating layer, wherein the enteric coating layer is composed of a pore-forming agent, a film forming agent and the like;

(4) And (5) filling capsules.

The existing lansoprazole enteric capsule preparation technology mainly aims at solving the problems of poor stability, low release degree, poor reproducibility and the like in the storage process of the lansoprazole enteric capsule.

CN100574759C discloses a preparation method of lansoprazole enteric-coated pellets, and a certain amount of cosolvent, sodium dodecyl sulfate and L-arginine are added into a drug-containing layer, so that the drug can be quickly released, and the bioavailability is improved. However, according to the technical scheme, a large amount of surfactant is added to the pill, so that a certain safety risk may exist for human health.

CN102119927B discloses a proton pump inhibitor enteric pellet preparation and a preparation method thereof, and two isolation layers are designed according to the conventional preparation method of lansoprazole enteric capsule, wherein the first isolation layer contains an alkalizing agent to better improve the stability of the preparation, and the second isolation layer isolates the acidic enteric layer from directly contacting with the first isolation layer (in alkaline state) so as to avoid the decline of acid resistance of the preparation. The auxiliary materials of the technical scheme are basically the same as those of the lansoprazole enteric-coated capsules on the market, but compared with the prior art, an isolating layer is added, so that the auxiliary materials of the components are various, the procedures are complicated, the release speed is low, and the release is incomplete.

CN103381268B discloses a solid pharmaceutical composition comprising a proton pump inhibitor, the active ingredient being in the presence of at least one inactive ingredient in a manner to reduce the particle size by a suitable method, improving the drug release rate and bioavailability. Compared with other prior art, the technical proposal introduces a crushing process, has certain requirement on the particle size after crushing, increases the difficulty of the production process and is not beneficial to the control of the production cost.

CN103356489B discloses a proton pump inhibitor enteric-coated pellet, its preparation and preparation method. The preparation comprises a blank pill core, a medicine carrying layer, a protective layer, an isolation layer, a water-resistant layer and an enteric layer, wherein zein is used as a water-resistant material in the water-resistant layer, so that the problem of moisture absorption of the medicine in storage and the problem of burst effect in water (dissolution medium) can be effectively avoided, and the quality and stability of the product are improved. However, the preparation has the advantages of various auxiliary materials, complicated procedures and higher production cost.

CN104523641B discloses lansoprazole enteric-coated preparation and a preparation method thereof. The preparation is prepared from lansoprazole as a main drug by adopting three layers of coatings, wherein the three layers of coatings are respectively from inside to outside: an alkaline protective layer, an isolating layer and an enteric layer. Wherein the alkaline protective layer comprises two isolating layers, so as to improve the stability of lansoprazole and reduce deterioration during storage. The technical scheme also has the problems of complicated procedures and higher production cost.

Therefore, the existing lansoprazole enteric-coated capsule has the problems of poor drug stability, easiness in degrading impurities and unqualified in-vitro release degree in a long-term placement process, slow in-vitro release, poor reproducibility, complex procedures, high production cost and the like. The conventional preparation process at least comprises four process steps of preparation of the medicine-containing pill, preparation of the isolation pill, preparation of the enteric-coated pill and filling of the capsule, wherein the preparation of the enteric-coated pill adopts a micropill coating technology, and the coating reproducibility and uniformity are difficult to control well. Meanwhile, the lansoprazole enteric capsules on the market at present all use gelatin capsule shells, but the water content of the gelatin capsule shells is higher, and in the long-term placing process, the water content of the gelatin capsule shells can migrate into the interior of the pellets, so that the stability of the preparation is poor, and meanwhile, along with the loss of the water content of the gelatin capsule shells, the brittleness of the capsule shells is increased, so that the dissolution is greatly influenced.

Disclosure of Invention

The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a lansoprazole enteric capsule and a preparation method thereof. According to the invention, the raw material components and the preparation process of the lansoprazole enteric capsule are optimized and improved, so that an enteric capsule preparation with strong acid resistance, high release speed, high dissolution and good stability is obtained; compared with the conventional preparation process, the method has the advantages of fewer auxiliary materials and working procedure steps, better reproducibility, low production cost, simplicity and easiness in operation.

To solve the above technical problems, a first aspect of the present invention provides a lansoprazole enteric capsule, including a pill, a capsule shell, and an enteric coating; the capsule shell is filled with the medicine-containing pills to form capsule particles; the enteric coating is coated on the surface of the capsule particles; the capsule shell is hydroxypropyl methyl cellulose capsule shell, the capsule shell is hydroxypropyl methyl cellulose (HPMC) capsule shell, and the enteric coating comprises the following raw material components in parts by weight: 24.13-43.37 parts of enteric coating material, 1.45-6.50 parts of plasticizer and 2.41-4.34 parts of titanium dioxide; the plasticizer accounts for 6-15% of the mass of the enteric coating material.

Specifically, the preparation process of the enteric capsule is reduced, the capsule shell is adopted as a protective layer between the drug-containing pellet and the enteric coating, and the hydroxypropyl methyl cellulose capsule shell is adopted, so that compared with the gelatin capsule adopted by the lansoprazole enteric capsule on the market, the stability of the preparation can be effectively improved while the multi-unit release mechanism of the pellet is maintained.

Meanwhile, in order to avoid the contact degradation of active substances and gastric acid after the preparation is taken, the invention adopts a capsule coating technology to carry out enteric coating on the capsule particles. Compared with the conventional pellet coating, the size of the pellet is not required to be considered, and the influence on the drug release behavior of the whole preparation caused by errors or defects of individual pellets in the preparation of the enteric coating is avoided, so that the reproducibility and consistency of the drug release rule are better; compared with tablets, the characteristics of pellet multi-unit release are maintained, after the capsule passes through the stomach, under the influence of the pH of the small intestine, the enteric coating film and the capsule shell are dissolved, and the medicine is not blocked by the isolation layer, so that the medicine can be released more rapidly and fully.

