WO2022116796A1 - 肠溶微丸及其制备方法和包含它的制剂 - Google Patents

肠溶微丸及其制备方法和包含它的制剂 Download PDF

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WO2022116796A1
WO2022116796A1 PCT/CN2021/130394 CN2021130394W WO2022116796A1 WO 2022116796 A1 WO2022116796 A1 WO 2022116796A1 CN 2021130394 W CN2021130394 W CN 2021130394W WO 2022116796 A1 WO2022116796 A1 WO 2022116796A1
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Prior art keywords
enteric
ilaprazole
coated
pellets
layer
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PCT/CN2021/130394
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English (en)
French (fr)
Inventor
李普成
莫雅婷
张象娜
侯雪梅
崔艳南
李菁
陈乐平
成彩华
胡斯文
王涛
涂增清
张裕容
谭文绘
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Livzon Pharmaceutical Group Inc
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Livzon Pharmaceutical Group Inc
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Priority to JP2023519152A priority Critical patent/JP7541617B2/ja
Priority to US18/255,163 priority patent/US20240033224A1/en
Priority to KR1020237014432A priority patent/KR20230079406A/ko
Priority to EP21899830.0A priority patent/EP4205729A4/en
Priority to CN202180081582.9A priority patent/CN116600792A/zh
Priority to MX2023006410A priority patent/MX2023006410A/es
Publication of WO2022116796A1 publication Critical patent/WO2022116796A1/zh
Priority to ZA2023/04712A priority patent/ZA202304712B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to an enteric-coated pellet, a preparation method thereof and a preparation containing the same, in particular to ilaprazole enteric-coated pellets, a preparation method thereof and a preparation containing the same.
  • Proton pump inhibitors are drugs that can selectively inhibit the H + /K + -ATPase (also known as proton pump or acid pump) on the tubular membrane secreted by human gastric mucosal cells. Since this H + /K + -ATPase is the final pathway to inhibit gastric acid secretion, its inhibition can significantly reduce gastric acid secretion. Therefore, proton pump inhibitors are usually used to treat gastrointestinal diseases induced or caused by gastric acid action. Diseases (ie, acid-related diseases), which include gastric and duodenal ulcers, gastroesophageal reflux disease, surgical anastomotic ulcers, and Zollinger-Ellison syndrome, among others.
  • H + /K + -ATPase also known as proton pump or acid pump
  • proton pump inhibitors are usually used to treat gastrointestinal diseases induced or caused by gastric acid action. Diseases (ie, acid-related diseases), which include gastric and duodenal ulcers, gastroesophageal reflux disease
  • known PPIs can be divided into irreversible PPIs and reversible PPIs (Reversible PPI, RPPIs).
  • the irreversible PPIs are mainly benzimidazole derivatives, which can quickly pass through the parietal cell membrane and accumulate in the strongly acidic secretory tubules, and then protonate into sulfenamides, which can interact with H + /K +
  • the sulfhydryl group on the cysteine residue in the ⁇ subunit of -ATPase forms a covalently bound disulfide bond, thereby irreversibly inactivating the H + /K + -ATPase and inhibiting its oxyntic activity (Zhang Xuan , "Proton Pump Inhibitor-Prazole Patent Technology Review", “Patent Literature Research 2018-Pharmaceuticals”, Intellectual Property Press, Beijing, 2019.9: p554-567).
  • Such drugs currently on the market are: Omeprazol
  • ilaprazole is an acid-labile compound.
  • Acid-labile compounds are substances that are unstable in acidic media but have better stability in neutral and basic media. A common feature of these compounds is that they undergo rapid degradation/transformation in acidic media to become biologically effective compounds. Acid-labile proton pump inhibitors are sensitive to degradation/transformation in acidic and neutral media, and when administered orally, exposure to gastric acid should be avoided to affect their stability.
  • the general method to solve this problem is to coat the oral preparations of such drugs with enteric materials to prepare enteric pellet preparations (for example, see CN1183047A, CN1146720A, US4786505, EP0519365).
  • enteric pellet formulations typically contain a pellet core, a buffer coating, and an outer enteric coating.
  • an alkalizing agent or buffer
  • an alkaline layer can be added to the pill core without alkalinizing agent to protect the PPIs Not destroyed by acid (see CN103705483A).
  • a buffer coating layer ie, isolation layer
  • a certain thickness is also required in the enteric coating layer.
  • CN87103285A discloses a pharmaceutical preparation of acid-labile substances (such as benzimidazoles) for oral administration.
  • the pharmaceutical preparation for treating gastrointestinal diseases consists of a core material, one or more subcoating layers (ie, isolation layers) and an enteric coating layer, and the core material contains an acid-labile compound and an alkaline
  • the subcoating layer contains inert reactive compounds soluble in water or rapidly disintegrating, or water soluble compounds
  • the polymeric compound capable of forming the membrane may, optionally, also contain an alkaline compound that buffers pH.
  • the alkaline compound for buffering pH can be magnesium oxide, magnesium hydroxide or magnesium carbonate, aluminum hydroxide or calcium hydroxide, aluminum carbonate or calcium carbonate, aluminum silicate or calcium silicate; composite aluminum/magnesium compound, For example Al2O3.6MgO.CO2.12H2O , ( Mg6Al2 ( OH ) 16CO3.4H2O ) , MgO.Al2O3.2SiO2.nH2O , where n is not an integer and less than 2, or similar compounds; or other pharmaceutically acceptable pH-buffering substances, such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids.
  • the alkaline compound for buffering pH can be magnesium oxide, magnesium hydroxide or magnesium carbonate, aluminum hydroxide or calcium hydroxide, aluminum carbonate or calcium carbonate, aluminum silicate or calcium silicate; composite aluminum/magnesium compound, For example Al2O3.6MgO.CO2.12H2O , (
  • the material used as the separation layer is selected from the pharmaceutically acceptable water-soluble inert compounds or polymers used as coating films, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, Hydroxymethylcellulose, hydroxypropyl methylcellulose, etc.
  • the release layer common plasticizers, pigments, titanium dioxide, talc and other additives may also be included.
  • CN101036633A discloses an omeprazole enteric-coated pellet capsule and a preparation method thereof.
  • the contents of the capsule are omeprazole enteric-coated pellets, and the enteric-coated pellets comprise a blank pellet core, an active drug layer containing an alkaline component, an isolation layer and an enteric coating layer.
  • the isolation layer separates the alkaline omeprazole active drug layer from the acidic enteric material, and at the same time, magnesium oxide and titanium dioxide are added to the isolation layer as protective components, which significantly improves the stability of the drug through synergy.
  • CN102119927A discloses a proton pump inhibitor enteric-coated pellet preparation and a preparation method thereof.
  • the proton pump inhibitor enteric-coated pellet is composed of a blank pellet core, a drug-loading layer, isolation layers (I) and (II) and an enteric-coated layer.
  • Drug efficiency, the drug-loading layer and the isolation layer (I) simultaneously contain a water-soluble inorganic base, and the base used in the drug-loading layer contains sodium hydroxide and can form a buffer with sodium hydroxide in an aqueous solution and has a pH of 11-12 (excluding 11) Another water-soluble inorganic base in an alkaline environment.
  • CN106176669A discloses a pantoprazole sodium enteric-coated pellet, a preparation method thereof, and a capsule containing the pellet and a preparation method of the capsule.
  • the pantoprazole sodium enteric-coated pellet sequentially comprises a pill core, The first isolation layer, the second isolation layer and the enteric layer, the pill layer includes pantoprazole sodium and complex alkali (mixture of sodium phosphate salt);
  • the first isolation layer includes hydroxypropyl methylcellulose, Povidone k30, polyethylene glycol 600 (PEG-600), magnesium stearate, and talc;
  • second barrier layer includes hydroxypropyl methylcellulose, polyethylene glycol 400 (PEG-400), bicarbonate sodium, titanium dioxide and glycerol triacetate; and in the enteric-coated pellets, the mass ratio of the first isolation layer to the second isolation layer can significantly affect the final drug effect.
  • CN1785186A discloses an enteric-coated pellet of pantoprazole or its salt.
  • the pellet includes a pellet core, a subcoating layer, a drug layer, a buffer layer, an isolation layer and an enteric-coated layer from the inside to the outside.
  • factors such as the number of coating layers, the thickness of each layer, the amount of adhesive and stabilizer in the middle layer, etc. must be adjusted, so the weight gain of each layer is strictly limited in this document, otherwise it cannot be achieved. The desired effect of the invention.
  • the prior art methods for preparing prazole enteric-coated pellets and preparations thereof have the following disadvantages, resulting in that the prior art prazole enteric-coated pellets and preparations thereof cannot have good stability and acid resistance simultaneously ( In particular, acid resistance is not easy to be satisfied): in the isolation layer of the prazole enteric-coated pellets prepared by the prior art, the isolation layer adjacent to the core of the pill (that is, containing the pill) usually contains water that can prevent the pellet from sticking.
  • Insoluble inert substances such as talc, silicon dioxide, titanium dioxide, magnesium stearate, etc.
  • water-soluble basic compounds and/or water-soluble basic compounds, and the barrier layer immediately adjacent to the enteric layer usually contains basic compounds, both of which reduce intestinal Stability and/or acid resistance of dissolving pellets and their formulations.
  • one of the objects of the present invention is to provide a ilaprazole enteric-coated pellet, which overcomes the defects of the prior art and can have one, two or more of the following properties: Good stability, good acid resistance, increased dissolution and/or increased drug loading (also sometimes referred to herein as drug loading), and bioavailability.
  • the enteric-coated pellets sequentially include a pill core, a first isolation layer, a second isolation layer and an enteric layer from the inside out, wherein the pill core contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient.
  • the present invention provides an enteric-coated pellet
  • the enteric-coated pellet includes a pill core, a first isolation layer, a second isolation layer and an enteric layer in sequence from the inside to the outside, wherein the pill core Contains ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient
  • the enteric-coated pellets are characterized in that the first isolation layer contains a water-insoluble basic compound, the first The weight ratio between the excipients and ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole is 0.2-5:1.
  • the present invention provides an enteric-coated pellet
  • the enteric-coated pellet includes a pill core, a first isolation layer, a second isolation layer and an enteric layer in sequence from the inside to the outside, wherein the pill core A pharmaceutically acceptable salt containing ilaprazole and/or ilaprazole and a first excipient
  • the enteric-coated pellets are characterized in that the first isolation layer contains a water-insoluble basic compound and the first excipient is water
  • the insoluble basic compound, wherein the first separation layer contains the water-insoluble basic compound and the water-insoluble basic compound of the first auxiliary material may be the same or different.
  • the present invention provides an enteric-coated pellet
  • the enteric-coated pellet includes a pill core, a first isolation layer, a second isolation layer and an enteric layer in sequence from the inside to the outside, wherein the pill core
  • the enteric-coated pellets are characterized in that ilaprazole and/or ilaprazole are pharmaceutically acceptable
  • the particle size of the salt D90 ⁇ 100 ⁇ m, and the second isolation layer does not contain alkaline substances.
  • the enteric-coated pellets according to the present invention are further provided with a protective layer outside the enteric-coated layer.
  • the enteric-coated pellets according to the present invention there are no other layers between the pellet core and the first isolation layer.
  • the enteric-coated beads according to the present invention in the enteric-coated beads according to the present invention, no other layers are present between the second isolation layer and the enteric-coated layer.
  • the enteric-coated beads according to the present invention there are no other layers between the first isolation layer and the second isolation layer.
  • the first excipient in the enteric-coated pellets according to the present invention is a basic compound, preferably a water-insoluble basic compound, more preferably selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, carbonic acid Magnesium, calcium carbonate, calcium hydroxide.
  • the pharmaceutically acceptable salt of ilaprazole may be, for example, ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole Lithium or ilaprazole calcium, etc.
  • ilaprazole sodium ilaprazole magnesium
  • ilaprazole zinc ilaprazole
  • ilaprazole potassium ilaprazole Lithium or ilaprazole calcium, etc.
  • those skilled in the art can select appropriate salts as required.
  • the pellet core of the enteric-coated pellets according to the present invention further comprises a surfactant.
  • the surfactant is Tween 80 or sodium lauryl sulfate.
  • the weight ratio of the water-insoluble basic compound to ilaprazole and/or its pharmaceutically acceptable salt in the first separation layer is 0.2-5:1, preferably 0.25-4:1 , more preferably 0.3 to 3:1, especially preferably 0.5 to 2:1, most preferably 0.8 to 1.2:1, for example 1:1.
  • the second separation layer contains a water-insoluble inert substance that can prevent the pellets from sticking, and the amount of the binder and the binder by weight is 1-8:1.5-10, or 1- 10:1 to 20, or 4 to 26:7 to 44.
  • the particle size D90 of ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole may be a range selected between any two of the following endpoints: 0 ⁇ m (in the composition range excluding this point value) 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m, 80 ⁇ m, 90 ⁇ m, 100 ⁇ m.
  • the enteric-coated pellets according to the present invention can be a fully active pellet core or a blank pellet core coated with a drug-loading layer.
  • full active pill core refers to a pharmaceutically acceptable salt comprising ilaprazole and/or ilaprazole and a first excipient, and one or more other pharmaceutically acceptable excipients
  • the pill core wherein as the active ingredient ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole is dispersed in other ingredients (the first excipient and other one or more pharmaceutically acceptable excipients) etc.), but not independently or together with any other ingredients to form additional layers; in blank bead cores coated with a drug-loaded layer, the drug-loaded layer comprising ilaprazole and/or the pharmaceutics of ilaprazole an acceptable salt and a first adjuvant and optional excipients.
  • the first adjuvant in the pill core can be a conventional adjuvant used in the prior art for improving the stability of acid-labile compounds.
  • the first auxiliary material is a basic compound, including a water-insoluble basic compound and a water-soluble basic compound.
  • a water-insoluble basic compound is used as the first auxiliary material in the pill core; more preferably, the water-insoluble basic compound contained in the pill core is the same as the water-insoluble basic compound contained in the first isolation layer , thereby further enhancing the pH buffering effect of the isolation layer.
  • the water-insoluble basic compound may be selected from, but is not limited to, one or more of magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide .
  • the weight ratio of the basic compound to ilaprazole and/or its pharmaceutically acceptable salt is 0.2-5:1, preferably 0.25-4:1, more preferably 0.3-3:1, especially preferably 0.5- 2:1, most preferably 0.8 to 1.2:1, eg 1:1.
  • surfactants may also be included in the pill core. According to the results of the examples of the present invention, surfactants can improve the dissolution rate of ilaprazole and/or its pharmaceutically acceptable salts in enteric-coated pellets and their formulations, thereby effectively improving their bioavailability .
  • the surfactant contained in the pill core may be selected from the group consisting of nonionic surfactants, anionic surfactants and zwitterionic surfactants.
  • the nonionic surfactant can be selected from polyethylene glycol type, polyol type (such as Tween 80), etc.; the anionic surfactant can be selected from higher fatty acid salts, sulfate ester salts, sulfonate salts, etc., such as Sodium lauryl sulfate; zwitterionic surfactants can be selected from the group of phosphorous esters.
  • the particle size of ilaprazole and/or a pharmaceutically acceptable salt thereof can affect the dissolution rate and/or drug loading of enteric-coated beads.
  • the particle size of ilaprazole and/or a pharmaceutically acceptable salt thereof may be a particle size D90 ⁇ 100 ⁇ m; in this case, the enteric-coated pellets have good dissolution rate , and further can improve the bioavailability of the enteric-coated pellet preparation prepared from the enteric-coated pellets.
  • the particle size D90 of ilaprazole and/or its pharmaceutically acceptable salt may be selected from the range between any two of the following endpoints: 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m , 80 ⁇ m, 90 ⁇ m, 100 ⁇ m, especially D90 ⁇ 50 ⁇ m, which can achieve improved drug loading.
  • the above-mentioned blank micropellet cores are conventionally used blank micropellet cores in the prior art.
  • the blank pellet cores may be selected from, but not limited to, microcrystalline cellulose pellet cores, sucrose pellet cores or mannitol pellet cores, and the particle size may be 50-500 ⁇ m, preferably 100-400 ⁇ m , more preferably 250 to 350 ⁇ m, and most preferably about 300 ⁇ m.
  • the drug-loaded layer as described above may further comprise a binder.
  • the binder can be selected from, but is not limited to, hydroxypropyl cellulose, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, One or more of polyvinyl alcohol, polyethylene glycol, syrup and starch.
  • the binder may be selected from the group consisting of hydroxypropyl cellulose-SSL (eg commercially available series from Nisso), hypromellose E5, polyvinylpyrrolidone K30, polyvinyl alcohol, methyl alcohol One or more of cellulose and polyethylene glycol.
  • the basic function of the barrier layer of enteric-coated pellets is to separate the pellet core in an alkaline environment from the enteric layer containing free carboxyl groups to prevent ilaprazole and/or its pharmaceutically acceptable salts from coating. Degradation or discoloration during processing or during storage.
  • the inventors found that conventional preparation methods in the prior art (eg, when preparing the isolation layer closely adjacent to the pellet core) can prevent the Water-insoluble inert substances (such as talc, silicon dioxide, titanium dioxide, magnesium stearate, etc.) and/or water-soluble basic compounds to which the pellets are bound, and generally when preparing a barrier layer closely adjacent to the enteric layer
  • the use of basic compounds can reduce the stability and/or acid resistance of the enteric pellets and their formulations, especially for relatively low stability acid labile compounds such as ilaprazole, which results in their enteric coating Pellets and their formulations cannot meet the requirements for stability and acid resistance at the same time.
  • the term "closely adjacent” refers to the absence of additional layers between the pellet core of the enteric pellet and its coating or coating layer, or between the two layers each other.
  • the isolation layer (corresponding to the first isolation layer according to the present invention) contained in the isolation layer immediately adjacent to the core of the pill can prevent the problem.
  • the compatibility between the water-insoluble inert substance in which the pellets are stuck and the acid-labile compound contained in the pellet core differs due to the different stabilities of the acid-labile compound, i.e., in the In enteric-coated pellets and preparations thereof, when the acid-labile compound (such as ilaprazole) contained in the pellet core has low stability, the isolation layer closely adjacent to the pellet core can prevent the pellets from sticking.
  • the isolation layer of the enteric-coated pellets may be affected under long-term high temperature and high humidity conditions. Inhalation of free water leads to the dissolution of water-soluble alkaline compounds, so that the alkalinity of the isolation layer closely adjacent to the enteric layer increases and becomes alkaline. The layer dissolves in advance, resulting in reduced acid resistance of enteric-coated pellets and their formulations.
  • the principle of premature dissolution of the enteric layer due to the presence of alkali in the isolation layer immediately adjacent to the enteric layer is also applicable when the isolation layer immediately adjacent to the enteric layer (corresponding to the second isolation layer according to the present invention) In the case of containing basic compounds.
  • the enteric-coated pellets comprise at least two isolation layers comprising inert substances, namely at least a first isolation layer close to the pill core and closely adjacent to the pill core and a distance away from the pill core compared to the first isolation layer Or a second isolation layer closely adjacent to the enteric layer, wherein the first isolation layer contains a water-insoluble basic compound, but does not contain a water-soluble basic compound and a water-insoluble inert substance capable of preventing the pellets from sticking, and the second The isolation layer does not contain basic compounds.
  • the enteric-coated pellets include three or more isolation layers
  • other isolation layers between the first isolation layer and the second isolation layer may be in accordance with the definition of the first isolation layer or the second isolation layer according to the present invention
  • the isolation layer can also be the isolation layer commonly used in the prior art.
  • the water-insoluble basic compound may be a water-insoluble basic compound commonly used in the prior art for improving the stability of acid-labile compounds.
  • the water-insoluble basic compound may be selected from, but is not limited to, one or more of magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide .
  • the water-insoluble inert substance capable of preventing the pellets from sticking can be selected from one or more conventional lubricants, glidants and anti-sticking agents (that is, anti-sticking agents, the same hereinafter) in pharmacy- species or more.
  • the water-insoluble inert substance capable of preventing the pellets from sticking can be selected from, but not limited to, silica, calcium silicate, colloidal silica, aluminum silicate, calcium aluminum silicate , magnesium silicate, sodium stearate, zinc stearate, magnesium stearate, talc and titanium dioxide, etc.
  • the first isolation layer of the enteric-coated pellets does not contain the following water-insoluble inert substances that can prevent the pellets from sticking: talc, silicon dioxide One or more of , titanium dioxide and magnesium stearate.
  • the first release layer consists essentially of a water-insoluble alkaline compound and a binder
  • the second release layer consists essentially of a water-insoluble inert substance and a binder capable of preventing the pellets from sticking .
  • the proportion of each component can be as follows: when the amount of ilaprazole is 5-15 parts by weight, in the first isolation layer Contains 5 to 36 parts by weight of binder and 5 to 36 parts by weight of water-insoluble basic compounds; the second separation layer contains 4 to 26 parts by weight of binder, and 7 to 44 parts of water-insoluble inert substances that can prevent pellets from sticking parts by weight.
  • the binder can be selected from pharmaceutically acceptable water-soluble inert compounds or polymers used as coating films, such as hydroxypropyl cellulose, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose One or more of cellulose, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, syrup and starch.
  • enteric layer commonly used in enteric-coated pellet formulations in the prior art is also suitable for the present invention.
  • CN87103285A the Chinese cognate of US4786505 describes the detailed introduction of the enteric layer; the inventors take this as a reference, and The content of said document in relation to the enteric layer and the relevant content of all documents cited therein are incorporated into the present application.
  • the enteric layer may contain one or more substances selected from the group consisting of acrylic resins, celluloses such as carboxymethyl ethyl cellulose, enteric coating materials such as Opadry, and the like, and optionally One or more additives selected from plasticizers, anti-sticking agents, lubricants.
  • the enteric layer may comprise an acrylic resin-based enteric coating material, a plasticizer (such as polyethylene glycol, triacetin, triethyl citrate, phthalate) etc.), anti-sticking agent (such as talc, glycerol monostearate, etc.).
  • the acrylic resin enteric coating material is selected from cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, solution or dispersion of methacrylic acid copolymer L30D55, hydroxypropylmethyl acetate succinate
  • cellulose polyvinyl acetate phthalate, shellac.
  • the weight ratio of the enteric coating material contained in the enteric layer to ilaprazole and/or its pharmaceutically acceptable salt is 2 ⁇ 20:1.
  • the weight ratio of plasticizer to ilaprazole and/or its pharmaceutically acceptable salt is 0.6-6:1, preferably 0.8-4 : 1, more preferably 1 to 2:1.
