RU2821366C1 - Enteric coated pellets, method for their production and compositions containing them - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutics, namely, to pellets of ilaprazole with enteric coating, a method of producing pellets, a pharmaceutical composition for treating and/or preventing gastrointestinal diseases, a method of treating and/or preventing gastrointestinal diseases and using an enteric coated pellet for preparing a drug. Pellet with an enteric coating for treating and/or preventing gastrointestinal diseases, comprising a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer successively from the inside out, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a water-insoluble basic compound as a first auxiliary substance, wherein the enteric coated pellet is characterized by that the first insulating layer contains a water-insoluble basic compound; wherein the enteric coated ilaprazole pellet contains the following components in the specified ranges in weight parts: 1) pellet core: empty pellet core 5–15, drug loading layer containing: ilaprazole (or its pharmaceutically acceptable salt) 5–15, water-insoluble basic compound 5–15, surfactant 0.2–0.6, binder 8–24; 2) first insulating layer: binder, 5–36, water-insoluble basic compound 5–36; 3) second insulating layer: 4) binder 4–26; 5) anti-adhesive 7–44; 6) enteric coating layer:enteric coating materials 30–100 (content of solid substance), anti-adhesive 1–5, plasticizer 9–30; 7) protective layer: 8) binder 0.5–4; 9) anti-adhesion agent 0.5–5; wherein the water-insoluble basic compound is selected from one or more of magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide; wherein the binder is selected from one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol; wherein the anti-adhesion agent isselected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide. Weight ratio of the first excipient to ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole is 0.2:1–5:1; wherein the water-insoluble basic compound contained in the first insulating layer and the water-insoluble basic compound of the first auxiliary substance can be the same or different; wherein the enteric coated pellet is characterized by that the particle size D₉₀ of ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole is less than or equal to 100 mcm, and the second insulating layer does not contain basic substances. Method of producing a pellet with an enteric coating involves the following steps: 1) obtaining a pellet core containing ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient; 2) applying a first insulating layer and then applying a second insulating layer; 3) applying a layer of enteric coating; and 4) applying a protective layer. Pharmaceutical composition for treating and/or preventing gastrointestinal diseases, selected from an enteric coated pellet comprising an enteric coated pellet and a second excipient and optionally a film coating; capsule containing enteric coated pellets with protective layer, and a dry suspension containing enteric coated pellets and dry suspended particles. Method of treating and/or preventing gastrointestinal diseases includes a step of administering to a patient in need of such treatment and/or prevention, a therapeutic and/or prophylactic effective amount of an enteric coated pellet, or a pharmaceutical composition. Use of an enteric coated pellet or a pharmaceutical composition for preparing a drug for treating and/or preventing gastrointestinal diseases, wherein said gastrointestinal diseases are selected from heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and recurrent duodenal ulcer, NSAID-associated gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, gastric acidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), associated with Helicobacter pylori disease or elimination of helicobacter pylori, all degrees of erosive esophagitis, short bowel syndrome, gastric ulcer, peptic ulcer caused by non-steroidal anti-inflammatory compounds, and gastrointestinal bleeding and associated ulcers caused by antiplatelet preparations, as well as any combination of the above diseases.

EFFECT: said group of solutions enables to obtain pellets which have good stability, good acid resistance, high solubility and/or improved drug loading and bioavailability.

14 cl, 6 dwg, 18 tbl, 5 ex

Description

Related application and priority claim

This application claims priority based on Application No. 202011391266.5 filed with the State Intellectual Property Rights Administration of the People's Republic of China on December 2, 2020, the entire contents of which are incorporated herein by reference.

Technical field

The present invention relates to an enteric-coated pellet, a method for producing it and a composition containing it, in particular to an enteric-coated pellet of Ilaprazole, a method for producing it and a composition containing it.

State of the art

A proton pump inhibitor (PPI) is a drug that selectively inhibits the apical membrane H ⁺ -K ⁺ -ATPase in the secretory tubules of parietal cells of the gastric mucosa (also known as the proton or acid pump). Because the H ⁺ /K ⁺ -ATPase catalyzes the final step in gastric acid secretion, its inhibition can significantly reduce gastric acid secretion. Proton pump inhibitors are commonly used to treat gastrointestinal diseases (i.e., acid-related diseases) that are induced or caused by gastric acid, including gastric and duodenal ulcers, gastroesophageal reflux ulcers, surgical anastomotic ulcers, Zollinger-Ellison syndrome, etc. Depending on the mechanism of action, known proton pump inhibitors (PPIs) can be divided into two groups: irreversible and reversible proton pump inhibitors (RPPIs). Among them, irreversible proton pump inhibitors are mainly benzimidazole derivatives, which quickly pass through the cell membrane of the cell wall and accumulate in the strongly acidic secretory tubules, and are then averaged and converted into sulfamide compounds capable of forming a covalently linked disulfide bridge with thioglycol groups on cysteine residues in a- subunits of H ⁺ , K ⁺ -ATPase, thereby irreversibly inactivating the H ⁺ /K ⁺ -ATPase and inhibiting its acidic activity (Zhangxuan, "Review of Proton Pump Inhibitor - Prazoles Pharmaceutical Patent Technology", Patent Document Research (2018) - Pharmaceutical Medicine , Intellectual Property Publishing House, Beijing, 2019.9: p 554-567). Such drugs currently on the market worldwide include omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, ilaprazole, dexlansoprazole, etc.

Like other prazoles, ilaprazole is an acid-labile compound. However, ilaprazole has lower stability than other currently available prazoles. Acid-stable compounds are substances that are unstable in acidic environments, but have better stability in neutral and alkaline environments. A common feature of these compounds is that they become biologically effective compounds as a result of rapid degradation/transformation in acidic environments. Acid-stable proton pump inhibitors are susceptible to degradation/transformation in acidic and neutral environments, and when administered orally, they must be protected from contact with gastric acid, which may affect their stability. A common approach to solve this problem is to coat the oral formulations of such drugs with an enteric coating to produce enteric-coated pellets (for example, see CN 1183047 A, CN 1146720 A, US 4786505 and EP 0519365). These enteric coated pellets typically contain a pellet core, a buffer coating layer and an outer enteric coating layer. For the pellet core, an alkalizing agent (also known as a buffer) may be added to the pharmaceutical composition of the pellet core to improve the stability of the PPI, or an alkaline layer containing no alkalizing agent may be added to the pellet core to protect the PPI from degradation by acid (see CN 103705483 A). In addition, to avoid the influence of the free carboxyl group in the enteric-coated materials on the stability of such drugs, a buffer coating layer (ie, an insulating layer) with a specific thickness is required within the enteric coating layer.

As for the insulating layer, a number of technical solutions have already been disclosed in existing technologies, for example:

CN 87103285 A (a member of the Chinese patent family of the aforementioned US 4786505) discloses pharmaceutical compositions of acid labile substances (eg, benzimidazole compounds) for oral administration. This pharmaceutical preparation, used for the treatment of gastrointestinal diseases, consists of a core material, one or more subcoating layers (i.e., insulating layers), and enteric coatings in which the core material contains acid-labile and alkali-reactive compounds or selective alkali salts containing acid-labile and basic connections; the subcoating layer contains inert reaction compounds that are soluble in water or disintegrate rapidly in water, and optionally may also contain basic pH buffering compounds. In addition, the final enteric-coated dosage form is processed appropriately to reduce the moisture content to a very low level to obtain a dosage form with good long-term storage stability. For pH buffering, the base compounds may be magnesium oxide, magnesium hydroxide or magnesium carbonate, aluminum hydroxide or calcium hydroxide, aluminum carbonate or calcium carbonate, aluminum silicate or calcium silicate; complex aluminum / magnesium compounds, for example Al ₂ O ₃ ⋅6MgO⋅CO ₂ ⋅12H ₂ O, (Mg ₆ Al ₂ (OH)16CO ₃ ⋅4H ₂ O), or MgO⋅Al ₂ O ₃ ⋅2SiO ₂ ⋅nH ₂ O, where n is not an integer and is less than 2, or similar compounds; or other pharmaceutically acceptable pH buffering agents such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids. The materials used as the insulating layer are selected from pharmaceutically acceptable water-soluble inert compounds or polymers used as the coating film, such as saccharide, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, etc. The insulating layer may also contain conventional plasticizers, pigments, titanium dioxide, talc and other additives.

CN 101036633 A discloses enteric-coated omeprazole pellet capsules and a method for their preparation. The composition of such a capsule is an enteric-coated omeprazole pellet, which contains a pellet core without the active substance, an active drug layer containing alkaline ingredients, an insulating layer and an enteric coating layer. The insulating layer isolates the alkaline layer with the active drug omeprazole from the acidic enteric material, while adding magnesium oxide and titanium dioxide as protective components, which greatly improves the stability of the drug through a synergistic effect.

CN 102119927 A discloses enteric-coated pellet compositions of proton pump inhibitors and a method for their preparation. The enteric coated proton pump inhibitor pellet consists of a core containing no active substance, a drug layer, insulating layers (I) and (II) and an enteric coating layer. In order to improve the stability of the drug and improve the drug loading efficiency reduced by the addition of water-insoluble alkalis, both the drug loading layer and the insulating layer (I) contain water-soluble inorganic alkali, and the alkali used in the drug containing layer contains hydroxide sodium and another water-soluble inorganic alkali, which can form a buffer and alkaline environment pH 11-12 (with the exception of 11) with sodium hydroxide in aqueous solution.

CN 106176669 A discloses enteric-coated antoprazole pellets and a method for their preparation, as well as capsules containing said pellets and a method for their preparation. The composition of an antoprazole pellet with an enteric coating sequentially from the inside out includes a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, where the pellet core contains pantoprazole sodium and complex alkaline substances (a mixture of sodium phosphates); the first insulating layer contains hydroxypropyl methylcellulose polyvinylpyrrolidone k30, polyethylene glycol 600 (PEG-600), magnesium stearate and talc; the second insulating layer contains hydroxypropyl methylcellulose, polyethylene glycol 400 (PEG-400), sodium bicarbonate, titanium dioxide and triacetate; and in an enteric coated pellet, the weight ratio of the first insulating layer to the second insulating layer can have a significant impact on the final effectiveness.

CN 1785186 A discloses enteric-coated pantoprazole pellets or salts thereof, which are composed from the inside outwards of a pellet core, a sub-coating layer, a drug-containing layer, a buffer layer, an insulating layer, an enteric coating layer. To obtain the desired effect, the number of coating layers, the thickness of each layer, the dosage of the intermediate layer binder and stabilizers, etc. must be adjusted, therefore, herein, the increase in weight of each layer is strictly limited, otherwise the expected effect of this invention cannot be achieved.

The method for producing enteric-coated prazole pellets and their compositions in existing technologies has disadvantages, which leads to the fact that the enteric-coated prazole pellets and their compositions in the prior art cannot have good stability and acid resistance at the same time (especially acid resistance cannot be easily achieved) : In the insulating layer of an enteric-coated Prazole pellet prepared according to the prior art, the insulating layer immediately adjacent to the pellet core generally contains water-insoluble inert substances (for example, talc, silicon dioxide, titanium dioxide and stearate) that can prevent the pellets from sticking together magnesium) and/or water-soluble alkaline (basic) compounds, and the insulating layer closely adjacent to the enteric coating layer typically contains alkaline (basic) compounds that reduce the stability and/or acid resistance of the enteric coated pellets and their compositions.

The essence of the invention

As set forth above, one object of the present invention is to provide an enteric-coated ilaprazole pellet that overcomes the disadvantages of the prior art and may have one, two or more of the following properties: good stability, good acid stability, increased solubility and/or improved drug loading. (sometimes also referred to herein as drug administration rate) and bioavailability.

The above problem is achieved by using an enteric coated pellet according to the present invention, containing sequentially from the inside out a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, where the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient.

According to the first aspect of the present invention, there is provided an enteric coated pellet comprising sequentially from the inside outwards a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient, said enteric-coated pellets are characterized in that the first insulating layer contains a water-insoluble main compound and the mass ratio of the first excipient to ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole is 0.2:1-5:1.

According to a second aspect of the present invention, there is provided an enteric-coated pellet comprising, sequentially from the inside out, a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient, wherein the pellets with an enteric coating are characterized in that the first insulating layer contains a water-insoluble base compound and the first excipient is a water-insoluble base compound, wherein the water-insoluble base compound and the water-insoluble base compound of the first excipient contained in the first insulation layer can be the same or different.

According to a third aspect of the present invention, there is provided an enteric coated pellet comprising sequentially from inside to outside a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, among them, the pellet core contains ilaprazole and/or a pharmaceutically acceptable ilaprazole salt and a first excipient, and enteric coated pellets are characterized in that the particle size D ₉₀ of ilaprazole and/or pharmaceutically acceptable salt of ilaprazole is less than or equal to 100 μm, and the second insulating layer does not contain basic substances.

According to one embodiment of the present invention, a protective layer is further applied to the enteric coating layer of the enteric coated pellet according to the present invention.

According to one embodiment of the present invention, the enteric coated pellet of the present invention has no other layers between the pellet core and the first insulating layer.

According to one embodiment of the present invention, the enteric coated pellet of the present invention has no other layers between the second insulating layer and the enteric coating layer.

According to one embodiment of the present invention, the enteric coated pellet of the present invention has no other layers between the first insulating layer and the second insulating layer.