In addition, the enteric coating of the present invention is prepared from an enteric coating material, a plasticizer and titanium dioxide, wherein: the dosage of the enteric coating material directly influences the film thickness of the enteric coating of the preparation and the sealing effect of the joint of the capsule shell, thereby influencing the acid resistance and the release rate of the preparation; the plasticizer can reduce the glass transition temperature of the enteric coating material, thereby affecting the film forming property of the enteric coating; titanium dioxide is an opacifier. The invention obtains the optimal acid resistance and dissolution rate of the preparation by controlling the dosage range of each raw material.

Preferably, the enteric coating comprises the following raw material components in parts by weight: 33.75-43.36 parts of enteric coating material, 2.03-6.50 parts of plasticizer and 3.34-4.34 parts of titanium dioxide.

Preferably, the plasticizer accounts for 8-12% of the mass of the enteric coating material.

As a further improvement of the scheme, the raw material components of the pill comprise the following components in parts by weight: 30 parts of lansoprazole, 50-100 parts of a sucrose pellet core, 20-60 parts of sucrose powder, 5-15 parts of corn starch, 10-30 parts of a pH value regulator and 10-30 parts of low-substituted hydroxypropyl cellulose.

Preferably, the raw material components of the pill comprise the following components in parts by weight: 30 parts of lansoprazole, 70-90 parts of a sucrose pellet core, 40-60 parts of sucrose powder, 8-12 parts of corn starch, 20-30 parts of a pH value regulator and 20-30 parts of low-substituted hydroxypropyl cellulose.

As a further improvement of the scheme, the particle size of the sucrose pellets ranges from 0.5 mm to 1.0mm.

Preferably, the particle size of the sucrose pellets ranges from 0.6 to 0.71mm.

As a further improvement of the above scheme, the pH adjustor is selected from any one of sodium carbonate, sodium bicarbonate, light magnesium carbonate, heavy magnesium carbonate, sodium hydroxide, disodium hydrogen phosphate, and potassium hydrogen phosphate.

Preferably, the pH regulator is selected from any one of sodium bicarbonate, light magnesium carbonate and heavy magnesium carbonate.

As a further improvement of the above, the enteric coating material is selected from any one of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, and styrene maleic acid copolymer.

Preferably, the enteric coating material is selected from methacrylic acid copolymers.

As a further improvement of the above scheme, the plasticizer is selected from any one of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, triethyl citrate (abbreviated as TEC) and triethyl glycerinum.

Preferably, the plasticizer is selected from polyethylene glycol 6000 or triethyl citrate.

The second aspect of the invention provides a preparation method of lansoprazole enteric-coated capsules, which is used for preparing the lansoprazole enteric-coated capsules according to the first aspect of the invention, and comprises the following steps:

(1) Preparing a pill;

(2) Filling the medicine-containing pills into hydroxypropyl methyl cellulose capsule shells to obtain capsule particles;

(3) Dissolving a plasticizer, adding titanium dioxide for dispersion, then adding the plasticizer into a water dispersion solution of an enteric coating material, and sieving to obtain an enteric coating solution; and spraying the enteric coating solution onto the surface of the capsule particles to carry out capsule coating, and drying to obtain the lansoprazole enteric capsule.

As a further improvement of the above scheme, the preparation method of the lansoprazole enteric capsule comprises the following steps:

(1) Preparing a pill comprising the following components:

A. slowly adding the hydroxypropyl cellulose into purified water, stirring until the hydroxypropyl cellulose is completely dissolved, and preparing a hydroxypropyl cellulose aqueous solution with the concentration of 2% (w/w) as an adhesive for standby; the preparation amount of the adhesive is 50% of the weight of the powder for the pill, and the actual amount is based on the end amount of the pill;

B. premixing lansoprazole, sucrose powder, corn starch, light magnesium carbonate and low-substituted hydroxypropyl cellulose, sieving with a 120-mesh sieve, and then transferring to a fixed hopper mixer for uniform mixing to obtain powder;

C. putting the sucrose pellet core into a centrifugal granulator, spraying the adhesive prepared in the step A, and uniformly powdering and coating the powder prepared in the step B on the surface of the sucrose pellet core;

D. and (3) drying the pellets prepared by centrifugal granulation for at least 16 hours in a baking oven at 45 ℃, and sieving to obtain pellets between 16 and 30 meshes to obtain the buccal pellets.

(2) Filling the capsule:

E. according to the medicine content, the actual unit dosage is converted, and the qualified medicine-containing pills are filled into the hydroxypropyl methyl cellulose capsule shell by a capsule filling machine to obtain capsule particles;

(3) Capsule coating:

F. Adding triethyl citrate into purified water, stirring and dissolving, adding titanium dioxide for uniform dispersion, slowly adding into the Eudragit L30D-55 water dispersion solution, and sieving with 100 meshes to obtain an enteric coating solution;

G. and E, putting the capsule particles prepared in the step E into a film coating machine, setting proper air inlet temperature, air inlet quantity and pot rotating speed, uniformly spraying the enteric coating solution prepared in the step F onto the surfaces of the capsule particles, and drying at 45 ℃ for 30-60min to obtain the lansoprazole enteric capsule.

Specifically, when the preparation method is used for preparing the pill, a powder lamination process is adopted, a sucrose pill core is used as a substrate, a mixture containing active substances and inactive substances is used as powder supply, a hydroxypropyl cellulose aqueous solution is used as an adhesive, and the pill is prepared in a centrifugal granulation pill making machine to obtain pills with certain strength; the hydroxypropyl methyl cellulose capsule shell is adopted for filling capsules and is used as a protective layer between the medicine-containing layer and the enteric layer, so that the stability of the preparation is improved; the lansoprazole enteric-coated capsule preparation with high stability and fast intestinal release is obtained by using a film coating machine to carry out enteric coating on the capsule particles, wherein the coating weight is 15-25%.

As a further improvement of the scheme, the rotating speed of the pot is 5-15rpm in the capsule coating process. Preferably, the pot speed is 7-12rpm.