  • the enteric-coated pellets may also be provided with a protective layer outside the enteric-coated layer, preferably, the protective layer is closely adjacent to the enteric-coated layer.
  • the protective layer can prevent possible adhesion between various semi-finished products/products during the placement process before being prepared into the preparation, or during the preparation process of the preparation thereof, or during the placement process after being prepared into the preparation.
  • setting the protective layer can also effectively improve the dissolution rate of the enteric-coated pellets, thereby improving the bioavailability of the enteric-coated pellet preparation prepared therefrom.
  • the protective layer may comprise an adhesive as well as an anti-sticking agent.
  • the binder may be selected from one or more of hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, and polyethylene glycol.
  • the anti-sticking agent may be selected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide.
  • the amount of the anti-adherent agent in the protective layer can improve the acid resistance of the enteric-coated pellets.
  • the amount of the anti-adherent agent when ilaprazole and/or a pharmaceutically acceptable salt thereof is 5-15 parts by weight, the amount of the anti-adherent agent is 0.5-15 parts by weight. 5 parts by weight.
  • the present invention provides a method for preparing enteric-coated pellets, the method comprising at least the following steps: 1) preparing a pharmaceutically acceptable salt comprising ilaprazole and/or ilaprazole and the pill core of the first excipient; 2) coating the first isolation layer and then coating the second isolation layer; and 3) coating the enteric layer.
  • step 2) comprises: preparing a first suspension comprising a water-insoluble basic compound and not comprising a water-soluble basic compound and a water-insoluble inert substance capable of preventing the pellets from sticking, and mixing the first suspension with Coating on the pill core obtained in step 1); preparing a second suspension containing no basic compound, and coating the second suspension as a second isolation layer, preferably as closely adjacent to the enteric layer The second isolation layer is coated;
  • the first auxiliary material acts together with the water-insoluble basic compound contained in the first isolation layer, thereby making ilaprazole and/or ilaprazole pharmaceutically acceptable
  • the salt achieves storage stability.
  • the preparation method of enteric-coated pellets further comprises step 4): coating a protective layer.
  • the preparation method of enteric-coated pellets may comprise one or more of the following steps:
  • step 2) Coating at least a first suspension and a second suspension from the inside to the outside, respectively, onto the pellet core obtained in step 1) by, for example, a fluidized bed method, wherein the first suspension comprises a water-insoluble The basic compound, without the water-soluble basic compound and the water-insoluble inert substance capable of preventing the pellets from sticking, forms a first separation layer; the second suspension does not contain the basic compound, forming a second separation layer; thereby Preparation of isolation pills;
  • enteric coating material and one or more selected from the group consisting of plasticizers, anti-adherents, lubricants and emulsifiers are made into an enteric layer suspension;
  • the layer suspension is coated on the isolation pellets obtained in step 2) to prepare enteric-coated pellets.
  • the preparation method of the above-mentioned enteric-coated pellets may further comprise step 4): selecting from hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose
  • step 4) selecting from hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose
  • One or more binders of ethylene glycol and polyethylene glycol are added to purified water to prepare a protective layer coating liquid, and the protective layer coating liquid is coated in step 3) by, for example, a fluidized bed method
  • enteric-coated pellets with a protective layer were prepared.
  • the above-mentioned enteric-coated pellets according to the present invention can be used to prepare an enteric-coated pellet formulation of ilaprazole, and the dosage form of the enteric-coated pellet formulation can be tablet, capsule, dry suspension or pill.
  • the present invention provides a kind of ilaprazole enteric-coated pellet tablet
  • the enteric-coated pellet tablet comprises the enteric-coated pellet according to the present invention and a tableting adjuvant (the second adjuvant, which is different from excipients described in the pellet core of enteric-coated pellets).
  • the enteric-coated micropellet tablet further comprises a film coating.
  • the enteric-coated pellets used for preparing the enteric-coated pellet tablet may be enteric-coated pellets with a protective layer or enteric-coated pellets without a protective layer.
  • the tableting adjuvant can be the conventional tableting adjuvant used when the enteric-coated micropill tablet is compressed in the prior art in the art.
  • the tableting adjuvants include fillers, diluents, disintegrants and lubricants, wherein the fillers and/or diluents may be selected from, but not limited to, starch, pregelatinized starch, One or more of lactose, mannitol, and microcrystalline cellulose; disintegrants may be selected from, but not limited to, crospovidone, croscarmellose sodium, and croscarmellose One or more of sodium; the lubricant may be selected from, but not limited to, one or more of talc, magnesium stearate, sodium stearyl fumarate and silicon dioxide.
  • the film coating can be the conventional film coating used when film-coating enteric-coated micropellets in the prior art in the art.
  • the film coating comprises a coating powder, which may be selected from, but not limited to, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, polyethylene glycol One or more of , talc, lake and Opadry.
  • the tableting method of preparing the enteric-coated pellets according to the present invention into enteric-coated pellets, and optionally, the method of coating the film-coating, are the prior art in the art for the enteric-coated pellets for tableting and Conventional methods of coating.
  • the present invention provides an enteric-coated micropellet capsule of ilaprazole, the enteric-coated micropellet capsule comprising the above-mentioned enteric-coated micropellet with a protective layer according to the present invention.
  • the capsule can be a conventional capsule used in the prior art for filling enteric-coated pellets according to the required dosage specifications; for example, the capsule can be a capsule shell sealed with a capsule sealing material; wherein the capsule
  • the capsule shell material can be selected from, but not limited to, one or more of gelatin, starch, sodium alginate and hydroxypropyl methylcellulose;
  • the capsule sealing material can be selected from, but not limited to, gelatin, Hypromellose, methylcellulose, acrylic resin, beta-cyclodextrin, ethyl cellulose, modified starch, cellulose acetate, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and carboxymethyl one or more of sodium cellulose.
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • the method for preparing the enteric-coated pellets according to the present invention into enteric-coated pellets and capsules can be a conventional method for preparing enteric-coated pellets and capsules in the prior art in the art.
  • the present invention provides a dry suspension of ilaprazole pellets, which comprises the enteric-coated pellets and dry suspension particles according to the present invention.
  • the method for preparing the enteric-coated pellets according to the present invention into a dry suspension of enteric-coated pellets can be a conventional method for preparing a dry suspension of enteric-coated pellets in the prior art in the art.
  • formulations comprising enteric-coated micropellets according to the present invention exhibit beneficial effects in the treatment and/or prevention of gastrointestinal diseases, which are mainly Includes heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and duodenal ulcer Ulcer recurrence, NSAID-related gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux Disease (GERD), H. pylori-related disease or eradication of H. pylori, erosive esophagitis of all grades, short bowel syndrome, or a combination of any of the above.
  • gastrointestinal diseases which are mainly Includes heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic
  • the present invention provides a method of treating and/or preventing gastrointestinal diseases.
  • the method comprises 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 formulation according to the present invention.
  • the enteric-coated micropellet formulation according to the present invention is the ilaprazole enteric-coated micropellet tablet, the ilaprazole enteric-coated micropellet capsule or the ilaprazole enteric-coated micropellet according to the present invention. Pill dry suspension.
  • gastrointestinal diseases that can be treated and/or prevented using this method include, but are not limited to, heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, Stress ulcers, hemorrhagic peptic ulcers, duodenal ulcers and recurrence of duodenal ulcers, gastric ulcers associated with NSAIDs, active benign gastric ulcers in adults, infectious enteritis, colitis, hyperacidity, Dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), H. pylori-related disease or H. pylori eradication, erosive esophagitis of all grades, short bowel syndrome , or any combination of the above.
  • the present invention provides the use of the enteric-coated pellets and the preparation thereof according to the present invention in the preparation of a medicament for the treatment and/or prevention of gastrointestinal diseases
  • the gastrointestinal tract diseases include , but 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 Duodenal ulcer recurrence, NSAID-related gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, Gastroesophageal reflux disease (GERD), H. pylori-related or eradication of H. pylori, erosive esophagitis of all grades, short bowel syndrome, or a combination of any of the above.
  • the gastrointestinal tract diseases include , but not limited to, heartburn, inflammatory bowel
  • the enteric-coated pellets and their preparations of the present invention are used to prepare medicines for the treatment and/or prevention of gastrointestinal diseases
  • the gastrointestinal diseases include, but are not limited to, duodenal ulcers and ulcers. Relapse, gastric ulcer, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases; or the drug can be used to eradicate Helicobacter pylori, and can also prevent peptic ulcer disease caused by non-steroidal anti-inflammatory drugs, prevent anti-inflammatory drugs Gastrointestinal bleeding and associated ulcers caused by platelet aggregation drugs (including, but not limited to, clopidogrel, prasugrel, ticagrelor, etc.).
  • the inventor finds and eliminates the influencing factors that restrict ilaprazole enteric-coated pellets and their preparations from having good stability and acid resistance (especially acid resistance) at the same time, and through the technical solution of the present invention, The following beneficial effects are achieved:
  • the enteric-coated pellets and their preparations according to the present invention can have better stability and acid resistance at the same time.
  • the ilaprazole enteric-coated pellets and their preparations of the present invention have a good acid-suppressing effect in the human body, and can suppress gastric acid to pH 4 or more within 1 hour after taking, and achieve clinical onset effects.
  • the enteric-coated micropellet tablet according to the present invention can achieve the effect of rapid onset of action, thereby relieving the pain of the patient more quickly.
  • Fig. 1 is the cumulative dissolution rate of micropellet tablets according to the present invention and comparative micropellet tablets 7 and 8 (referred to as micropellet tablet 7 and micropellet tablet 8 in the figure) with different barrier layer formulations in the accelerated stability test.
  • pellet tablet 11 and pellet tablet 16 are the cumulative dissolution rate of the pellet tablet according to the present invention and the comparative pellet tablets 11 and 16 with different pellet layers (referred to as pellet tablet 11 and pellet tablet 16 in the figure) in the accelerated stability test.
  • Fig. 3 is according to the micropellet tablet of the present invention and the comparative micropellet tablet 3 and 4 (referred to as micropellet tablet 3, micropellet tablet 4) in the accelerated stability Cumulative dissolution in testing.
  • micropellet tablet 12 is the cumulative dissolution rate of the micropellet tablet according to the present invention and the comparative micropellet tablet 12 without a protective layer (referred to as the micropellet tablet 12 in the figure) in the accelerated stability test.
  • Fig. 5 is the real-time detection of pH in human stomach according to the micropellet tablet of the present invention and the comparative micropellet tablet 1 and the comparative micropellet tablet 2 (referred to as micropellet tablet 1, micropellet tablet 2 in the figure) prepared according to the prior art method Average record.
  • Fig. 6 is according to the micropellet sheet of the present invention and the comparative micropellet sheet 1 and the comparative micropellet sheet 2 (referred to as micropellet sheet 1, micropellet sheet 2 in the figure) prepared according to the prior art method in the Beagle. drug concentration curve.
  • enteric-coated pellet tablet and dry suspension of ilaprazole according to the present invention will be mainly used as preferred examples, and the enteric-coated pellet formulation according to the present invention and the preparation method thereof will be exemplarily shown. .
  • the ilaprazole enteric-coated micro-pill tablet comprises a micro-pill (which sequentially includes a pill core, a first isolation layer, a second isolation layer, an enteric layer and a protective layer from the inside out), a tableting auxiliary material and a film coating;
  • the pill core includes a blank pellet core and a drug-loading layer
  • the drug-loading layer includes ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole (its particle size D90 is preferably ⁇ 50 ⁇ m), a basic compound , a surfactant and a binder
  • the first isolation layer contains a water-insoluble alkaline compound and a binder, but does not contain a water-soluble alkaline compound and a water-insoluble inert substance that can prevent the pellets from sticking
  • the second isolation layer The layer mainly contains a binder and a water-insoluble inert substance (such as talc, silica, titanium dioxide, magnesium ste
  • the basic compound contained in the pill core is a water-insoluble basic compound; more preferably, the water-insoluble basic compound contained in the pill core is the same as the water-insoluble basic compound contained in the first isolation layer .
  • each composition and proportioning in the ilaprazole enteric-coated pellets can be, but are not limited to, as follows: (in parts by weight)
  • Drug-loaded layers including:
  • Ilaprazole (or a pharmaceutically acceptable salt thereof) 5-15;
  • Enteric coating material 30 ⁇ 100 (referring to solid content);
  • Anti-sticking agent 0.5 ⁇ 5;
  • the enteric-coated pellets have high stability and acid resistance at the same time, and are suitable for ilaprazole with very low stability; and the ilaprazole enteric-coated pellets also have good drug loading and high High dissolution/bioavailability.
  • the enteric-coated pellets A-G according to the present invention will be prepared by taking ilaprazole and/or a pharmaceutically acceptable salt thereof as an example, as well as preparations for comparing the composition layers of the enteric-coated pellets. Comparative pellets 3-18 of the effect of different formulations on the properties of enteric-coated pellets and their formulations.
  • the comparative pellets 3 and 4 have different ilaprazole particle sizes in the drug-loading layer; the comparative pellets 5-10, 14-15 have different isolation Layers; Comparative Pellets 11, 16, 17 had drug loading layers with altered formulations; and different protective layers for Pellets 12-13; Comparative Pellets 18 had altered ilaprazole and/or its pharmaceutically acceptable The ratio of salt to first excipient.
  • a pellet containing a blank pellet core and a drug-loaded layer ie, a pellet core was prepared.
  • Pill-containing prescription W1 (unit: g)
  • Ilaprazole particle size D90 is 46.8 ⁇ m
  • Cane sugar pellets particle size 250-350 ⁇ m
  • magnesium hydroxide 100
  • Polysorbate 80 4 Hydroxypropyl Cellulose-SSL 150 purified water 3000
  • Pill-containing prescription W2 (unit: g)
  • Ilaprazole magnesium particle size D90 ⁇ 50 ⁇ m
  • Microcrystalline cellulose pellets 50 Hydroxypropyl Cellulose-SSL 100 Sodium dodecyl sulfate 2 magnesium carbonate 150 purified water 2000
  • Pill-containing prescription W3 (unit: g)
  • Ilaprazole Zinc Particle Size D90 ⁇ 50 ⁇ m
  • Cane sugar pellets 150 Polyvinylpyrrolidone K30 240 Sodium dodecyl sulfate 6 calcium carbonate 150 purified water 4800
  • Pill-containing prescription W4 (unit: g)
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Mannitol pill core 100
  • Polyvinylpyrrolidone K30 180 Polysorbate 80 6
  • Pill-containing prescription W5 (unit: g)
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Cane sugar pellets Hypromellose E5
  • Polysorbate 80 6 magnesium hydroxide 50 purified water 1600
  • Pill-containing prescription W6 (unit: g)
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Cane sugar pellets 250-350 ⁇ m
  • Hydroxypropyl Cellulose-SSL 100 purified water 3000
  • Pill-containing prescription W7 (unit: g)
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Cane sugar pellets 250-350 ⁇ m
  • magnesium hydroxide 100 Hydroxypropyl Cellulose-SSL 100 purified water 3000
  • the particle size D90 of ilaprazole is greater than or equal to 80 ⁇ m and less than or equal to 100 ⁇ m.
  • Ilaprazole particle size D90 is 46.8 ⁇ m
  • Cane sugar pellets particle size 250-350 ⁇ m
  • Polysorbate 80 4 Hydroxypropyl Cellulose-SSL 150 purified water 3000
  • Pill-containing prescription W11 (unit: g)
  • Ilaprazole magnesium particle size D90 ⁇ 50 ⁇ m
  • Microcrystalline cellulose pellets 50 Hydroxypropyl Cellulose-SSL 100 Sodium dodecyl sulfate 2 magnesium carbonate 200 purified water 2000
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Cane sugar pellets Hypromellose E5
  • Ilaprazole particle size D90 ⁇ 50 ⁇ m
  • Microcrystalline cellulose pellets 50 Hydroxypropyl Cellulose-SSL 100 Sodium dodecyl sulfate 2 magnesium carbonate 30 purified water 2000
  • isolation layer G4 for comparison pellet 9) (unit: g)
  • Isolation layer prescription G6 for comparison pellet 5) (unit: g)
  • Isolation layer prescription G7 for comparison pellet 6) (unit: g)
  • Isolation layer prescription G8 (for comparison pellet 8) (unit: g)
  • Isolation layer prescription G9 for comparison pellet 14 (unit: g)
  • Ilaprazole enteric-coated pellets 100 Hypromellose E5 2.5 Magnesium stearate 1.2 purified water 50
  • Ilaprazole enteric-coated pellets 100 Hydroxypropyl Cellulose-SSL 0.5 Magnesium stearate 0.5 purified water 10
  • a protective layer coating solution 0.5 g of hydroxypropyl cellulose-SSL in a recipe quantity was weighed and dissolved in 10 g of purified water, then 0.5 g of magnesium stearate was added, and uniformly dispersed under high shear at 3000 rpm to obtain a protective layer coating solution.
  • the protective layer coating solution was sprayed onto the enteric-coated beads through a GLATT GPCG-1 fluidized bed.
  • Ilaprazole enteric-coated pellets 100 Hydroxypropyl Cellulose-SSL 4 Magnesium stearate 5 purified water 80
  • hydroxypropyl cellulose-SSL in a recipe quantity was weighed and dissolved in 80 g of purified water, then 5 g of magnesium stearate was added, and the solution was uniformly dispersed by high shear at 5000 rpm to obtain a protective layer coating solution.
  • the protective layer coating solution was sprayed onto the enteric-coated beads through a GLATT GPCG-1 fluidized bed.
  • hydroxypropyl cellulose-SSL in recipe quantity and dissolve it in 50g of purified water, then add 1.2g of talc, and disperse uniformly under high shear at 5000 rpm to prepare a protective layer coating liquid.
  • the protective layer coating solution was sprayed onto the enteric-coated beads through a GLATT GPCG-1 fluidized bed.
  • Ilaprazole enteric-coated pellets 100 Hydroxypropyl Cellulose-SSL 2.5 Titanium dioxide 1.2 purified water 50
  • hydroxypropyl cellulose-SSL in recipe quantity and dissolve it in 50g of purified water, then add 1.2g of titanium dioxide, disperse uniformly under high shear at 5000rpm, and prepare a protective layer coating solution.
  • the protective layer coating solution was sprayed onto the enteric-coated beads through a GLATT GPCG-1 fluidized bed.
  • Ilaprazole enteric-coated pellets 100 Hypromellose E5 2.5 Magnesium stearate 0.2 purified water 50
  • Enteric-coated pellets A-G according to the present invention as shown in Table 1 below were prepared according to the formulations of each constituent layer of the enteric-coated pellets listed in the above section (1).
  • Table 1 Formulation composition of enteric-coated micropellets (tablets) A-G according to the present invention.
  • W x rate of drug-containing pills (the actual content of the pills) / (theoretical content of the pills) ⁇ 100%
  • Table 2-1 The formulation composition of the comparative pellets (tablets) 5-10 and 14-15 mainly used for the isolation layer research.
  • Table 2-2 Formulation composition of comparative pellets (tablets) 3-4, 11-13, 16-18 used for the composition layer study of enteric pellets.
  • ilaprazole with uniform (or specific) particle size D90 is used here. According to the present invention, those skilled in the art should know that the particle size D90 is not limited to this.
  • enteric-coated pellets A-G according to the present invention and comparative pellets 3-18 prepared in Example 1 were prepared into enteric-coated pellets A-G according to the present invention, and comparative pellets Pieces 3-18.
  • enteric-coated micropill tablet of the prior art with ilaprazole (particle size D90 is 46.8 ⁇ m, in order to facilitate the comparison between the data) as the medicinal active substance, prepared the comparative micropellet tablet 1 (according to CN1134666A) and comparative pellet 2 (according to CN102525990A).
  • Enteric-coated pellets shown in Table 1 and Tables 2-1 and 2-2 were prepared into enteric-coated pellets through the following steps of tableting and coating:
  • Ilaprazole overcoated pellets 200 Microcrystalline Cellulose PH102 339.2 Crospovidone-XL 113.1 Sodium Stearyl Fumarate 12.8
  • ilaprazole enteric-coated outer-coated pellets microcrystalline cellulose PH102, crospovidone-XL, and sodium stearyl fumarate into a 3-liter mixing hopper according to the above recipe, and mix at 10 rpm for 15 minutes. Then place it in a tablet press to perform tablet compression, the tablet hardness is 8-12kg, and the tablet weight is equivalent to 5 mg of ilaprazole in each tablet.
  • Pills 1 According to the preparation method and process of enteric-coated pellets in Example 16 of CN1134666A, using the outer coating of Example 15, using ilaprazole as the active pharmaceutical substance, and adding a surfactant to the drug-loading layer, a comparative micro-powder was prepared. Pills 1. The method is as follows:
  • hydroxypropyl cellulose E5 2.5 g was weighed and dissolved in 51.3 g of purified water, then 0.08 g of magnesium stearate was added, and the solution was uniformly dispersed under high shear at 5000 rpm to obtain a protective layer coating solution.
  • the protective layer coating solution was sprayed onto the enteric-coated beads through a GLATT GPCG-1 fluidized bed.
  • Ilaprazole enteric-coated pellets 173.9 Microcrystalline Cellulose PH102 869.5 Crospovidone 17.39 Sodium Stearyl Fumarate 17.39
  • ilaprazole enteric-coated pellets, microcrystalline cellulose, crospovidone, and sodium stearyl fumarate into a 3-liter mixing hopper according to the above recipe, and mix at 10 rpm for 15 minutes. Then place it in a tablet press to perform tablet compression, the tablet hardness is 8-12 kg, and the tablet weight is equivalent to 5 mg of ilaprazole in each tablet.
  • Comparative pellet tablet 1 was prepared.
  • the comparative pellet tablet 2 was prepared by using ilaprazole as a pharmaceutical active substance.
  • the preparation method of the drug solution the hydroxypropyl methylcellulose and magnesium oxide of the above-mentioned recipe quantities are dissolved in an 80% (v/v) ethanol aqueous solution, and the pH of the solution is adjusted with a 4% (m/v) sodium hydroxide solution About 12, add the prescribed amount of ilaprazole and stir well.
  • the viscosity of the drug solution was 13.22cp.
  • the isolation liquid needs to adjust the pH value to above 10.5 before coating, the isolation layer solution viscosity is 15.24cp, and the operating parameters are shown in the following table:
  • Pellet tableting prescription (unit: g)
  • Comparative pellet tablet 2 was prepared.