According to one embodiment of the present invention, the first excipient of the enteric coated pellet according to the present invention is a base compound, preferably less soluble in water, and more preferably selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide.

According to one embodiment of the present invention, the pharmaceutically acceptable salt of ilaprazole may be, for example, ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium or ilaprazole calcium, etc. In this case, those skilled in the art can select a suitable salt according to with needs.

According to one embodiment of the present invention, the enteric coated pellet core of the present invention further contains a surfactant. Preferably, the surfactant is Tween 80 or sodium dodecyl sulfate.

According to one embodiment of the present invention, the weight ratio of water-insoluble basic compounds in the first insulating layer to ilaprazole and/or a pharmaceutically acceptable salt thereof is 0.2:1-5:1, preferably 0.25:1-4:1, more preferably 0.3:1-3:1, especially preferably 0.5:1-2:1, most preferably 0.8:1-1.2:1, for example 1:1.

According to one embodiment of the present invention, the second insulating layer contains a water-insoluble inert substance capable of preventing the pellets from sticking together, and the mass ratio of the water-insoluble inert substance to the binder is 1-8: 1.5-10, 1-10: 1-20, or 4-26:7-44.

According to one embodiment of the present invention, the particle size D ₉₀ of ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole can be in a range selected from the ranges between any two of the following endpoints: 0 μm (this value is excluded when generating the range), 10 μm, 20 µm, 30 µm, 40 µm, 50 µm, 60 µm, 70 µm, 80 µm, 90 µm and 100 µm.

Those skilled in the art will appreciate that one or more features of various aspects and embodiments herein may be freely combined to form new technical solutions, and that the resulting technical solutions fall within the scope of the present invention. The technical solution, terms and principles of the invention are described in more detail below.

Enteric coated pellet core:

The enteric coated pellet core (or known as a drug containing core) according to the present invention may be a fully active core or an empty pellet core, i.e. not containing a drug, coated with a layer containing a drug. As used herein, the term “fully active pellet core” means ilaprazole and/or a pharmaceutically acceptable salt thereof and a first excipient, as well as a core of one or more other pharmaceutically available excipients in which ilaprazole and/or a pharmaceutically acceptable salt thereof is used as the active ingredient is dispersed in the other ingredients (in the specified primary excipient and one or more other available excipients, etc.) without forming another layer independently or together with any other ingredient; in the empty pellet core coated with a drug-containing layer, the drug-containing layer comprises ilaprazole and/or a pharmaceutically acceptable salt thereof, as well as a first excipient and optionally an excipient.

When ilaprazole and/or a pharmaceutically acceptable salt thereof in the core cannot provide sufficient storage stability under the influence of the water-insoluble base compound contained in the first insulating layer alone, a first excipient further added to the core may improve the storage stability of ilaprazole and/or its pharmaceutically acceptable salt.

The first excipient in the pellet core may be a common excipient used in existing technologies to improve the stability of acid-labile compounds. Preferably, the first excipient is a basic compound, either water-insoluble or water-soluble. Preferably, according to the present invention, a water-insoluble base compound is used as the first excipient in the pellet core; more preferably, the water-insoluble base compound contained in the pellet core is the same as the water-insoluble base compound contained in the first insulating layer, which can further enhance the pH buffering effect of the insulating layer. In an embodiment of the present invention, the water-insoluble base compounds may be selected from one or more of the following (but are not limited to): magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide. The optimal weight ratio of the main compounds to ilaprazole and/or its pharmaceutically acceptable salt is 0.2:1-5:1, preferably 0.25:1-4:1, more preferably 0.3:1-3:1, particularly preferred 0.5:1-2:1, most preferably 0.8:1-1.2:1, for example 1:1.

According to the present invention, the pellet core may further contain a surfactant. The results of embodiments of the present invention indicate that the surfactant can improve the solubility of ilaprazole and/or a pharmaceutically acceptable salt thereof in enteric-coated pellets and formulations thereof, thereby effectively improving their bioavailability. In an embodiment of the present invention, the surfactants contained in the pellet core may be selected from nonionic surfactants, anionic surfactants and amphoteric surfactants. Preferably, the nonionic surfactants may be selected from polyethylene glycol, polyol (eg, Tween-80), etc.; Anionic surfactants may be selected from higher fatty acid salts, sulfuric acid salts, sulfonate salts, etc., such as sodium dodecyl sulfate; amphoteric surfactants may be selected from phospholipids.

According to the present invention, the particle size of ilaprazole and/or a pharmaceutically acceptable salt thereof may influence the solubility and/or loading rate of the enteric coated pellets. In a preferred embodiment of the present invention, ilaprazole and/or a pharmaceutically acceptable salt thereof may have a particle size D ₉₀ ≤100 μm; At the same time, enteric-coated pellets have good solubility, which makes it possible to improve the bioavailability of the composition prepared from enteric-coated pellets. More preferably, the particle size D ₉₀ of ilaprazole and/or a pharmaceutically acceptable salt thereof may be in a range selected from the ranges between any two of the following endpoints: 10 µm, 20 µm, 30 µm, 40 µm, 50 µm, 60 µm, 70 µm, 80 µm, 90 µm, 100 µm, in particular D ₉₀ ≤50 µm, which allows for an improved loading rate.

According to one embodiment of the present invention, the above-mentioned empty pellet core is one commonly used in the art. In an embodiment of the present invention, the empty pellet core may be selected from (but not limited to) a microcrystalline cellulose pellet core, a sucrose pellet core, or a mannitol pellet core and may have a particle size of 50-500 μm, preferably 100-400 μm, more preferably 250-350 µm, most preferably about 300 µm.

According to one embodiment of the present invention, said drug-containing layer may further comprise a binder. The binder may be selected from, but is not limited to, one or more of the following: hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, sugar syrup and starch. In an embodiment of the present invention, the binder may be selected from one or more of the following: hydroxypropylcellulose-SSL (eg, from the commercially available series from Nisso), hydroxypropylmethylcellulose E5, polyvinylpyrrolidone K30, polyvinyl alcohol, methylcellulose, and polyethylene glycol.

Enteric coated pellet insulating layer:

The primary function of the enteric coated pellet insulating layer is to isolate the core in an alkaline environment from the enteric coating layer containing free carboxyl groups to prevent degradation or discoloration of ilaprazole and/or its pharmaceutically acceptable salt during the coating process or during storage. In the course of studying enteric-coated ilaprazole pellets and their formulations, the present inventors have discovered that the use of water-insoluble inerts (e.g., talc, silica, titanium dioxide, and magnesium stearate) and/or water-soluble base compounds can prevent pellet sticking and commonly used in conventional preparation methods known in the art (e.g., when preparing a barrier layer immediately adjacent to the core), and the main compounds typically used in the preparation of a barrier layer closely adjacent to the enteric coating layer may reduce stability and/or acid resistance of enteric coated pellets and their formulations, especially for acid labile compounds with relatively low stability such as ilaprazole, which results in enteric coated pellets and their formulations not meeting stability and acid resistance requirements. As used herein, the term “closely adjacent” means the absence of other layers between the enteric coated pellet core and its coating or coating layers or between these two layers.

One of the reasons for this technical problem, which the inventors of the present invention have experimentally demonstrated and believed (but not limited to), is that the compatibility between the water-insoluble inert substances contained in the insulating layer (corresponding to the first insulating layer according to the present invention) ), closely adjacent to the core, and the acid-labile compounds contained in the core, varies depending on the stability of the acid-labile compounds, that is, in enteric-coated pellets and their compositions prepared according to the prior art, the compatibility between water-insoluble inert substances capable of preventing pellet sticking (for example, talc) contained in the insulating layer tightly adjacent to the core, and acid-labile compounds, decreases accordingly with the low stability of acid-labile compounds in the core (for example, ilaprazole). Therefore, even with the protection of the main compounds contained in the core and/or insulating layer acting as stabilizers, there is still a significant increase in the substances of interest (i.e., impurities) in the accelerated test results, which reduces the stability of the enteric coated pellets. This to some extent limits the range of acid labile compounds applicable to enteric coated pellets and their formulations prepared using existing technologies, i.e. recipes or combinations of enteric-coated pellets and their formulations prepared using existing technologies may not be well applied to ilaprazole and/or its pharmaceutically acceptable salt. In addition, when water-soluble alkaline (basic) compounds are contained in the insulating layer (corresponding to the first insulating layer according to the present invention) adjacent to the core, under prolonged conditions of high temperature and humidity, the insulating layer of the enteric coated pellet absorbs free water, resulting in dissolving water-soluble alkaline (basic) compounds, causing the insulating layer adjacent to the enteric coating layer to show alkalinity by increasing alkalinity; and when water penetrates the enteric coating layer in an acidic environment, premature dissolution of the enteric coating layer occurs, resulting in reduced acid resistance of the enteric coated pellets and their formulations. The principle of premature dissolution of the enteric coating layer due to the alkalinity of the insulating layer closely adjacent to the enteric coating layer also applies to the case where alkaline (basic) compounds are contained in the insulating layer (corresponding to the second insulating layer according to the present invention) closely adjacent to the layer enteric coating.

Thus, according to the present invention, the enteric coated pellet contains at least two insulating layers containing an inert substance, i.e. at least a first insulating layer located next to the pellet core and closely adjacent to it, and a second insulating layer located far from the core compared to the first insulating layer or closely adjacent to the enteric coating layer, including the first insulating layer containing insoluble in water is the main compound and does not contain water-soluble alkaline compounds and water-insoluble inert substances that can prevent the pellets from sticking together, the second insulating layer does not contain alkaline (basic) compounds. When the enteric coated pellets contain three or more insulating layers, the other insulating layer located between the first insulating layer and the second insulating layer may be an insulating layer meeting the definition of a first insulating layer or a second insulating layer according to the present invention, or may be an insulating layer commonly used in existing technologies.

According to the present invention, the water-insoluble basic compound may be a water-insoluble base compound commonly used in the art to improve the stability of acid-labile compounds. In an embodiment of the present invention, the water-insoluble base compound may be selected from one or more of the following (but not limited to): magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide.

According to the present invention, the water-insoluble inert substances capable of preventing pellet sticking may be selected from one or more commonly used pharmaceutical substances such as lubricants, glidants and anti-adhesives (ie, anti-adhesive agents, hereinafter the same). In an embodiment of the present invention, the water-insoluble inert substances capable of preventing pellet sticking may be selected from, but are not limited to, silica, calcium silicate, colloidal silica, aluminum silicate, aluminum-calcium silicate, magnesium silicate, sodium stearate, zinc stearate, magnesium stearate, talc, titanium dioxide, etc. In one embodiment of the enteric-coated ilaprazole pellets of the present invention, the first insulating layer of the enteric-coated ilaprazole pellet does not contain one or more anti-caking water-insoluble inert substances such as such as talc, silicon dioxide, titanium dioxide and magnesium stearate.

In a preferred embodiment of the present invention, the first insulating layer is mainly composed of a water-insoluble base compound and a binder, and the second insulating layer is mainly composed of a water-insoluble inert substance capable of preventing pellet sticking together and a binder. According to the present invention, the solubility of enteric-coated pellets, and therefore their bioavailability, can be affected by adjusting the dosage of water-insoluble base compounds and binders contained in the first insulating layer, or adjusting the dosage of water-insoluble inert substances capable of preventing the pellets from sticking together. , and binders. For example, in a preferred embodiment of the enteric-coated ilaprazole pellet tablets of the present invention, the component ratio may be as follows: when the amount of ilaprazole is 5-15 parts by weight, the first insulating layer contains 5-36 parts by weight of binder and 5-36 parts by weight of insoluble in water the main compound; the second insulating layer contains 4-26 parts by weight of a binder and 7-44 parts by weight of a water-insoluble inert substance that can prevent the pellets from sticking together.

The above-mentioned binders are conventional binders used in the insulating layer in accordance with the prior art. According to the present invention, the binder may be selected from one or more pharmaceutically acceptable water-soluble inert compounds or polymers used as the coating film, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, sugar syrup and starch.

Enteric coated pellet layer:

The enteric coating layer commonly used in enteric coated pellets prepared according to the prior art is also applicable to the present invention, for example, a detailed description of the enteric coating layer is given in CN 87103285 A (a member of Chinese patent family US 4786505); The inventors use this document by reference and have incorporated it into this application with respect to the enteric coating layers, as well as the corresponding contents of all literature cited therein.

According to the present invention, the enteric coating layer may be selected from one or more of the following: acrylic resin, hydroxymethylethylcellulose and other celluloses, opadry and other enteric coating materials, and one or more optional additives selected from plasticizers, release agents, lubricants. In an embodiment of the present invention, the enteric coating layer may comprise an acrylic resin enteric coating material, a plasticizer (e.g., polyethylene glycol, triacetin, triethyl citrate, phthalate, etc.), a release agent (e.g., talc, glyceryl monostearate, etc.) . Among them, the acrylic resin enteric coating material is selected from one or more of the following: solution or dispersants L30D55 of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac. In a preferred embodiment of the enteric coated ilaprazole pellets of the present invention, the weight ratio of the enteric coating material contained in the enteric coating layer to ilaprazole and its pharmaceutically acceptable salt is 2:1 to 20:1. In a preferred embodiment of the enteric coated ilaprazole pellets of the present invention, the weight ratio of plasticizer to ilaprazole and pharmaceutically acceptable salt thereof is 0.6:1-6:1, preferably 0.8:1-4:1, more preferably 1:1 -2:1.