Specifically, the flowing state of the capsule in the coating pan is influenced by the pan rotating speed, the capsule shell is easily turned over in the coating pan to be uneven in the coating pan, the sticking pan is caused, or the coating is uneven, and the capsule shell is easily impacted and aggravated due to the too-high pan rotating speed, so that the capsule shell is cracked or the coating is uneven.

As a further improvement of the scheme, in the capsule coating process, the air inlet frequency/air exhaust frequency is preferably 600-1500Hz, and the air inlet frequency/air exhaust frequency is preferably 800-1200Hz.

Specifically, the air inlet frequency/air exhaust frequency influences the coating effect of the capsule in the coating pan, the too low air inlet frequency/air exhaust frequency easily causes the drying rate of the capsule shell in the coating pan to be too low, so that the capsule is sticky or dissolved, and the too high air inlet frequency/air exhaust frequency easily causes the spray drying loss of the coating liquid, so that the coating efficiency is lower.

As a further improvement of the above scheme, the atomization pressure is 0.2-1.0bar in the capsule coating process. Preferably, the atomization pressure is from 0.3 to 0.8bar.

Specifically, the atomization pressure influences the atomization effect of the coating liquid, so that the coating effect is further influenced, and too low atomization pressure easily causes too large atomized liquid drops, so that the capsule shell is sticky or dissolved; the atomizing pressure is too high to easily cause atomizing liquid drops to be too thin so as to cause the spray drying loss of coating liquid, and the coating efficiency is reduced due to the fact that the atomizing liquid drops are easily sprayed on the inner wall of a coating pot, meanwhile, compared with the common tablet coating, the capsule coating is hollow in the capsule, if the atomizing pressure is too high, the impact force on the surface of the capsule shell is larger, the risk of collapse deformation of the capsule shell is easily caused, and the coating effect is poor.

As a further improvement of the scheme, the temperature of the materials in the capsule coating process is 28-40 ℃. Preferably, the material temperature is 28-35 ℃.

Specifically, the control of material temperature belongs to key process parameters of capsule coating, and influences coating effect and product quality of enteric capsules. If the material temperature is controlled to be too low, the corresponding drying effect is weak, and the capsule shell is easy to adhere; too high a temperature control of the material may deteriorate the coating effect of the capsule and affect the final acid resistance of the product.

Compared with the prior art, the technical scheme of the invention has at least the following technical effects or advantages:

(1) The invention reduces the preparation process of enteric capsule, adopts hydroxypropyl methyl cellulose capsule shell as the protective layer between the drug-containing pill and the enteric coating, improves the stability of the preparation while maintaining the multi-unit release mechanism of the pellet, obviously improves the in vitro release speed compared with the conventional pellet coating technology, ensures safer release and improves the production efficiency.

(2) The invention adopts the capsule coating technology to prevent the active ingredient from being degraded by gastric acid after the preparation is taken, compared with the conventional pellet coating technology, the invention avoids the influence on the drug release behavior of the whole preparation caused by the error or defect of individual pellets in the enteric coating preparation, thus having better reproducibility and consistency in the drug release rule; meanwhile, the problem of coating uniformity caused by the roughness of the pellet surface is avoided, the surface smoothness of the capsule shell is high, and the adhesiveness between the coating material and the capsule shell is stronger, so that the acid-resistant uniformity and strength of the preparation can be improved by the capsule coating.

Detailed Description

The present invention is described in detail below with reference to examples to facilitate understanding of the present invention by those skilled in the art. It is specifically pointed out that the examples are given solely for the purpose of illustration of the invention and are not to be construed as limiting the scope of the invention, since numerous insubstantial modifications and variations of the invention will be within the scope of the invention, as described above, will become apparent to those skilled in the art. Meanwhile, the raw materials mentioned below are not specified, and are all commercial products; the process steps or preparation methods not mentioned in detail are those known to the person skilled in the art.

The raw material components of the lansoprazole enteric capsule of the following example are shown in table 1, in which the particle size of the sucrose pellet core is 0.5-1.0mm.

Table 1: raw material composition table of lansoprazole enteric capsule

/>

The proportion of auxiliary materials in the components of the pill in table 1 determines the filling amount of the final capsule, and the filling amount influences the size of the movable space of the pill in the capsule shell, and if the movable space of the capsule is too large in the subsequent capsule coating process, the pill can be damaged in the coating process, so that the final quality of the product is influenced. In addition, a small number of pellets inside the capsule shell may also cause the capsule shell to not smoothly turn over in the coating machine, resulting in non-uniformity of the coating film.

The invention is illustrated by taking HPMC capsule shell No. 1 as an example, and the technology can be applied to other types of hydroxypropyl methylcellulose capsule shells.

Example 1

A preparation method of lansoprazole enteric capsule, comprising the following steps:

(1) Preparation of a single capsule containing 125mg of pellets:

hydroxypropyl cellulose (2.25 g) was slowly added to purified water (110.25 g) and stirred until completely dissolved to prepare an aqueous solution of hydroxypropyl cellulose at a concentration of 2% (w/w) as a binder for use. Premixing lansoprazole, sucrose powder, corn starch, light magnesium carbonate and low-substituted hydroxypropyl cellulose, sieving with a 120-mesh sieve, and then transferring to a fixed hopper mixer for mixing for 10min to obtain powder. Putting the sucrose pellet core into a centrifugal granulator, spraying 2% hydroxypropyl cellulose aqueous solution, and uniformly powdering and coating the powder on the surface of the sucrose pellet core. The pellets obtained by centrifugal granulation are dried for at least 16 hours by a baking oven at 45 ℃, and then the pellets between 16 and 30 meshes are sieved to obtain the pellets, and the raw material components are shown in the table 2.

Table 2: example 1 raw materials composition table of the pill

(2) Filling the capsule:

and (3) filling the qualified medicine-containing pellets prepared in the step (1) into hydroxypropyl methyl cellulose capsule shells by a capsule filling machine to obtain capsule pellets, wherein the raw material components of the capsule pellets are shown in table 3.