  • ilaprazole protective layer-coated pellets A (W 1 +G 2 +C 1 +B 1 ) were filled into a No. 3 capsule shell through a capsule filler, each capsule+ containing 5 mg of ilaprazole.
  • test solution take the test solution under related substances, accurately measure 5mL, put it in a 50mL volumetric flask, dilute to the mark with mobile phase, shake well, filter, and take the subsequent filtrate as the test solution.
  • Preparation of reference substance solution Take an appropriate amount of ilaprazole reference substance, accurately weigh it, add diluent to dissolve and dilute to make a solution containing about 20 ⁇ g per 1mL, as reference substance solution.
  • System suitability solution take impurity I (ilaprazole sulfone, chemical name: 2-[[(4-methoxy-3-methyl)-2-pyridyl]methyl]-sulfonyl-5-( 1H-pyrrol-1-yl)-1H-benzimidazole) reference substance and ilaprazole reference substance in appropriate amount, add diluent to dissolve and dilute to make a solution containing 20 ⁇ g of impurity I and ilaprazole each in 1 mL.
  • impurity I ilaprazole sulfone, chemical name: 2-[[(4-methoxy-3-methyl)-2-pyridyl]methyl]-sulfonyl-5-( 1H-pyrrol-1-yl)-1H-benzimidazole
  • ilaprazole reference substance add diluent to dissolve and dilute to make a solution containing 20 ⁇ g of impurity I and ilaprazole each in 1 mL
  • Chromatographic conditions use octadecylsilane-bonded silica gel as filler, use acetonitrile 400mL and phosphate buffer solution (take 2.28g of dipotassium hydrogen phosphate, dissolve in water and dilute to 1000mL, adjust pH to 7.5 with phosphoric acid) to 1000mL
  • the flow rate was 1.0 mL/min
  • the detection wavelength was 237 nm
  • the column temperature was 25 °C.
  • Determination method Precisely measure 20 ⁇ L of the reference solution and the test solution, respectively, inject them into a liquid chromatograph, and record the chromatogram.
  • Test solution take an appropriate amount of the dissolved solution, filter, accurately measure 5mL of the subsequent filtrate, immediately add 1mL of 0.15mol/L sodium hydroxide solution precisely, shake well, filter, and take the subsequent filtrate as the test solution.
  • Reference substance solution about 10mg of ilaprazole reference substance, accurately weighed, placed in a 20mL volumetric flask, add an appropriate amount of acetonitrile to dissolve, dilute to the mark with acetonitrile, shake well, accurately measure 1mL and place it in a 100mL volumetric flask, add phosphoric acid Salt buffer solution (pH6.8) (take 700mL of 0.086mol/L disodium hydrogen phosphate solution and 300mL of 0.1mol/L hydrochloric acid solution, and mix well) to dilute to the mark, shake well, accurately measure 5mL, and add it immediately and accurately 1 mL of 0.05mol/L sodium hydroxide solution, shake well, filter, and take the subsequent filtrate as the reference solution.
  • phosphoric acid Salt buffer solution pH6.8
  • Test solution take 10 tablets of this product, put it in a 250mL volumetric flask, add 125mL of 0.05mol/L sodium hydroxide solution, shake it in a shaker (250 rpm) for 20 minutes, add 50mL methanol and ultrasonicate for 10 minutes, Dilute to volume with water, shake well, centrifuge, and take the supernatant.
  • Control solution Precisely measure an appropriate amount of the test solution and dilute it with a diluent to prepare a solution containing about 1 ⁇ g of ilaprazole per 1 mL.
  • Sensitivity solution Precisely measure 1mL of the control solution, put it in a 10mL volumetric flask, dilute to the mark with diluent, and shake well.
  • Impurity I reference substance stock solution take about 6 mg of impurity I, put it in a 100mL volumetric flask, and dilute to the mark with diluent.
  • System suitability solution Take about 3 mg of ilaprazole reference substance, put it in a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve, and accurately add 1 mL of impurity I reference substance stock solution, dilute to the mark with diluent, and shake well.
  • Chromatographic conditions use octadecylsilane-bonded silica gel as packing (Gemini-NX C18 150 ⁇ 4.6mm, 5 ⁇ m or equivalent chromatographic column), 0.01mol/L dipotassium hydrogen phosphate solution (adjust pH with 10% phosphoric acid) value to 7.5) as mobile phase A, acetonitrile as mobile phase B, and perform linear gradient elution according to the following table; the flow rate is 1.0 mL/min; the detection wavelength is 237 nm; the column temperature is 25 °C.
  • System suitability solution requirements In the system suitability solution chromatogram, the resolution between the impurity I peak and the ilaprazole peak should be greater than 2.0. In the sensitivity solution chromatogram, the signal-to-noise ratio of the peak height of ilaprazole should be greater than 10.
  • Determination method Precisely measure 20 ⁇ L of the test solution and the control solution, respectively, inject them into a liquid chromatograph, and record the chromatogram.
  • Test plan The enteric-coated pellets A-G and the capsules of Example 3 were packaged in HDPE bottles, 14 pieces (grains) per bottle, and the packaged pellets or capsules were placed in an accelerated stability test at 40°C/RH75% In the box, samples were taken after 1/3/6 months to detect related substances in enteric-coated pellets or capsules of different prescriptions.
  • the stability data of the enteric-coated micropill tablets A-G obtained and the capsules of Example 3 are shown in the following table 3-1:
  • Table 3-1 Stability data of enteric-coated pellet tablets A-G and Example 3 capsules according to the present invention:
  • pellet tablets A-G and capsules prepared from the enteric-coated pellets according to the present invention have good stability, and their total impurities do not exceed 1.5%.
  • the acid resistance is investigated according to the enteric-coated micropill tablets A-G of the present invention and the capsule of Example 3, and the concrete method is as follows:
  • Table 3-2 Acid resistance data of enteric-coated pellet tablets A-G and Example 3 capsules according to the present invention:
  • enteric-coated pellet tablets A-G and capsules prepared from the enteric-coated pellets according to the present invention have good acid resistance, and the acid resistance is above 90%.
  • Example 4.2 taking enteric-coated pellets as an example, the effects of the ingredients and proportions of enteric-coated pellets on its stability and acid resistance were compared.
  • the enteric-coated micropellet tablets A according to the present invention and comparative micropellet tablets 5, 6, 9, 10 and 14 were subjected to accelerated stability studies.
  • the comparative micropellet tablet 5 only has an inert substance isolation layer that does not contain basic compounds; the comparative micropellet tablets 6, 9, 10 and 14 all have the same
  • the first separation layer is a mixed layer (the so-called mixed layer refers to a mixture containing a basic compound and a water-insoluble inert substance that can prevent the pellets from sticking in addition to the binder.
  • the first separation layer is a basic layer mainly comprising a binder and a water-soluble basic compound
  • the first separation layer is a mixed layer, and it contains a water-soluble alkaline compound as an alkaline compound.
  • Test scheme The enteric-coated pellets A according to the present invention and the comparative pellets 5, 6, 9, 10, and 14 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellets were placed at 40° C. /RH75% accelerated stability test box, take samples after 1/3/6 months to detect related substances in pellets with different prescriptions.
  • the measured stability data of pellets are shown in Table 4-1 below:
  • Table 4-1 Stability data of pellet A according to the present invention and comparative pellets 5, 6, 9, 10 and 14:
  • Comparative pellet tablet 5 Comparative pellet tablet 6 Comparative pellets 9 Comparative pellet tablet 10 Comparative pellet tablet 14 0 days 0.12% 0.35% 0.89% 0.24% 0.20% 0.49% 1 month 0.15% 0.72% 1.26% 0.63% 0.43% 0.61% 3 months 0.36% 1.25% 1.89% 0.96% 0.66% 1.05% 6 months 0.87% 1.87% 2.68% 1.79% 0.89% 1.68%
  • the enteric-coated pellets had good stability; in addition, for ilaprazole with low stability, when its enteric-coated pellets only contained basic compounds in the pellet core (ie, compared with When the pellet tablet 6) is used, the requirement of stability cannot be met (that is, the total impurities do not exceed 1.5%).
  • Enteric-coated pellet tablets A according to the present invention and comparative pellet tablets 10, 14 and 15 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellet tablets were placed at 40°C/RH75% for accelerated stability
  • enteric-coated pellet tablets A according to the present invention and comparative pellet tablets 10, 14 and 15 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellet tablets were placed at 40°C/RH75% for accelerated stability
  • In the test box take samples after 1/3/6 months, and then use 300 mL of 0.1 mol/L hydrochloric acid solution (take 9.0 mL of hydrochloric acid, add water to 1000 mL) as the dissolution medium, and operate at a speed of 100 revolutions per minute.
  • Table 4-2 Comparison of acid resistance data of enteric-coated micropellet tablet A according to the present invention and comparative micropellet tablets 10, 14, and 15.
  • the acid resistance of the comparative pellets (such as the comparative pellets 14) with inherently lower stability in the stability test is also lower;
  • the acid resistance of the comparative micropellet tablet 10 with the first isolation layer comprising different types of basic compounds (ie, water-soluble basic compounds) gradually deteriorated (at 6 months, The remaining ilaprazole content in the comparative pellet 10 is 85.6%), which is lower than the required standard (ie, the average acid resistance of 6 tablets is not lower than 90%).
  • the type of the basic compound will affect the acid resistance of the enteric-coated micropellet tablet.
  • using the isolation layer containing the water-insoluble alkaline compound as the first isolation layer of the enteric-coated micropellet tablet can improve and enhance the enteric-coated micropellet.
  • the acid resistance of the tablet it can also be seen from Table 4-2 that the acid resistance of the comparative pellet sheet 15, which does not contain a water-insoluble inert substance capable of preventing pellets from sticking in the second separating layer, is not affected.
  • the various isolation layer components included in the enteric-coated pellets at least two isolation layers are provided, and for the first isolation layer that is closely adjacent to the core of the pill, when the first isolation layer contains water-insoluble
  • the basic compound does not contain a water-soluble basic compound and a water-insoluble inert substance that can prevent the pellets from sticking
  • the ilaprazole enteric-coated pellets prepared from the enteric-coated pellets can have very good properties at the same time. Good stability and acid resistance.
  • the accelerated stability investigation was carried out on the enteric-coated micropellet tablet A according to the present invention and the comparative micropellet tablets 7 and 8.
  • the amount of the water-insoluble basic compound contained in the first isolation layer is larger, for example, when the amount of ilaprazole is 10 parts, the amount of the water-insoluble basic compound contained in the first isolation layer is greater than 36 parts; in the comparative pellet sheet 8, the anti-sticking agent (equivalent to the anti-sticking agent according to the present invention) contained in the second isolation layer
  • the dosage of the water-insoluble inert substance for the sticking of the pellets is relatively large, for example, when the dosage of ilaprazole is 10 parts, the dosage of the anti-sticking agent in the second isolation layer is greater than 44 parts.
  • enteric-coated pellets A according to the present invention and the comparative pellets 7 and 8 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellets were placed in an accelerated stability test chamber at 40°C/RH75%. Among them, samples were taken after 1/3/6 months to detect related substances in enteric-coated pellets of different prescriptions.
  • the measured stability data of enteric-coated pellets are shown in Table 5-1 below:
  • Table 5-1 Stability data of enteric-coated pellet tablet A and comparative pellet tablets 7 and 8 according to the present invention:
  • Comparative pellet tablet 7 Comparative pellet tablet 8 0 days 0.12% 0.25% 0.23% 1 month 0.15% 0.34% 0.50% 3 months 0.36% 0.67% 0.87% 6 months 0.87% 0.92% 0.95%
  • the comparative pellet tablet 7 with different composition ratios of the isolation layer (different proportions in the first isolation layer)
  • the stability of 8 (different ratio in the second isolation layer) is still within the standard range (total impurities do not exceed 1.5%). That is to say, the change of the composition ratio of the isolation layer will not affect the stability of the enteric-coated micropellet tablet.
  • the acid resistance test was carried out on the enteric-coated micropellet tablet A according to the present invention and the comparative micropellet tablets 7 and 8.
  • the specific method please refer to the acid resistance investigation in 4.2.1.
  • Table 5-2 Acid resistance data of enteric-coated micropellet tablets A according to the present invention and comparative micropellet tablets 7 and 8.
  • the comparative micropellet tablet 7 with different composition ratios of the isolation layer (the formulation in the first isolation layer
  • the acid resistance is still within the standard range (that is, the average acid resistance of 6 pieces is not less than 90%). That is to say, the change of the composition ratio of the isolation layer will not affect the acid resistance of the enteric-coated micropellet tablet.
  • Table 5-3 Acid resistance data of enteric-coated micropellet tablets A, F, G and micropellet tablets 17, 18 according to the present invention.
  • Example 4.3 taking ilaprazole enteric-coated pellets as an example, the composition of the pill core included in the enteric-coated pellets and the influence of the particle size of ilaprazole on its stability were compared.
  • the pill core of the comparative pellet sheet 11 does not contain basic compounds and surfactants
  • the pill core of the comparative pellet sheet 16 does not contain surfactants but contains basic compounds
  • the pill core of the comparative pellet sheet 17 Does not contain basic compounds but does contain surfactants.
  • Test plan The enteric-coated pellets A and comparative pellets 11 and 16 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged enteric-coated pellets were placed in an accelerated stability test at 40°C/RH75% In the box, samples were taken after 1/3/6 months to detect the related substances of different prescription enteric-coated pellets.
  • the stability data of the measured enteric-coated pellets are shown in Table 6 below:
  • Table 6 Stability data of enteric-coated pellet A according to the present invention and comparative pellets 11, 16, 17:
  • Comparative pellet tablet 11 Comparative pellet tablet 16 Comparative pellet tablet 17 0 days 0.12% 0.23% 0.26% 1.54% 1 month 0.15% 0.89% 0.57% 3.25% 3 months 0.36% 1.69% 0.86% 6.26% 6 months 0.87% 2.76% 1.05% 8.12%
  • the stability requirements cannot be met. (ie, the total impurities do not exceed 1.5%); in addition, the pelleted tablet obtained in the case where the pellet core does not contain basic compounds but only contains surfactants does not meet the stability requirements.
  • the accelerated stability investigation was carried out on the enteric-coated micropellet tablet A according to the present invention and the comparative micropellet tablets 3 and 4.
  • the ilaprazole particle size D90 of the pellet layer of the enteric-coated pellet in the comparative pellet tablet 3 is greater than or equal to 80 ⁇ m and less than or equal to 100 ⁇ m
  • the comparative pellet tablet 4 The particle size D90 of ilaprazole in the pellet layer of the enteric-coated pellets is greater than 100 ⁇ m.
  • the specific method is as follows:
  • Test plan The pellets A and pellets 3 and 4 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellets were placed in an accelerated stability test box at 40°C/RH75%, 1/ Samples were taken after 3/6 months to detect related substances in pellets of different prescriptions.
  • the measured stability data of pellet tablets are shown in Table 7 below:
  • Table 7 Stability data for enteric-coated micropellet tablets A according to the present invention and comparative micropellet tablets 3 and 4.
  • Comparative pellet tablet 3 Comparative pellet tablet 4 0 days 0.12% 0.25% 0.22% 1 month 0.15% 0.46% 0.22% 3 months 0.36% 0.78% 0.64% 6 months 0.87% 0.99% 0.85%
  • the Comparative Micropellet Tablet 3 (Ilaprazole Granules 3) comprising pellet cores with different ilaprazole particle sizes D90 was compared to Enteric-coated Micropellet Tablet A according to the present invention.
  • the stability of the diameter D90 is greater than or equal to 80 ⁇ m and less than or equal to 100 ⁇ m) and the stability of the comparative pellet 4 (Ilaprazole particle size D90 is greater than 100 ⁇ m) is still within the standard range (total impurities do not exceed 1.5%), that is, enteric-coated
  • the change of the particle size D90 of ilaprazole contained in the pellet layer will not affect the stability of the enteric-coated pellet.
  • the particle size of ilaprazole contained in the pellet core of the enteric-coated pellets will not affect the stability and acid resistance of the enteric-coated pellets prepared from the enteric-coated pellets.
  • Example 4.4 taking ilaprazole enteric-coated pellets as an example, the effects of the setting of the protective layer in the enteric-coated pellets and the dosage of the components on its stability or acid resistance were compared.
  • Test plan The pellets A and the pellets 12 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellets were placed in an accelerated stability test box at 40°C/RH75%, 1/3/ Samples were taken after 6 months to detect related substances in pellets of different prescriptions.
  • the measured stability data of pellets are shown in Table 8-1 below:
  • Table 8-1 Stability data of pellet A according to the present invention and comparative pellet 12.
  • the stability of the comparative pellet tablet 12 whose enteric-coated pellet does not include a protective layer is still within the standard range ( The total impurities do not exceed 1.5%). That is to say, whether the enteric-coated micropellet contains a protective layer or not will not affect the stability of the enteric-coated micropellet tablet.
  • the acid resistance test was carried out on the enteric-coated micropellet tablet A according to the present invention and the comparative micropellet tablet 12.
  • the specific method refer to the acid resistance investigation in 4.2.1.
  • Table 8-2 Acid resistance data of enteric-coated pellet tablet A according to the present invention and comparative pellet tablet 12.
  • the acid resistance of the comparative micropellet tablet 12 without a protective layer outside the enteric layer is slightly lower than the standard range (ie, the average acid resistance of 6 tablets is not lower than 90%).
  • the reason for the low acid resistance data of this assay is that the enteric-coated pellets without a protective layer are easy to stick to each other, and part of the drug is degraded during the treatment process, which leads to this assay.
  • the acid resistance data is low.
  • enteric-coated pellet formulation can be prepared by means other than the setting of a protective layer, such as timely mixing with preparation auxiliary materials, etc., to prevent the occurrence of enteric-coated pellets Adhesion, then, whether a protective layer is provided or not will not affect the acid resistance of the formulation.
  • the content of the anti-sticking agent (such as magnesium stearate) in the protective layer of the enteric-coated pellet prepared into the comparative pellet sheet 13 is low, for example, when the amount of ilaprazole is 5-15 parts, the anti-sticking agent The dosage is less than 0.5 part.
  • Test plan The pellets A and the pellets 13 were packaged in HDPE bottles, 14 pieces per bottle, and the packaged pellets were placed in an accelerated stability test box at 40°C/RH75%, 1/3/ Sampling after 6 months to test the acid resistance of the pellets, namely: placing the pellets in a 0.1M hydrochloric acid solution, collecting the pellets after 2 hours, and detecting the remaining ilaprazole content in the pellets.
  • the acid resistance data of the measured pellets are shown in Table 9 below:
  • Table 9 Comparison of acid resistance data of enteric-coated micropellet tablet A according to the present invention and comparative micropellet tablet 13.
  • Table 10 Dissolution data for Micropellet Tablet A according to the present invention and Comparative Micropellet Tablet 15.
  • T/min Pellets A Comparative pellet tablet 15 0 0% 0% 10 35.80% 34.5% 15 68.50% 66.3% 20 82.90% 80.1%
  • both the enteric-coated micropellet tablet A according to the present invention and the comparative micropellet tablet 15 have a good dissolution rate (the dissolution rate is not less than 80%).
  • the second release layer only contains a binder and does not contain a water-insoluble inert substance (such as an anti-sticking agent) that can prevent the pellets from sticking, it will not affect the dissolution rate of the enteric pellet formulation, and thus also It should not affect its in vivo bioavailability.
  • Table 11 Dissolution data for pellet A according to the invention and comparative pellets 7, 8.
  • the enteric-coated micropellet tablet A according to the present invention has a good dissolution (dissolution is not less than 80%).
  • the dissolution rates of the comparative micropellet tablets 7 and 8 are significantly reduced outside the required standard range (the dissolution rate is not less than 80%), which indicates that these The release of enteric-coated pellets is significantly slowed down, which will delay the onset of action in the body, which in turn will affect the bioavailability in the body.
  • the change of the distribution ratio of each component in the isolation layer of the enteric-coated pellet will not affect the stability and acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellet.
  • the change of the distribution ratio of each component in the isolation layer of the enteric-coated micropellet will affect the dissolution rate of the corresponding enteric-coated micropellet tablet, thereby affecting the in vivo bioavailability of the preparation.
  • the distribution ratio of each component in the isolation layer of the enteric-coated pellets can be as follows: when the dosage of ilaprazole is 5-15 parts, the first isolation layer contains 5-36 parts of binders, 5-36 parts of water-insoluble basic compounds, 4-26 parts of binders, and 7-44 parts of water-insoluble inert substances that can prevent pellets from sticking in the second separation layer.
  • Table 12 Dissolution data of enteric-coated micropellet tablets A according to the present invention and comparative micropellet tablets 11, 16.
  • the dissolution rate of the comparative micropellet tablet 11 is significantly reduced outside the standard range (the dissolution rate is not lower than 80 %).
  • the pellet core does not contain surfactant, and although the drug dissolution rate of the preparation is within the standard range, it is lower than that of the enteric-coated pellet tablet A, and the dissolution rate is lower than 85%.
  • the surfactant contained in the pellet core of enteric-coated pellets will not affect its stability, but will affect the dissolution rate of the formulation, that is, in the pellet core of enteric-coated pellets Adding a surfactant can effectively improve the dissolution rate of the preparation, thereby effectively improving the bioavailability.
  • enteric-coated micropellet tablets A according to the present invention and comparative micropellet tablets 3, 4 were compared for dissolution according to the method described in Section 4.1 above.
  • the measured dissolution data of pellet tablets are shown in Table 13 and Figure 3 below:
  • Table 13 Dissolution data for micropellet tablets A according to the invention and comparative micropellet tablets 3, 4.
  • enteric-coated micropellet Tablet A according to the present invention and Comparative Micropellet Tablet 12 were compared for dissolution according to the method described in Section 4.1 above.
  • the measured dissolution data of pellet tablets are shown in Table 14 and Figure 4 below:
  • Table 14 Dissolution data for enteric-coated micropellet tablet A according to the present invention and comparative micropellet tablet 12.
  • the dissolution rate of the comparative micropellet tablet 12 without the protective layer was significantly reduced to about the standard value (dissolution degree not less than 80%).
  • the inventors found in experiments that the reason for the obvious decrease in the dissolution rate is that the enteric-coated pellets without a protective layer according to the present invention are prone to stick together, thereby affecting their release rate in the dissolution medium. Therefore, when there is a protective layer, the enteric-coated pellet A will not stick in the dissolution medium, and the release is relatively high; the comparative pellet 12 has no protective layer, and the pellet will stick in the medium, and the release is low.
