WO2022028264A1 - 富马酸奥比特嗪肠溶微丸及其制备方法和用途 - Google Patents

富马酸奥比特嗪肠溶微丸及其制备方法和用途 Download PDF

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WO2022028264A1
WO2022028264A1 PCT/CN2021/108360 CN2021108360W WO2022028264A1 WO 2022028264 A1 WO2022028264 A1 WO 2022028264A1 CN 2021108360 W CN2021108360 W CN 2021108360W WO 2022028264 A1 WO2022028264 A1 WO 2022028264A1
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enteric
coated
fumarate
weight
oxidazine
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PCT/CN2021/108360
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English (en)
French (fr)
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程立仁
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深圳市真兴医药技术有限公司
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Priority to JP2023532638A priority Critical patent/JP7448275B2/ja
Priority to EP21853332.1A priority patent/EP4193991A4/en
Publication of WO2022028264A1 publication Critical patent/WO2022028264A1/zh

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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
    • A61K9/48—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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine and chemical industry, and in particular, relates to an enteric-coated oxidazine fumarate pellet, a preparation method thereof, and its use in the preparation of an antitumor drug for prevention and/or treatment.
  • Obitrazine fumarate chemical name (4-benzyl-[1,4]diazepan-1-yl)-acetyl(3-allyl-2-hydroxy-methylenebenzene) Hydrazine fumarate, the chemical structure is as follows:
  • the inventor of the present application has carried out a large number of experimental studies on the formulation and preparation process of oxidazine fumarate, and developed an enteric-coated pellet formulation of oxbitzine fumarate.
  • Obitrazine has good compatibility, and the preparation has good stability and high safety, and can be rapidly disintegrated and released smoothly in intestinal fluid, thereby improving the bioavailability of oxbitzine fumarate.
  • the enteric-coated pellets adopt the extrusion spheronization process to prepare the drug-containing pellets, which is conducive to expanding the drug-loading range of the pellets, facilitates the adjustment of the dosage specifications of the pellets according to clinical needs, and realizes industrialized production, and at the same time, the time-consuming is short and the effect is good.
  • the first aspect of the present invention provides an enteric-coated pellet of oxidazine fumarate; the second aspect of the present invention provides a capsule or tablet containing the enteric-coated pellet; the third aspect of the present invention provides a A method for preparing the enteric-coated pellets; the fourth aspect of the present invention provides the use of the enteric-coated pellets or the capsules or tablets in preparing a medicament for preventing and/or treating tumors.
  • a fifth aspect of the present invention provides the enteric-coated pellets or the capsules or tablets for preventing and/or treating tumors.
  • a sixth aspect of the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the enteric-coated micropellets or the capsules or tablets.
  • the first aspect of the present invention provides an enteric-coated pellet, which comprises a) a pellet core containing oxidazine fumarate, b) an isolation layer and c) an enteric layer.
  • the pellet core further comprises a diluent, a disintegrant and a co-solvent.
  • the diluent is selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch.
  • the diluent is microcrystalline cellulose.
  • the diluent is lactose.
  • the diluent is pregelatinized starch.
  • the disintegrant is one or more selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone kind.
  • the cosolvent is one or more selected from surfactants such as polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, and sodium lauryl sulfate. kind.
  • the cosolvent is polyvinylpyrrolidone.
  • the co-solvent is Tween-20.
  • the co-solvent is Tween-60.
  • the co-solvent is Tween-80.
  • the co-solvent is sodium lauryl sulfate.
  • the co-solvent is a combination of polyvinylpyrrolidone and Tween-20.
  • the diluent in the pellet core is one or more selected from microcrystalline cellulose, lactose and pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linking One or more of sodium carboxymethyl cellulose and crospovidone; cosolvent is selected from polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, sodium lauryl sulfate one or more of.
  • the disintegrant is:
  • the disintegrant is: sodium carboxymethyl starch.