Table 3: example 1 raw material composition table of capsule

Raw materials	Component (g)
		Pill containing medicine	375
Hydroxypropyl methyl cellulose capsule shell	25 (3000 granules)
		Total amount of	400 (3000 granules)

3000 capsules in theoretical batch, each hydroxypropyl methylcellulose capsule shell weight being about 83mg,3000 blank capsule shells weight = 83mg x 3000 ≡1000 = 25g

(3) Capsule coating:

triethyl citrate is added into purified water (193.07 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (241.33 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 4.

Table 4: example 1 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	400 (3000 granules)
Methacrylic acid copolymer	72.4
		Citric acid triethyl ester	10.9
Titanium dioxide	7.2
		Total amount of	490.5
Theoretical coating weight gain	22.63％

Example 2

preparation of a single capsule pack 265mg pill:

hydroxypropyl cellulose (4.95 g) was slowly added to purified water (242.55 g), and stirred until completely dissolved, to prepare an aqueous solution of hydroxypropyl cellulose having a concentration of 2% (w/w) as a binder for use. Premixing lansoprazole, sucrose powder, corn starch, light magnesium carbonate and low-substituted hydroxypropyl cellulose, sieving with a 120-mesh sieve, and then transferring to a fixed hopper mixer for mixing for 10min to obtain powder. Putting the sucrose pellet core into a centrifugal granulator, spraying 2% hydroxypropyl cellulose aqueous solution, and uniformly powdering and coating the powder on the surface of the sucrose pellet core. The pellets obtained by centrifugal granulation were dried in an oven at 45℃for at least 16 hours, and then sieved to obtain pellets of 16-30 mesh, the raw material composition of which is shown in Table 5.

Table 5: example 2 raw materials composition table of the pellets

Raw materials	Component (g)
		Lansoprazole	90
Sucrose pill core	300
		Sucrose powder	180
Corn starch	45
		Light magnesium carbonate	90
Low substituted hydroxypropyl cellulose	90
		Total amount of	795

Since the theoretical batch was unchanged for example 2 and example 1, the capsule filling number was unchanged, and the capsule filling and coating composition process for example 2 was consistent with example 1 in order to maintain the same coating time and enteric layer thickness.

Example 3

preparation of a single capsule fill 203.67mg of a pill:

hydroxypropyl cellulose (3.61 g) was slowly added to purified water (176.89 g) and stirred until completely dissolved to prepare an aqueous solution of hydroxypropyl cellulose at a concentration of 2% (w/w) as a binder for use. Premixing lansoprazole, sucrose powder, corn starch, light magnesium carbonate and low-substituted hydroxypropyl cellulose, sieving with a 120-mesh sieve, and then transferring to a fixed hopper mixer for mixing for 10min to obtain powder. Putting the sucrose pellet core into a centrifugal granulator, spraying 2% hydroxypropyl cellulose aqueous solution, and uniformly powdering and coating the powder on the surface of the sucrose pellet core. The pellets obtained by centrifugal granulation were dried in an oven at 45℃for at least 16 hours, and then sieved to obtain pellets of 16-30 mesh, the raw material composition of which is shown in Table 6.

Table 6: example 3 raw materials composition table of the pill

Since example 3 and example 1 were the same theoretical batch, the capsule fill and coating composition process was consistent with example 1, with a theoretical coating weight gain of 15% for maintaining the same coating time and enteric layer thickness.

Example 4

preparation of a single capsule 100mg pill:

hydroxypropyl cellulose (2 g) was slowly added to purified water (98 g), and stirred until completely dissolved, to prepare an aqueous solution of hydroxypropyl cellulose having a concentration of 2% (w/w) as a binder for use. Premixing lansoprazole, sucrose powder, corn starch, light magnesium carbonate and low-substituted hydroxypropyl cellulose, sieving with a 120-mesh sieve, and then transferring to a fixed hopper mixer for mixing for 10min to obtain powder. Putting the sucrose pellet core into a centrifugal granulator, spraying 2% hydroxypropyl cellulose aqueous solution, and uniformly powdering and coating the powder on the surface of the sucrose pellet core. The pellets obtained by centrifugal granulation were dried in an oven at 45℃for at least 16 hours, and then sieved to obtain pellets of 16-30 mesh, the raw material composition of which is shown in Table 7.

Table 7: example 4 raw materials composition table of the pill

Raw materials	Component (g)
		Lansoprazole	90
Sucrose pill core	100
		Sucrose powder	50
Corn starch	12
		Light magnesium carbonate	24
Low substituted hydroxypropyl cellulose	24
		Total amount of	300

Since the theoretical batch was unchanged for example 4 and example 1, the capsule filling number was unchanged, and the capsule filling and coating composition process for example 4 was consistent with example 1 in order to maintain the same coating time and enteric layer thickness.

Comparative example 1

Comparative example 1 differs from example 1 only in that comparative example 1 uses a gelatin hollow capsule shell of size 1 in place of the hydroxypropyl methylcellulose capsule shell of example 1. Wherein: the raw material composition of the capsule particles is shown in Table 8.

Table 8: comparative example 1 raw material composition table of capsule particles

Raw materials	Component (g)
		Pill containing medicine	375
Gelatin hollow capsule shell	22.5 (3000 granules)
		Total amount of	397.5 (3000 granules)

The theoretical batch is 3000 capsules, each capsule shell weight is about 75mg,3000 capsules shell weight = 75mg x 3000/1000 = 22.5g.

Performance test 1

1. Crushing condition of micropill

20 lansoprazole enteric capsules prepared in examples 1-4 were taken respectively, the contents were collected, the appearance of the drug-containing pellets was observed, the pellets were weighed and sieved through a 30-mesh sieve, and the passing rate of the crushed pellets was counted, and the results are shown in Table 9.