  • the enteric-coated pellet formulation can be prepared by means other than setting a protective layer, such as mixing with preparation auxiliary materials in time, etc., to prevent the occurrence of enteric-coated pellets Adhesion, or, by adding other isolation layers between the first isolation layer and the second isolation layer, the enteric-coated pellets are not prone to adhesion, then, whether to provide a protective layer will not affect the dissolution rate of the preparation .
  • a protective layer such as mixing with preparation auxiliary materials in time, etc.
  • the particle size of ilaprazole contained in the pellet core of the enteric-coated pellets does not affect the stability and acid resistance of the enteric-coated pellets prepared from the enteric-coated pellets; the enteric-coated pellets
  • the particle size of ilaprazole contained in the pellet core of the dissolving pellets will affect the dissolution rate of the enteric-coated pellets, thereby affecting the bioavailability in vivo.
  • the particle size of the ilaprazole contained in the pellet core of the enteric-coated pellet will also affect the drug-loading capacity of the pellet core of the enteric-coated pellet.
  • the particle size D90 of ilaprazole in the pill layer of the enteric-coated pellets according to the present invention can be ⁇ 100 ⁇ m; more preferably, the pellets of the enteric-coated pellets according to the present invention
  • the particle size D90 of ilaprazole in the layer can be ⁇ 50 ⁇ m.
  • Example 5 Acid suppression effect of enteric-coated pellets according to the present invention
  • This study was a single-center study with a randomized, open-label, crossover design, including 18 healthy subjects. During one cycle of the experiment, 18 subjects were randomly divided into three groups, with 6 people in each group, taking the pills A, the comparative pills 1 and the comparative pills 2 respectively. Each person took the drug once on an empty stomach, and the pH value in the stomach was measured for 24 hours.
  • Intragastric pH recording The intragastric pH recording will use a pH testing system from Medtronic, Denmark. The catheter was placed in the stomach through the nasal cavity, and a section of the catheter was connected to a Digitrapper MKIII recording device. The secondary recording device can be linked by a microprocessor to record the pH value in the subject's stomach. The catheter will be placed 8-10 cm from the lower esophageal sphincter, and the scale on the surface of the catheter will indicate its position. The probe is in the same position in each pH recording and must be calibrated at 2 points with buffers of pH 7.01 and pH 1.07 before each pH monitoring. After each recording, the data in Digitrapper MKIII is downloaded to the computer for further analysis.
  • Test results The recorded gastric pH values of each group of subjects were processed, and the average pH values at each time point of multiple patients were analyzed to draw a curve, as shown in Figure 5.
  • the enteric-coated pellet A of the present invention has a rapid onset of action, and can suppress gastric acid to pH 4 or more within 1 hour after taking it to achieve clinical onset effect.
  • the comparative pellet 1 achieved clinical onset effect at about 3 hours after taking; the comparative pellet 2 achieved clinical effect at about 2.5 hours after taking. It can be seen that the enteric-coated micropill tablet according to the present invention can achieve the effect of rapid onset of action, so as to solve the pain of the patient more quickly.
  • Table 15 Stability data for Comparative Bead Tablet 1 and Comparative Bead Tablet 2.
  • Table 16 Acid resistance data for Comparative Bead Tablet 1 and Comparative Bead Tablet 2.
  • Comparative pellet tablet 1 Comparative pellet tablet 2 0 days 92.6% 90.1% 1 month 88.3% 85.5% 3 months 83.5% 81.3% 6 months 80.6% 78.9%
  • Example 6 Pharmacokinetic test of ilaprazole enteric-coated pellets according to the present invention in beagle dogs
  • Test animal Beagle.
  • Quantity a total of 12 animals, half male and half male, divided into 3 groups (pellet tablet A, comparative pellet tablet 1, and comparison pellet tablet 2).
  • Dosing method and frequency oral gavage, once administered (0.024mL/kg half an hour before administration
  • Pentagastrin (Pentagastrin) at 0.25 mg/mL was administered intramuscularly.
  • Blood collection points 0h 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 collection points.
  • the dosing regimen for beagle dogs is as follows:
  • the enteric-coated pellet A according to the present invention has higher bioavailability in Beagle dogs, and the time to inhibit gastric acid secretion is faster.
  • the Beagle dogs had lower cumulative plasma concentrations of the comparative pellets 1 and 2, indicating that the bioavailability of the comparative pellets 1 and 2 was low.
  • Table 17 Degradation residuals of different prazoles at different times in pH 6.8 media.
  • Table 18 Degradation residuals of different prazoles at different times in pH 8.0 media.
  • the ilaprazole pellet dry suspension will be prepared by taking the ilaprazole enteric-coated pellets according to the present invention as an example.
  • Preparation method After mixing xanthan gum, chitosan, CCNA and aspartame evenly, add the dry granulator to granulate.
  • the process parameters are: the spacing between the pressing rollers is 0.2 mm, the feeding speed is 30 rpm, the rotational speed of the pressing roller is 5 rpm, and the rotational speed of the whole pellet is 10 rpm.
  • sieve for granulation After the granulation is completed, sieve for granulation, and control the particle size between 0.5-0.7mm. A dry suspension of granules V is obtained.
  • Ilaprazole enteric-coated pellets E 60.5 mg are mixed with 2.0 g of the above-mentioned dry suspension particles V, and bottled to obtain ilaprazole enteric-coated dry suspension E-V with a specification of 5 mg.

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Abstract

一种肠溶微丸、其制备方法和包含它的制剂，特别是涉及艾普拉唑肠溶微丸、其制备方法和包含它的制剂。

Description

肠溶微丸及其制备方法和包含它的制剂
相关申请与优先权
本申请要求2020年12月2日向中国国家知识产权局提交的专利申请号为202011391266.5的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及一种肠溶微丸、其制备方法和包含它的制剂，特别是涉及艾普拉唑肠溶微丸、其制备方法和包含它的制剂。
背景技术
质子泵抑制剂(Proton Pump Inhibitors，PPIs)是能够选择地抑制人体胃黏膜细胞分泌小管膜上的H +/K +-ATP酶(又称质子泵或酸泵)的药物。由于该H +/K +-ATP酶是抑制胃酸分泌的最终途径，对其进行抑制可明显降低胃酸的分泌，因此，质子泵抑制剂通常被用于治疗消化道由于胃酸作用而诱发或导致的疾病(即酸相关疾病)，其包括胃和十二指肠溃疡、胃食管反流病、手术吻合口溃疡和卓-艾综合症等。根据作用机理，可以将已知的PPIs分为非可逆性PPIs和可逆性PPIs(Reversible PPI，RPPIs)。其中，非可逆性PPIs主要为苯并咪唑衍生物，能迅速穿过壁细胞膜并蓄积在强酸性的分泌小管中，然后质子化转化为次磺酰胺类化合物，后者可与H +/K +-ATP酶α亚基中的半胱氨酸残基上的巯基形成共价结合的二硫键，由此使H +/K +-ATP酶不可逆地失活、抑制其泌酸活性(张璇，“质子泵抑制剂-拉唑类药物专利技术综述”，《专利文献研究2018-医药制药》，知识产权出版社，北京，2019.9：p554-567)。目前全球已经上市的此类药物有：奥美拉唑(Omeprazole)、兰索拉唑(Lansoprazole)、泮托拉唑(Pantoprozole)、雷贝拉唑(Rabeprazole)、埃索美拉唑(Esomeprazole)、艾普拉唑(Ilaprazole)、右兰索拉唑(Delansoprazole)等。
与其他的拉唑类药物相似，艾普拉唑也属于酸不稳定性化合物。只是，相比于现有的其他拉唑类药物，艾普拉唑具有更低的稳定性。酸不稳定性化合物是在酸性介质中不稳定但是在中性和碱性介质中具有较好稳定性的物质。这些化合物的共同特点是，在酸介质中，经过迅速地降解/转变，可以成为生物学上有效的化合物。酸不稳定的质子泵抑制剂在酸性和中性介质中对降解/转化敏感，用于口服时，应避免其与胃酸接触而影响其稳定性。解决该问题的一般方法是将这类药物的口服制剂以肠溶材料包衣，制备成肠溶微丸制剂(例如参见CN1183047A、CN1146720A、US4786505、EP0519365)。这些肠溶微丸制剂通常包含有药丸芯、缓冲衣层以及外层的肠溶衣层。针对药丸芯，可以在该药丸芯的药物组合物中加入碱化剂(或称缓冲剂)以增加PPIs的稳定性，或者在不含碱化剂的药丸芯上附加碱性层，以保护PPIs不被酸破坏(参见CN103705483A)。此外，为了避免肠溶材料中游离羧基对该类药物的稳定性的影响，在肠溶衣层内还需要具有一定厚度的缓冲衣层(即隔离层)。
关于该隔离层，现有技术中已经公开了许多技术方案，例如：
CN87103285A(上述US4786505的中国同族)公开了一种用于口服的酸不稳定物质(例如苯并咪唑类化合物)的药用制剂。该用于治疗胃肠疫病的药用制剂由芯子材料、一层或多层底包衣层(即隔离层)和肠溶衣层组成，该芯子材料含有酸不稳定性化合物与呈碱性反应的化合物，或含有酸不稳定性化合物有选择的碱性盐与碱性化合物；底包衣层含有在水中可溶解的或能迅速崩解的呈惰性反应的化合物，或水中可溶的能形成膜的聚合化合物，可选地,还可以含有缓冲pH的碱性化合物。此外，以适当的方法处理最后的肠包衣剂型，使水份含量降低到很低的水平，以得到在长期贮存中具有良好的稳定性的剂型。其中，该缓冲pH的碱性化合物可以是氧化镁，氢氧化镁或碳酸镁、氢氧化铝或氢氧化钙，碳酸铝或碳酸钙，硅酸铝或硅酸钙；复合的铝/镁化合物，例如Al 2O 3·6MgO·CO 2·12H 2O，(Mg 6Al 2(OH) 16CO 3.4H 2O)，MgO·Al 2O 3·2SiO 2·nH 2O，其中n不是整数并小于2，或为类似化合物；或者为其他药用合格的pH-缓冲物质，例如磷酸、柠檬酸或其他合适的弱无机酸或有机酸的钠、钾、钙、镁和铝盐。用做隔离层的材料选自药用合格的水可溶的惰性化合物或用做包衣膜的聚合物，例如糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素等。 在隔离层中，也可包含普通的增塑剂、色素、二氧化钛、滑石粉和其他添加剂。
CN101036633A公开了一种奥美拉唑肠溶微丸胶囊及其制备方法。该胶囊内容物为奥美拉唑肠溶微丸，该肠溶微丸包含有空白丸芯、含有碱性成份的活性药物层、隔离层和肠溶衣层。该隔离层将碱性的奥美拉唑活性药物层与呈酸性的肠溶材料隔离开，同时在隔离层增加氧化镁和钛白粉作为保护成份，通过协同作用明显地提高了药物的稳定性。
CN102119927A公开了一种质子泵抑制剂肠溶微丸制剂及其制备方法。该质子泵抑制剂肠溶微丸由空白丸芯、载药层、隔离层(I)和(II)及肠溶层组成，为了提高药物稳定性并改善由于水不溶性碱的加入而降低的载药效率，该载药层和隔离层(I)同时含有水溶性无机碱，且载药层所用碱包含氢氧化钠和能与氢氧化钠在水溶液中形成缓冲且pH为11-12(不包括11)的碱性环境的另外一种水溶性无机碱。
CN106176669A公开了一种泮托拉唑钠肠溶微丸、其制备方法和包含该微丸的胶囊和胶囊制备方法，该泮托拉唑钠肠溶微丸由内至外顺次包括药丸芯、第一隔离层、第二隔离层和肠溶层，该药丸层中包括泮托拉唑钠和复合碱性物(磷酸钠盐的混合物)；第一隔离层包括羟丙基甲基纤维素、聚维酮k30、聚乙二醇600(PEG-600)、硬脂酸镁和滑石粉；第二隔离层包括羟丙基甲基纤维素、聚乙二醇400(PEG-400)、碳酸氢钠、二氧化钛和丙三醇三乙酸酯；且在该肠溶微丸中，第一隔离层与第二隔离层的质量比能显著地影响最终的药物效果。
CN1785186A公开了一种泮托拉唑或其盐的肠溶微丸，所述微丸从内到外包括丸芯、底衣层、药层、缓冲层、隔离层和肠溶层。为了获得期望的效果，必须对其中的包衣层数、各层厚度、中间层粘合剂和稳定剂的用量等因素进行调整，因而该文献中严格限制了各层的增重量，否则不能达到发明期望达到的效果。
用于制备拉唑类肠溶微丸及其制剂的现有技术方法存在如下不利之处，导致现有技术的拉唑类肠溶微丸及其制剂无法同时具有良好的稳定性和耐酸性(尤其是耐酸性不易得到满足)：在通过现有技术制备的拉唑类肠溶微丸的隔离层中，紧邻药丸芯(亦即含药丸)的隔离层通常含有能够防止微丸发生粘连的水不溶性惰性物质(如滑石粉，二氧化硅，二氧化钛，硬脂酸镁等)和/或水溶性碱性化合物，以及紧邻肠溶层的隔离层通常含有碱性化合物，这两者均会降低肠溶微丸及其制剂的稳定性和/或耐酸性。
发明内容
因此，本发明的目的之一在于提供一种艾普拉唑肠溶微丸，该肠溶微丸克服了现有技术的缺陷，可以具有下述性质之一、两者或两者以上：具有良好的稳定性、良好的耐酸性，提高的溶出度和/或提高的载药量(在本文中有时也称上药率)以及生物利用度。
上述目的通过根据本发明的肠溶微丸得以实现，该肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料。
根据本发明的第一方面，本发明提供了一种肠溶微丸，该肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，第一隔离层中含有水不溶性碱性化合物，所述第一辅料与艾普拉唑和/或艾普拉唑的药学上可接受的盐之间的重量比为0.2～5:1。
根据本发明的第二方面，本发明提供了一种肠溶微丸，该肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，第一隔离层含有水不溶性碱性化合物和第一辅料为水不溶性碱性化合物，其中第一隔离层含有水不溶性碱性化合物与第一辅料的水不溶性碱性化合物可以相同或不同。
根据本发明的第三方面，本发明提供了一种肠溶微丸，该肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，艾普拉唑和/或艾普拉唑的药学上可接受的盐的粒径D90≤100μm，和第二隔离层不含碱性物质。
根据本发明的一个实施方案，根据本发明的肠溶微丸在肠溶层外侧还设有保护层。
根据本发明的一个实施方案，在根据本发明的肠溶微丸中，在药丸芯与第一隔离层之间不存在其他的层。
根据本发明的一个实施方案，在根据本发明的肠溶微丸中，在第二隔离层与肠溶层之间不存在其他的层。
根据本发明的一个实施方案，在根据本发明的肠溶微丸中，在第一隔离层与第二隔离层之间不存在其他的层。
根据本发明的一个实施方案，根据本发明的肠溶微丸中的第一辅料为碱性化合物，优选为水不溶性碱性化合物，更优选选自氢氧化镁、氢氧化铝、氧化镁、碳酸镁、碳酸钙、氢氧化钙。
根据本发明的一个实施方案，艾普拉唑的药学上可接受的盐可以例如为艾普拉唑钠、艾普拉唑镁、艾普拉唑锌、艾普拉唑钾、艾普拉唑锂或艾普拉唑钙等。在此，本领域技术人员可以根据需要选择合适的盐。
根据本发明的一个实施方案，根据本发明的肠溶微丸的药丸芯还包含表面活性剂。优选地，所述表面活性剂为吐温80或十二烷基硫酸钠。
根据本发明的一个实施方案，第一隔离层中的水不溶性碱性化合物与艾普拉唑和/或其药学上可接受的盐的重量比为0.2～5:1，优选0.25～4:1，更优选0.3～3:1，尤其优选0.5～2:1，最优选0.8～1.2:1，例如1:1。
根据本发明的一个实施方案，第二隔离层中包含能够防止微丸发生粘连的水不溶性惰性物质，其与粘合剂的用量按重量计的比例在1～8:1.5～10，或者1-10:1～20，或者4～26:7～44范围内。
根据本发明的一个实施方案，艾普拉唑和/或艾普拉唑的药学上可接受的盐的粒径D90可以为选自任意两个下述端点之间的范围：0μm(在组成范围时不包括该点值)10μm，20μm，30μm，40μm，50μm，60μm，70μm，80μm，90μm，100μm。