Protective layer of pellets with enteric coating:

According to the present invention, the protective layer can be further applied outside the enteric coating layer of the enteric coated pellet, preferably the protective layer is closely adjacent to the enteric coating layer. Said protective layer prevents possible sticking that may occur between different semi-finished products/products during placement before preparation of the composition, or during preparation of the composition, or during placement after preparation of the composition. In addition, the application of a protective layer can effectively improve the solubility of enteric-coated pellets, thereby improving the bioavailability of formulations prepared from enteric-coated pellets.

In an embodiment of the present invention, the protective layer may contain binders and release agents. The binder may be selected from one or more of the following: hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol. The release agent may be selected from one or more of the following: talc, magnesium stearate, titanium dioxide and silicon dioxide.

According to the present invention, the acid resistance of enteric coated pellets can be increased by increasing the amount of release agents in the protective layer. In a preferred embodiment of the enteric-coated ilaprazole pellets of the present invention, when the content of ilaprazole and its pharmaceutically acceptable salt is 5-15 parts by weight, the content of the release agents is 0.5-5 parts by weight.

According to a fourth aspect of the present invention, there is provided a method for producing enteric coated pellets, comprising at least the following steps: 1) producing a core containing ilaprazole and a pharmaceutically acceptable salt thereof and a first excipient; 2) coating the first insulating layer followed by coating the second insulating layer; and 3) coating the enteric coating layer.

Preferably, step 2) includes: preparing a first suspension containing a water-insoluble base compound and free from water-soluble alkaline compounds and water-insoluble inert substances capable of preventing the pellets from sticking together, followed by coating the core obtained in step 1 with the first suspension ); as well as preparing a second suspension that does not contain alkaline (basic) compounds, followed by coating with the second suspension as a second insulating layer, preferably as a second insulating layer closely adjacent to the enteric coating layer;

Preferably, in step 1), the first excipient and the water-insoluble base compound contained in the first insulating layer act together to provide storage stability of ilaprazole and/or a pharmaceutically acceptable salt thereof.

Preferably, the method of preparing enteric coated pellets also includes step 4): applying a protective layer.

In an embodiment of the present invention, a method for preparing enteric coated pellets may include one or more of the following steps:

1) providing a coating on the empty core with a layer containing a drug containing ilaprazole and/or a pharmaceutically acceptable salt thereof, alkaline (basic) compounds as a first excipient and binders, for example, by a fluidized bed method to obtain a pellet core;

2) providing a coating on the core obtained in step 1), sequentially from the inside out, with at least a first suspension and a second suspension, for example, by a fluidized bed method to form a first insulating layer and a second insulating layer, respectively, to obtain an insulating pellet in which the first suspension contains water-insoluble basic compounds and does not contain water-soluble alkaline compounds and water-insoluble inert substances that can prevent pellets from sticking together; and the second suspension does not contain alkaline compounds;

3) preparing a suspension of the enteric coating layer to obtain an enteric coating material and one or more substances selected from plasticizers, release agents, lubricants and emulsifiers; providing a coating on the insulating pellet obtained in step 2) with a suspension of an enteric coating layer, for example, by a fluidized bed method to produce enteric coated pellets.

Preferably, the above method for producing enteric coated pellets may further comprise step 4): adding one or more binders selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose and polyethylene glycol to the purified water to obtain a film-forming protective solution layer, then coat the enteric-coated pellets obtained in step 3 with the film-forming solution of the protective layer, for example, using the fluidized bed method to obtain enteric-coated pellets with a protective layer.

According to the present invention, optionally, enteric-coated ilaprazole pellets can be prepared using the above enteric-coated pellets according to the present invention, in which the dosage form is a tablet, capsule, dry suspension or granule.

According to a fifth aspect of the present invention, there is provided an enteric-coated ilaprazole pellet tablet comprising enteric-coated pellets and tablet excipients (a second excipient different from the excipient described in the section "Enteric-coated pellet core") according to the present invention .

Optionally, enteric-coated pellet tablets additionally contain a film coating.

According to the present invention, the enteric-coated pellets used to produce a tablet may be enteric-coated pellets containing a protective layer and enteric-coated pellets not containing a protective layer.

According to the present invention, the tablet excipients may be conventional tablet excipients used in the prior art for enteric-coated pellet tablets. In an embodiment of the present invention, the tablet excipients include fillers, diluents, disintegrants and lubricants, among which the fillers and/or diluents may be selected from, but are not limited to, one or more of the following: starch, prepeptized starch, lactose, mannitol and microcrystalline cellulose; disintegrants may be selected from one or more of the following (but are not limited to): crospovidone, croscarboxymethylcellulose sodium and cross-linked croscarboxymethylcellulose sodium; lubricants may be selected from one or more of the following (but are not limited to): talc, magnesium stearate, sodium stearyl fumarate and silicon dioxide.

According to the present invention, the film coating may be a conventional film coating used in the prior art for enteric coated pellet tablets. In an embodiment of the present invention, the film coating comprises a coating powder which may be selected from, but is not limited to, one or more of the following: hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methyl cellulose, polyethylene glycol, talc, glaze and gastric soluble opadry.

The method for tableting enteric-coated pellets according to the present invention, and optionally the film coating method, are conventional tableting and coating methods for enteric-coated pellets in the prior art.

According to a sixth aspect of the present invention, there is provided an enteric-coated ilaprazole pellet capsule comprising the above enteric-coated pellets with a protective layer provided in accordance with the present invention.

According to the present invention, capsules can be commonly used in the art for filling enteric coated pellets to the required quantity or specification; for example, the capsule may be a capsule shell sealed with a capsule sealing material; wherein the capsule shell material may be selected from, but is not limited to, one or more of the following: gelatin, starch, sodium alginate, and hydroxypropyl methylcellulose. Capsule sealing materials may be selected from one or more of (but are not limited to): gelatin, hydroxypropyl methylcellulose, methylcellulose, acrylic resin, P-cyclodextrin, ethylcellulose, modified starch, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethylcellulose.

The method for preparing enteric coated pellets in capsules according to the present invention may be a conventional method for preparing enteric coated pellet capsules known in the art.

According to a seventh aspect of the present invention, there is provided a dry suspension of ilaprazole pellets comprising enteric coated pellets according to the present invention and particles of the dry suspension.

The method for preparing a dry enteric-coated pellet slurry according to the present invention may be a conventional method for preparing a dry enteric-coated pellet slurry known in the art.

In experimental animal studies, the present inventors have found that formulations containing the enteric-coated pellets of the present invention have beneficial effects in the treatment and/or prevention of gastrointestinal diseases, wherein gastrointestinal diseases mainly include heartburn, inflammatory diseases intestines, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and recurrent duodenal ulcer, NSAID-associated gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, increased acidity of gastric juice, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-associated diseases or eradication of Helicobacter pylori, all degrees of erosive esophagitis, short bowel syndrome or any combination of the above diseases.

Thus, according to the eighth aspect of the present invention, a method for treating and/or preventing gastrointestinal diseases is provided. The method includes the step of administering to a patient in need of such treatment and/or prophylaxis a therapeutically and/or prophylactically effective amount of the enteric-coated pellet formulations of the present invention. In one embodiment of the present invention, the enteric-coated pellet formulations of the present invention are enteric-coated ilaprazole pellet tablets, enteric-coated ilaprazole pellet capsules, or enteric-coated ilaprazole dry suspension of the present invention. Gastrointestinal diseases that may be treated and/or prevented by this method include, but are not limited to, heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcer and relapse of duodenal ulcer, NSAID-associated gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, increased acidity of gastric juice, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), associated with Helicobacter pylori disease or destruction of Helicobacter pylori, all degrees of erosive esophagitis, short bowel syndrome or any combination of the above diseases.

Accordingly, according to a ninth aspect of the present invention, there is provided the use of enteric-coated pellets and compositions thereof in the preparation of a medicament for the treatment and/or prevention of gastrointestinal diseases in accordance with the present invention. These gastrointestinal diseases include, but are not limited to, heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and recurrent duodenal ulcer, NSAID-associated gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, increased acidity of gastric juice, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-associated diseases or destruction of helicobacter pylori, all degrees of erosive esophagitis, short bowel syndrome or any combination of the above diseases.

In addition, enteric-coated pellets and their compositions disclosed herein are used for the preparation of a medicament for the treatment and/or prevention of gastrointestinal diseases. These gastrointestinal diseases include, but are not limited to, duodenal ulcers and recurrent duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD) and Helicobacter pylori-associated diseases; or the drug may be used to kill helicobacter pylori and may also be used to prevent peptic ulcers caused by nonsteroidal anti-inflammatory compounds and gastrointestinal bleeding and associated ulcers caused by antiplatelet drugs (including, but not limited to, clopidogrel, prasugrel and ticagrelor) and the like.

In the present invention, the inventors have identified and eliminated the influencing factors that limit the ability of enteric-coated ilaprazole pellets and their formulations to have both good stability and acid resistance (especially acid resistance), and the following beneficial effects have been achieved with the technical solutions of the present invention:

1) Enteric coated pellets and their compositions in accordance with the present invention can have both better stability and acid resistance by applying at least two insulating layers (a first insulating layer and a second insulating layer and, optionally, other insulating layers) in enteric-coated ilaprazole pellets and limitations on the composition of these insulating layers (especially the first insulating layer and the second insulating layer).

2) By adjusting the particle size of ilaprazole and/or a pharmaceutically acceptable salt thereof, the weight ratio of water-insoluble base compounds to binders in the first insulating layer, or the weight ratio of anti-caking water-insoluble inert substances to binders in the second insulating layer, or additional application of a protective layer, enteric-coated pellets and their compositions in accordance with the present invention may have improved solubility of the active ingredients, thereby realizing improved bioavailability.

3) Enteric-coated ilaprazole pellets and their compositions according to the present invention have good acid-suppressing effect in the human body and can inhibit gastric acid secretion to pH 4 or more within 1 hour after administration, thereby achieving clinical effect. The enteric-coated pellet tablets of the present invention can quickly achieve an effect, thereby quickly relieving the suffering of patients.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In fig. 1 shows the cumulative solubility in an accelerated stability test of pellets of the present invention and comparative pellets 7 and 8 (known in the figures as pellets 7 and 8) having different insulating layer formulas.

In fig. 2 shows the cumulative solubility in an accelerated stability test of pellets of the present invention and comparative pellets 11 and 16 (known in the figures as pellets 11 and 16) having a different core.

In fig. 3 shows the cumulative solubility in an accelerated stability test of the pellet tablets of the present invention and comparative pellet tablets 3 and 4 (known in the figures as pellet tablets 3 and pellet tablets 4) having different particle sizes of ilaprazole in the core formula.

In fig. 4 shows the cumulative solubility in an accelerated stability test of pellets of the present invention and a comparative pellet 12 (known in the figures as pellet 12) without a protective layer.

In fig. 5 shows an average recording of pH values in the human stomach in real time for pellet tablets according to the present invention and comparative pellet tablets 1 and 2 (known in the figures as pellet tablets 1 and 2), prepared in accordance with the method known from the level technology.

In fig. 6 shows a curve of changes in blood plasma concentration in Beagle dogs for pellet tablets according to the present invention and comparative pellet tablets 1 and 2 (known in the figures as pellet tablets 1 and 2), prepared in accordance with a method known in the prior art.

Detailed Description of the Invention

This section provides examples of the compositions of the enteric-coated pellet tablets of the present invention and the method for their preparation, mainly taking the enteric-coated ilaprazole pellet tablets and the dry suspension of the present invention as preferred examples.

Ilaprazole enteric-coated pellet tablets include pellets (which consist of a core, a first insulating layer, a second insulating layer, an enteric coating layer and a barrier layer in sequence from inside to outside), tablet excipients and a film coating; among them, the core contains an empty pellet core and a drug loading layer containing ilaprazole and/or a pharmaceutically acceptable salt thereof (particle size D ₉₀ preferably ≤50 μm), alkaline (basic) compounds, surfactants and binders; the first insulating layer contains water-insoluble basic compounds and binders, and does not contain water-soluble alkaline compounds and water-insoluble inert substances that can prevent the pellets from sticking together; and the second insulating layer mainly contains binders and water-insoluble inert substances (such as talc, silica, titanium dioxide and magnesium stearate, which can be used as a release agent) that can prevent the pellets from sticking together, but does not contain alkali compounds.

Preferably, the basic compounds contained in the core are water-insoluble basic compounds; and more preferably, the water-insoluble basic compounds contained in the core are the same as the water-insoluble basic compounds contained in the first insulating layer.

Specifically, the components and proportions of enteric-coated ilaprazole pellet tablets may be, but are not limited to, the following: (in parts by weight)

Enteric coated ilaprazole pellets:

1) Pellet core: Empty pellet core 5-15; Drug loading layer containing: Ilaprazole (or a pharmaceutically acceptable salt thereof) 5-15; Main connection 5-15; Surface-active substance 0.2-0.6; Binder 8-24; 2) First insulating layer: Binder 5-36; Water-soluble alkaline compound 5-36; 3) Second insulating layer: Binder 4-26; Release agent 7-44; 4) Enteric coating layer: Enteric coating materials 30-100 (solid content); Release agent 1-5; Plasticizer 9-30; 5) Protective layer: Binder 0.5-4; Release agent 0.5-5; Tablet 6) excipient for tabletting: Filler 100-600; Diluent 50-200; Baking powder 5-20; Lubricant 1-20; 7) Film coating: Coating powder 10-40.