Table 9: table of crushing conditions of pellets of examples 1 to 4

As can be seen from Table 9, the micropellets of examples 1-3 were all relatively low in crushing rate, and example 4 was greater in crushing rate > 3.0%, indicating that capsules of different filling amounts were filled, and the pellets of lower filling amount were more likely to be damaged due to larger space for the pellets to collide with each other. Meanwhile, the surface part of the enteric capsule of the example 4 is not completely coated, and the number of the enteric capsule is supposed to be too small, and the capsule is not smooth to turn over in a coating pot, so that 125-265mg of the capsule is loaded in a No. 1 capsule shell, and the enteric coating effect is good.

2. Dissolution Rate test

The dissolution rate test of the invention is carried out according to the dissolution rate and release rate measurement method (the second method of the fourth rule 0931 of the edition 2020 of Chinese pharmacopoeia), 900mL of phosphate buffer solution with pH of 6.8 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, and the sample is measured according to high performance liquid chromatography (rule 0512)Dissolution rate of the product at different times. Lansoprazole enteric-coated capsules of examples 1 to 4 and Lansoprazole enteric-coated capsules (trade name) commercially available from Tianjin Wuta drug Co., ltd

) The dissolution rates at various times are shown in table 10.

Table 10: lansoprazole enteric capsule of examples 1-4

Dissolution rate comparison table for different times

As can be seen from Table 10, the dissolution rates at different time points in examples 1-3 were substantially uniform in the phosphate buffer at pH6.8, and the dissolution rate in example 4 was much faster than that in examples 1-3, probably due to the fact that the pellets were more broken during coating, resulting in an increase in the contact surface of the pellets in the dissolution medium and thus an increase in the dissolution rate. Although example 4 may have an increased dissolution rate compared to examples 1-3, which may facilitate rapid release and absorption of the pellets in the upper intestinal tract, improving bioavailability, pellet disruption is an uncontrolled process and detrimental to quality control of the product, so example 4 is not an optional range of pellet-containing components.

Comparison

Examples 1-3 released more rapidly and substantially completely, and as lansoprazole is absorbed primarily in the upper small intestine, the faster release facilitates improved bioavailability in vivo.

3. Stability test

Lansoprazole of examples 1-4 and comparative example 1Respectively filling the enteric capsule samples into 60mL high-density polyethylene bottles, sealing the bottle mouth with a gasket in a heat-sealing way, screwing the bottle mouth, putting the bottle mouth into a 60 ℃ high-temperature stabilizing box, and simultaneously putting the bottle mouth into a high-temperature stabilizing box

The complete package was placed in the same stabilizing box and the stability of the samples was examined for 5 days, 10 days, 20 days, and 30 days. Wherein: the appearance of the stable content, the stability-related substances and the stability dissolution are shown in tables 11 to 14, respectively.

Table 11: lansoprazole enteric capsules and formulations of examples 1-4 and comparative example 1

Stability content appearance comparison table

Table 12: lansoprazole enteric capsules and formulations of examples 1-4 and comparative example 1

Stability content comparison table

/>

Table 13: lansoprazole enteric capsules and formulations of examples 1-4 and comparative example 1

Stability-related substance comparison Table

Table 14: lansoprazole enteric capsules and formulations of examples 1-4 and comparative example 1

Stability dissolution rate comparison table

The stability results in tables 11-14 show that the pellets in examples 1-4 do not have significant changes in color during stability at 60 ℃ and dissolution and content are substantially consistent with those in 0 days; lansoprazole enteric-coated capsules which are marketed

After 20 days, the color of the pellets is obviously changed, the content reduction trend is obvious, and the impurity growth amplitude is large. In contrast, examples 1-4 use HPMC capsule shells as protective layers for the drug-containing layer and enteric layer significantly improved the stability of the formulation.

Meanwhile, examples 1 to 4 using HPMC capsule shells as the protective layer according to the present invention have remarkable advantages in terms of stability including content, related substances and dissolution rate, as compared with comparative example 1 using gelatin hollow capsule shells. The water content of the common gelatin hollow capsule shell is generally more than 12%, and the water content of the HPMC capsule shell is generally less than 5%, so that the water content of the gelatin hollow capsule shell is easy to migrate to the pill-containing tablets in the stability process to form a local high-humidity environment, and the degradation of active substances is aggravated. In addition, the increased brittleness of the gelatin hollow capsule shell after water loss is susceptible to cross-linking, resulting in slower dissolution.

Therefore, the raw material components of the pill-containing pill comprise the following components in parts by weight: 30 parts of lansoprazole, 50-100 parts of a sucrose pellet core, 20-60 parts of sucrose powder, 5-15 parts of corn starch, 10-30 parts of a pH value regulator, 10-30 parts of low-substituted hydroxypropyl cellulose and 125-265 parts of the total weight of the pill.

Example 5

(1) Preparation of a single capsule fill 203.67mg of a pill:

the corresponding pellets were prepared as the raw material components and the preparation process of the pellets of example 3.

(2) Filling the capsule:

the qualified capsules were filled into hydroxypropyl methylcellulose capsule shells by a capsule filling machine to obtain capsule granules, the raw material components of which are shown in table 15.

Table 15: example 5 raw material composition table of capsule

Raw materials	Component (g)
		Pill containing medicine	611
Hydroxypropyl methyl cellulose capsule shell	25 (3000 granules)
		Total amount of	636 (3000 granules)

The theoretical batch is 3000 capsules, each of which has a weight of about 75mg, and 3000 blank capsules having a weight=75 mg×3000/1000=25 g.

(3) Capsule coating: (in each enteric capsule, the amount of methacrylic acid copolymer used was 24.13 mg)

Triethyl citrate is added into purified water (193.07 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (241.33 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 16.

Table 16: example 5 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	72.4
		Citric acid triethyl ester	10.9
Titanium dioxide	7.2
		Total amount of	726.5
Theoretical coating weight gain	14.23％

Example 6

the preparation process of the pill and capsule filling is the same as in example 5.