本领域技术人员能够理解，本文中各个方面以及各个实施方案中的一个或更多个特征可以自由组合，以形成新的技术方案，同时通过这些组合获得的技术方案也落入本发明的范围之内。在下文进一步对本发明的技术方案、术语和原理进行阐述。
关于肠溶微丸的药丸芯：
根据本发明的肠溶微丸的药丸芯(或称为含药丸)可以是全活性药丸芯或包覆有载药层的空白微丸芯。在本文中，术语“全活性药丸芯”是指包含艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，以及其他一种或多种可药用赋形剂的药丸芯，其中作为活性成分的艾普拉唑和/或艾普拉唑的药学上可接受的盐分散在其它成分(所述第一辅料和其他一种或多种可药用赋形剂等)中，而不独立地或者与任意其它成分一起形成另外的层；在包覆有载药层的空白微丸芯中，载药层包含艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料和任选的赋形剂。
当药丸芯中的艾普拉唑和/或其药学上可接受的盐仅在第一隔离层包含的水不溶性碱性化合物的作用下，无法实现足够的贮存稳定性时，另外在药丸芯中加入的第一辅料可以实现其贮存稳定性的提高。
药丸芯中的第一辅料可以为现有技术中用于提高酸不稳定性化合物的稳定性所使用的常规辅料。优选地，第一辅料为碱性化合物，包括水不溶性碱性化合物和水溶性碱性化合物。根据本发明优选地，使用水不溶性碱性化合物作为药丸芯中的第一辅料；更优选地，使药丸芯中包含的水不溶性碱性化合物与第一隔离层中包含的水不溶性碱性化合物相同，由此可以进一步增强隔离层缓冲pH的作用。在根据本发明的实施方案中，水不溶性碱性化合物可以选自，但不限于，氢氧化镁、氢氧化铝、氧化镁、碳酸镁、碳酸钙、氢氧化钙中的一种或更多种。优选地，碱性化合物与艾普拉唑和/或其药学上可接受的盐的重量比为0.2～5:1，优选0.25～4:1，更优选0.3～3:1，尤其优选0.5～2:1，最优选0.8～1.2:1，例如1:1。
根据本发明，在药丸芯中还可以包含表面活性剂。根据本发明的实施例结果证明，表面活性剂可以提高肠溶微丸及其制剂中的艾普拉唑和/或其药学上可接受的盐的溶出度，进而有效地改善它们的生物利用度。在根据本发明的实施例中，药丸芯包含的表面活性剂可以选自非离子表面活性剂、阴离子表面活性剂和两性离子表面活性剂。优选地，非离子表面活性剂可以选自聚乙二醇型、多元醇型(如吐温80)等；阴离子表面活性剂可以选自高级脂肪酸盐、硫酸酯盐、磺酸盐等，如十二烷基硫酸钠；两性离子表面活性剂可以选自磷酯类。
根据本发明，艾普拉唑和/或其药学上可接受的盐的粒径可以影响肠溶微丸的溶出度和/或载药量。在根据本发明的优选实施方案中，艾普拉唑和/或其药学上可接受的盐的粒径可以为粒径D90≤ 100μm；在这种情况下，肠溶微丸具有良好的溶出度，进而可以提高由肠溶微丸制备的肠溶微丸制剂的生物利用度。更优选地，艾普拉唑和/或其药学上可接受的盐的粒径D90可以为选自任意两个下述端点之间的范围：10μm，20μm，30μm，40μm，50μm，60μm，70μm，80μm，90μm，100μm，尤其是D90≤50μm，由此可以达到提高的载药量。
根据本发明的一个实施方案，上述空白微丸芯为现有技术中常规使用的空白微丸芯。在根据本发明的实施方案中，空白微丸芯可以选自，但不限于，微晶纤维素丸芯、蔗糖丸芯或甘露醇丸芯，其粒径可以为50～500μm，优选100～400μm，更优选250～350μm，最优选约300μm。
根据本发明的一个实施方案，如上所述的载药层还可以包含粘合剂。粘合剂可以选自，但不限于，羟丙基纤维素、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙二醇、糖浆和淀粉的一种或更多种。在根据本发明的实施方案中，粘合剂可以选自羟丙基纤维素-SSL(例如来自Nisso的可商购系列)、羟丙甲纤维素E5、聚乙烯吡咯烷酮K30、聚乙烯醇、甲基纤维素和聚乙二醇的一种或更多种。
关于肠溶微丸的隔离层：
肠溶微丸的隔离层的基本功能是用于将处于碱性环境的药丸芯与含游离羧基的肠溶层隔离，以防止艾普拉唑和/或其药学上可接受的盐在包衣过程或在贮存过程中的降解或变色。在针对艾普拉唑肠溶微丸及其制剂的研究中，发明人发现，采用现有技术中的常规制备方法(例如在制备与药丸芯紧密相邻的隔离层时)通常使用的能够防止微丸发生粘连的水不溶性惰性物质(如滑石粉，二氧化硅，二氧化钛，硬脂酸镁等)和/或水溶性碱性化合物，以及在制备与肠溶层紧密相邻的隔离层时通常使用的碱性化合物，会降低肠溶微丸及其制剂的稳定性和/或耐酸性，尤其是对于稳定性相对低的酸不稳定性化合物如艾普拉唑而言，这导致其肠溶微丸及其制剂无法同时达到关于稳定性和耐酸性的要求。在本文中，术语“紧密相邻”是指肠溶微丸的药丸芯与其包衣或包覆层之间或者两个层彼此之间不存在另外的层。
导致该技术问题的原因之一，发明人经试验证明并认为(但不受此局限)，与药丸芯紧密相邻的隔离层(对应于根据本发明的第一隔离层)中包含的能够防止微丸发生粘连的水不溶性惰性物质和药丸芯包含的酸不稳定性化合物两者之间的相容性由于酸不稳定性化合物的不同的稳定性而不同，即：在根据现有技术制备的肠溶微丸及其制剂中，当药丸芯包含的酸不稳定性化合物(如艾普拉唑)的稳定性低时，与药丸芯紧密相邻的隔离层中包含的能够防止微丸发生粘连的水不溶性惰性物质(如滑石粉)与酸不稳定性化合物的相容性也会降低。因此，即使在药丸芯和/或隔离层中包含的作为稳定剂的碱性化合物的保护下，依然会造成加速试验结果中有关物质(即杂质)的明显增加，从而降低肠溶微丸制剂的稳定性。这在一定程度上限制了能够适用于根据现有技术制备的肠溶微丸及其制剂的酸不稳定性化合物的范围，即：根据现有技术制备的肠溶微丸及其制剂的配方或组成无法很好地适用于稳定性相对低的艾普拉唑和/或其药学上可接受的盐。此外，当在与药丸芯紧密相邻的隔离层(对应于根据本发明的第一隔离层)包含水溶性碱性化合物时，在长期的高温高湿条件下，肠溶微丸的隔离层会吸入游离水而导致水溶性碱性化合物溶解，从而使得与肠溶层紧密相邻的隔离层的碱性升高而显碱性，当在酸性介质下肠溶层有水渗入时，造成肠溶层提前溶解，从而导致肠溶微丸及其制剂的耐酸性降低。由于与肠溶层紧密相邻的隔离层显碱性而导致肠溶层提前溶解的原理亦适用于当与肠溶层紧密相邻的隔离层(对应于根据本发明的第二隔离层)中包含碱性化合物的情况。
因此，根据本发明，肠溶微丸包括至少两个包含惰性物质的隔离层，即至少包括靠近药丸芯而与药丸芯紧密相邻的第一隔离层和与第一隔离层相比远离药丸芯或与肠溶层紧密相邻的第二隔离层，其中，第一隔离层包含水不溶性碱性化合物，而不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质，第二隔离层不包含碱性化合物。当肠溶微丸包括三个或以上的隔离层时，位于第一隔离层与第二隔离层之间的其他隔离层可以是符合根据本发明的第一隔离层或者第二隔离层的定义的隔离层，也可以是现有技术中通常使用的隔离层。
根据本发明，水不溶性碱性化合物可以是现有技术中用于提高酸不稳定性化合物的稳定性通常使用的不溶于水的碱性化合物。在根据本发明的实施方案中，水不溶性碱性化合物可以选自，但不限于，氢氧化镁、氢氧化铝、氧化镁、碳酸镁、碳酸钙、氢氧化钙中的一种或更多种。
根据本发明，能够防止微丸发生粘连的水不溶性惰性物质可以选自药剂学中常规的一种或更多种润滑剂、助流剂和抗粘剂(亦即抗黏剂,下文同)一种或更多种。在根据本发明的实施方案中，能够 防止微丸发生粘连的水不溶性惰性物质可以选自，但不限于，二氧化硅、硅酸钙、胶态二氧化硅、硅酸铝、硅酸铝钙、硅酸镁、硬脂酸钠、硬脂酸锌、硬脂酸镁、滑石粉和二氧化钛等。在根据本发明的艾普拉唑肠溶微丸的一个实施方案中，肠溶微丸的第一隔离层中不包含如下能够防止微丸发生粘连的水不溶性惰性物质：滑石粉、二氧化硅、二氧化钛和硬脂酸镁中的一种或更多种。
在根据本发明的优选实施方案中，第一隔离层主要由水不溶性碱性化合物和粘合剂组成，以及第二隔离层主要由能够防止微丸发生粘连的水不溶性惰性物质和粘合剂组成。根据本发明，通过调节第一隔离层中包含的水不溶性碱性化合物与粘合剂的用量或者第二隔离层中包含的能够防止微丸发生粘连的水不溶性惰性物质与粘合剂的用量，能够影响肠溶微丸制剂的溶出度，进而影响其生物利用度。例如，在根据本发明的艾普拉唑肠溶微丸片的优选实施方案中，各成分的配比可以为如下：当艾普拉唑用量为5～15重量份时，第一隔离层中包含粘合剂5～36重量份，水不溶性碱性化合物5～36重量份；第二隔离层中包含粘合剂4～26重量份，能够防止微丸发生粘连的水不溶性惰性物质7～44重量份。
上述粘合剂为根据现有技术的隔离层中通常使用粘合剂。根据本发明，粘合剂可以选自药用合格的水可溶性惰性化合物或用做包衣膜的聚合物，如羟丙基纤维素、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙二醇、糖浆和淀粉中的一种或更多种。
关于肠溶微丸的肠溶层：
在现有技术中的肠溶微丸制剂通常使用的肠溶层也适用于本发明，例如CN87103285A(US4786505的中国同族)中记载了关于肠溶层的详细介绍；发明人将其作为参考，并将所述文献中与肠溶层相关的内容和其中引用的所有文献的相关内容引入本申请中。
根据本发明，肠溶层可以包含一种或更多种选自下组的物质：丙烯酸树脂类、羧甲乙纤维素等纤维素类、欧巴代等的肠溶包衣材料，以及任选的一种或更多种选自增塑剂、抗粘剂、润滑剂的添加剂。在根据本发明的实施方案中，肠溶层可以包含丙烯酸树脂类肠溶包衣材料、增塑剂(如聚乙二醇、三乙酸甘油酯、柠檬酸三乙酯、邻苯二甲酸酯等)、抗粘剂(如滑石粉、单硬脂酸甘油酯等)。其中，丙烯酸树脂类肠溶包衣材料选自醋酸邻苯二甲酸纤维素、邻苯二甲酸羟丙甲基纤维素、甲基丙烯酸共聚物的溶液或分散液L30D55、醋酸琥珀酸羟丙甲基纤维素、聚乙酸邻苯二甲酸乙烯、虫胶中的一种或更多种。在根据本发明的艾普拉唑肠溶微丸的优选实施方案中，肠溶层所含的肠溶包衣材料与艾普拉唑和/或其药学上可接受的盐重量比为2～20:1。在根据本发明的艾普拉唑肠溶微丸的优选实施方案中，增塑剂与艾普拉唑和/或其药学上可接受的盐重量比为0.6～6:1，优选0.8～4:1，更优选1～2:1。
关于肠溶微丸的保护层：
根据本发明，肠溶微丸还可以在肠溶层外侧设有保护层，优选保护层与肠溶层紧密相邻。所述保护层可以防止在制备成制剂之前的放置过程、或者在其制剂的制备过程中、或者制备成制剂后的放置过程中各种半成品/产品之间可能发生的粘连。此外，设置保护层还可以有效地提高肠溶微丸的溶出度，从而改善由其制备的肠溶微丸制剂的生物利用度。
在根据本发明的实施方案中，保护层可以包含粘合剂以及抗粘剂。粘合剂可以选自羟丙甲纤维素、羟丙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、甲基纤维素和聚乙二醇中的一种或更多种。抗粘剂可以选自滑石粉、硬脂酸镁、二氧化钛和二氧化硅中的一种或更多种。
根据本发明，增大保护层中的抗粘剂的用量可以提高肠溶微丸的耐酸性。在根据本发明的艾普拉唑肠溶微丸的优选实施方案中，当艾普拉唑和/或其药学上可接受的盐为5～15重量份时，抗粘剂的用量为0.5～5重量份。
根据本发明的第四方面，本发明提供了肠溶微丸的制备方法，所述方法至少包括以下步骤：1)制备包含艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料的药丸芯；2)包覆第一隔离层和之后包覆第二隔离层；以及3)包覆肠溶层。
优选地，在步骤2)包括：制备包含水不溶性碱性化合物并且不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质的第一混悬液，并将第一混悬液包覆在步骤1)中获得的药丸芯上；制备不包含碱性化合物的第二混悬液，并将第二混悬液包覆为第二隔离层，优选作为与肠溶层紧密相邻的第二隔离层进行包覆；
优选地，在步骤1)中，所述第一辅料与所述第一隔离层包含的水不溶性碱性化合物共同作用， 从而使得艾普拉唑和/或艾普拉唑的药学上可接受的盐实现贮存稳定性。
优选地，肠溶微丸的制备方法还包括步骤4)：包覆保护层。
在根据本发明的实施方案中，肠溶微丸的制备方法可以包括下述步骤的一个或更多个：
1)通过例如流化床法在空白微丸芯上包覆载药层，制备药丸芯，载药层包含艾普拉唑和/或艾普拉唑的药学上可接受的盐、作为第一辅料的碱性化合物以及粘合剂；
2)通过例如流化床法从内向外地分别将至少第一混悬液和第二混悬液包覆到在步骤1)中所获得的药丸芯上，其中，第一混悬液包含水不溶性碱性化合物，而不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质，形成第一隔离层；第二混悬液不包含碱性化合物，形成第二隔离层；由此制备隔离丸；
3)将肠溶包衣材料和选自增塑剂、抗粘剂、润滑剂和乳化剂的一种或更多种制成肠溶层混悬液；通过例如流化床法，将肠溶层混悬液包覆在步骤2)中获得的隔离丸上，制备肠溶微丸。
优选地，上述肠溶微丸的制备方法还可以包括步骤4)：将选自羟丙基纤维素、羟丙甲纤维素、甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、羧甲基纤维素和聚乙二醇中的一种或更多种的粘合剂加入纯化水中，制备保护层包衣液，通过例如流化床法，将保护层包衣液包覆到在步骤3)中所获得的肠溶微丸上，制备具有保护层的肠溶微丸。
根据本发明，可选地，可以使用上述根据本发明的肠溶微丸制备艾普拉唑肠溶微丸制剂，肠溶微丸制剂的剂型可以是片剂、胶囊剂、干混悬剂或者丸剂。
根据本发明的第五方面，本发明提供了一种艾普拉唑肠溶微丸片，该肠溶微丸片包含根据本发明的肠溶微丸和压片辅料(第二辅料，以区别于肠溶微丸的药丸芯中所述的辅料)。
可选地，该肠溶微丸片还包括薄膜衣。
根据本发明，用于制备肠溶微丸片的肠溶微丸可以为包含保护层的肠溶微丸或者不包含保护层的肠溶微丸。
根据本发明，压片辅料可以为本领域现有技术中对肠溶微丸片进行压片时所使用的常规压片辅料。在根据本发明的实施方案中，压片辅料包括填充剂、稀释剂、崩解剂和润滑剂，其中，填充剂和/或稀释剂可以选自，但不限于，淀粉、预胶化淀粉、乳糖、甘露醇以及微晶纤维素中的一种或更多种；崩解剂可以选自，但不限于，交联聚维酮、交联羧甲基纤维素钠和交联羧甲基淀粉钠中的一种或更多种；润滑剂可以选自，但不限于，滑石粉、硬脂酸镁、硬脂富马酸钠和二氧化硅中的一种或更多种。
根据本发明，薄膜衣可以为本领域现有技术中对肠溶微丸片进行薄膜包衣时所使用的常规薄膜衣。在根据本发明的实施方案中，薄膜衣包括包衣粉，包衣粉可以选自，但不限于，羟丙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、甲基纤维素、聚乙二醇、滑石粉、色淀和欧巴代胃溶中的一种或更多种。
将根据本发明的肠溶微丸制备成肠溶微丸片的压片方法，以及可选地包覆薄膜衣的方法，均为本领域现有技术中对肠溶微丸片进行压片和包衣的常规方法。
根据本发明的第六方面，本发明提供了一种艾普拉唑肠溶微丸胶囊，该肠溶微丸胶囊包括根据本发明的具有保护层的上述肠溶微丸。
根据本发明，胶囊可以为本领域现有技术中根据所需用量规格用于填充肠溶微丸时所使用的常规胶囊；例如，胶囊可以为使用胶囊封口材料进行密封的胶囊壳；其中，胶囊的胶囊壳材料可以选自，但不限于，明胶、淀粉、海藻酸钠和羟丙基甲基纤维素中的一种或更多种；该胶囊封口材料可以选自，但不限于，明胶、羟丙甲基纤维素、甲基纤维素、丙烯酸树脂、β-环糊精、乙基纤维素、改性淀粉、醋酸纤维素、聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)和羧甲基纤维素钠中的一种或更多种。
将根据本发明的肠溶微丸制备成肠溶微丸片胶囊的方法，可以为本领域现有技术中制备肠溶微丸胶囊的常规方法。
根据本发明的第七方面，本发明提供了一种艾普拉唑微丸干混悬剂，其包含根据本发明的肠溶微丸和干混悬颗粒。
将根据本发明的肠溶微丸制备成肠溶微丸干混悬剂的方法可以为本领域现有技术中制备肠溶微丸干混悬剂的常规方法。
在已在进行的动物实验研究中，发明人发现，包含根据本发明的肠溶微丸的制剂在胃肠道疾病的治疗和/或预防方面表现出有益的效果，所述胃肠道疾病主要包括胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二 指肠溃疡复发、与NSAID相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病或根除幽门螺旋杆菌、所有级别的糜烂性食管炎、短肠综合征，或者任何以上疾病的组合。
因此，根据本发明的第八方面，本发明提供了一种治疗和/或预防胃肠道疾病的方法。该方法包括给需要此治疗和/或预防的患者施用治疗和/或预防有效量的根据本发明的肠溶微丸制剂的步骤。在根据本发明的实施方案中，根据本发明的肠溶微丸制剂为根据本发明的艾普拉唑肠溶微丸片、艾普拉唑肠溶微丸胶囊或者艾普拉唑肠溶微丸干混悬剂。其中，可使用该方法治疗和/或预防的胃肠道疾病包括，但不限于，胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二指肠溃疡复发、与NSAID相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病或根除幽门螺旋杆菌、所有级别的糜烂性食管炎、短肠综合征，或者任何以上疾病的组合。
相应地，根据本发明的第九方面，本发明提供了根据本发明的肠溶微丸及其制剂在制备治疗和/或预防胃肠道疾病的药物时的用途，所述胃肠道疾病包括，但不限于，胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二指肠溃疡复发、与NSAID相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病或根除幽门螺旋杆菌、所有级别的糜烂性食管炎、短肠综合征，或者任何以上疾病的组合。
更进一步地，本发明的肠溶微丸及其制剂在用于制备治疗和/或预防胃肠道疾病的药物时，所述胃肠道疾病包括，但不限于，十二指肠溃疡及溃疡复发，胃溃疡，胃食管返流疾病(GERD)，幽门螺旋杆菌相关的疾病；或所述药物可用于根除幽门螺旋杆菌，还可以预防非甾体抗炎药造成的消化性溃疡疾病，预防抗血小板聚集药物(包括，但不限于氯吡格雷、普拉格雷、替格瑞洛)等造成的胃肠道出血及相关的溃疡。
在本发明中，发明人发现并排除了制约艾普拉唑肠溶微丸及其制剂无法同时具有良好的稳定性和耐酸性(尤其是耐酸性)的影响因素，并且通过本发明的技术方案，达到了如下的有益效果：
1)通过在艾普拉唑的肠溶微丸中设置至少两个隔离层(第一隔离层和第二隔离层以及任选的其它隔离层)并限定这些隔离层(尤其是第一隔离层和第二隔离层)的组成，根据本发明的肠溶微丸及其制剂能够同时具有更良好的稳定性和耐酸性。
2)通过调节艾普拉唑和/或其药学上可接受的盐的粒径，调节第一隔离层中水不溶性碱性化合物与粘合剂的重量比、或者调节该第二隔离层中能够防止微丸发生粘连的水不溶性惰性物质与粘合剂的重量比，或者额外地包覆保护层，可以使得根据本发明的肠溶微丸及其制剂具有提高的活性成分溶出度，从而可以实现提高的生物利用度。
3)本发明所述的艾普拉唑肠溶微丸及其制剂具有良好的人体内抑酸效果，在服用后1h内就可抑制胃酸到pH 4以上，达到临床起效效果。根据本发明的肠溶微丸片能达到快速起效的效果，从而更快速地解除患者的痛苦。
附图说明
图1为根据本发明的微丸片与具有不同隔离层处方的对比微丸片7和8(图中简称微丸片7、微丸片8)在加速稳定性测试中的累积溶出度。
图2为根据本发明的微丸片与具有不同药丸层的对比微丸片11和16(图中简称微丸片11、微丸片16)在加速稳定性测试中的累积溶出度。
图3为根据本发明的微丸片与具有不同艾普拉唑粒径的药芯丸处方的对比微丸片3和4(图中简称微丸片3、微丸片4)在加速稳定性测试中的累积溶出度。
图4为根据本发明的微丸片与不具有保护层的对比微丸片12(图中简称微丸片12)在加速稳定性测试中的累积溶出度。
图5为根据本发明的微丸片与根据现有技术方法制备的对比微丸片1和对比微丸片2(图中简称微丸片1、微丸片2)在人体胃内pH实时检测平均值记录。
图6为根据本发明的微丸片与根据现有技术方法制备的对比微丸片1和对比微丸片2(图中简称微丸片1、微丸片2)在比格犬体内的血药浓度变化曲线。
具体实施方式
在本章节中，将主要以艾普拉唑的根据本发明的肠溶微丸片剂和干混悬剂为优选例，示例性地示出根据本发明的肠溶微丸制剂及其制备方法。
其中，该艾普拉唑肠溶微丸片包括微丸(其从内向外依次包括药丸芯、第一隔离层、第二隔离层、肠溶层和保护层)、压片辅料和薄膜衣；其中，药丸芯包括空白微丸芯和载药层，载药层包含艾普拉唑和/或艾普拉唑的药学上可接受的盐(其粒径D90优选为≤50μm)、碱性化合物、表面活性剂以及粘合剂；该第一隔离层包含水不溶性碱性化合物和粘合剂，而不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质；该第二隔离层主要包含粘合剂和能够防止微丸发生粘连的水不溶性惰性物质(如可以作为抗粘剂的滑石粉、二氧化硅、二氧化钛、硬脂酸镁等)，而不包含碱性化合物。
优选地，该药丸芯中包含的碱性化合物为水不溶性碱性化合物；更优选地，该药丸芯中包含的水不溶性碱性化合物与该第一隔离层中所包含的水不溶性碱性化合物相同。
具体地，该艾普拉唑肠溶微丸片中各组成及配比可以，但不限于，如下所示：(以重量份为单位)
艾普拉唑肠溶微丸：
1)药丸芯：
空白微丸芯                        5～15；
载药层，包括：
艾普拉唑(或其药学上可接受的盐)5～15；
碱性化合物                        5～15；
表面活性剂                        0.2～0.6；
粘合剂                            8～24；
2)第一隔离层：
粘合剂                            5～36；
水不溶性碱性化合物                5～36；
3)第二隔离层：
粘合剂                            4～26；
抗粘剂                            7～44；
4)肠溶层：
肠溶包衣材料                      30～100(指固含量)；
抗粘剂                            1～5；
增塑剂                            9～30；
5)保护层：
粘合剂                            0.5～4；
抗粘剂                            0.5～5；
压片
6)压片辅料：
填充剂                            100～600；
稀释剂                            50～200；
崩解剂                            5～20；
润滑剂                            1～20；
7)薄膜衣：
包衣粉                            10～40。
该肠溶微丸片同时具有很高的稳定性和耐酸性，适用于稳定性很低的艾普拉唑；并且，该艾普拉唑肠溶微丸片还具有良好的载药量和很高的溶出度/生物利用度。
下面结合具体实施例和附图对本发明作进一步的说明，但本发明不应受到下面公开的具体实施例的限制。下述实施例中所用方法如无特别说明均为常规方法。对下述实施例中的测试数据结果所能够表明的结论，可以是本领域技术人员能够基于本领域常识而合理推论得出的结论，而不局限于下面公 开的文字记载。
实施例1：肠溶微丸的制备
在本实施例1中，将以艾普拉唑和/或其药学上可接受的盐为例，制备根据本发明的肠溶微丸A-G，以及制备用于比较肠溶微丸各组成层的不同处方对肠溶微丸及其制剂的性能的影响的对比微丸3-18。其中，与根据本发明的肠溶微丸A-G相比，对比微丸3和4在载药层中具有不同的艾普拉唑粒径；对比微丸5-10、14-15具有不同的隔离层；对比微丸11、16、17具有改变处方的载药层；以及对微丸12-13具有不同的保护层；对比微丸18具有改变的艾普拉唑和/或其药学上可接受的盐与第一辅料的比例。