Enteric-coated pellet tablets are highly stable and acid-resistant and are suitable for ilaprazole, which has a rather low stability. In addition, the enteric coated ilaprazole pellet tablet also has good drug loading and high solubility/bioavailability.

The present invention will be described below with reference to specific examples and figures, which, however, are not intended to limit the present invention. The methods used in the following examples are conventional unless otherwise noted. The conclusions that may be shown from the test results in the examples below can be reasonably inferred by those skilled in the art based on generally known knowledge in the field, and are not limited to the following text.

Example 1. Preparation of enteric coated pellets

In this Example 1, taking ilaprazole and/or a pharmaceutically acceptable salt thereof as an example, enteric-coated pellets A-G were prepared in accordance with the present invention, and comparative pellets 3-18 were prepared to compare the effect of different compositions of enteric-coated pellet component layers on the properties enteric-coated pellets and their compositions. Compared with the enteric-coated pellets A-G of the present invention, comparative pellets 3 and 4 had different particle sizes of ilaprazole in the drug-containing layer; comparative pellets 5-10 and 14-15 have different insulating layers; comparative pellets 11, 16 and 17 have layers containing a drug with a modified composition; comparative pellets 12-13 had different protective layers; and comparative pellet 18 had a modified ratio of ilaprazole and/or a pharmaceutically acceptable salt thereof to the first excipient.

(I) Composition for preparing enteric-coated pellet layers:

1.1 Composition and method of preparation of the pellet core (W), and the degree of drug loading

In this example, a drug containing pellet (ie, pellet core) was prepared consisting of an empty pellet core and a drug loading layer.

1) Composition W1 of the pellet containing the drug (unit: g)

Cooking process:

Weighed 150 g of hydroxypropyl cellulose-SSL and 4 g of polysorbate-80 and dissolved in 3000 g of purified water to obtain a hydroxypropyl cellulose binder solution, added 100 g of magnesium hydroxide to the binder solution and mixed them for 5 min at a high shear rate of 10,000 rpm, then injected 100 g of Ilaprazole D ₉₀ starting material with a particle size of 46.8 μm into a binder containing magnesium hydroxide and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the Ilaprazole suspension onto the sucrose pellet core through the GLATT fluidized bed GPCG-1.

The specific process parameters are given below:

The degree of loading of the drug W ₁ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 95.6%.

2) Composition W2 of the pellet containing the drug (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl cellulose-SSL and 2 g of sodium dodecyl sulfate according to the composition, dissolved in 2000 g of purified water, added 150 g of magnesium carbonate and dispersed for 5 min at a high shear rate of 10,000 rpm; then injected 50 g of ilaprazole magnesium into a binder containing magnesium carbonate and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole magnesium suspension onto the microcrystalline cellulose pellet core through the GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

Drug loading rate W2 into drug pellet = (actual content of drug pellet)/(theoretical content of drug pellet)×100%=91.4%.

3) Composition of W3 pellet containing medicinal product (unit: g)

Cooking process:

Weighed 240 g of polyvinylpyrrolidone K30 and 6 g of sodium dodecyl sulfate according to the composition and dissolved in 4800 g of purified water, added 150 g of calcium carbonate and dispersed them evenly at a high shear rate of 10,000 rpm, then added 150 g of zinc ilaprazole to the binder containing carbonate calcium, and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the zinc ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

Loading rate of drug W3 into the pellet core = (actual pellet core content)/(theoretical pellet core content)×100%=92.4%.

4) Composition W4 of the pellet core (unit: g)

Cooking process:

Weighed 180 g of polyvinylpyrrolidone K30 and 6 g of polysorbate-80 according to the composition and dissolved in 3000 g of purified water, added 50 g of magnesium oxide and dispersed evenly at a high shear rate of 10,000 rpm, then injected 150 g of ilaprazole into the binder containing magnesium oxide , and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole suspension onto the mannitol pellet core through the GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₄ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 93.3%.

5) Composition W5 of the pellet core (unit: g)

Cooking process:

Weighed 80 g of hydroxypropyl methylcellulose-E5 and 6 g of polysorbate-80 according to the composition and dissolved in 1600 g of purified water, added 50 g of magnesium hydroxide and uniformly dispersed at a high shear rate of 10,000 rpm; then injected 150 g of ilaprazole into a binder containing magnesium hydroxide and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₅ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 94.1%.

6) Composition of W6 pellet core (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl cellulose-SSL according to the composition, dissolved in 3000 g of purified water to obtain a hydroxypropyl cellulose binder solution, then introduced 100 g of ilaprazole starting material into the binder solution, and uniformly dispersed it at a high shear rate of 10,000 rpm, and then sprayed suspension of ilaprazole onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₆ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 93.4%.

7) Composition of W7 pellet core (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl cellulose-SSL according to the formula, dissolved in 3000 g of purified water to obtain a hydroxypropyl cellulose binder solution, then added 100 g of ilaprazole starting material and 100 g of magnesium hydroxide into the binder solution, and dispersed it evenly at a high shear rate of 10,000 rpm. min and then sprayed the ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₇ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 95.4%.

8) Composition of W8 pellet core

This composition is identical to the composition of the W1 pellet core except that the particle size D ₉₀ of ilaprazole was greater than or equal to 80 µm and less than or equal to 100 µm. The degree of loading of the drug W ₈ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 87.2%.

9) Composition of W9 pellet core

This composition is identical to the composition of the W1 pellet core, except that the particle size D ₉₀ of ilaprazole was 100 μm. The degree of loading of the drug W ₉ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 79.3%.

10) Composition of W10 pellet core (unit: g)

Cooking process:

Weighed 150 g of hydroxypropyl cellulose-SSL and 4 g of polysorbate-80 and dissolved in 3000 g of purified water to obtain a hydroxypropyl cellulose binder solution, added 100 g of 46.8 μm Ilaprazole D ₉₀ starting material to the binder containing polysorbate-80, and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₁₀ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 97.6%.

Wl 1) Composition W11 of the pellet core (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl cellulose-SSL and 2 g of sodium dodecyl sulfate according to the composition, dissolved in 2000 g of purified water, added 200 g of magnesium carbonate and dispersed for 5 min at a high shear rate of 10,000 rpm; then injected 50 g of ilaprazole magnesium into a binder containing magnesium carbonate and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole magnesium suspension onto the microcrystalline cellulose pellet core through the GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₁₁ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 92.5%.

12) Composition of W12 pellet core (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl methylcellulose-E5 and 6 g of polysorbate-80 according to the composition and dissolved it in 2000 g of purified water, added 50 g of magnesium hydroxide and uniformly dispersed it at a high shear rate of 10,000 rpm; then injected 200 g of ilaprazole into a binder containing magnesium hydroxide and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₁₂ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 93.8%.

13) Composition of W13 pellet core (unit: g)

Cooking process:

Weighed 100 g of hydroxypropyl cellulose-SSL and 2 g of sodium dodecyl sulfate according to the composition, dissolved in 2000 g of purified water, added 30 g of magnesium carbonate and dispersed for 5 min at a high shear rate of 10,000 rpm; then injected 180 g of ilaprazole into a binder containing magnesium carbonate and uniformly dispersed at a high shear rate of 10,000 rpm, and then sprayed the ilaprazole suspension onto the microcrystalline cellulose pellet core through the GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

The degree of loading of the drug W ₁₃ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100% = 94.5%.

1.2 Composition for preparing the insulating layer (G)

1) Composition G1 of the insulating layer (unit: g)

Cooking process:

10 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 200 g of purified water, then 10 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 8 g of hydroxypropyl cellulose-SSL were weighed and dissolved in 160 g of purified water, then 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the drug-containing pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

2) Composition G2 of the insulating layer (unit: g)

Cooking process:

23 g of hydroxypropyl cellulose-SSL was weighed according to the composition and dissolved in 460 g of purified water, then 23 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 17.2 g of hydroxypropyl cellulose-SSL was weighed and dissolved in 344 g of purified water, then 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the drug-containing pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

3) Composition G3 of the insulating layer (for comparative pellet 7) (unit: g)

Cooking process:

88 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 1140 g of purified water, then 88 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 17.2 g of hydroxypropyl cellulose-SSL was weighed and dissolved in 520 g of purified water, then 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

4) Composition G4 of the insulating layer (for comparative pellet 9) (unit: g)

Cooking process:

23 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 460 g of purified water, then 23 g of magnesium carbonate and 11.5 g of talc were added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 17.2 g of hydroxypropyl cellulose-SSL was weighed and dissolved in 344 g of purified water, then 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

5) Composition G5 of the insulating layer (for comparative pellet 10) (unit: g)

Cooking process:

23 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 460 g of purified water, then 23 g of sodium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 17.2 g of hydroxypropyl cellulose-SSL was weighed and dissolved in 344 g of purified water, then 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

6) Composition G6 of the insulating layer (for comparative pellet 5) (unit: g)

Cooking process:

33 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 890 g of purified water, then 57 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain an insulating layer coating slurry. Suspensions of the insulating layer coatings were sprayed onto the drug-containing pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

7) Composition G7 of the insulating layer (for comparative pellet 6) (unit: g)

Cooking process:

23 g of povidone K30 was weighed according to the formula and dissolved in 460 g of purified water, then 23 g of titanium dioxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 26 g of povidone K30 was weighed and dissolved in 520 g of purified water, then 44 g of silica was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a first insulation layer coating slurry; Suspensions of two insulating layers were sequentially sprayed onto the drug-containing pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

8) Composition of G8 insulating layer (for comparative pellet 8) (unit: g)

Cooking process:

23 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 720 g of purified water, then 23 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 52 g of hydroxypropyl cellulose-SSL was weighed and dissolved in 1040 g of purified water, then 100 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

9) Composition G9 of the insulating layer (for comparative pellet 14) (unit: g)

Cooking process:

10 g of hydroxypropyl cellulose-SSL, 5 g of sodium carbonate and 5 g of talc were weighed according to the formula and dissolved in 200 g of purified water to obtain a coating slurry of the first insulating layer. 8 g of hydroxypropyl cellulose-SSL were weighed and dissolved in 160 g of purified water, then 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

10) Composition of G10 insulating layer (unit: g)

Cooking process:

15 hydroxypropyl methylcellulose-E5 was weighed according to the formula and dissolved in 300 g of purified water, then 15 g of magnesium oxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 12 g of hydroxypropyl methylcellulose-E5 was weighed and dissolved in 240 g of purified water, then 21 titanium dioxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

11) Composition of G11 insulating layer (unit: g)

Cooking process:

20 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 400 g of purified water, then 20 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 8 g of hydroxypropyl cellulose-SSL were weighed and dissolved in 160 g of purified water, then 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

12) Composition of G12 insulating layer (unit: g)

Cooking process:

23 g of hydroxypropyl cellulose-SSL was weighed according to the formula and dissolved in 460 g of purified water, then 23 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating slurry of the first insulating layer. 46 g of hydroxypropyl cellulose-SSL were weighed and dissolved in 920 g of purified water to obtain a second insulating layer coating slurry. Suspensions of the coatings of the two insulating layers were sprayed sequentially onto the pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see the composition of the G1 insulating layer.

1.3 Composition for preparing the enteric coating layer (C) Composition C1 of the enteric coating layer (unit: g)

Cooking process:

Weighed 20.1 g of triethyl citrate according to the formula, dissolved in 447.6 g of purified water, added 3.4 g of talc, uniformly dispersed at a high shear rate of 10,000 rpm; then add 223.8 g of Eudragit L30D-55, disperse for 45 minutes to obtain an enteric coating solution, spray the film-forming enteric coating solution onto the insulating pellet through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

1.4 Preparation of the protective layer (B)

1) Composition of the protective layer B1 (unit: g)

Cooking process:

2.5 g of hydroxypropyl methylcellulose-E5 was weighed according to the formula and dissolved in 50 g of purified water, then 1.2 g of magnesium stearate was added and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

2) Composition of the protective layer B2 (unit: g)

Cooking process:

Weighed 0.5 g of hydroxypropyl cellulose-SSL according to the formula and dissolved in 10 g of purified water, then added 0.5 g of magnesium stearate and uniformly dispersed at a high shear speed of 3000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see composition B1 of the protective layer.

3) Composition of the protective layer VZ (unit: g)

Cooking process:

Weighed 4 g of hydroxypropyl cellulose-SSL according to the formula and dissolved in 80 g of purified water, then added 5 g of magnesium stearate and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see composition B1 of the protective layer.

4) Composition of the protective layer B4 (unit: g)

Cooking process:

Weighed 2.5 g of hydroxypropylcellulose-SSL according to the formula and dissolved it in 50 g of purified water, then added 1.2 g of talc and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see composition B1 of the protective layer.

5) Composition of the protective layer B5 (unit: g)

Cooking process:

2.5 g of hydroxypropyl cellulose-SSL was weighed according to the formula, dissolved in 50 g of purified water, then 1.2 g of titanium dioxide was added and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see composition B1 of the protective layer.

6) Composition B6 of the protective layer (for comparative pellet 13) (unit: g)

Cooking process:

Weighed 2.5 g of hydroxypropyl methylcellulose-E5 according to the formula and dissolved it in 50 g of purified water, then added 0.2 g of magnesium stearate and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

For specific technological parameters, see composition B1 of the protective layer.