  • the disintegrant is: Croscarmellose sodium.
  • the disintegrant is: crospovidone.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.
  • the mass ratio of the low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 0.1-3.5:1 , such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and croscarmellose sodium.
  • the mass ratio of the low-substituted hydroxypropyl cellulose and croscarmellose sodium 0.1 to 3.5:1, such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and crospovidone.
  • the mass ratio of the low-substituted hydroxypropyl cellulose and crospovidone is 0.1-3.5:1 , such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the pellet core comprises: in parts by weight
  • the pellet core comprises: in parts by weight
  • the pellet core comprises: in parts by weight
  • the isolation layer comprises isolation material
  • the isolation layer further includes an anti-sticking agent.
  • the insulating material is one or two selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl cellulose.
  • the release material is hydroxypropyl methylcellulose.
  • the release material is selected from hydroxypropyl cellulose.
  • the release material is a combination of hydroxypropyl methylcellulose and hydroxypropyl cellulose.
  • the anti-sticking agent in the release layer is talc.
  • the enteric layer comprises an enteric material
  • the enteric layer further includes a plasticizer and/or an anti-sticking agent.
  • the enteric material is a member selected from the group consisting of acrylic resin, hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and cellulose acetate phthalate. one or more.
  • the enteric material is an acrylic resin.
  • the enteric material is hydroxypropyl methylcellulose acetate succinate.
  • the enteric material is hypromellose phthalate.
  • the enteric material is cellulose acetate phthalate.
  • the plasticizer is triethyl citrate.
  • the anti-adherent agent in the enteric layer is talc or glycerol monostearate or a combination of the two.
  • the anti-adherent in the enteric layer is talc.
  • the anti-adherent in the enteric layer is glycerol monostearate.
  • the anti-adherent in the enteric layer is a combination of talc and glycerol monostearate.
  • the enteric-coated micropellets wherein a) the pellet core containing oxidazine fumarate, b) the isolation layer and c) the mass percentage of the enteric-coated layer are as follows:
  • the enteric-coated micropellets wherein a) the pellet core containing oxidazine fumarate, b) the isolation layer and c) the mass percentage of the enteric-coated layer are as follows:
  • the enteric-coated pellets wherein the weight of the isolation layer is 10%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-18% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-16% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 16%-26% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 16%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 17%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 18%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets comprise: in parts by weight
  • the enteric-coated pellets comprise: in parts by weight
  • the enteric-coated micropellets are between 0.3-1.5 mm in size.
  • the enteric-coated pellets wherein the oxidazine fumarate is amorphous, crystalline form A or crystalline form B.
  • the particle size D90 of the oxidazine fumarate particles in the enteric-coated pellets is less than or equal to 50 ⁇ m.
  • the particle size D90 of the oxidazine fumarate particles in the enteric-coated pellets is less than or equal to 30 ⁇ m.
  • the second aspect of the present invention provides a capsule or tablet, which is made of the enteric-coated micropellet described in any of the foregoing embodiments of the present invention in a canned capsule or by tableting.
  • the content of oxidazine fumarate in the capsule or tablet is 0-200 mg.
  • the amount of oxidazine fumarate in the capsule or tablet is 5 mg, 10 mg, 25 mg, 50 mg, 100 mg or 200 mg.
  • a third aspect of the present invention provides a preparation method of enteric-coated pellets, which comprises the following steps:
  • Obitrazine fumarate is mixed with diluent, disintegrating agent to obtain premix;
  • the premix is a mixture of the co-solvent and ethanol having a concentration of 50% to 70% (preferably 55% to 65%, such as 60%) Obtained after mixing the aqueous solution;
  • the fourth aspect of the present invention provides the use of the enteric-coated pellets or the capsules or tablets in the preparation of a medicament for preventing and/or treating tumors.
  • a fifth aspect of the present invention provides the enteric-coated pellets or the capsules or tablets for preventing and/or treating tumors.