Capsule coating: (in each enteric capsule, the amount of methacrylic acid copolymer used was 33.77 mg)

Triethyl citrate is added into purified water (270.03 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (337.67 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 17.

Table 17: example 6 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	101.3
		Citric acid triethyl ester	15.2
Titanium dioxide	10.1
		Total amount of	762.6
Theoretical coating weight gain	19.91％

Example 7

Capsule coating: (in each enteric capsule, the amount of methacrylic acid copolymer used was 43.37 mg)

Triethyl citrate is added into purified water (347.17 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (433.33 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 18.

Table 18: example 7 raw material composition table of enteric capsule

Comparative example 2

Capsule coating: (in each enteric capsule, the amount of methacrylic acid copolymer used was 53.4 mg)

Adding triethyl citrate into purified water (427 g), stirring for dissolution, adding titanium dioxide for uniform dispersion, slowly adding the prepared solution into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (534 g), and sieving with 100 mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and then the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsules of the comparative example are obtained, and the raw material components are shown in table 19.

Table 19: comparative example 2 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	160.2
		Citric acid triethyl ester	24
Titanium dioxide	16
		Total amount of	836.2
Theoretical coating weight gain	31.48％

Performance test II

1. Acid resistance strength test

The acid resistance strength test of the invention is measured according to a dissolution rate and release rate measuring method (the first method of the fourth rule 0931 of the edition 2020 edition of Chinese pharmacopoeia), 1000mL of hydrochloric acid solution (9-1000) is used as a dissolution medium, the rotating speed is 100 revolutions per minute, after acid resistance is 1h, 2h and 3h, the content of active ingredients in the residual balls in the dissolution cup is measured by adopting an ultraviolet-visible spectrophotometry, and the acid resistance strength is represented by the content, namely, the larger content indicates the stronger acid resistance. The results of acid strength testing of the lansoprazole enteric capsules of examples 5-7 and comparative example 2 are shown in table 20.

Table 20: acid strength comparative table of lansoprazole enteric capsules of examples 5-7 and comparative example 2

As is clear from Table 20, although the capsules were slightly deformed after 3 hours of acid resistance in examples 5 and 6, the capsules were not broken, and the analysis reasons were probably due to the water entering through the pore channels of the enteric film, resulting in a slight dissolution of the capsule shell, and from the data of acid resistance, the acid resistance of examples 5 to 7 and comparative example 2 were all good.

2. Dissolution Rate test

Determination of examples 5-7, comparative examples 2 and

the dissolution rates at different times are shown in Table 21.

Table 21: lansoprazole enteric capsules and formulations of examples 5-7 and comparative example 2

Is a comparison table of the dissolution rates of (2)

/>

As can be seen from table 21, comparative example 2 has a slower dissolution rate and a lower dissolution plateau due to the excessive weight gain of the coating. Examples 5 to 7 and

the formulation releases more rapidly than it does, and substantially complete release is achieved.

Example 8

Capsule coating: (triethyl citrate was added to the methacrylic acid copolymer at a weight gain of 6%)

Triethyl citrate is added into purified water (233.63 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (337.67 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 22.

Table 22: example 8 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	101.3
		Citric acid triethyl ester	6.1
Titanium dioxide	10.1
		Total amount of	753.5

Example 9

Capsule coating: (triethyl citrate was 10% by weight of methacrylic acid copolymer)

Triethyl citrate is added into purified water (249.63 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (337.67 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the embodiment is obtained, and the raw material components are shown in table 23.

Table 23: example 9 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	101.3
		Citric acid triethyl ester	15.2
Titanium dioxide	10.1
		Total amount of	762.6

Comparative example 3

Capsule coating: (triethyl citrate was 3% by weight of methacrylic acid copolymer)

Triethyl citrate is added into purified water (221.23 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (337.67 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and then the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the comparative example is obtained, and the raw material components are shown in table 24.

Table 24: comparative example 3 raw material composition table of enteric capsule

Raw materials	Component (g)
		Capsule granule	636 (3000 granules)
Methacrylic acid copolymer	101.3
		Citric acid triethyl ester	3
Titanium dioxide	10.1
		Total amount of	750.4

Comparative example 4

Capsule coating: (triethyl citrate was 20% by weight of methacrylic acid copolymer)

Triethyl citrate is added into purified water (290.43 g) to be stirred and dissolved, then titanium dioxide is added to be evenly dispersed, the prepared solution is slowly added into 30% (w/w) methacrylic acid copolymer aqueous dispersion solution (337.67 g), and the solution is sieved by a 100-mesh sieve to obtain 20% (w/w) enteric coating solution. The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-12rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.3-0.8bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and then the capsule particles are dried at 45 ℃ for 30-60min, so that the lansoprazole enteric capsule of the comparative example is obtained, and the raw material components are shown in table 25.

Table 25: comparative example 4 raw material composition table of enteric capsule

Performance test III

1. Acid strength and coating effect test

The dissolution and release degree measurement method (the fourth rule 0931 first method of the year of the pharmacopoeia 2020) is adopted to measure, 1000mL of hydrochloric acid solution (9-1000) is used as a dissolution medium, the rotating speed is 100 revolutions per minute, after acid resistance is carried out for 2 hours, the ultraviolet-visible spectrophotometry is adopted to measure the content of active ingredients in the residual balls in the dissolution cup, and the content is used for representing the strength of acid resistance, namely, the larger content indicates the stronger acid resistance. The acid strength of the lansoprazole enteric capsules of examples 6, 8-9 and comparative examples 3-4 was measured, and the appearance of the capsules was visually examined to evaluate the presence or absence of a significant defect on the capsule surface, and the test results are shown in table 26.