(II) Preparation of enteric coated pellets:

1) Preparation of enteric-coated pellets in accordance with the present invention:

Enteric coated pellets A-G according to the present invention, as shown in table. 1 below are prepared in accordance with the compositions of the enteric coated pellet component layers listed in section (I) above.

Among them: The degree of loading of the drug W ₄ into the pellet core = (actual content of the pellet core) / (theoretical content of the pellet core) × 100%

2) Preparation of comparative pellets 3-16:

Comparative pellets 3-15, shown in table. 2-1 and table. 2-2 below are prepared according to the formula of the enteric coated pellet component layers listed in section (I) above.

Example 2. Preparation of enteric-coated pellet tablets

In this Example 2, the AG enteric-coated pellets of the present invention and the comparative pellets 3-18 shown in Example 1 are prepared into the AG enteric-coated pellets of the present invention and the comparative pellets 3-18. In addition, comparative pellet 1 (according to CN 1134666 A) and comparative pellet 2 (according to CN 102525990 A) are also prepared in accordance with the method of preparing enteric-coated pellet tablets based on existing technologies, while ilaprazole (particle size D ₉₀ 46.8 µm, for ease of data comparison) served as a pharmaceutically active substance.

2.1 Preparation of enteric coated pellets A-G according to the present invention and comparative pellets 3-18

Enteric coated pellets shown in table. 1, 2-1 and 2-2 above are prepared into enteric-coated pellet tablets by the following tableting and coating steps, respectively.

1) Preparation of pellet tablets (unit: g)

Tablet preparation process:

Enteric-coated ilaprazole pellets, microcrystalline cellulose PH102, crospovidone-XL, sodium stearyl fumarate were added to a 3-liter hopper mixer according to the above formula and dispersed at a speed of 10 rpm for 15 minutes, then the mixture was placed in a tablet press for tableting and obtained tablets with a hardness of 8-12 kg weighing equivalent to 5 mg of ilaprazole contained in each tablet.

2) Pellet coating (unit: g)

Coating powder preparation process:

20 g of opadry coating solution were weighed, dissolved in 166.5 g of purified water, and ilaprazole pellet tablets were coated using an efficient coating apparatus.

2.2 Preparation of comparative pellet tablet 1:

According to the method and process for producing enteric coated pellet tablets shown in Example 16 of CN 1134666 A, comparative pellet tablet 1 was prepared using the outer coating described in Example 15, with ilaprazole as a pharmaceutical active substance and a surfactant, added to the drug loading layer. The method is given below:

1) Preparation of the pellet core

Composition of the pellet core (unit: g)

Cooking process:

Weigh 150 g of hydroxypropyl methylcellulose-E5 and 3 g of Tween-80, dissolve in purified water to obtain a hydroxypropyl methylcellulose binder solution, inject ilaprazole D ₉₀ starting material with a particle size of less than 50 μm into the binder, and disperse at a high shear rate of 10,000 rpm for 5 min and then sprayed the ilaprazole suspension onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

2) Preparation of insulating pellets

Composition of insulating pellets (unit: g)

Cooking process:

Weigh 103 g of hydroxypropyl cellulose-SSL, dissolve in 387.5 g of purified water to obtain a hydroxypropyl cellulose binder solution, then add 42.5 g of talc and 2.75 g of magnesium stearate to the binder solution, and disperse it for 5 minutes at high shear rate of 10,000 rpm, and then sprayed the insulating layer coating solution onto the ilaprazole pellet core through a GLATT GPCG-1 fluidized bed. The specific process parameters are given below:

The specific process parameters are given below:

3) Preparation of enteric coated pellets

Composition of enteric coated pellets (unit: g)

Cooking process:

Weighed 1.8 g of polysorbate-80, 3.8 g of triethyl citrate and 1.9 g of glyceryl monostearate, dissolved in 50 g of purified water at a temperature of 70 ° C, dispersed for 5 min at a high shear rate of 5000 rpm, left until room temperature; then add 127 g of Eudragit L30D-55, disperse the mixture for 45 min for subsequent use, spray the enteric coating solution onto the insulating pellet through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

4) Preparation of pellets with a protective layer

Composition of the protective layer (unit: g)

Cooking process:

2.5 g of hydroxypropyl cellulose-E5 was weighed and dissolved in 51.3 g of purified water, then 0.08 g of magnesium stearate was added and uniformly dispersed at a high shear speed of 5000 rpm to obtain a film-forming protective layer solution. The film-forming solution of the protective layer was sprayed onto the enteric-coated pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters are given below:

5) Preparation of pellet tablets (unit: g)

Tablet preparation process:

Enteric-coated ilaprazole pellets, microcrystalline cellulose, crospovidone, sodium stearyl fumarate were added to a 3-liter hopper mixer according to the above formula and dispersed at a speed of 10 rpm for 15 minutes, then the mixture was placed in a tablet press for tableting and tablets with a hardness of 8 were obtained. -12 kg equivalent to 5 mg of ilaprazole contained in each tablet.

6) Preparation of pellet coating (unit: g)

40 g of opadry coating solution was weighed, dissolved in 333 g of purified water, and ilaprazole pellet tablets were coated using an efficient coating apparatus. Comparative pellet 1 was prepared.

2.3 Preparation of comparative pellet tablet 2:

Comparative pellet 2 was prepared according to the method for the preparation of enteric-coated pellets described in CN 102525990 A, with ilaprazole as the pharmaceutically active substance.

1) Preparation of drug-containing pellet core

Composition of drug-containing pellet core (unit: g)

Cooking process:

Sift empty sucrose kernels (0.25-0.3 mm) using a 50 mesh sieve and a 60 mesh sieve respectively, and take kernels between 50 mesh and 60 mesh for drug application. Method for preparing drug application solution: hydroxypropyl methylcellulose and magnesium oxide according to the formula were dissolved in 80% (v/v) water-ethanol solution, and the resulting solution was adjusted to pH 12 with 4% (w/v) sodium hydroxide solution ; then ilaprazole was added according to the formula, and the mixture was uniformly dispersed. The viscosity of the drug application solution was 13.22 cP.

The specific process parameters are given below:

310 g of light yellow ilaprazole pellets were prepared with a yield of 90.3%.

2) Preparation of insulating pellets

Composition of insulating pellets (unit: g)

Cooking process:

After bringing the pH of the insulating solution to more than 10.5, including the viscosity of the insulating solution being 15.24 sr, cover 300 g of the drug-containing pellet with the insulating layer solution. Operating parameters are shown in the table:

345 g of pellets were prepared with a yield of 94.5%.

3) Preparation of enteric coated pellets

Composition of enteric coated pellets (unit: g)

Cooking process:

Add 6.5 ml of 4% (w/w) aqueous sodium hydroxide solution to Eudragit L30D-55, add polyethylene glycol 6000 with stirring, and sift the mixture using an 80 mesh sieve. The insulating pellet was coated with an enteric coating. Main parameters: material temperature 25-30°C, incoming air temperature 28-35°C, spray speed 10-30 rpm, fan frequency 30-40. 214.1 g of pellets were prepared with a yield of 99.9%.

4) Preparation of pellet tablets

Composition of pellet tablets (unit: g)

The materials were mixed and compressed according to the composition given in the table to obtain tablets, the weight of each tablet being 314.9 mg. A comparative pellet tablet 2 has been prepared.

Example 3. Preparation of enteric-coated pellet capsules

600 g of pellets A (W ₁ +G ₂ +C ₁ +B ₁ ), coated with a protective layer of ilaprazole pellets, were loaded into capsule shells No. 3 using capsule filler, each capsule containing 5 mg of ilaprazole.

Example 4. Test on the properties of enteric-coated pellet tablets and pellet capsules

In Example 4, the pellet tablets and enteric-coated pellet capsules prepared in the above examples were tested for content, solubility, accompanying substances, etc., and comparative pellet tablets 3-16 were compared based on the test results, the pellet tablets according to the present invention serve as ilaprazole.

Test method:

1. Content definition:

1) Operating method: For the general method, see Chinese Pharmacopoeia, Volume IV, 2015 Edition, Chapter 0512.

Specific Method:

Preparation of sample solution: Accurately measure 5 ml of sample solution according to the accompanying substance test section, place in a 50 ml volumetric flask, dilute to volume with the mobile phase, shake and filter, use the subsequent filtrate as sample solution.

Preparation of control solution: Accurately weigh the appropriate amount of ilaprazole control, add diluent, and dilute to a solution containing approximately 20 μg of ilaprazole control per ml. The dilution solution was used as a control solution.

System Suitability Solution: Weigh out the appropriate amount of impurity control I (ilaprazole sulfone, chemical name: 2-[[(4-methoxy-3-methyl)-2-pyridyl]methyl]-sulfonyl-5-(1H-pyrrol- 1-yl)-1H-benzimidazole) and ilaprazole control, diluent was added, and diluted to a solution containing 20 μg of impurity I and ilaprazole per ml.

Chromatography conditions: octadecyl silica gel is used as a filler, diluted with 400 ml of acetonitrile with phosphate buffer (2.28 g of potassium hydroxide was dissolved in water, the resulting solution was diluted with water to 1000 ml and adjusted to pH 7.5 with phosphoric acid) to 1000 ml for use as mobile phase, flow rate was 1.0 ml/min, control wavelength was 237 nm, column temperature was 25°C.

System suitability requirement: In the system suitability solution chromatogram, the number of theoretical plates should be at least 2500 calculated from the ilaprazole peak, and the resolution between the impurity I peak and the ilaprazole peak should be as per the standard.

Determination method: 20 μL of each of the control solution and sample solution was accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded.

2) Calculation method: The average content of 10 tablets was calculated from the peak area using the external standard method.

3) Standard: the content of ilaprazole (C ₁₉ H ₁₈ N ₄ O ₂ S) should be 90.0% - 110.0% of the labeled amount.

2. Determination of solubility:

1) Operating method: solubility determination by the content uniformity method (for the general method, see Chinese Pharmacopoeia, Volume IV, 2015 Edition, Chapter 0931, Second Method 1). Specific method:

The product was dissolved in 300 ml of 0.1 mol/l hydrochloric acid solution (dissolution solution, 9.0 ml of hydrochloric acid was diluted with water to 1000 ml) according to the method of determining the uniformity of content at a speed of 100 rpm; immediately after 120 minutes, 700 ml of 0.086 mol/l sodium hydroxide solution was added to the dissolution beaker (30.8 g of disodium hydrogen phosphate and 7 g of Tween-80 were diluted with water to 1000 ml), preheated to 37 ± 0.5 ° C, and stirred evenly at a constant rotation speed according to this method; after 45 minutes the mixture is taken for sampling.

Sample solution: Filter an appropriate amount of dissolution solution, accurately measure 5 ml of the subsequent filtrate; and immediately accurately added 1 ml of 0.15 mol/L sodium hydroxide solution, shaken evenly and filtered, and the subsequent filtrate was used as the sample solution.

Control solution: Accurately weigh about 10 mg of control substance ilaprazole, add to a 20 ml volumetric flask, dissolve in the appropriate amount of acetonitrile, dilute to volume with acetonitrile and shake evenly; accurately measured 1 ml of the diluted solution, placed it in a 100 ml volumetric flask, diluted to volume with a phosphate buffer solution (pH 6.8) (700 ml of 0.086 mol/l sodium hydrogen phosphate solution was mixed evenly with 300 ml of 0.1 mol/l hydrochloric acid solution l) and shaken evenly; accurately weighed 5 ml of the diluted solution, immediately and accurately added 1 ml of 0.05 mol/L sodium hydroxide solution, shaken and filtered the resulting mixture evenly, and the subsequent filtrate was used as a control solution.

Calculation of tablet solubility was carried out using the method described in the content determination section.

3. Testing of associated substance:

1) Operating method: determination according to high-performance liquid chromatography (for the general method, see Chinese Pharmacopoeia, Volume IV, 2015 Edition, Chapter 0512).

Specific method:

Diluent: 0.05 mol/l sodium hydroxide-methanol-water=50:20:30.

Sample solution: Place 10 tablets of the product in a 250 ml volumetric flask, add 125 ml of 0.05 mol/l sodium hydroxide solution, and shake the resulting mixture on an oscillator (250 rpm) for 20 min; and 50 ml of methanol was added, and the resulting mixture was shaken for 10 min, diluted with water to the mark, shaken evenly and centrifuged to obtain the supernatant.

Control solution: Accurately measure the appropriate amount of sample solution and dilute with diluent to obtain a solution containing approximately 1 µg of ilaprazole per ml.

Susceptibility solution: Accurately measure 1 ml of control solution, add to a 10 ml volumetric flask, dilute to volume with diluent and shake evenly.

Impurity I control stock solution: Approximately 6 mg of Impurity I was weighed out, added to a 100 mL volumetric flask, and diluted to volume with diluent.

System Suitability Solution: Approximately 3 mg of Ilaprazole control was weighed, placed in a 10 ml volumetric flask, dissolved in the appropriate amount of diluent, 1 ml of Impurity I control stock solution was added accurately, the resulting mixture was diluted to volume with diluent and shaken evenly.

Chromatography conditions: octadecyl silica gel (Gemini-NX C18 150×4.6 mm, 5 µm or equivalent chromatography column), 0.01 mol/l potassium hydroxide solution (adjusted to pH 7.5 with 10% phosphoric acid) was used as filler ) was used as mobile phase A, acetonitrile was used as mobile phase B, and linear gradient elution was carried out according to the following table; flow rate is 1.0 ml/min; the control wavelength is 237 nm; column temperature - 25°C.