  • a sixth aspect of the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the enteric-coated micropellets or the capsules or tablets.
  • the tumor is acute promyelocytic leukemia, large cell lung cancer, liver cancer, or non-small cell lung cancer.
  • mass percent refers to the weight of the individual components in the formulation divided by the total weight of all components of the formulation and then multiplied by 100%.
  • % refers to mass percentage unless otherwise specified.
  • D90 refers to the particle size at which the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that particles with a particle size smaller than it account for 90%, for example, "D 90 is less than or equal to 50 ⁇ m” means “90% particles with a particle size not greater than 50 ⁇ m”.
  • AUCo - ⁇ refers to the area under the concentration time curve (AUC) when extrapolated to infinity or the AUC+ (last assay concentration/elimination rate constant) to the last assay time point.
  • Cmax is defined as the measured maximum plasma concentration of the active ingredient.
  • compositions provided by the present invention can be administered to patients alone, or can be co-administered or combined with other active formulations.
  • co-administration and “combination” include the simultaneous or sequential administration of two or more therapeutic agents without a specific time limit.
  • the agents are present in a cell or in an individual at the same time, or exert a biological or therapeutic effect at the same time.
  • each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form.
  • prior to administration of the second therapeutic agent eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago
  • administration of the first agent e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after
  • diluent includes, but is not limited to, microcrystalline cellulose, lactose, compressible sugars, dextrose, mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium chloride, calcium carbonate, Magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, starch, barium sulfate, magnesium trisilicate, aluminum hydroxide, and combinations thereof.
  • the diluents described herein include at least microcrystalline cellulose.
  • the diluent of the present invention comprises microcrystalline cellulose and one selected from the group consisting of mannitol, lactose, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, sucrose, or variety.
  • disintegrant includes, but is not limited to, corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone (cross-linked polyvinylpyrrolidone) Vidone, PVP), alginic acid, sodium alginate and guar gum, etc.
  • co-solvent includes, but is not limited to, sodium benzoate, citric acid, calcium lactate, ethanol, isooctyl alcohol, polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, sodium lauryl sulfate Wait.
  • the enteric-coated pellet preparation of oxidazine fumarate provided by the invention has good compatibility with the selected excipients and oxidazine fumarate, and has good preparation stability and high safety, and can be rapidly disintegrated in intestinal fluid. , stable release, thereby improving the bioavailability of oxidazine fumarate.
  • the enteric-coated pellets adopt the extrusion spheronization process to prepare the drug-containing pellets, which is conducive to expanding the drug-loading range of the pellets, facilitates the adjustment of the dosage specifications of the pellets according to clinical needs, and realizes industrialized production, and at the same time, the time-consuming is short and the effect is good.
  • rpm refers to revolutions per minute
  • RRT refers to relative retention time
  • min refers to minutes
  • ND refers to no detection
  • DCPA refers to anhydrous calcium hydrogen phosphate
  • MCC PH200 refers to microcrystalline cellulose PH200
  • SDS refers to dodecyl Sodium sulfate
  • HPMC-AS refers to hydroxypropyl methylcellulose acetate succinate
  • HPMCP refers to hypromellose phthalate
  • API refers to oxbitzine fumarate
  • SD refers to standard deviation.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • Obitrazine fumarate was purchased from Dongguan Changan Dongyang Pharmaceutical Research and Development Co., Ltd.
  • microcrystalline cellulose was purchased from Asahi Kasei, Japan
  • sodium carboxymethyl starch was purchased from Anhui Shanhe Accessories Co., Ltd.
  • low-substituted hydroxypropyl cellulose was purchased from Anhui Shanhe Accessories Co., Ltd.
  • Tween 20/Tween 80 were purchased from Nanjing Weir Chemical
  • polyvinylpyrrolidone (k30) was purchased from Ashland
  • pregelatinized starch was purchased from Roquette
  • hydroxypropylmethyl cellulose ( E3) was purchased from Anhui Shanhe Accessories Co., Ltd.