Table 26: comparative table of acid strength and coating effect of lansoprazole enteric capsules of examples 6, 8-9 and comparative examples 3-4

As can be seen from Table 26, TEC is used in an amount of from 6% to 15% of the polymer weight gain, which has little effect on acid resistance; when the TEC is used at 20%, the phenomenon of sticking to the pan is more likely to occur in the coating process, so that a small part of the capsule is broken or collapsed; meanwhile, the plasticizer is also a pore-forming agent of the enteric layer, so that the excessive dosage has a certain influence on the acid resistance of the finished product of the preparation. When the TEC dosage is 3%, the coating film is not compact due to insufficient plasticizer dosage, and the acid resistance is unqualified.

2. Dissolution Rate test

The dissolution rates of examples 6, 8 to 9 and comparative examples 3 to 4 were measured at different times, and the test results are shown in Table 27.

Table 27: comparative table of the dissolution rates of lansoprazole enteric-coated capsules of examples 6, 8-9 and comparative examples 3-4

As can be seen from Table 27, when TEC was used in an amount of 3-15%, the enteric-coated capsules had comparable dissolution rates without significant differences; when the TEC consumption reaches 20%, the dissolution is faster, and the pore-forming effect is obvious due to the excessively high plasticizing consumption.

Example 10

In the embodiment, the influence of different pan speeds on the capsule coating effect is examined, the appearance after coating and the coating efficiency are used as evaluation indexes, the raw material components of the capsule coating are referred to in the embodiment 8, and the technological parameters are examined as follows:

The capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 5-20rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.5bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, then the capsule particles are dried at 45 ℃, the actual coating efficiency is calculated after the drying is finished, and the specific technological parameters are shown in a table 28.

Table 28: capsule coating process parameter table of example 10

Experiment number	GZ-1	GZ-2	GZ-3	GZ-4	GZ-5	GZ-6
							Pot rotation rpm	5	7	10	12	15	20
Air inlet temperature DEG C	38-50	38-50	38-50	38-50	38-50	38-50
							Air intake frequency Hz	1200	1200	1200	1200	1200	1200
Frequency of exhaust air Hz	1200	1200	1200	1200	1200	1200
							Atomization pressure bar	0.5	0.5	0.5	0.5	0.5	0.5
The temperature of the materials is DEG C	28-35	28-35	28-35	28-35	28-35	28-35
							Drying temperature (DEG C)	45	45	45	45	45	45

After coating, 20 capsules were randomly sampled and the coating appearance of the capsules was observed in a black background, and the actual coating efficiency was calculated, and the results are shown in table 29.

Table 29: coating appearance and coating efficiency comparison table at different pan speeds

As can be seen from Table 29, the pan speed had a significant effect on capsule coating, with a capsule coating efficiency of greater than 80% when the pan speed was between 5 and 15rpm, while there were small portions of capsules with defects in GZ-1 and GZ-5, they were still acceptable, while more capsules had severe edging and a reduced coating efficiency when the pan speed was 20 rpm.

Example 11

In this example, the influence of different air inlet frequencies/air outlet frequencies on the capsule coating effect is examined, the appearance after coating and the coating efficiency are used as evaluation indexes, the components of the capsule coating are referred to in example 8, and the technological parameters are examined as follows:

the capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 10rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.5bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, and then the capsule particles are dried at 45 ℃. The actual coating efficiency was calculated after the end of drying and the specific process parameters are shown in table 30.

Table 30: table of capsule coating process parameters of example 11

Experiment number	JF-1	JF-2	JF-3	JF-4	JF-5
						Pot rotation rpm	10	10	10	10	10
Air inlet temperature DEG C	38-50	38-50	38-50	38-50	38-50
						Air intake frequency Hz	600	800	1000	1200	1500
Frequency of exhaust air Hz	600	800	1000	1200	1500
						Atomization pressure bar	0.5	0.5	0.5	0.5	0.5
The temperature of the materials is DEG C	28-35	28-35	28-35	28-35	28-35
						Drying temperature (DEG C)	45	45	45	45	45

After coating, 20 capsules were randomly sampled and the coating appearance of the capsules was observed in a black background, and the actual coating efficiency was calculated, and the results are shown in table 31.

Table 31: coating appearance and coating efficiency comparison table for different air inlet frequency/air outlet frequency

As can be seen from Table 31, the capsule coating efficiency is greater than 80% when the air inlet frequency/air outlet frequency is between 800 and 1200 Hz; when the air inlet frequency/air exhaust frequency is 600Hz, the drying rate is insufficient, and the capsule shell is easy to be sticky; when the air inlet frequency/air exhaust frequency is 1500Hz, the drying speed is too high, the coating efficiency is low, and the surface roughness of the capsule is obvious.

Example 12

In this example, the study of capsule coating effect by different atomization pressures was examined, the appearance after coating and coating efficiency were used as evaluation indexes, the components of the capsule coating were referred to in example 8, and the process parameters were examined as follows:

the capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 10rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.2-1.2bar, the material temperature is maintained at 28-35 ℃, the enteric coating solution is uniformly sprayed on the surface of the capsule particles, then the capsule particles are dried at 45 ℃, the actual coating efficiency is calculated after the drying is finished, and the specific technological parameters are shown in a table 32.

Table 32: capsule coating process parameter table of example 12

Experiment number	WH-1	WH-2	WH-3	WH-4
					Pot rotation rpm	10	10	10	10
Air inlet temperature DEG C	38-50	38-50	38-50	38-50
					Air intake frequency Hz	1000	1000	1000	1000
Frequency of exhaust air Hz	1000	1000	1000	1000
					Atomization pressure bar	0.2	0.8	1.0	1.2
The temperature of the materials is DEG C	28-35	28-35	28-35	28-35
					Drying temperature (DEG C)	45	45	45	45

After coating, 20 capsules were randomly sampled and the coating appearance of the capsules was observed in a black background, and the actual coating efficiency was calculated, and the results are shown in table 33.

Table 33: coating appearance and coating efficiency comparison table at different atomization pressures

/>

As can be seen from Table 33, an atomization pressure of 1.2bar easily resulted in coating liquid being sprayed onto the inner wall of the coating pan, while the capsule particles turned over severely and the spraying was not uniform.