(一)肠溶微丸各组成层的制备处方：
1.1含药丸(W)的制备处方、方法、以及其含药丸上药率
在本实施例中制备的是包括空白微丸芯和载药层的含药丸(即药丸芯)。
1)含药丸处方W1(单位：g)
艾普拉唑(粒径D90为46.8μm) 100
蔗糖丸芯(粒径250-350μm) 100
氢氧化镁 100
聚山梨酯80 4
羟丙基纤维素-SSL 150
纯化水 3000
制备过程：
称取150g羟丙基纤维素-SSL、4g聚山梨酯80溶于3000g纯化水中得羟丙基纤维素粘合剂溶液，然后将100g氢氧化镁加入到粘合剂溶液中，采用高剪切分散10000rpm分散5min，然后将D90粒径为46.8μm的艾普拉唑原料100g分散到含氢氧化镁的粘合剂中，10000rpm高剪切分散均匀，然后通过GLATT GPCG-1流化床将艾普拉唑混悬液喷涂到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000001
W 1含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝95.6％
2)含药丸处方W2(单位：g)
艾普拉唑镁(粒径D90≤50μm) 50
微晶纤维素丸芯 50
羟丙基纤维素-SSL 100
十二烷基硫酸钠 2
碳酸镁 150
纯化水 2000
制备过程：
称取处方量100g羟丙基纤维素-SSL、2g十二烷基硫酸钠溶于2000g纯化水中，加入150g碳酸镁高剪切10000rpm分散5min；然后将50g艾普拉唑镁分散到含碳酸镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑镁混悬液喷到微晶纤维素丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000002
Figure PCTCN2021130394-appb-000003
W 2含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝91.4％
3)含药丸处方W3(单位：g)
艾普拉唑锌(粒径D90≤50μm) 150
蔗糖丸芯 150
聚乙烯吡咯烷酮K30 240
十二烷基硫酸钠 6
碳酸钙 150
纯化水 4800
制备过程：
称取处方量240g聚乙烯吡咯烷酮K30、6g十二烷基硫酸钠溶于4800g纯化水中，加入150g碳酸钙10000rpm高剪切分散均匀，然后将150g艾普拉唑锌分散到含碳酸钙的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑锌混悬液喷到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000004
W 3含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝92.4％
4)含药丸处方W4(单位：g)
艾普拉唑(粒径D90≤50μm) 150
甘露醇丸芯 100
聚乙烯吡咯烷酮K30 180
聚山梨酯80 6
氧化镁 50
纯化水 3000
制备过程：
称取处方量180g聚乙烯吡咯烷酮K30、6g聚山梨酯80溶于3000g纯化水中，加入50g氧化镁，10000rpm高剪切分散均匀，然后将150g艾普拉唑分散到含氧化镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑混悬液喷到甘露醇丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000005
W 4含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝93.3％
5)含药丸处方W5(单位：g)
艾普拉唑(粒径D90≤50μm) 150
蔗糖丸芯 150
羟丙甲纤维素E5 80
聚山梨酯80 6
氢氧化镁 50
纯化水 1600
制备过程：
称取处方量80g羟丙甲纤维素E5、6g聚山梨酯80溶于1600g纯化水中，加入50g氢氧化镁，10000rpm高剪切分散均匀，然后将150g艾普拉唑分散到含氢氧化镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑混悬液喷到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000006
W 5含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝94.1％
6)含药丸处方W6(单位：g)
艾普拉唑(粒径D90≤50μm) 100
蔗糖丸芯(250-350μm) 100
羟丙基纤维素-SSL 100
纯化水 3000
制备过程：
称取处方量100g羟丙基纤维素-SSL溶于3000g纯化水中得羟丙基纤维素粘合剂溶液，然后将100g艾普拉唑原料分散到粘合剂溶液中，10000rpm高剪切分散均匀，然后通过GLATT GPCG-1流化床将艾普拉唑混悬液喷涂到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000007
W 6含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝93.4％
7)含药丸处方W7(单位：g)
艾普拉唑(粒径D90≤50μm) 100
蔗糖丸芯(250-350μm) 100
氢氧化镁 100
羟丙基纤维素-SSL 100
纯化水 3000
制备过程：
称取处方量100g羟丙基纤维素-SSL溶于3000g纯化水中得羟丙基纤维素粘合剂溶液，然后将100g艾普拉唑原料和100g氢氧化镁分散到粘合剂溶液中，10000rpm高剪切分散均匀，然后通过GLATT GPCG-1流化床将艾普拉唑混悬液喷涂到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000008
W 7含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝95.4％
8)含药丸处方W8
同含药丸处方W1，不同之处仅在于艾普拉唑粒径D90大于等于80μm且小于等于100μm。W 8含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝87.2％
9)含药丸处方W9
同含药丸处方W1，不同之处仅在于艾普拉唑粒径D90＞100μm。W 9含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝79.3％
10)含药丸处方W10(单位：g)
艾普拉唑(粒径D90为46.8μm) 100
蔗糖丸芯(粒径250-350μm) 100
聚山梨酯80 4
羟丙基纤维素-SSL 150
纯化水 3000
制备过程：
称取150g羟丙基纤维素-SSL、4g聚山梨酯80溶于3000g纯化水中得羟丙基纤维素粘合剂溶液，然后将D90粒径为46.8μm的艾普拉唑原料100g分散到含聚山梨酯80的粘合剂中，10000rpm高剪切分散均匀，然后通过GLATT GPCG-1流化床将艾普拉唑混悬液喷涂到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000009
W 10含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝97.6％
W11)含药丸处方W11(单位：g)
艾普拉唑镁(粒径D90≤50μm) 50
微晶纤维素丸芯 50
羟丙基纤维素-SSL 100
十二烷基硫酸钠 2
碳酸镁 200
纯化水 2000
制备过程：
称取处方量100g羟丙基纤维素-SSL、2g十二烷基硫酸钠溶于2000g纯化水中，加入200g碳酸镁高剪切10000rpm分散5min；然后将50g艾普拉唑镁分散到含碳酸镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑镁混悬液喷到微晶纤维素丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000010
W 11含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝92.5％
12)含药丸处方W12(单位：g)
艾普拉唑(粒径D90≤50μm) 200
蔗糖丸芯 150
羟丙甲纤维素E5 100
聚山梨酯80 6
氢氧化镁 50
纯化水 2000
制备过程：
称取处方量100g羟丙甲纤维素E5、6g聚山梨酯80溶于2000g纯化水中，加入50g氢氧化镁，10000rpm高剪切分散均匀，然后将200g艾普拉唑分散到含氢氧化镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑混悬液喷到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000011
W 12含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝93.8％
13)含药丸处方W13(单位：g)
艾普拉唑(粒径D90≤50μm) 180
微晶纤维素丸芯 50
羟丙基纤维素-SSL 100
十二烷基硫酸钠 2
碳酸镁 30
纯化水 2000
制备过程：
称取处方量100g羟丙基纤维素-SSL、2g十二烷基硫酸钠溶于2000g纯化水中，加入30g碳酸镁高剪切10000rpm分散5min；然后将180g艾普拉唑分散到含碳酸镁的粘合剂中，10000rpm高剪切分散均匀，通过GLATT GPCG-1流化床，将艾普拉唑混悬液喷到微晶纤维素丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000012
W 13含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％＝94.5％
1.2隔离层(G)的制备处方
1)隔离层处方G1(单位：g)
Figure PCTCN2021130394-appb-000013
制备过程：
称取处方量10g羟丙基纤维素-SSL溶于200g纯化水中，然后加入10g碳酸镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取8g羟丙基纤维素-SSL溶于160g纯化水中，加入14g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先 后将两层隔离衣混悬液，喷到含药丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000014
2)隔离层处方G2(单位：g)
Figure PCTCN2021130394-appb-000015
制备过程：
称取处方量23g羟丙基纤维素-SSL溶于460g纯化水中，然后加入23g碳酸镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取17.2g羟丙基纤维素-SSL溶于344g纯化水中，加入28.8g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液，喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
3)隔离层处方G3(用于对比微丸7)(单位：g)
Figure PCTCN2021130394-appb-000016
制备过程：
称取处方量88g羟丙基纤维素-SSL溶到1140g纯化水中，然后加入88g碳酸镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取17.2g羟丙基纤维素-SSL溶到520g纯化水中，加入28.8g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
4)隔离层处方G4(用于对比微丸9)(单位：g)
Figure PCTCN2021130394-appb-000017
Figure PCTCN2021130394-appb-000018
制备过程：
称取处方量23g羟丙基纤维素-SSL溶于460g纯化水中，然后加入23g碳酸镁、11.5g滑石粉，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取17.2g羟丙基纤维素-SSL溶于344g纯化水中，加入28.8g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
5)隔离层处方G5(用于对比微丸10)(单位：g)
Figure PCTCN2021130394-appb-000019
制备过程：
称取处方量23g羟丙基纤维素-SSL溶于460g纯化水中，然后加入23g碳酸钠，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取17.2g羟丙基纤维素-SSL溶于344g纯化水中，加入28.8g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
6)隔离层处方G6(用于对比微丸5)(单位：g)
艾普拉唑含药丸 90
羟丙基纤维素SSL 33
滑石粉 57
纯化水 890
制备过程：
称取处方量33g羟丙基纤维素-SSL溶于890g纯化水中，然后加入57g滑石粉，10000rpm高剪切分散均匀，制备隔离衣混悬液。通过GLATT GPCG-1流化床，将隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
7)隔离层处方G7(用于对比微丸6)(单位：g)
Figure PCTCN2021130394-appb-000020
制备过程：
称取处方量23g聚维酮K30溶于460g纯化水中，然后加入23g二氧化钛，10000rpm高剪切分 散均匀，制备第一层隔离衣混悬液。称取26g聚维酮K30溶于520g纯化水中，然后加入44g二氧化硅，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液；通过GLATT GPCG-1流化床，先后将两层隔离混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
8)隔离层处方G8(用于对比微丸8)(单位：g)
Figure PCTCN2021130394-appb-000021
制备过程：
称取处方量23g羟丙基纤维素-SSL溶于720g纯化水中，然后加入23g碳酸镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取52g羟丙基纤维素-SSL溶于1040g纯化水中，加入100g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
9)隔离层处方G9(用于对比微丸14)(单位：g)
Figure PCTCN2021130394-appb-000022
制备过程：
称取处方量10g羟丙基纤维素-SSL、5g碳酸钠、5g滑石粉溶于200g纯化水中，制备第一层隔离衣混悬液。称取8g羟丙基纤维素-SSL溶于160g纯化水中，加入14g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
10)隔离层处方G10(单位：g)
Figure PCTCN2021130394-appb-000023
制备过程：
称取处方量15g羟丙甲纤维素-E5溶于300g纯化水中，然后加入15g氧化镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取12g羟丙甲纤维素-E5溶于240g纯化水中，加入21g二氧化钛，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
11)隔离层处方G11(单位：g)
Figure PCTCN2021130394-appb-000024
制备过程：
称取处方量20g羟丙基纤维素-SSL溶于400g纯化水中，然后加入20g氢氧化镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取8g羟丙基纤维素-SSL溶于160g纯化水中，加入14g滑石粉，10000rpm高剪切分散均匀，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
12)隔离层处方G12(单位：g)
Figure PCTCN2021130394-appb-000025
制备过程：
称取处方量23g羟丙基纤维素-SSL溶于460g纯化水中，然后加入23g氢氧化镁，10000rpm高剪切分散均匀，制备第一层隔离衣混悬液。称取46g羟丙基纤维素-SSL溶于920g纯化水中，制备第二层隔离衣混悬液。通过GLATT GPCG-1流化床，先后将两层隔离衣混悬液喷到含药丸芯上。
具体工艺参数参见上述隔离层处方G1。
1.3肠溶层(C)的制备处方
肠溶层处方C1(单位：g)
艾普拉唑隔离丸 92
尤特奇L30D-55 223.8
滑石粉 3.4
柠檬酸三乙酯 20.1
纯化水 447.6
制备过程：
称取处方量20.1g柠檬酸三乙酯溶于447.6g纯化水中，加入3.4g滑石粉，10000rpm高剪切分散均匀，然后与223.8g尤特奇L30D-55搅拌45min制得肠溶层包衣液备用，通过GLATT GPCG-1流化床将肠溶层包衣液喷到隔离微丸上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000026
1.4保护层(B)的制备
1)保护层处方B1(单位：g)
艾普拉唑肠溶微丸 100
羟丙甲纤维素E5 2.5
硬脂酸镁 1.2
纯化水 50
制备过程：
称取处方量2.5g羟丙甲纤维素E5溶于50g纯化水中，然后加入1.2g硬脂酸镁，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000027
2)保护层处方B2(单位：g)
艾普拉唑肠溶微丸 100
羟丙基纤维素-SSL 0.5
硬脂酸镁 0.5
纯化水 10
制备过程：
称取处方量0.5g羟丙基纤维素-SSL溶于10g纯化水中，然后加入0.5g硬脂酸镁，3000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数参见上述保护层处方B1。
3)保护层处方B3(单位：g)
艾普拉唑肠溶微丸 100
羟丙基纤维素-SSL 4
硬脂酸镁 5
纯化水 80
制备过程：
称取处方量4g羟丙基纤维素-SSL溶于80g纯化水中，然后加入5g硬脂酸镁，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数参见上述保护层处方B1。
4)保护层处方B4(单位：g)
Figure PCTCN2021130394-appb-000028
制备过程：
称取处方量2.5g羟丙基纤维素-SSL溶于50g纯化水中，然后加入1.2g滑石粉，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数参见上述保护层处方B1。
5)保护层处方B5(单位：g)
艾普拉唑肠溶微丸 100
羟丙基纤维素-SSL 2.5
二氧化钛 1.2
纯化水 50
制备过程：
称取处方量2.5g羟丙基纤维素-SSL溶于50g纯化水中，然后加入1.2g二氧化钛，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数参见上述保护层处方B1。
6)保护层处方B6(用于对比微丸13)(单位：g)
艾普拉唑肠溶微丸 100
羟丙甲纤维素E5 2.5
硬脂酸镁 0.2
纯化水 50
制备过程：
称取处方量2.5g羟丙甲纤维素E5溶于50g纯化水中，然后加入0.2g硬脂酸镁，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数参见上述保护层处方B1。
(二)制备肠溶微丸：
1)制备根据本发明的肠溶微丸：
根据上述章节(一)中列举出的肠溶微丸各组成层的处方，制备如下表1所示的根据本发明的肠溶微丸A-G。
表1：根据本发明的肠溶微丸(片)A-G的处方组成。
Figure PCTCN2021130394-appb-000029
其中，W x含药丸上药率＝(含药丸实际含量)/(含药丸理论含量)×100％
2)制备对比微丸3-16：
根据上述章节(一)中列举出的肠溶微丸各组成层的处方，制备如下表2-1和2-2所示的对比微丸3-15。
表2-1：主要用于隔离层研究的对比微丸(片)5-10、14-15的处方组成。
Figure PCTCN2021130394-appb-000030
Figure PCTCN2021130394-appb-000031
*：为了便于针对各数据之间的比较，在此使用了具有统一粒径D90的艾普拉唑。根据本发明，本领域技术人员应该知晓，粒径D90并不局限于此。
表2-2：用于肠溶微丸组成层研究的对比微丸(片)3-4、11-13、16-18的处方组成。
Figure PCTCN2021130394-appb-000032
*：为了便于针对各数据之间的比较，在此使用了具有统一(或具体)粒径D90的艾普拉唑。根据本发明，本领域技术人员应该知晓，粒径D90并不局限于此。
实施例2：肠溶微丸片的制备
在本实施例2中，将在实施例1中所制备的根据本发明的肠溶微丸A-G、以及对比微丸3-18制备成根据本发明的肠溶微丸片A-G、以及对比微丸片3-18。此外，还根据现有技术的肠溶微丸片的制备方法，以艾普拉唑(粒径D90为46.8μm，以便于数据之间的比较)为药物活性物质，制备了对比微丸片1(根据CN1134666A)和对比微丸片2(根据CN102525990A)。
2.1制备根据本发明的肠溶微丸片A-G、以及对比微丸片3-18
通过如下压片、包衣的步骤，将在上表1和表2-1、2-2中所示出的肠溶微丸分别制备成肠溶微丸片：
1)制备微丸压片(单位：g)
艾普拉唑外包衣微丸 200
微晶纤维素PH102 339.2
交联聚维酮-XL 113.1
硬脂富马酸钠 12.8
片剂制备过程：
将艾普拉唑肠溶外包衣微丸与微晶纤维素PH102、交联聚维酮-XL、硬脂富马酸钠根据上述处方量放入3升混料斗中，10rpm混合15min。然后置于压片机进行压片，片剂硬度8-12kg，片重折合每片含艾普拉唑5mg。
2)微丸片剂包衣(单位：g)
微丸片 400
欧巴代包衣粉 20
纯化水 166.5
包衣制备过程：
称取欧巴代包衣液20g，溶于166.5g纯化水中，采用高效包衣锅对艾普拉唑微丸片进行包衣。
2.2制备对比微丸片1：
根据CN1134666A实施例16中肠溶微丸片的制备方法和工艺，采用实施例15的外包衣，以艾普拉唑为药物活性物质，并在载药层添加了表面活性剂，制备了对比微丸片1。方法具体如下：
1)含药丸的制备
含药丸处方(单位：g)
蔗糖丸芯 100
艾普拉唑 148
羟丙甲纤维素E5 22
聚山梨酯80 3
纯化水 700
制备过程：
称取150g羟丙甲纤维素E5、3g吐温80溶于纯化水中得羟丙甲纤维素粘合剂溶液，然后将粒径D90小于50μm的艾普拉唑原料分散到粘合剂中，10000rpm分散5min，然后通过GLATT GPCG-1流化床将艾普拉唑混悬液喷涂到蔗糖丸芯上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000033
2)隔离丸的制备
隔离丸处方(单位：g)
艾普拉唑含药丸 103
羟丙基纤维素-SSL 11
滑石粉 42.5
硬脂酸镁 2.75
纯化水 387.5
制备过程：