System suitability solution requirement: In the system suitability solution chromatogram, the resolution between the impurity I peak and the ilaprazole peak must be greater than 2.0. In the solution chromatogram to determine sensitivity, the signal-to-noise ratio of the ilaprazole peak must be greater than 10.

Determination method: 20 μL of each of the sample solution and control solution was accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded.

4.1 Testing the stability and acid resistance of enteric-coated pellet tablets and pellet capsules

1) In this example, enteric coated pellets A-G according to the present invention and capsules in Example 3 were subjected to accelerated stability testing.

Specific methods are given below:

Test option: Enteric coated pellets A-G and capsules in Example 3 are packed in HDPE bottles of 14 tablets (capsules) respectively, and the packaged pellets or capsules are placed in an accelerated stability test chamber at 40°C/RH75% and selected after 1/3/6 months to detect related substances of enteric-coated pellet tablets or capsules according to various compositions. Data on the stability of enteric-coated pellet tablets A-G and capsules in example 3, obtained as a result of the test, are given in table. 3-1 down.

As can be seen from table. 3-1, pellet tablets A-G and capsules prepared from enteric-coated pellets according to the present invention have good stability and a total impurity content of no more than 1.5%.

2) In this example, the enteric coated pellets A-G of the present invention and the capsules in Example 3 were subjected to an acid resistance test.

Specific methods are given below:

6 tablets of enteric-coated granular tablets A-G and capsule samples were dissolved in 300 ml of 0.1 mol/l hydrochloric acid solution (dissolution medium, 9.0 ml of hydrochloric acid was diluted with water to 1000 ml) at a speed of 100 rpm; after 120 minutes, remove the dissolution cup, filter the hydrochloric acid using a filtration device, and collect the remaining tablets in a 50-ml volumetric flask; added 20 ml of sodium hydroxide solution 0.05 mol/l, shook the resulting mixture in an oscillator (250 rpm) for 20 minutes; 30 ml of methanol was added, and the resulting mixture was sonicated for 10 min, diluted to the mark with water, shaken evenly and centrifuged to obtain the supernatant. The remaining content of the drug in the pellets was determined, i.e. acid resistance of samples.

As can be seen from table. 3-2, pellet tablets A-G and capsules prepared from enteric-coated pellets according to the present invention have good acid resistance above 90%.

4.2 Testing the stability and acid resistance of enteric-coated pellets

In this Example 4.2, taking enteric-coated pellet tablets as an example, the effect of the components and their ratios in enteric-coated pellet tablets on their stability and acid resistance was compared.

4.2.1 The effect of the insulating layer components included in the enteric-coated tablets is given below:

1) Comparison between enteric-coated pellet A according to the present invention and comparative pellets 5, 6, 9, 10 and 14 in terms of stability:

In this example, enteric-coated pellet A of the present invention and comparative pellets 5, 6, 9, 10 and 14 were subjected to accelerated stability testing. In this test, compared with the enteric-coated pellet A of the present invention, the comparative pellet 5 has only one inert insulating layer containing no alkali compounds; comparative tablets 6, 9, 10 and 14 have a first insulating layer immediately adjacent to the pellet core and a second insulating layer immediately adjacent to the enteric coating layer; however, in comparative pellet 6, the first insulating layer contains binders and release agents, but does not contain alkali compounds; in comparative pellet 9, the first insulating layer is a mixed layer (by which is meant a layer containing, in addition to binders, alkaline compounds and water-insoluble inert substances capable of preventing the pellets from sticking together), and contains water-insoluble basic compounds as the main ones connections; in the comparative pellet 10, the first insulating layer is an alkaline layer, containing mainly binders and water-soluble alkaline (basic) compounds; in the comparative pellet 14, the first insulating layer is a mixed layer containing water-soluble alkali (basic) compounds as alkali compounds.

Test option: Enteric coated pellet A of the present invention and comparative pellets 5, 6, 9, 10 and 14 are packaged in HDPE bottles of 14 tablets, respectively, and the packaged pellets are placed in a chamber for accelerated stability testing at 40°C/RH75% and selected after 1/3/6 months to control related substances in pellet tablets with various compositions. Data on the stability of pellet tablets obtained as a result of testing are given in table. 4-1 down.

As can be seen from table. 4-1, the stability requirement (i.e., total impurities should not exceed 1.5%) cannot be met for low stability ilaprazole when its enteric-coated pellet contains only one barrier layer (i.e. . comparative pellet tablet 5). When the enteric coated pellet contains at least a first barrier layer and a second barrier layer, its stability may also be affected by the components of those barrier layers, for example: when the first barrier layer is a mixed layer containing alkaline (basic) compounds and insoluble compounds. water inert substances that can prevent the pellets from sticking together (for example, comparative pellet tablets 9 and 14), the content of associated substances is still significantly increased (total impurity content is 1.79% and 1.68%, respectively) even under the protection of alkaline (basic ) connections and the stability requirement cannot be met; on the contrary, when the first insulating layer is an alkaline layer containing alkaline (basic) compounds and without water-insoluble inert substances that can prevent the pellets from sticking together (for example, pellet pellet A and comparative pellet pellet 10), an enteric coated pellet has good stability; In addition, the stability requirement (i.e. total impurities should not exceed 1.5%) cannot be met for low stability ilaprazole when its enteric coated pellet contains alkaline (basic) compounds only in the pellet core (i.e. comparative pellet 6).

2) Comparison between the enteric-coated pellet A of the present invention and the comparative pellets 10, 14 and 15 in terms of acid resistance: In this example, the enteric-coated pellet A of the present invention and the comparative pellets 10, 14 and 15 were subjected to acid resistance testing. In this test, the comparative pellet 15 differs from the enteric coated pellet A of the present invention in that: the second insulating layer of the comparative pellet 15 does not contain water-insoluble inert substances that can prevent the pellets from sticking together.

Specific method:

Enteric-coated pellet A of the present invention and comparative pellets 10, 14 and 15 were packaged in HDPE bottles containing 14 tablets, respectively; and packaged pellet tablets were placed in an accelerated stability test chamber at 40°C/RH75% and sampled after 1/3/6 months; then, according to the method, the pellet tablets were dissolved in 300 ml of 0.1 mol/l hydrochloric acid solution (dissolution medium, 9.0 ml of hydrochloric acid was diluted with water to 1000 ml) at speed. 100 rpm; after 120 minutes, remove the dissolution cup, filter the hydrochloric acid using a filtration device, and collect the remaining tablets in a 50-ml volumetric flask; added 20 ml of 0.05 mol/l sodium hydroxide solution, shook the resulting mixture in an oscillator (250 rpm) for 20 minutes; 30 ml of methanol was added, and the resulting mixture was sonicated for 10 min, diluted to the mark with water, shaken evenly and centrifuged to obtain the supernatant. The remaining content of the drug in the pellets was determined, i.e. acid resistance of samples. Data on the acid resistance of pellet tablets obtained as a result of the test are given in table. 4-2 down.

As can be seen from the results given in table. 4-2, the comparative pellet (eg, comparative pellet 14), which already had lower stability in the stability test, also had lower acid resistance under accelerated conditions; comparative pellet 10 with a first insulating layer containing various alkaline compounds (e.g., water-soluble alkaline compounds) became less acid-resistant (remaining ilaprazole content in comparative pellet 10 at month 6 was 85.6%) compared to enteric-coated pellet tablet A according to the present invention, and the acid resistance was below the required standard (i.e., the average acid resistance of 6 tablets should be at least 90%). That is, although alkaline compounds as the first insulating layer can provide good tablet stability enteric-coated pellet, the types of alkali compounds affect the acid resistance of the enteric-coated pellet. Compared with the first insulating layer containing water-soluble alkali compounds, the insulating layer containing water-insoluble basic compounds as the first insulating layer of the enteric-coated pellet can improve and enhance the acid resistance of the enteric-coated pellet. In addition, from table. 4-2 also shows that the acid resistance of the comparative pellet pellet 15, in which the second insulating layer does not contain water-insoluble inert substances that can prevent the pellets from sticking together, does not change.

As can be seen from the above, in relation to the components of the various insulating layers included in the enteric-coated pellet tablet, at least two insulating layers are applied, and for the first insulating layer directly adjacent to the pellet core, when the first insulating layer contains water-insoluble basic compounds, and does not contain water-soluble alkaline compounds and water-insoluble inert substances that can prevent pellets from sticking together, enteric-coated ilaprazole tablet prepared from enteric-coated pellets can have good stability and acid resistance.

4.2.2 The influence of the ratio of components of the insulating layer included in the enteric coated pellets of the present invention:

1) Comparison between enteric-coated pellet A according to the present invention and comparative pellets 7 and 8 in terms of stability:

In this example, enteric-coated pellet A of the present invention and comparative pellets 7 and 8 were subjected to accelerated stability testing. In particular, compared with the enteric-coated pellet A of the present invention, the comparative pellet 7 has a larger amount of water-insoluble basic compounds contained in the first insulating layer; for example, when the amount of ilaprazole is 10 parts by mass, the amount of water-insoluble basic compounds contained in the first insulating layer is more than 36 parts by mass; the comparative pellet 8 has a greater amount of anti-adhesive (equivalent to water-insoluble inert substances capable of preventing the adhesion of pellets in accordance with the present invention) contained in the second insulating layer; for example, when the amount of ilaprazole is 10 ppm, the amount of the release agent in the second insulating layer is more than 44 parts by mass.

Specific methods are shown below:

Enteric coated pellet A of the present invention and comparative pellets 7 and 8 were packaged in HDPE bottles of 14 tablets each, and the packaged pellets were placed in an accelerated stability test chamber at 40°C/RH75%, after 1 /3/6 months samples were taken to monitor concomitant substances from enteric-coated pellet tablets with various compositions. Data on the stability of enteric-coated pellet tablets obtained as a result of testing are given in table. 5-1.

From the table 5-1 shows that the stability of comparative pellets 7 (with different proportions in the first insulating layer) and 8 (with different proportions in the second insulating layer) with different proportions of components in the insulating layer compared to pellet A with an enteric coating according to the present invention remained within the standard range (total impurity content not more than 1.5%). In other words, changing the proportion of components in the insulating layer does not affect the stability of these enteric-coated pellets.

2) Comparison between enteric-coated pellet A according to the present invention and comparative pellets 7 and 8 in terms of acid resistance:

In this example, enteric-coated pellet A of the present invention and comparative pellets 7 and 8 were subjected to an acid resistance test. The acid resistance test described in section 4.2.1 was carried out for the specific method.

The results obtained are shown in table. 5-2 down.

As can be seen from the results given in table. 5-2, acid resistance of comparative pellet 7 (with different proportions of components in the first insulating layer) and 8 (with different proportions of components in the second insulating layer) with different proportions of components in the insulating layer compared to pellet A with an enteric coating according to of the present invention was still within the standard range (ie, the average acid resistance of 6 tablets was at least 90%). In other words, changing the ratio of components in the insulating layer will not affect the acid resistance of these enteric-coated pellets.

As stated above, changing the ratio of components in the insulating layer of enteric-coated pellets does not affect the stability and acid resistance of enteric-coated pellet tablets prepared from these enteric-coated pellets.

4.2.3 Comparison between enteric-coated pellets A, F and G according to the present invention and comparative pellets 17 and 18 in terms of acid resistance:

In this example, enteric-coated pellets A, F and G according to the present invention and comparative pellets 17 and 18 were subjected to acid resistance testing. The acid resistance test described in section 4.2.1 was carried out for the specific method.

The results obtained are shown in table. 5-3 below.

As can be seen from the results given in table. 5-3, the acid resistance of comparative pellet pellet 17 was reduced by degradation under accelerated stability conditions, resulting in a decrease in the measured acid resistance value. The decrease in acid resistance of pellet tablets 18 is also due to the partial degradation of ilaprazole during the acceleration process. A, G, H pellet tablets prepared according to the pellet core formula of the present invention can obtain good acid resistance values.

4.3 The influence of the composition of the pellet core included in the composition of enteric-coated pellets on the stability of their enteric-coated pellet tablets:

In this example 4.3, using an enteric-coated ilaprazole pellet tablet as an example, a comparison was made of the effect of the composition of the pellet core included in the enteric-coated pellets and the particle size of ilaprazole on their stability.

Influence of pellet core components contained in enteric coated pellets:

Comparison between enteric-coated pellet A of the present invention and comparative pellets 11, 16 and 17 in terms of stability:

In this example, enteric-coated pellet A of the present invention and comparative pellets 11, 16 and 17 were subjected to accelerated stability testing. In particular, the comparative pellet core 11 does not contain alkaline (basic) compounds and surfactants, the comparative pellet core 16 does not contain surfactants but contains alkaline compounds, and the comparative pellet core 17 does not contain alkaline compounds. compounds, but contains surfactants.

Test option: enteric coated pellet A and comparative pellets 11 and 16 are packaged in HDPE bottles of 14 tablets, and the packaged pellets are placed in an accelerated stability test chamber at 40°C/RH75%, after 1 /3/6 months to take samples to control associated substances from enteric-coated pellet tablets with various compositions. Data on the stability of enteric-coated pellet tablets obtained as a result of testing are given in table. 6.