Example 13

In this example, the influence of different material temperatures on the capsule coating effect is examined, the appearance after coating, coating efficiency and acid resistance are used as evaluation indexes, the components of the capsule coating refer to example 8, and the technological parameters are examined as follows:

the capsule particles are put into a film coating machine, the rotating speed of the pan is set to be 10rpm, the air inlet temperature is 38-50 ℃, the air inlet frequency is 600-1500Hz, the air outlet frequency is 600-1500Hz, the atomization pressure is 0.5bar, the material temperature is maintained to be 25-28 ℃ (target 26 ℃), 28-31 ℃ (target 30 ℃), 32-35 ℃ (target 34 ℃), 35-40 ℃ (target 38 ℃), the enteric coating solution is uniformly sprayed on the surfaces of the capsule particles, and then the capsule particles are dried at 45 ℃. The actual coating efficiency was calculated after the end of drying and the specific process parameters are shown in table 34.

Table 34: capsule coating process parameter table of example 13

After coating, 20 capsules were randomly sampled and the coating appearance of the capsules was observed in a black background, and the actual coating efficiency was calculated, and the results are shown in table 35.

Table 35: coating appearance and coating efficiency comparison table at different material temperatures

The acid strength at various material temperatures was measured and the results are shown in Table 36.

Table 36: acid resistance comparison table at different material temperatures

/>

As can be seen from Table 36, the capsule coating effect is poor when the material temperature is less than 28 ℃; the material temperature is 28-31 ℃ (target 30 ℃), 32-35 ℃ (target 34 ℃) and 35-40 ℃ (target 38 ℃), the coating effect is good, and the acid resistance is qualified.

And (4) performance test: process reproducibility

Raw material components of capsule coating referring to example 8, the capsule coating process parameters were set as shown in table 37, and 3 batches of samples were continuously prepared to examine the reproducibility of the capsule coating process of the present invention.

Table 37: capsule coating process parameter table for 3 batches of samples

Experiment number	CX-1	CX-2	CX-3
				Pot rotation rpm	10	10	10
Air inlet temperature DEG C	38-50	38-50	38-50
				Air intake frequency Hz	1000	1000	1000
Frequency of exhaust air Hz	1000	1000	1000
				Atomization pressure bar	0.5	0.5	0.5
The temperature of the materials is DEG C	28-35	28-35	28-35
				Drying temperature (DEG C)	45	45	45

1. Coating effect test

After coating, 20 capsules were randomly sampled and the coating appearance of the capsules was observed in a black background, and the actual coating efficiency was calculated, and the results are shown in table 38.

Table 38: coating appearance and coating efficiency comparison table for 3 batches of samples

2. Acid resistance strength test

The acid strength of 3 batches of samples was measured and the results are shown in Table 39.

Table 39: acid resistance comparison table for 3 batches of samples

/>

3. Dissolution Rate test

The dissolution rates of 3 batches of samples at different times were measured and the results are shown in table 40.

Table 40: dissolution rate comparison table for 3 batches of samples

Detecting items	CX-1	CX-2	CX-3
				Dissolution for 5 min%	0	0	0
Dissolution for 10 min%	34	36	36
				Dissolution for 15 min%	65	63	64
Dissolution for 20 min%	82	82	81
				Dissolution for 30 min%	95	93	93
45min dissolution%	95	95	96

As can be seen from tables 38-40, the process reproducibility of the present invention is good.

It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the inventive concept. Accordingly, it is intended that all such modifications as would be within the scope of this invention be included within the scope of this invention. The above embodiments are preferred embodiments of the present invention, and all similar processes and equivalent modifications are intended to fall within the scope of the present invention.

Claims

1. The lansoprazole enteric capsule is characterized by comprising a pill, a capsule shell and an enteric coating; the capsule shell is filled with the medicine-containing pills to form capsule particles; the enteric coating is coated on the surface of the capsule particles; the capsule shell is hydroxypropyl methyl cellulose capsule shell, and the enteric coating comprises the following raw material components in parts by weight: 24.13-43.37 parts of enteric coating material, 1.45-6.50 parts of plasticizer and 2.41-4.34 parts of titanium dioxide; the plasticizer accounts for 6-15% of the mass of the enteric coating material.

2. The lansoprazole enteric capsule of claim 1, wherein the raw material components of the pill include, in parts by weight: 30 parts of lansoprazole, 50-100 parts of a sucrose pellet core, 20-60 parts of sucrose powder, 5-15 parts of corn starch, 10-30 parts of a pH value regulator and 10-30 parts of low-substituted hydroxypropyl cellulose.

3. Lansoprazole enteric capsule according to claim 2, characterized in that the particle size of the sucrose pellet core ranges from 0.5 to 1.0mm.

4. The lansoprazole enteric capsule of claim 2, wherein the pH adjustor is selected from any one of sodium carbonate, sodium bicarbonate, light magnesium carbonate, heavy magnesium carbonate, sodium hydroxide, disodium hydrogen phosphate, and potassium hydrogen phosphate.

5. The lansoprazole enteric capsule of claim 1, wherein the enteric coating material is selected from any of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, styrene maleic acid copolymer; the plasticizer is selected from any one of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, triethyl citrate and triethyl glycerate.

6. A process for the preparation of lansoprazole enteric capsules, characterized in that it is used for the preparation of lansoprazole enteric capsules according to any one of claims 1 to 5, comprising the following steps:

(1) Preparing a pill;

7. The method for preparing lansoprazole enteric capsule according to claim 6, characterized in that the pot rotation speed is 5-15rpm during the capsule coating process.

8. The method for preparing lansoprazole enteric capsule according to claim 6, wherein the air intake frequency/exhaust frequency is 600-1500Hz in the capsule coating process.

9. The method for preparing lansoprazole enteric capsule according to claim 6, characterized in that the atomization pressure is 0.2-1.0bar during the capsule coating process.

10. The method for preparing lansoprazole enteric capsule according to claim 6, wherein the material temperature is 28-40 ℃ during the capsule coating process.