称取103g羟丙基纤维素-SSL溶于387.5g纯化水中得羟丙基纤维素粘合剂溶液，然后将42.5g滑石粉、2.75g硬脂酸镁加入到粘合剂溶液中，采用高剪切分散10000rpm分散5min，然后通过GLATT GPCG-1流化床将隔离层包衣液喷涂到艾普拉唑含药丸上。具体工艺参数如下：
具体工艺参数如下：
Figure PCTCN2021130394-appb-000034
3)肠溶丸的制备
肠溶丸处方(单位：g)
Figure PCTCN2021130394-appb-000035
制备过程：
称取1.8g聚山梨酯80、3.8g柠檬酸三乙酯、1.9g单硬脂酸甘油酯溶于50g的70℃纯化水中，高剪切5000rpm，5min，放置至室温，然后与127g尤特奇L30D-55搅拌45min备用，通过GLATT GPCG-1流化床将肠溶包衣液喷到隔离微丸上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000036
Figure PCTCN2021130394-appb-000037
4)保护层微丸的制备
保护层处方(单位：g)
艾普拉唑肠溶丸 171.3
羟丙甲纤维素E5 2.5
硬脂酸镁 0.08
纯化水 51.3
制备过程：
称取2.5g羟丙基纤维素E5溶于51.3g纯化水中，然后加入0.08g硬脂酸镁，5000rpm高剪切分散均匀，制得保护层包衣液。通过GLATT GPCG-1流化床，将保护层包衣液喷到肠溶微丸上。
具体工艺参数如下：
Figure PCTCN2021130394-appb-000038
5)微丸压片的制备(单位：g)
艾普拉唑肠溶包衣微丸 173.9
微晶纤维素PH102 869.5
交联聚维酮 17.39
硬脂富马酸钠 17.39
片剂制备过程：
将艾普拉唑肠溶包衣微丸与微晶纤维素、交联聚维酮、硬脂富马酸钠根据上述处方量放入3升混料斗中，10rpm混合15min。然后置于压片机进行压片，片剂硬度8-12kg，片重折合每片含艾普拉唑5mg。
6)微丸片剂包衣的制备(单位：g)
微丸片 1000
欧巴代包衣粉 40
纯化水 333
称取欧巴代包衣液40g，溶于333g纯化水中，采用高效包衣锅对艾普拉唑微丸片进行包衣。制得对比微丸片1。
2.3制备对比微丸片2：
根据CN102525990A的肠溶微丸片的制备方法，以艾普拉唑为药物活性物质，制备了对比微丸片2。
1)含药丸芯的制备
含药丸芯的处方(单位：g)
蔗糖丸芯 300
艾普拉唑 30
氧化镁 3
羟丙甲纤维素 10
80％(v/v)乙醇水溶液 850
制备过程：
取空白蔗糖丸芯(0.25～0.3mm)，用50目和60目分别筛分，取50目到60目之间微丸进行上药。上药溶液配制方法：将上述处方量的羟丙基甲基纤维素、氧化镁溶于80％(v/v)乙醇水溶液中，用4％(m/v)的氢氧化钠溶液调节溶液pH约为12，加入处方量艾普拉唑，搅拌均匀。上药溶液粘度为13.22cp。
具体工艺参数见下：
Figure PCTCN2021130394-appb-000039
制得浅黄色艾普拉唑微丸310g，收率为90.3％。
2)隔离丸的制备
隔离丸的处方(单位：g)
艾普拉唑含药素丸 300
HPMC 5CP 15
滑石粉 50
80％v/v乙醇水溶液 535
制备过程：
取含药微丸300g，隔离液需调节pH值至10.5以上再进行包衣，隔离层溶液粘度为15.24cp，操作参数见下表：
Figure PCTCN2021130394-appb-000040
制得微丸345g，收率为94.5％。
3)肠溶丸的制备
肠溶丸的处方(单位：g)
艾普拉唑隔离丸 150
尤特奇L30D-55 180
聚乙二醇6000 10
吐温80 0.3
水 200
制备过程：
向尤特奇L30D-55中加入4％(m/v)氢氧化钠水溶液6.5ml，在搅拌下加入聚乙二醇6000，过 80目筛。取隔离丸进行肠溶衣包覆操作。主要参数为：物料温度25～30℃，进风温度28～35℃，喷液速度10～30rpm，风机频率30-40。制得微丸214.1g，收率为99.9％。
4)微丸压片的制备
微丸压片处方(单位：g)
艾普拉唑肠溶包衣微丸 150
预胶化淀粉 50
淀粉 50
甘露醇 50
微晶纤维素PH101 240
4％淀粉浆 10
按照表中处方量进行混合，压片，片重314.9mg。制得对比微丸片2。
实施例3：肠溶微丸胶囊的制备
将600g艾普拉唑保护层包衣微丸A(W 1+G 2+C 1+B 1)通过胶囊填充剂装入3号胶囊壳中，每粒胶囊中+包含5mg艾普拉唑。
实施例4：肠溶微丸片和胶囊的性能测试
在本实施例4中，对上述实施例中制备的肠溶微丸片和胶囊进行了含量、溶出度、有关物质等测试，并以根据本发明的微丸片A为参照物，比较了对比微丸片3-16的各项检测结果。测试方法具体如下：
1.含量测定：
1)操作方法：(通用方法参见《中国药典》2015年版四部通则0512)
具体方法如下：
供试品溶液制备：取有关物质项下供试品溶液，精密量取5mL，置50mL量瓶中，用流动相稀释至刻度，摇匀，滤过，取续滤液作为供试品溶液。
对照品溶液制备：取艾普拉唑对照品适量，精密称定，加稀释剂溶解并稀释制成每1mL中约含20μg的溶液，作为对照品溶液。
系统适用性溶液：取杂质Ⅰ(艾普拉唑砜，化学名称：2-[[(4-甲氧基-3-甲基)-2-吡啶基]甲基]-磺酰基-5-(1H-吡咯-1-基)-1H-苯并咪唑)对照品与艾普拉唑对照品适量，加稀释剂溶解并稀释制成每1mL中含杂质Ⅰ与艾普拉唑各20μg的溶液。
色谱条件：用十八烷基硅烷键合硅胶为填充剂，以乙腈400mL用磷酸盐缓冲溶液(取磷酸氢二钾2.28g，加水溶解并稀释至1000mL，用磷酸调pH至7.5)稀释至1000mL为流动相，流速为1.0mL/min，检测波长为237nm；柱温25℃。
系统适用性要求：系统适用性溶液色谱图中，理论板数按艾普拉唑峰计算不低于2500，杂质Ⅰ峰与艾普拉唑峰间的分离度应符合规定。
测定法：分别精密量取对照品溶液及供试品溶液20μL，注入液相色谱仪，记录色谱图。
2)计算方法：按外标法以峰面积计算10片的平均含量。
3)标准规定：含艾普拉唑(C19H18N4O2S)应为标示量的90.0％～110.0％。
2.溶出度测定：
1)操作方法：按照溶出度与释放度测定法(通用方法参见《中国药典》2015年版四部通则0931第二法方法1)测定。具体方法如下：
取本品，以0.1mol/L盐酸溶液(取盐酸9.0mL，加水至1000mL)300mL为溶出介质，转速为每分钟100转，依法操作，经120分钟时，随即在各溶出杯中加入预热至37±0.5℃的0.086mol/L磷酸氢二钠溶液(取30.8g磷酸氢二钠和7g吐温80，加水至1000mL)700mL，混匀，转速不变，继续依法操作，经45分钟时取样。
供试品溶液：取溶出液适量，滤过，精密量取续滤液5mL，立即精密加入0.15mol/L氢氧化钠溶液1mL，摇匀，滤过，取续滤液作为供试品溶液。
对照品溶液：艾普拉唑对照品约10mg，精密称定，置20mL量瓶中，加乙腈适量使溶解，用乙腈稀释至刻度，摇匀，精密量取1mL置100mL量瓶中，用磷酸盐缓冲液(pH6.8)(取0.086mol/L 磷酸氢二钠溶液700mL与0.1mol/L盐酸溶液300mL，混匀，即得)稀释至刻度，摇匀，精密量取5mL，立即精密加入0.05mol/L氢氧化钠溶液1mL，摇匀，滤过，取续滤液作为对照品溶液。
照含量测定项下的方法测定，计算每片溶出量。
3.有关物质测试：
1)操作方法：按照高效液相色谱法(通用方法参见《中国药典》2015年版四部通则0512)测定。具体方法如下：
稀释剂：0.05mol/L氢氧化钠-甲醇-水＝50:20:30
供试品溶液：取本品10片，置250mL量瓶中，加0.05mol/L氢氧化钠溶液125mL，置振荡器中振摇(250转/分钟)20分钟，加50mL甲醇超声10分钟，用水稀释至刻度，摇匀，离心，取上清液。
对照溶液：精密量取供试品溶液适量，用稀释剂稀释制成每1mL中约含艾普拉唑1μg的溶液。
灵敏度溶液：精密量取对照溶液1mL，置10mL量瓶中，用稀释剂稀释至刻度，摇匀。
杂质Ⅰ对照品贮备液：取杂质Ⅰ约6mg，置100mL量瓶中，用稀释剂稀释至刻度。
系统适用性溶液：取艾普拉唑对照品约3mg，置10mL量瓶中，加稀释剂适量使溶解，精密加入杂质Ⅰ对照品贮备液1mL，用稀释液稀释至刻度，摇匀。
色谱条件：用十八烷基硅烷键合硅胶为填充(Gemini-NX C18 150×4.6mm，5μm或效能相当的色谱柱)，以0.01mol/L磷酸氢二钾溶液(用10％磷酸调节pH值至7.5)为流动相A，以乙腈为流动相B，按下表进行线性梯度洗脱；流速为1.0mL/min；检测波长为237nm；柱温25℃。
时间(min) 流动相A(％) 流动相B(％)
0 77 23
5 66 34
15 50 50
40 50 50
40.5 77 23
50 77 23
系统适用性溶液要求：系统适用性溶液色谱图中，杂质Ⅰ峰与艾普拉唑峰之间的分离度应大于2.0。灵敏度溶液色谱图中，艾普拉唑峰峰高的信噪比应大于10。
测定法：精密量取供试品溶液和对照溶液各20μL，分别注入液相色谱仪，记录色谱图。
4.1根据本发明的肠溶微丸片和胶囊的稳定性测试及耐酸性测试
1)在本实施例中，对根据本发明的肠溶微丸片A-G及实施例3胶囊进行了加速稳定性考察，具体方法如下：
试验方案：将肠溶微丸片A-G和实施例3胶囊分别用HDPE瓶包装，每瓶14片(粒)，将包装后的微丸片或胶囊放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方肠溶微丸片或胶囊的有关物质。检测而得的肠溶微丸片A-G和实施例3胶囊的稳定性数据如下表3-1所示：
表3-1：根据本发明的肠溶微丸片A-G和实施例3胶囊的稳定性数据：
时间 微丸片A 微丸片B 微丸片C 微丸片D 微丸片E 微丸片F 微丸片G 胶囊
0天 0.12％ 0.16％ 0.19％ 0.15％ 0.13％ 0.18％ 0.26％ 0.20％
1个月 0.15％ 0.22％ 0.26％ 0.24％ 0.20％ 0.36％ 0.54％ 0.34％
3个月 0.36％ 0.25％ 0.89％ 0.77％ 0.97％ 0.47％ 0.87％ 0.58％
6个月 0.87％ 1.07％ 1.28％ 0.82％ 0.99％ 0.68％ 1.02％ 0.98％
从表3-1中可以看出，由根据本发明的肠溶微丸制备而成的微丸片A-G和胶囊具有良好的稳定性，其总杂质不超过1.5％。
2)在本实施例中，对根据本发明的肠溶微丸片A-G及实施例3胶囊进行了耐酸性考察，具体方法如下：
取肠溶微丸片A-G及胶囊样品各6片，以0.1mol/L盐酸溶液(取盐酸9.0mL，加水至1000mL)300mL为溶出介质，转速为每分钟100转，依法操作，经120分钟时，取出溶出杯，采用抽滤装置，过滤掉盐酸，剩余微丸收集到50mL容量瓶中，加入20mL 0.05mol/L氢氧化钠溶液，置振荡器中振 摇(250转/分钟)20分钟，加30mL甲醇超声10分钟，用水稀释至刻度，摇匀，离心，取上清液。测定微丸中剩余的药物含量，即样品的耐酸性。
表3-2:根据本发明的肠溶微丸片A-G和实施例3胶囊的耐酸性数据：
时间 微丸片A 微丸片B 微丸片C 微丸片D 微丸片E 微丸片F 微丸片G 胶囊
0天 99.6％ 99.1％ 97.9％ 96.5％ 97.4％ 98.4％ 98.7％ 96.8％
1个月 98.8％ 98.6％ 98.2％ 96.8％ 97.8％ 98.2％ 98.5％ 96.3％
3个月 98.3％ 97.9％ 98.1％ 95.9％ 98.2％ 98.1％ 97.8％ 97.2％
6个月 98.2％ 98.0％ 97.6％ 95.6％ 97.5％ 97.6％ 97.9％ 96.6％
从表3-2中可以看出，由根据本发明的肠溶微丸制备而成的肠溶微丸片A-G和胶囊具有良好的耐酸性，耐酸性都在90％以上。
4.2肠溶微丸片的稳定性和耐酸性测试：
在本实施例4.2中，以肠溶微丸片为例，比较了肠溶微丸片的成分及配比对其稳定性和耐酸性的影响。
4.2.1肠溶微丸所包含的隔离层的成分的影响：
1)根据本发明的肠溶微丸片A与对比微丸片5、6、9、10和14的稳定性测试比较：
在本实施例中，对根据本发明的肠溶微丸片A与对比微丸片5、6、9、10和14进行了加速稳定性考察。其中，相比于根据本发明的肠溶微丸片A，对比微丸片5仅具有一层不包含碱性化合物的惰性物质隔离层；对比微丸片6、9、10和14均具有与药丸芯紧密相邻的第一隔离层和与肠溶层紧密相邻的第二隔离层，然而，在对比微丸片6中，第一隔离层包括粘合剂和抗粘剂，不包含碱性化合物；在对比微丸片9中，该第一隔离层为混合层(所谓混合层是指除了包含粘合剂，还同时包含碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质的层)，且其所包含的碱性化合物为水不溶性碱性化合物；在对比微丸片10中，该第一隔离层为主要包含粘合剂和水溶性碱性化合物的碱性层；在对比微丸片14中，该第一隔离层为混合层，且其包含作为碱性化合物的水溶性碱性化合物。
试验方案：将根据本发明的肠溶微丸片A和对比微丸片5、6、9、10和14分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方微丸片的有关物质。所测得的微丸片的稳定性数据如下表4-1所示：
表4-1：根据本发明的微丸片A与对比微丸片5、6、9、10和14的稳定性数据：
时间 微丸片A 对比微丸片5 对比微丸片6 对比微丸片9 对比微丸片10 对比微丸片14
0天 0.12％ 0.35％ 0.89％ 0.24％ 0.20％ 0.49％
1个月 0.15％ 0.72％ 1.26％ 0.63％ 0.43％ 0.61％
3个月 0.36％ 1.25％ 1.89％ 0.96％ 0.66％ 1.05％
6个月 0.87％ 1.87％ 2.68％ 1.79％ 0.89％ 1.68％
从表4-1中可以看出，对于稳定性低的艾普拉唑，当其肠溶微丸片仅包含一层隔离层(即对比微丸片5)时，无法满足稳定性的要求(即总杂质不超过1.5％)。当该肠溶微丸片至少包含第一隔离层和第二隔离层时，这些隔离层的成分也会对其稳定性造成影响，例如：当第一隔离层为包含碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质的混合层(即对比微丸片9和14)时，即使是有碱性化合物保护的情况下，有关物质依然明显增加(总杂质含量分别为1.79％和1.68％)，无法满足稳定性的要求；与之相比，当第一隔离层为包含碱性化合物而不包含能够防止微丸发生粘连的水不溶性惰性物质的碱性层(例如微丸片A和对比微丸片10)时，该肠溶微丸片具有良好的稳定性；此外，对于稳定性低的艾普拉唑，当其肠溶微丸片仅在药丸芯中包含碱性化合物(即对比微丸片6)时，无法满足稳定性的要求(即总杂质不超过1.5％)。
2)根据本发明的肠溶微丸片A与对比微丸片10、14、15的耐酸性比较：在本例中，对根据本发明的肠溶微丸片A和对比微丸片10、14、15进行了耐酸性测试。其中，相比于根据本发明的肠溶微丸片A，对比微丸片15与其的不同之处在于：对比微丸片15的第二隔离层中不包含能够防止微丸发生粘连的水不溶性惰性物质。具体方法如下：
将根据本发明的肠溶微丸片A和对比微丸片10、14和15分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，随后，以0.1mol/L 盐酸溶液(取盐酸9.0mL，加水至1000mL)300mL为溶出介质，转速为每分钟100转，依法操作，经120分钟时，取出溶出杯，采用抽滤装置，过滤掉盐酸，剩余微丸收集到50mL容量瓶中，加入20mL 0.05mol/L氢氧化钠溶液，置振荡器中振摇(250转/分钟)20分钟，加30mL甲醇超声10分钟，用水稀释至刻度，摇匀，离心，取上清液。测定微丸中剩余的药物含量，即样品的耐酸性。所测得的微丸片的耐酸性数据如下表4-2所示：
表4-2：根据本发明的肠溶微丸片A与对比微丸片10、14、15的耐酸性数据比较。
时间 微丸片A 对比微丸片10 对比微丸片14 对比微丸15
0天 96.7％ 96.2％ 95.3％ 97.9％
1个月 95.9％ 95.6％ 92.1％ 97.6％
3个月 95.5％ 92.1％ 87.5％ 95.5％
6个月 95.3％ 85.6％ 82.5％ 96.3％
从表4-2中的结果可以看出，在加速条件下，在稳定性测试中原本稳定性就较低的对比微丸片(如对比微丸片14)的耐酸性也较低；相比于根据本发明的肠溶微丸片A，具有包含不同碱性化合物种类(即水溶性碱性化合物)的第一隔离层的对比微丸片10的耐酸性逐渐变差(6个月时，该对比微丸片10中剩余的艾普拉唑含量为85.6％)，低于所需达到的标准(即6片耐酸平均值不低于90％)。也就是说，虽然以碱性化合物作为第一隔离层可以使得该肠溶微丸片具有良好的稳定性，然而，碱性化合物的种类会影响该肠溶微丸片的耐酸性。与包含水溶性碱性化合物的第一隔离层相比，根据本发明，将包含水不溶性碱性化合物的隔离层作为肠溶微丸片的第一隔离层，可以改善并提高该肠溶微丸片的耐酸性。此外，还可以从表4-2中看出，第二隔离层中不包含能够防止微丸发生粘连的水不溶性惰性物质的对比微丸片15的耐酸性没有受到影响。
综上可知，关于肠溶微丸所包括的各种隔离层成分，设置至少两层隔离层，并且针对与药丸芯紧密相邻的第一隔离层而言，当该第一隔离层包含水不溶性碱性化合物，而不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质时，可以使得由此肠溶微丸制备而得的艾普拉唑肠溶微丸片同时具备很好的稳定性和耐酸性。
4.2.2根据本发明的肠溶微丸所包括的隔离层中各成分的配比的影响：
1)根据本发明的肠溶微丸片A与对比微丸片7、8的稳定性测试比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片7、8进行了加速稳定性考察。其中，与根据本发明的肠溶微丸片A相比，在对比微丸片7中，第一隔离层中所含的水不溶性碱性化合物用量较大，例如，当艾普拉唑用量为10份，第一隔离层中所含的水不溶性碱性化合物用量大于36份；在对比微丸片8中，第二隔离层中所包含的抗粘剂(相当于根据本发明的能够防止微丸发生粘连的水不溶性惰性物质)用量较大，例如，当艾普拉唑用量为10份，第二隔离层中抗粘剂用量大于44份。
其具体方法如下：
将根据本发明的肠溶微丸片A和对比微丸片7、8分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方肠溶微丸片的有关物质。所测得的肠溶微丸片的稳定性数据如下表5-1所示：
表5-1：根据本发明的肠溶微丸片A与对比微丸片7、8的稳定性数据：
时间 微丸片A 对比微丸片7 对比微丸片8
0天 0.12％ 0.25％ 0.23％
1个月 0.15％ 0.34％ 0.50％
3个月 0.36％ 0.67％ 0.87％
6个月 0.87％ 0.92％ 0.95％
从表5-1中的结果可以看出，相比于根据本发明的肠溶微丸片A，具有不同隔离层组分配比的对比微丸片7(在第一隔离层的配比不同)和8(在第二隔离层的配比不同)的稳定性依然处于标准范围内(总杂质不超过1.5％)。也就是说，隔离层组分配比的改变，不会影响该肠溶微丸片的稳定性。
2)根据本发明的肠溶微丸片A与对比微丸片7、8的耐酸性比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片7、8进行了耐酸性检测。具体方法参考4.2.1中耐酸性考察。
其结果如下表5-2中所示：
表5-2：根据本发明的肠溶微丸片A与对比微丸片7、8的耐酸性数据。
时间 微丸片A 对比微丸片7 对比微丸片8
0天 96.7％ 95.6％ 96.4％
1个月 95.9％ 95.8％ 95.8％
3个月 95.5％ 96.1％ 96.2％
6个月 95.3％ 95.4％ 94.6％
从表5-2所示出的结果可以看出，相比与于根据本发明的肠溶微丸片A，具有不同隔离层组分配比的对比微丸片7(在第一隔离层的配比不同)和8(在第二隔离层的配比不同)的耐酸性依然处于标准范围内(即6片耐酸平均值不低于90％)。也就是说，隔离层组分配比的改变，不会影响该肠溶微丸片的耐酸性。
综上可知，在肠溶微丸的隔离层中各组分配比的改变，不会影响由该肠溶微丸制备而成的肠溶微丸片的稳定性和耐酸性。
4.2.3根据本发明的肠溶微丸片A、F、G与微丸片17、18的耐酸性比较：
在本实施例中，对根据本发明的肠溶微丸片A、F、G与微丸片17、18进行了耐酸性检测。具体方法参考4.2.1中耐酸性考察。
其结果如下表5-3中所示：
表5-3：根据本发明的肠溶微丸片A、F、G与微丸片17、18的耐酸性数据。
时间 微丸片A 微丸片G 微丸片H 对比微丸片17 对比微丸片18
0天 96.7％ 98.4％ 98.7％ 96.1％ 97.1％
1个月 95.9％ 98.2％ 98.5％ 92.4％ 96.5％
3个月 95.5％ 98.1％ 97.8％ 90.5％ 95.6％
6个月 95.3％ 97.6％ 97.9％ 88.1％ 94.8％
从表5-3所示出的结果可以看出，对比微丸片17耐酸性降低，因为微丸片17在加速稳定性条件下药物降解，从而导致测定的耐酸数值降低。微丸片18的耐酸数值也有降低，也是由于加速过程中，有部分艾普拉唑降解导致。而采用本发明的药丸芯的配方的微丸片A、G、H均能得到很好的耐酸性值。
4.3肠溶微丸所包括的药丸芯组成对其肠溶微丸片的稳定性的影响：
在本实施例4.3中，以艾普拉唑肠溶微丸片为例，比较了肠溶微丸所包括的药丸芯的成分及艾普拉唑粒径对其稳定性的影响。
肠溶微丸所包含的药丸芯的成分的影响：
根据本发明的肠溶微丸片A与对比微丸片11、16、17的稳定性测试比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片11、16、17进行了加速稳定性考察。其中，对比微丸片11的药丸芯中不包含碱性化合物和表面活性剂，对比微丸片16的药丸芯中不包含表面活性剂但含有碱性化合物，对比微丸片17的药丸芯中不包含碱性化合物但含有表面活性剂。
试验方案：将肠溶微丸片A和对比微丸片11、16分别用HDPE瓶包装，每瓶14片，将包装后的肠溶微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方肠溶微丸片的有关物质。所测得的肠溶微丸片的稳定性数据如下表6所示：
表6：根据本发明的肠溶微丸片A与对比微丸片11、16、17的稳定性数据：
时间 微丸片A 对比微丸片11 对比微丸片16 对比微丸片17
0天 0.12％ 0.23％ 0.26％ 1.54％
1个月 0.15％ 0.89％ 0.57％ 3.25％
3个月 0.36％ 1.69％ 0.86％ 6.26％
6个月 0.87％ 2.76％ 1.05％ 8.12％
从表6中的结果可以看出，当艾普拉唑肠溶微丸中的药丸芯不包含碱性化合物和表面活性剂时(即对比微丸片11)，该肠溶微丸片无法满足稳定性的要求(总杂质不超过1.5％)；当艾普拉唑肠溶微丸中的药丸芯不包含碱性化合物时(即对比微丸片17)，微丸片制备完成后，有关物质就已经 非常高，超过1.5％。与之相比，药丸芯只包含碱性化合物而不包含表面活性剂的对比微丸片16的加速试验的稳定性结果良好。
综上可知，对于稳定性低的艾普拉唑，当其肠溶微丸片仅在第一隔离层中包含水不溶性碱性化合物(即对比微丸片11)时，无法满足稳定性的要求(即总杂质不超过1.5％)；另外，药丸芯不包含碱性化合物而仅包含表面活性剂的情况下获得的微丸片也未满足稳定性要求。
4.3.2肠溶微丸所包括的药丸芯中的艾普拉唑粒径对肠溶微丸片的稳定性的影响
根据本发明的肠溶微丸片A与对比微丸片3和4的稳定性测试比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片3、4进行了加速稳定性考察。其中，相比于根据本发明的肠溶微丸片A，对比微丸片3中肠溶微丸的药丸层的艾普拉唑粒径D90大于等于80μm且小于等于100μm，对比微丸片4中肠溶微丸的药丸层的艾普拉唑粒径D90大于100μm。其具体方法如下：