As can be seen from the results given in table. 6, when the enteric-coated ilaprazole pellet core does not contain alkaline (basic) compounds and surfactants (i.e., comparative pellet 11), the enteric-coated pellet cannot meet the stability requirements (the total impurity content is not more than 1.5%); When the enteric coated ilaprazole pellet core did not contain alkaline compounds (i.e. comparative pellet tablet 17), the content of associated substances was very high, more than 1.5%, in the freshly prepared pellet tablets. In contrast, comparative pellet 16, in which the core contains only an alkaline compound and no surfactants, showed good stability results in accelerated testing.

From the above, it is clear that the stability requirement (i.e. total impurities should not exceed 1.5%) cannot be met for low stability ilaprazole when its enteric coated pellet contains only water-insoluble basic compounds in the first insulating layer (i.e. comparative pellet 11); In addition, pellet tablets obtained in the case where the pellet core does not contain alkaline (basic) compounds, but contains only surfactants, also do not meet the stability requirements.

4.3.2 Effect of particle size of ilaprazole in the pellet core included in enteric-coated pellets on the stability of enteric-coated pellet tablets:

Comparison between enteric-coated pellet A of the present invention and comparative pellets 3 and 4 in terms of stability:

In this example, enteric-coated pellet A of the present invention and comparative pellets 3 and 4 were subjected to accelerated stability testing. In this test, the D ₉₀ particle size of ilaprazole in the enteric-coated pellet core in comparative pellet 3 was greater than or equal to 80 μm and less than or equal to 100 μm, and the D ₉₀ particle size of ilaprazole in the enteric-coated pellet core in comparative pellet 4 is greater than 100 µm compared to that of the enteric-coated pellet A according to the present invention. Specific methods are shown below:

Test option: pellet tablet A and pellet tablets 3 and 4 were packaged in HDPE bottles of 14 tablets each, the packaged pellet tablets were placed in a chamber for accelerated stability testing at 40°C/RH75%, after 1/3/6 months samples were taken to control concomitant substances from enteric-coated pellet tablets with various compositions. The measured data on the stability of pellet tablets are given in table. 7.

As can be seen from the results given in table. 7, stability comparative pellet tablets 3 (Ilaprazole D ₉₀ particle size greater than or equal to 80 μm and less than or equal to 100 μm) and 4 (Ilaprazole D ₉₀ particle size greater than 100 μm) containing pellet cores with different Ilaprazole D ₉₀ particle sizes, remained within the standard range (total impurity content should not exceed 1.5%) compared to the enteric coated pellet A of the present invention.

As stated above, the particle size of the ilaprazole contained in the enteric-coated pellet core does not affect the stability and acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellet.

4.4 The influence of the protective layer in an enteric-coated pellet on the stability and acid resistance of an enteric-coated pellet:

In this example 4.4, using an enteric-coated ilaprazole pellet tablet as an example, a comparison is made of the effect of the protective layer device in an enteric-coated pellet and the number of its components on its stability and acid resistance.

4.4.1 Effect of the protective layer arrangement in the enteric-coated pellet: 1) Comparison between the enteric-coated pellet A of the present invention and the comparative pellet 12 in terms of stability:

In this example, enteric-coated pellet A of the present invention and comparative pellet 12 were subjected to accelerated stability testing. In this test, enteric coated pellets formulated as comparative pellet pellet 12 do not contain a protective layer.

Test option: pellet tablet A and pellet tablets 12 are packed in HDPE bottles of 14 tablets each, packaged pellet tablets are placed in a chamber for accelerated stability testing at 40°C/RH75%, samples are taken after 1/3/6 months for the control of related substances from enteric-coated pellet tablets with various compositions. The measured data on the stability of pellet tablets are given in table. 8-1.

As can be seen from the results presented in table. 8-1, the stability of comparative pellet 12, in which the enteric coated pellet does not contain a protective layer, was still within the standard range (total impurity content should not exceed 1.5%) compared with the stability of pellet A with enteric coating according to the present invention. In other words, the presence of a protective layer in an enteric-coated pellet does not affect the stability of a given enteric-coated pellet.

2) Comparison between enteric-coated pellet A according to the present invention and comparative pellet 12 in terms of acid resistance:

In this example, the enteric-coated pellet A of the present invention and the comparative pellet 12 were subjected to an acid resistance test. The acid resistance test described in section 4.2.1 was carried out for the specific method.

The results obtained are shown in table. 8-2 below.

As can be seen from table. 8-2, the acid resistance of comparative pellet tablet 12, which did not contain a protective layer on the outside of the enteric coating layer, was slightly below the standard range (i.e., the average acid resistance of 6 tablets should be at least 90%). However, during the experiment, the inventors discovered that the low measured acid resistance data is due to the fact that pellets with an enteric coating without a protective layer easily stick to each other and are partially degraded during processing. Thus, it will be understood by those skilled in the art that the presence of a protective layer will not affect the acid resistance of the composition if, during the preparation of this composition, sticking between the enteric coated pellets can be prevented not only by the protective layer, for example, by timely mixing with the excipients of the composition .

4.4.2 Influence of the content of protective layer components in enteric-coated pellets:

In this example, enteric-coated pellet A of the present invention and comparative pellet 13 were tested and compared for acid resistance:

In this example, enteric-coated pellet A of the present invention and comparative pellet 13 were subjected to accelerated stability testing. In this test, the release agent content (such as magnesium stearate) in the protective layer of the enteric-coated pellets formulated into comparative pellet pellet 13 remained low; for example, when the amount of ilaprazole was 5-15 parts by mass, the amount of antiblocking agent was less than 0.5 parts by mass.

Test option: pellet tablet A with an enteric coating and pellet tablet 13 are packaged in HDPE bottles of 14 tablets each, the packaged pellet tablets are placed in a chamber for rapid stability testing at 40°C/RH75%, after 1/3/6 months to take samples to control the acid resistance of the pellet, namely: pellet tablets are placed in a 0.1 M hydrochloric acid solution, after 2 hours the pellets are collected and the content of the remaining ilaprazole is determined. The measured data on the acid resistance of pellet tablets are given in table. 9.

Results in table. 9 show that the acid resistance of the enteric-coated pellet 13 also tended to decrease in acid resistance after accelerating over the six month long-term trial (i.e. from 96.9% at baseline to 91.6% after six months). The inventors discovered that after 6 months of acceleration in the acid resistance test, a portion of the enteric coated pellets of comparative pellet pellet 13 stuck to the bottom of the dissolution cup, resulting in decreased acid resistance. This shows that too low a content of water-insoluble inert substances (e.g. talc, magnesium stearate, titanium dioxide) in the protective layer that can prevent pellet sticking leads to a deterioration of the protective effect, and does not effectively prevent sticking between enteric-coated pellets, which affects acid resistance.

4.5 Solubility test for enteric-coated pellets

4.5.1 Comparison between enteric-coated pellet A of the present invention and comparative pellet 15 in terms of solubility:

In this example, enteric-coated pellet A of the present invention and comparative pellet 15 were compared for solubility in accordance with the method described in section 4.1 above. The measured data on the solubility of pellet tablets are given in table. 10.

From the solubility results given in table. 10, it can be seen that the enteric-coated pellet tablets A of the present invention and pellet tablet 15 have good solubility (solubility of not less than 80%). This shows that if the second insulating layer contains only a binder, but does not contain water-insoluble inert substances (for example, anti-blocking agents) that can prevent the pellets from sticking together, this does not affect the solubility of the composition of these enteric coated pellets and therefore should not affect on their bioavailability in the body.

4.5.2 Comparison between enteric-coated pellet A of the present invention and comparative pellets 7 and 8 in terms of solubility:

In this example, enteric-coated pellet A of the present invention and comparative pellets 7 and 8 were compared for solubility according to the method described in section 4.1 above. The measured data on the solubility of pellet tablets are given in table. 11 and fig. 1.

From the results shown in Fig. 1 and table. 11, it can be seen that the enteric-coated pellet tablet A of the present invention has good solubility (solubility of not less than 80%). Compared to the enteric-coated pellet A of the present invention, the solubility of comparative pellets 7 and 8 is well below the required standard range (at least 80% solubility), indicating a noticeable slowdown in the release of these enteric-coated pellets, which will result in to delay their action in the body, which, in turn, will affect bioavailability in the body.

As stated above, changing the ratio of components in the insulating layer of enteric-coated pellets does not affect the stability and acid resistance of enteric-coated pellet tablets prepared from these enteric-coated pellets. However, changing the ratio of components in the insulating layer of enteric-coated pellets affects the solubility of the corresponding enteric-coated pellet tablets, which in turn affects the bioavailability of the composition in the body. Thus, to further improve bioavailability in the body, in accordance with the present invention, the ratio of components in the insulating layer of enteric-coated pellets can be as follows: with an ilaprazole content of 5-15, 5-36 parts by weight of binder are present in the first insulating layer, 5-36 parts by mass of a water-insoluble base compound, the second insulating layer contains 4-26 parts by mass of a binder, 7-44 parts by mass of a water-insoluble inert substance that can prevent sticking of pellets.

4.5.3 Comparison between enteric-coated pellet A of the present invention and comparative pellets 11 and 16 in terms of solubility:

In this example, enteric-coated pellet A of the present invention and comparative pellets 11 and 16 were compared for solubility according to the method described in section 4.1 above. The measured data on the solubility of pellet tablets are given in table. 12 and fig. 2.

As can be seen from the results shown in Fig. 2 and table. 12, the solubility of the comparative pellet 11 was significantly lower than the required standard (the solubility should be at least 80%) compared to the solubility of the enteric-coated pellet A according to the present invention. In comparative pellet 16, the core contained no surfactants, and the solubility of the drug formulation was within the standard range, but remained lower than that of enteric-coated pellet A, and the solubility was less than 85%.

As stated above, the surfactants contained in the enteric-coated pellet core do not affect its stability, but do affect the solubility of the composition, i.e. The addition of surfactants to the enteric-coated pellet core can effectively increase the solubility of the formulation, which in turn effectively improves bioavailability.

4.5.4 Comparison between enteric-coated pellet A of the present invention and comparative pellets 3 and 4 in terms of solubility:

In this example, enteric-coated pellet A of the present invention and comparative pellets 3 and 4 were compared for solubility according to the method described in section 4.1 above. The measured data on the solubility of pellet tablets are given in table. 13 and fig. 3.

As can be seen from the solubility results shown in FIG. 3 and in table. 13, the solubility of comparative pellet tablets 3 and 4 was significantly reduced compared with the solubility of the enteric-coated pellet tablet A according to the present invention, when the particle size D ₉₀ of ilaprazole in the enteric-coated pellet core was greater than 100 μm ( i.e., for example, comparative pellet tablet 4), the solubility was below the standard range (i.e., the solubility should be at least 80%).

4.5.5 Comparison between enteric-coated pellet A of the present invention and comparative pellet 12 in terms of solubility:

In this example, enteric-coated pellet A of the present invention and comparative pellet 12 were compared for solubility according to the method described in section 4.1 above. The measured data on the solubility of pellet tablets are given in table. 14 and fig. 4.

From the results shown in Fig. 4 and in table. 14, it can be seen that in comparison with the enteric-coated pellet A of the present invention, the solubility of the comparative pellet 12 without a protective layer is significantly reduced to approximately standard values (solubility of at least 80%). During the experiment, the inventors discovered that the reason for the noticeable decrease in solubility is the tendency for adhesion between the enteric coated pellets of the present invention without a protective layer, which affects the rate of their release in the dissolving medium. Thus, in the presence of a protective layer, enteric-coated pellet tablets A do not stick to each other in a dissolving medium and are released at a higher rate; Comparative pellet 12 without a protective layer creates clumping in the environment and therefore has a lower release rate. Thus, it will be understood by those skilled in the art that the presence of a protective layer will not affect the solubility of the composition if, during the preparation of this composition, sticking between the enteric coated pellets can be prevented not only by the protective layer, for example, by timely mixing with the excipients of the composition , or adding other insulating layers between the first and second insulating layers.

4.6 Influence of the particle size of ilaprazole in the pellet core included in enteric-coated pellets on the loading level of enteric-coated pellet tablets

As can be seen from a comparison of the degree of loading W of the drug given in the section “Composition and method of preparation of the pellet core (W), and the degree of loading of the drug” in example 1, the degree of loading W ₈ and W ₉ in the pellet cores W8 and W9 contained in comparative pellets 3 and 4 are 87.2% and 79.3%, respectively. In comparison, with the particle size of Ilaprazole D9 ≤50 μm contained in the enteric-coated pellet core, the loading rate of its pellet core (eg W1-W5) is more than 90%.

As stated above, the particle size of ilaprazole contained in the enteric-coated pellet core does not affect the stability and acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellet; The particle size of the ilaprazole contained in the enteric-coated pellet core affects the solubility of these enteric-coated pellet tablets, which in turn affects the bioavailability in the body. In addition, the particle size of the ilaprazole contained in the core of a given enteric-coated pellet affects the core loading rate of the given enteric-coated pellet.

Thus, to further improve the bioavailability in the body, preferably, the particle size of ilaprazole D ₉₀ in the enteric coated pellet layer of the present invention may be ≤100 μm; more preferably, the particle size of Ilaprazole D ₉₀ in the enteric-coated pellet layer of the present invention can be ≤50 μm, and not only the release rate of its enteric-coated pellet tablet composition is relatively high, that is, within 30 minutes, the release volume reaches more than 90%, but the pellet core also has a high degree of loading (more than 90%).