试验方案：将微丸片A和微丸片3、4分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方微丸片的有关物质。所测得的微丸片的稳定性数据如下表7所示：
表7：根据本发明的肠溶微丸片A与对比微丸片3和4的稳定性数据。
时间 微丸片A 对比微丸片3 对比微丸片4
0天 0.12％ 0.25％ 0.22％
1个月 0.15％ 0.46％ 0.22％
3个月 0.36％ 0.78％ 0.64％
6个月 0.87％ 0.99％ 0.85％
从表7中的结果可以看出，相比与于根据本发明的肠溶微丸片A，包含具有不同艾普拉唑粒径D90的药丸芯的对比微丸片3(艾普拉唑粒径D90大于等于80μm且小于等于100μm)和对比微丸片4(艾普拉唑粒径D90大于100μm)的稳定性依然处于标准范围内(总杂质不超过1.5％)，也就是说，肠溶微丸药丸层所包含的艾普拉唑粒径D90的改变，不会影响该肠溶微丸片的稳定性。
综上可知，在肠溶微丸的药丸芯中所含有包含的艾普拉唑粒径，不会影响由该肠溶微丸制备而成的肠溶微丸片的稳定性和耐酸性。
4.4肠溶微丸中的保护层对肠溶微丸片的稳定性及耐酸性的影响
在本实施例4.4中，以艾普拉唑肠溶微丸片为例，比较了肠溶微丸中的保护层的设置及其组分用量对其稳定性或耐酸性的影响。
4.4.1肠溶微丸中的保护层的设置的影响：
1)根据本发明的微丸片A与对比微丸片12的稳定性测试比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片12进行了加速稳定性考察。其中，制备成对比微丸片12的肠溶微丸不包含保护层。
试验方案：将微丸片A和微丸片12分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测不同处方微丸片的有关物质。所测得的微丸片的稳定性数据如下表8-1所示：
表8-1：根据本发明的微丸片A与对比微丸片12的稳定性数据。
时间 微丸片A 对比微丸片12
0天 0.12％ 0.22％
1个月 0.15％ 0.3％
3个月 0.36％ 0.46％
6个月 0.87％ 0.79％
从表8-1中的结果可以看出，相比于根据本发明的肠溶微丸片A，其肠溶微丸不包含保护层的对比微丸片12的稳定性依然处于标准范围内(总杂质不超过1.5％)。也就是说，肠溶微丸是否包含保护层，不会影响该肠溶微丸片的稳定性。
2)根据本发明的肠溶微丸片A与对比微丸片12的耐酸性比较：
在本例中，对根据本发明的肠溶微丸片A与对比微丸片12进行了耐酸性检测。具体方法参考4.2.1中耐酸性考察。
其结果如下表8-2中所示：
表8-2：根据本发明的肠溶微丸片A与对比微丸片12的耐酸性数据。
时间 微丸片A 对比微丸片12
0天 96.7％ 88.4％
1个月 95.9％ 87.5％
3个月 95.5％ 87.3％
6个月 95.3％ 86.4％
从表8-2中可以看出，对比微丸片12在肠溶层外面没有保护层的情况下的耐酸性略低于标准范围(即6片耐酸平均值不低于90％)。然而，发明人在实验过程发现，该测定的耐酸性数据偏低的原因是，没有保护层的肠溶微丸由于容易相互之间发生粘连，在处理过程中部分的药物降解，从而导致该测定的耐酸性数据偏低。因此，在这里，本领域技术人员可以知晓，如果在制备该肠溶微丸制剂时能够通过除了设置保护层以外的手段，如及时与制剂辅料相混合等，以防止肠溶微丸之间发生粘连，那么，是否设置保护层将不会影响该制剂的耐酸性。
4.4.2肠溶微丸中的保护层的组分用量的影响：
在本实例中，对根据本发明的肠溶微丸片A与对比微丸片13的耐酸性进行测试比较：
在本实例中，对根据本发明的肠溶微丸片A与对比微丸片13进行了加速稳定性考察。其中，制备成对比微丸片13的肠溶微丸的保护层中抗粘剂(如硬脂酸镁)的含量偏低，例如，当艾普拉唑用量为5～15份时，抗粘剂用量小于0.5份。
试验方案：将微丸片A和微丸片13分别用HDPE瓶包装，每瓶14片，将包装后的微丸片放置于40℃/RH75％的加速稳定性试验箱中，1/3/6个月后取样，检测微丸片的耐酸性，即：将微丸片置于0.1M的盐酸溶液中，2h后将微丸收集，检测微丸中剩余的艾普拉唑含量。所测得的微丸片的耐酸性数据如下表9所示：
表9：根据本发明的肠溶微丸片A与对比微丸片13的耐酸性数据比较。
时间 微丸片A 对比微丸片13
0天 96.7％ 96.9％
1个月 95.9％ 96.6％
3个月 95.5％ 94.1％
6个月 95.3％ 91.6％
从表9中的结果可以看出，肠溶微丸片13在长期试验中，加速6个月耐酸性也有下降趋势(即从开始时的96.9％下降至到6个月后的91.6％)。发明人发现，加速6个月，在耐酸试验中，对比微丸片13有部分肠溶微丸在溶出杯底部粘连，从而导致耐酸性降低。这说明保护层中，能够防止微丸发生粘连的水不溶性的惰性材料(如滑石粉、硬脂酸镁、二氧化钛等)的用量太低时会导致保护效果差，无法有效地防止肠溶微丸之间的粘连，从而影响到耐酸性。
4.5肠溶微丸片的溶出度测试
4.5.1根据本发明的肠溶微丸片A与对比微丸片15的溶出度比较：
在本例中，根据上面章节4.1中所述方法，比较了根据本发明的肠溶微丸片A和对比微丸片15的溶出度。所测得的微丸片的溶出度数据如下表10所示：
表10:根据本发明的微丸片A与对比微丸片15的溶出度数据。
T/min 微丸A 对比微丸片15
0 0％ 0％
10 35.80％ 34.5％
15 68.50％ 66.3％
20 82.90％ 80.1％
30 95.20％ 94.2％
45 94.30％ 93.8％
60 92.20％ 91.5％
从表10中所示的溶出度结果可以看出，根据本发明的肠溶微丸片A与对比微丸片15均具有良好的溶出度(溶出度不低于80％)。这表明，当第二隔离层仅包含粘合剂而不包含能够防止微丸发生粘连的水不溶性惰性物质(如抗粘剂)时，不会影响该肠溶微丸制剂的溶出度，进而也应不会影响其体内生物利用度。
4.5.2根据本发明的肠溶微丸片A与对比微丸片7、8的溶出度比较：
在本例中，根据上面章节4.1中所述方法，比较了根据本发明的肠溶微丸片A和对比微丸片7、8的溶出度。所测得的微丸片的溶出度数据如下表11和图1所示：
表11：根据本发明的微丸片A与对比微丸片7、8的溶出度数据。
T/min 微丸A 对比微丸片7 对比微丸片8
0 0％ 0％ 0％
10 35.80％ 26.40％ 16.80％
15 68.50％ 35.70％ 25.60％
20 82.90％ 49.80％ 38.50％
30 95.20％ 57.20％ 49.50％
45 94.30％ 68.90％ 57.60％
60 92.20％ 72.60％ 66.60％
从图1和表11中所示的溶出度结果可以看出，根据本发明的肠溶微丸片A具有良好的溶出度(溶出度不低于80％)。相比于根据本发明的肠溶微丸片A，对比微丸片7、8的溶出度明显地降低至所需达到的标准范围(溶出度不低于80％)之外，这表明，这些肠溶微丸片的释放明显减慢，这将推迟在体内的起效时间，进而会影响体内生物利用度。
如上文所述，在肠溶微丸的隔离层中各组分配比的改变，不会影响由该肠溶微丸制备而成的肠溶微丸片的稳定性和耐酸性。然而，该肠溶微丸的隔离层中各组分配比的改变会影响相应其肠溶微丸片的溶出度，进而影响该制剂的体内生物利用度。因此，为了进一步改善体内生物利用度，根据本发明优选地，肠溶微丸的隔离层中各组分配比可以为：当艾普拉唑用量为5～15份时，第一隔离层中包含粘合剂5～36份，水不溶性碱性化合物5～36份，第二隔离层中包含粘合剂4～26份，能够防止微丸发生粘连的水不溶性惰性物质7～44份。
4.5.3根据本发明的肠溶微丸片A与对比微丸片11、16的溶出度比较：
在本例中，根据上面章节4.1中所述方法，比较了根据本发明的肠溶微丸片A和对比微丸片11、16的溶出度。所测得的微丸片的溶出度数据如下表12和图2所示：
表12:根据本发明的肠溶微丸片A与对比微丸片11、16的溶出度数据。
T/min 微丸A 对比微丸11 对比微丸16
0 0％ 0％ 0％
10 35.8％ 22.5％ 29.5％
15 68.5％ 27.6％ 46.3％
20 82.9％ 37.2％ 66.6％
30 95.2％ 45.4％ 78.3％
45 94.3％ 51.6％ 81.8％
60 92.2％ 60.5％ 83.9％
从图2和表12所示的结果可以看出，相比于根据本发明的肠溶微丸片A，对比微丸片11的溶出度明显降低至标准范围之外(溶出度不低于80％)。在对比微丸片16中，其药丸芯不含表面活性剂，其制剂的药物溶出度虽然在标准范围内，但是相较于肠溶微丸片A偏低，溶出度低于85％。
如上文所述，肠溶微丸片在药丸芯中所包含的表面活性剂不会影响其稳定性，但是会影响该制剂的溶出度，也就是说，在肠溶微丸片的药丸芯中添加表面活性剂，可以有效地提高该制剂的溶出度，进而有效地改善生物利用度。
4.5.4根据本发明的肠溶微丸片A与对比微丸片3、4的溶出度比较：
在本例中，根据上面章节4.1中所述方法，比较了根据本发明的肠溶微丸片A和对比微丸片3、 4的溶出度比较。所测得的微丸片的溶出度数据如下表13和图3所示：
表13:根据本发明的微丸片A与对比微丸片3、4的溶出度数据。
T/min 微丸片A 对比微丸片3 对比微丸片4
0 0％ 0％ 0％
10 35.8％ 20.5％ 13.5％
15 68.5％ 36.7％ 26.4％
20 82.9％ 56.8％ 45.6％
30 95.2％ 68.4％ 56.5％
45 94.3％ 75.8％ 60.5％
60 92.2％ 82.9％ 72.5％
从图3和表13中所示的溶出度结果可以看出，相比于根据本发明的肠溶微丸片A，对比微丸片3、4的溶出度明显降低，其中，当肠溶微丸的药丸芯的艾普拉唑粒径D90大于100μm时(即对比微丸片4)，其溶出度减低至标准范围(即溶出度不低于80％)之外。
4.5.5根据本发明的肠溶微丸片A与对比微丸片12的溶出度比较：
在本例中，根据上面章节4.1中所述方法，比较了根据本发明的肠溶微丸片A和对比微丸片12的溶出度比较。所测得的微丸片的溶出度数据如下表14和图4所示：
表14:根据本发明的肠溶微丸片A与对比微丸片12的溶出度数据。
T/min 微丸片A 对比微丸片12
0 0％ 0％
10 35.8％ 32.5％
15 68.5％ 46.8％
20 82.9％ 62.5％
30 95.2％ 75.6％
45 94.3％ 78.2％
60 92.2％ 79.2％
从图4和表14示出的结果可以看出，相比于根据本发明的肠溶微丸片A，不具有保护层的对比微丸片12的溶出度明显降低至大约的标准值(溶出度不低于80％)。发明人在实验中发现，其溶出度明显降低的原因是，不具有保护层的根据本发明的肠溶微丸之间容易发生粘连，从而影响其在溶出介质中的释放速度。因此，当具有保护层时，肠溶微丸片A在溶出介质中不会发生粘连，释放较高；对比微丸片12没有保护层，微丸片在介质中会粘连，释放偏低。因此，在这里，本领域技术人员可以知晓，如果在制备该肠溶微丸制剂时能够通过除了设置保护层以外的手段，如及时与制剂辅料相混合等，以防止肠溶微丸之间发生粘连，或者，通过在第一隔离层和第二隔离层之间添设其他隔离层而使得肠溶微丸之间不容易发生粘连，那么，是否设置保护层将不会影响该制剂的溶出度。
4.6肠溶微丸所包括的药丸芯中的艾普拉唑粒径对肠溶微丸片的载药量的影响
比较实施例1中第“1.1含药丸(W)的制备处方、方法、以及其含药丸上药率”章节中所示出的含药丸上药率W(即载药量)可以看出，对比微丸片3和4所包含的药丸芯W8和W9的载药量W 8和W 9分别为87.2％和79.3％。与之相比，当肠溶微丸片的药丸芯所包含的艾普拉唑粒径D90≤50μm时，其药丸芯(例如W1-W5)的载药量大于90％。
如上文所述，在肠溶微丸的药丸芯中所包含的艾普拉唑粒径不会影响由该肠溶微丸制备而成的肠溶微丸片的稳定性和耐酸性；该肠溶微丸的药丸芯中所包含的艾普拉唑粒径会影响其肠溶微丸片的溶出度，进而影响体内生物利用度。此外，该肠溶微丸的药丸芯中所包含的艾普拉唑粒径的大小还会影响该肠溶微丸的药丸芯的载药量。
因此，为了进一步改善体内生物利用度，优选地，根据本发明肠溶微丸的药丸层中的艾普拉唑粒径D90可以为≤100μm；更优选地，根据本发明肠溶微丸的药丸层中的艾普拉唑粒径D90可以为≤50μm，此时，不仅其肠溶微丸片的药物释放速度比较快，即30min内释放达到90％以上，而且其药丸芯还具有较高的载药量(大于90％)。
实施例5：根据本发明的肠溶微丸片的抑酸效果
研究目的：观察比较本发明的肠溶微丸片A和对比微丸片1、2在健康受试者口服用药第一天的抑酸效果。
试验方案：本研究为随机、开放、交叉设计的单中心研究，纳入健康受试者18例。试验一个周期，将18例受试者随机分为三组，每组6人，分别服药微丸片A、对比微丸片1和对比微丸片2。每人空腹服药一次，测定24h胃内pH值。
胃内pH记录：胃内pH记录将使用丹麦Medtronic公司的pH测试系统。将导管经鼻腔放置胃内，导管一段与Digitrapper MKIII记录装置相连。次记录装置通过微处理器能联系记录受试者胃内pH值。导管将置于食管下端括约肌8-10cm处，导管表面的刻度能显示其位置。探针在每次pH记录中在同一位置，在每次pH监测前，都必须使用pH 7.01和pH 1.07的缓冲液作2点标定。每次记录结束后Digitrapper MKIII内的数据都讲下载到计算机内做进一步分析。
试验结果：将每组受试者的胃pH记录值进行处理，分析得多个患者的每个时间点的pH平均值绘制成曲线，如图5所示。
从图5中可以看出，根据本发明的肠溶微丸片A的起效迅速，在服用后1h内就可抑制胃酸到pH4以上，达到临床起效效果。与之相比，对比微丸片1在服用后3h左右才达到临床起效效果；对比微丸片2在服用后2.5h左右达到临床起效效果。由此可见，根据本发明的肠溶微丸片能达到快速起效的效果，从而更快速地解决患者的痛苦。
此外，在本例中，还根据上述实施例中的方法，测试了对比微丸片1和对比微丸片2的稳定性和耐酸性，结果参见下表15和16。
表15：对比微丸片1与对比微丸片2的稳定性数据。
时间 对比微丸片1 对比微丸片2
0天 2.12％ 0.55％
1个月 4.15％ 1.82％
3个月 5.36％ 2.42％
6个月 9.87％ 5.79％
表16：对比微丸片1与对比微丸片2的耐酸性数据。
时间 对比微丸片1 对比微丸片2
0天 92.6％ 90.1％
1个月 88.3％ 85.5％
3个月 83.5％ 81.3％
6个月 80.6％ 78.9％
从表15和16中可以看出，根据现有技术制备的艾普拉唑肠溶微丸片(即对比微丸片1和对比微丸片2)在加速稳定测试过程中，具有显著地低于所需达到的标准(稳定性标准：总杂质不超过1.5％；耐酸性标准：耐受力不低于90％)的稳定性和耐酸性。
实施例6：根据本发明的艾普拉唑肠溶微丸片比格犬药代动力学试验
1)实验设计
试验动物：比格犬。
数量：共12只，雌雄各半，分3组(微丸片A、对比微丸片1、对比微丸片2)。
给药方式及次数：口服灌胃，给药一次(给药前半小时以0.024mL/kg的剂量
肌注给予0.25mg/mL的五肽胃泌素Pentagastrin)。
采血点：给药前0h，给药后1、1.5、1.75、2、2.5、3、3.5、4、5、6、8h，共12个采血点。
给药剂量：单片给药。
2)实验周期：单片给药、三周期三交叉，清洗期7天，共计15天。
比格犬给药方案如下：
Figure PCTCN2021130394-appb-000041
Figure PCTCN2021130394-appb-000042
3)样品分析：测血浆中艾普拉唑浓度(血浆样品处理时加1mol/L NaOH溶液碱化血浆)。分析方法：HPLC-MS/MS。
4)实验结果：见图6。
从图6中所示的比格犬体内药动数据图可知，根据本发明的肠溶微丸片A在比格犬体内的生物利用度更高，达到抑制胃酸分泌起效的时间更快。与之相比，对比微丸片1和对比微丸片2的比格犬体内累积血药浓度低，从而表明对比微丸片1和对比微丸片2的生物利用度较低。
实施例7：拉唑类药物的稳定性比较：
考察不同拉唑类药物原料在pH6.8和8.0介质中的稳定性：
配制含0.5％w/w十二烷基硫酸钠的pH6.8的磷酸缓冲盐介质和pH8.0的缓冲盐介质，放到溶出杯中，每杯1000mL，分别称取艾普拉唑、奥美拉唑镁、埃索美拉唑镁、雷贝拉唑钠、泮托拉唑、兰索拉唑各0.5mg，加入到溶出杯中，采用桨法150rpm搅拌，确保拉唑原料沉入到介质中溶解，分别在15min、30min、45min、60min时取样5mL加入到20mL氢氧化钠稳定介质中，然后用流动相定容到50mL。
按照《中国药典》2015年版二部中关于奥美拉唑镁、埃索美拉唑镁、雷贝拉唑钠、泮托拉唑钠、兰索拉唑的测定方法对介质中取的样进行含量测定，以确定各拉唑在pH6.8和8.0介质中的稳定性。测定结果如下表17和表18所示：
表17：不同拉唑类药物在pH6.8介质中不同时间降解剩余量。
时间点 艾普拉唑 奥美拉唑镁 埃索美拉唑镁 雷贝拉唑钠 泮托拉唑钠 兰索拉唑
0min 100.0％ 100.0％ 100.0％ 100.0％ 100.0％ 100.0％
15min 59.7％ 81.2％ 89.6％ 70.3％ 83.6％ 85.7％
30min 42.7％ 66.7％ 70.9％ 51.5％ 65.9％ 70.2％
45min 29.4％ 47.4％ 56.0％ 38.6％ 50.2％ 53.6％
60min 20.7％ 29.2％ 41.4％ 24.6％ 35.4％ 38.6％
表18：不同拉唑类药物在pH8.0介质中不同时间降解剩余量。
时间点 艾普拉唑 奥美拉唑镁 埃索美拉唑镁 雷贝拉唑钠 泮托拉唑钠 兰索拉唑
0min 100.0％ 100.0％ 100.0％ 100.0％ 100.0％ 100.0％
15min 94.3％ 98.2％ 99.2％ 97.3％ 98.6％ 98.7％
30min 91.5％ 95.4％ 98.6％ 93.5％ 95.9％ 96.2％
45min 88.6％ 96.3％ 97.6％ 90.6％ 92.2％ 95.3％
60min 84.6％ 91.2％ 96.4％ 88.5％ 91.4％ 93.5％
由表17和表18可以看出，不同拉唑类药物在pH6.8介质中的稳定性都比较差，其中，艾普拉唑的稳定性最差，埃索美拉唑镁的稳定性相对最好。
实施例8艾普拉唑微丸干混悬剂的制备
在本实施例8中，将以根据本发明的艾普拉唑肠溶微丸为例，制备艾普拉唑微丸干混悬剂。
1)干混悬颗粒V处方(单位：g)
组分 重量(g)
黄原胶 20
壳聚糖 1400
CCNA 75
阿斯巴甜 15
制备方法：将黄原胶、壳聚糖、CCNA和阿斯巴甜混合均匀后，加入干法制粒机进行制粒。工艺参数为：压轮间距0.2mm，喂料速度：30rpm，压轮转速5rpm，整粒转速10rpm。制粒完毕后，过筛进行整粒，控制粒径在0.5-0.7mm之间。得干混悬颗粒Ⅴ。
2)干混悬剂E-V的制备
艾普拉唑肠溶微丸E 60.5mg和2.0g上述干混悬颗粒Ⅴ混合，装瓶，即得规格5mg的艾普拉唑肠溶干混悬剂E-V。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (16)

  1. 肠溶微丸，所述肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，所述第一隔离层中含有水不溶性碱性化合物，所述第一辅料与艾普拉唑和/或艾普拉唑的药学上可接受的盐之间的重量比为0.2～5:1。
  2. 肠溶微丸，所述肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，第一隔离层含有水不溶性碱性化合物和第一辅料为水不溶性碱性化合物，其中第一隔离层含有水不溶性碱性化合物与第一辅料的水不溶性碱性化合物可以相同或不同。
  3. 肠溶微丸，该肠溶微丸从内向外依次包括药丸芯、第一隔离层、第二隔离层和肠溶层，其中，药丸芯含有艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料，所述肠溶微丸的特征在于，艾普拉唑和/或艾普拉唑的药学上可接受的盐的粒径D90≤100μm，和第二隔离层不含碱性物质。
  4. 根据权利要求1-3中任一项所述的肠溶微丸，其特征在于，在所述肠溶层外侧还设有保护层。
  5. 根据权利要求1-4中任一项所述的肠溶微丸，其特征在于，在所述药丸芯与所述第一隔离层之间不存在其他的层，和/或在第一隔离层与第二隔离层之间不存在其他的层，和/或在第二隔离层与肠溶层之间不存在其他的层。
  6. 根据权利要求1-5中任一项所述的肠溶微丸，其特征在于，所述第一辅料为碱性化合物，优选为水不溶性碱性化合物，更优选选自氢氧化镁、氢氧化铝、氧化镁、碳酸镁、碳酸钙、氢氧化钙。
  7. 根据权利要求1-5中任一项所述的肠溶微丸，其特征在于，艾普拉唑的药学上可接受的盐可以选自艾普拉唑钠、艾普拉唑镁、艾普拉唑锌、艾普拉唑钾、艾普拉唑锂或艾普拉唑钙。
  8. 根据权利要求1-5中任一项所述的肠溶微丸，其特征在于，所述药丸芯还包含表面活性剂；优选地，所述表面活性剂为吐温80或十二烷基硫酸钠。
  9. 根据权利要求1或2所述的肠溶微丸，其特征在于，所述第一隔离层中的水不溶性碱性化合物与艾普拉唑和/或其药学上可接受的盐的重量比为0.2～5:1，优选0.25～4:1，更优选0.3～3:1，尤其优选0.5～2:1，最优选0.8～1.2:1，例如1:1。
  10. 根据权利要求1或2所述的肠溶微丸，其特征在于，所述第二隔离层中包含能够防止微丸发生粘连的水不溶性惰性物质，其与粘合剂的用量按重量计的比例在1～8:1.5～10，或者1-10:1～20，或者4～26:7～44范围内。
  11. 根据权利要求1-10任一项所述的肠溶微丸，其特征在于，艾普拉唑和/或艾普拉唑的药学上可接受的盐的粒径D90选自由任意两个下述端点组成的范围：>0μm，10μm，20μm，30μm，40μm，50μm，60μm，70μm，80μm，90μm，100μm。
  12. 用于制备根据权利要求1-11任一项的肠溶微丸的方法，所述方法包括以下步骤：
    1)制备包含艾普拉唑和/或艾普拉唑的药学上可接受的盐和第一辅料的药丸芯；
    2)包覆第一隔离层和之后包覆第二隔离层；
    3)包覆肠溶层；和
    4)任选地包覆保护层。
  13. 根据权利要求12所述的方法，其特征在于，步骤2)包括：
    制备包含水不溶性碱性化合物并且不包含水溶性碱性化合物和能够防止微丸发生粘连的水不溶性惰性物质的第一混悬液，并将第一混悬液包覆在步骤1)中获得的药丸芯上；制备不包含碱性化合物的第二混悬液，并将第二混悬液包覆为第二隔离层，优选作为与肠溶层紧密相邻的第二隔离层进行包覆。
  14. 药物组合物，选自包含根据权利要求1-11任一项所述的肠溶微丸和第二辅料和任选的薄膜衣的肠溶微丸片，或包含具有保护层的根据权利要求1-11任一项所述的肠溶微丸的胶囊，或包含根据权利要求1-11任一项所述的肠溶微丸和干混悬颗粒的干混悬剂的形式。
  15. 治疗和/或预防胃肠道疾病的方法，包括给需要此治疗和/或预防的患者施用治疗和/或预防有效量的根据权利要求1-11任一项所述的肠溶微丸或根据权利要求14所述的药物组合物的步骤。
  16. 根据权利要求1-11任一项所述的肠溶微丸或根据权利要求14所述的药物组合物在制备治疗和/或预防胃肠道疾病的药物中的用途，所述胃肠道疾病选自胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二指肠溃疡复发、与NSAID相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病或根除幽门螺旋杆菌、所有级别的糜烂性食管炎、短肠综合征、胃溃疡、非甾体抗炎药造成的消化性溃疡疾病、抗血小板聚集药物等造成的胃肠道出血及相关的溃疡，或者任何以上疾病的组合。
PCT/CN2021/130394 2020-12-02 2021-11-12 肠溶微丸及其制备方法和包含它的制剂 Ceased WO2022116796A1 (zh)

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