Example 5: Acid suppression effect of enteric-coated pellet tablets of the present invention

Purpose of the study: To observe and compare the acid suppression effect of enteric-coated pellet tablets A and comparative pellet tablets 1 and 2 on the first day of oral administration in healthy subjects.

Trial design: This study is a single-center, randomized, open-label, crossover design including 18 cases with healthy subjects. During one test cycle, 18 subjects were randomly assigned to three groups of 6 people each to receive Pellet A, Pellet 1 and Pellet 2. Each person took the medication once on an empty stomach and had their stomach pH measured. within 24 hours.

Recording the pH value in the stomach: A pH test system from the Danish company Medtronic will be used to record the pH value in the stomach. The catheter is placed into the stomach through the nasal cavity, and one end of the catheter is connected to a Digitrapper MKIII recording device. Using a microprocessor in the recording device, the pH value in the subject's stomach can be continuously recorded. The catheter is placed at a distance of 8-10 cm from the lower esophageal sphincter, its position is indicated by a scale on the surface of the catheter. The probe is in the same position for each pH reading and must be calibrated at 2 points using pH 7.01 and pH 1.07 buffer before each pH reading. After each recording, the data from the Digitrapper MKIII is downloaded to a computer for further analysis.

Test Results: For each group of subjects, the recorded gastric pH values were processed and the average pH values at each time point for the multiple subjects analyzed were plotted as curves as shown in FIG. 5.

As can be seen from Fig. 5, the enteric-coated pellet tablet A of the present invention acts quickly, within 1 hour after administration, it can suppress stomach acid to a pH value of 4 or higher, which achieves clinical effect. Compared with enteric-coated pellet A, comparative pellet 1 achieved clinical effect approximately 3 hours after dosing; and the comparative pellet tablet 2 achieved clinical effect 2.5 hours after administration. Thus, the enteric-coated pellet tablets of the present invention are able to quickly achieve an effect and thereby quickly alleviate the suffering of the patient.

In addition, in this example, the stability and acid resistance of comparative pellet 1 and comparative pellet 2 were also tested in accordance with the methods given in the above examples, the specific results are shown in table. 15 and table. 16.

As can be seen from Tables 15 and 16, the stability and acid resistance of enteric-coated ilaprazole pellet tablets (i.e. comparative pellet 1 and comparative pellet 2) prepared using existing technology are significantly below the required standards when tested for accelerated stability (stability criterion: total impurity content no more than 1.5%; acid resistance criterion: stability no less than 90%).

Example 6: Beagle Pharmacokinetic Test of Enteric-Coated Ilaprazole Pellet Tablets of the Present Invention

1) Test animal: Beagle.

Quantity: 12 dogs in total, half male and half female, divided into 3 groups (pellet A, comparative pellet 1, comparative pellet 2).

Method and frequency of administration: 1 time orally and into the stomach (half an hour before administration, administer pentapeptide 0.25 mg/ml intramuscularly at a dose of 0.024 ml/kg).

Blood sampling points: 0 hours before administration, 1, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 8 hours after administration, a total of 12 blood sampling points.

Dosage: one tablet.

2) Experiment period: administration of one tablet, three cycles and three crossovers, cleaning period 7 days, total 15 days. The schedule for administering beagle tablets is given below.

3) Sample analysis: measurement of ilaprazole concentration in plasma (when processing plasma samples, a 1 mol/L NaOH solution is added to alkaline the plasma). Analysis method: HPLC-MS/MS.

4) The results of the experiment are shown in Fig. 6.

From the Beagle pharmacokinetic data chart shown in FIG. 6, it can be seen that the enteric-coated pellet tablets A of the present invention have higher bioavailability in the beagle body and achieve the effect of suppressing gastric acid secretion more quickly. In comparison, the cumulative plasma concentrations of Comparative Pellet 1 and Comparative Pellet 2 in Beagle were low, indicating low bioavailability of Comparative Pellet 1 and Comparative Pellet 2.

Example 7: comparison of the stability of prazoles:

Study of the stability of raw materials of various prazoles in pH 6.8 and 8.0 environments:

Prepare phosphate buffered saline medium pH 6.8 and buffered saline medium pH 8.0 containing 0.5% w/w. sodium dodecyl sulfate, put them in a dissolving glass, 1000 ml each, weigh ilaprazole, omeprazole magnesium, esomeprazole magnesium, rabeprazole sodium, pantoprazole and lansoprazole 0.5 mg each, add them to the dissolving glass and mix them with a paddle method at 150 rpm , ensure that the Prazole raw material is immersed in the dissolution medium, and take a 5 ml sample to add 20 ml to the stabilized sodium hydroxide medium for 15, 30, 45 and 60 minutes, then fix the volume to 50 ml using the mobile phase.

The content of samples collected in the medium was determined according to the determination method of omerazole magnesium, esomeprazole magnesium, rabeprazole sodium, pantoprazole sodium and lansoprazole in Volume II of the 2015 Chinese Pharmacopoeia to determine the stability of each prazole in pH 6.8 and 8.0 environments. The measured results are shown in table. 17 and table. 18 below.

As can be seen from table. 17 and 18, the stability of various prazoles in a pH 6.8 environment is low, of which the worst is ilaprazole, and the best is esomeprazole magnesium.

Example 8: Preparation of dry suspension of ilaprazole pellets

In this example 8, using the enteric coated ilaprazole pellet of the present invention as an example, a dry suspension of ilaprazole pellets will be obtained.

1) Composition of dry suspended particles V (unit: g)

Preparation method: After xanthan gum, chitosan, CCNA and aspartame were mixed uniformly, dry granulator was added for granulation. Technological parameters: pitch between pressure rollers 0.2 mm, feed speed: 30 rpm, pressure roller speed 5 rpm, rotation speed of the entire particle 10 rpm. After granulation it should be sieved; the control particle size is 0.5-0.7 mm. Then dry suspended particles V are obtained.

2) Preparation of dry E-V suspension

60.5 mg of enteric-coated ilaprazole E-V pellet and 2.0 g of dry suspended solids V were mixed and packaged in vials to obtain 5 mg enteric-coated ilaprazole dry suspension E-V.

For purposes of specific and detailed description, the above embodiments show only a few embodiments of the present invention, but should not be construed as limiting the scope of the patent for the present invention. It should be noted that ordinary specialists in this field, without breaking away from the idea of the present invention, can make a number of changes and improvements that fall under its protection. Therefore, the scope of protection of a patent for the present invention shall be determined by the appended claims.

Claims (37)

1. An enteric-coated pellet for the treatment and/or prevention of gastrointestinal diseases, comprising sequentially, from the inside out, a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a water-insoluble base compound as a first excipient, wherein the enteric-coated pellet is characterized in that the first insulating layer contains a water-insoluble base compound, wherein the weight ratio of the first excipient to ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole is 0. 2:1-5:1; wherein the enteric-coated ilaprazole pellet contains the following components in the indicated ranges in parts by weight: 1) pellet core: empty pellet core 5-15 drug loading layer containing: Ilaprazole (or a pharmaceutically acceptable salt thereof) 5-15 water-insoluble basic compound 5-15 surface-active substance 0.2-0.6 binder 8-24 2) first insulating layer: binder 5-36 water-insoluble basic compound 5-36 3) second insulating layer: binder 4-26 release agent 7-44 4) enteric coating layer: enteric coating materials 30-100 (solid content) release agent 1-5 plasticizer 9-30 5) protective layer: binder 0.5-4 release agent 0.5-5; wherein the water-insoluble base compound is selected from one or more of magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide; wherein the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol; wherein the release agent is selected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide. 2. An enteric-coated pellet for the treatment and/or prevention of gastrointestinal diseases, comprising sequentially, from the inside out, a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a water-insoluble base compound as a first excipient, wherein the enteric-coated pellet is characterized in that the first insulating layer contains a water-insoluble base compound, wherein the first excipient is a water-insoluble base compound, wherein the water-insoluble base compound the compound contained in the first insulating layer and the water-insoluble main compound of the first auxiliary substance may be the same or different; wherein the enteric-coated ilaprazole pellet contains the following components in the indicated ranges in parts by weight: 1) pellet core: empty pellet core 5-15 drug loading layer containing: Ilaprazole (or a pharmaceutically acceptable salt thereof) 5-15 water-insoluble basic compound 5-15 surface-active substance 0.2-0.6 binder 8-24 2) first insulating layer: binder 5-36 water-insoluble basic compound 5-36 3) second insulating layer: binder 4-26 release agent 7-44 4) enteric coating layer: enteric coating materials 30-100 (solid content) release agent 1-5 plasticizer 9-30 5) protective layer: binder 0.5-4 release agent 0.5-5; wherein the water-insoluble base compound is selected from one or more of magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide; wherein the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol; wherein the release agent is selected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide. 3. An enteric-coated pellet for the treatment and/or prevention of gastrointestinal diseases, comprising sequentially from the inside outwards a pellet core, a first insulating layer, a second insulating layer and an enteric coating layer, wherein the pellet core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a water-insoluble basic compound as a first excipient, wherein the enteric-coated pellet is characterized in that the particle size D ₉₀ of ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole is less than or equal to 100 μm, and the second insulating layer does not contain basic substances; wherein the enteric-coated ilaprazole pellet contains the following components in the indicated ranges in parts by weight: 1) pellet core: empty pellet core 5-15 drug loading layer containing: Ilaprazole (or a pharmaceutically acceptable salt thereof) 5-15 water-insoluble basic compound 5-15 surface-active substance 0.2-0.6 binder 8-24 2) first insulating layer: binder 5-36 water-insoluble basic compound 5-36 3) second insulating layer: binder 4-26 release agent 7-44 4) enteric coating layer: enteric coating materials 30-100 (solid content) release agent 1-5 plasticizer 9-30 5) protective layer: binder 0.5-4 release agent 0.5-5; wherein the water-insoluble base compound is selected from one or more of magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide; wherein the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol; wherein the release agent is selected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide. 4. Enteric-coated pellet according to any one of paragraphs. 1-3, characterized in that there is no other layer between the pellet core and said first insulating layer, and/or there is no other layer between the first and second insulating layers, and/or there is no other layer between the second insulating layer and the enteric coating layer. 5. Enteric-coated pellet according to any one of paragraphs. 1-4, characterized in that the pharmaceutically acceptable salt of ilaprazole can be selected from ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium or ilaprazole calcium. 6. Enteric-coated pellet according to any one of paragraphs. 1-4, characterized in that the pellet core additionally contains a surfactant; preferably the surfactant is Tween 80 or sodium dodecyl sulfate. 7. Enteric-coated pellet according to any one of paragraphs. 1 or 2, characterized in that the weight ratio of the water-insoluble basic compound to ilaprazole and/or a pharmaceutically acceptable salt thereof in the first insulating layer is 0.2:1-5:1, preferably 0.25:1-4:1, more preferably 0.3:1-3:1, more preferably 0.5:1-2:1, most preferably 0.8:1-1.2:1, for example 1:1. 8. Enteric-coated pellet according to any one of paragraphs. 1 or 2, characterized in that the mass ratio of anti-adhesive to binder is in the range of 1-8:1.5-10, or 1-10:1-20, or 4-26:7-44. 9. Enteric-coated pellet according to any one of paragraphs. 1-8, characterized in that the particle size D ₉₀ of ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole is selected from the ranges of any two of the following endpoints: > 0 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 µm, 70 µm, 80 µm, 90 µm, 100 µm. 10. Method for producing enteric-coated pellets according to any one of claims. 1-9, including the following stages: 1) obtaining a pellet core containing ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient; 2) applying the first insulating layer, and then applying the second insulating layer; 3) applying a layer of enteric coating; And 4) applying a protective layer. 11. The method according to claim 10, characterized in that stage 2) includes: obtaining a first suspension containing a water-insoluble base compound and not containing a water-soluble base compound and a water-insoluble inert substance capable of preventing the pellets from sticking together, and coating the pellet core obtained in step 1) using the first suspension; providing a second suspension not containing the base compound, and applying a coating using the second suspension as a second sealing layer, preferably the second sealing layer being in close proximity to the enteric coating layer. 12. Pharmaceutical composition for the treatment and/or prevention of gastrointestinal diseases, selected from enteric-coated pellet tablets containing an enteric-coated pellet according to any one of claims. 1-9 and a second excipient and, optionally, a film coating, capsules containing an enteric-coated pellet according to any one of paragraphs. 1-9 with a protective layer, and dry suspension containing pellet with an enteric coating according to any one of paragraphs. 1-9 and dry suspended particles. 13. A method for treating and/or preventing gastrointestinal diseases, including the step of administering to a patient in need of such treatment and/or prevention a therapeutic and/or prophylactic effective amount of an enteric-coated pellet according to any one of claims. 1-9, or the pharmaceutical composition according to claim 12. 14. Use of enteric-coated pellets according to any one of claims. 1-9 or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the treatment and/or prevention of gastrointestinal diseases, wherein said gastrointestinal diseases are selected from heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and recurrent duodenal ulcer, NSAID-associated gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity of gastric juice, dyspepsia, gastroparesis, Zollinger syndrome- Ellison, gastroesophageal reflux disease (GERD), Helicobacter pylori-associated disease or eradication of Helicobacter pylori, all degrees of erosive esophagitis, short bowel syndrome, gastric ulcers, peptic ulcers caused by non-steroidal anti-inflammatory compounds, and gastrointestinal bleeding and associated ulcers, caused by antiplatelet drugs, as well as any combination of the above diseases.

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