  • talc was purchased from Guangxi Longsheng Huamei Talc Development Co., Ltd.
  • Obitrazine fumarate raw material is passed through YK-60 equipment rocking granulator (Changsha Yi Pharmaceutical Machinery Co., Ltd.), passed through a 24-mesh sieve, and pretreated for standby;
  • mix soft materials weigh 1125.10g of pretreated raw materials, 625.12g of microcrystalline cellulose, 200.20g of sodium carboxymethyl starch, and 350.32g of low-substituted hydroxypropyl cellulose and add them to a wet granulator (Shenzhen Xinyite Technology Co., Ltd.), mix for 5 minutes under the condition that the rotating speed of the stirring paddle is 1-3 rps and the rotating speed of the cutting knife is 10-40 rps.
  • a wet granulator Shenzhen Xinyite Technology Co., Ltd.
  • extrusion spheronization the soft material prepared in the second step is extruded through an orifice plate of 0.3 to 1.5 mm using an extrusion spheronizer (Shenzhen Xinyite Technology Co., Ltd.) The spheronization is carried out at low speed (100-500rpm). The high-speed spheronization time and the low-speed spheronization time are adjusted according to specific conditions. During the spheronization process, an appropriate amount of 60% to 95% ethanol can be sprayed to help the pellets form.
  • drying the pellets (wet material) prepared by spheronization are dried in a fluidized bed (Shenzhen Xinyite Technology Co., Ltd.), the air inlet temperature is 45°C, the material temperature is controlled at 35-45°C, and the drying time is about 30min .
  • Preparation of coating solution Heat purified water of about 1/2 of the recipe amount to about 60°C, stir into a vortex, slowly add 241.12g of hydroxypropyl methylcellulose to disperse, add the remaining purified water (room temperature), stir until The solution was clarified, and then talc was added and stirred for 30 min for later use.
  • Coating Put the plain pellets into the fluidized bed, set the fan speed to 1750 ⁇ 2000rpm, set the inlet air temperature to 40 ⁇ 50°C, which can be adjusted according to the actual situation, preheat the pellets, control the material temperature to 37 ⁇ 39°C and then start the atomization
  • the pressure is 0.13-0.18Mpa
  • the peristaltic pump is turned on to start spraying, the speed of spraying is increased from slow to slow, and the speed of the peristaltic pump is controlled to 8-12rpm (inner diameter of the tube is 5mm). parameters to prevent pellet sticking.
  • Preparation of coating solution stir the weighed absolute ethanol into a vortex and slowly add 227.02g of hydroxypropyl methylcellulose acetate succinate to swell, slowly add purified water (cold water), stir until the solution is clear, and then add talc in turn Powder, triethyl citrate and glyceryl monostearate, stir for 30min for subsequent use;
  • Coating Put the isolation coat pellets into the fluidized bed (Shenzhen Xinyite Technology Co., Ltd.), set the fan speed to 1850 ⁇ 2200rpm, and the inlet air temperature to 42 ⁇ 49°C, preheat the pellets, and control the material temperature to 36 ⁇ 41°C. Turn on the atomization pressure of 0.11-0.18Mpa, turn on the peristaltic pump to start spraying, the speed of spraying is accelerated from slow to slow, and the speed of the peristaltic pump is controlled to 8-12rpm (the inner diameter of the tube is 5mm). Adjust the parameters according to the actual situation to prevent the pellets from sticking.
  • Capsule filling is carried out after determining the amount of capsules according to the content of enteric-coated pellets. Loading capacity: theoretical value ⁇ 5%, loading difference: ⁇ 7.5%.
  • Stability investigation method Under the conditions of 40 ⁇ 2°C and 75 ⁇ 5%RH, samples were taken in the 0th, 1st, 2nd and 3rd months to detect the related substances, acid resistance and release degree.
  • the specific detection method is as follows:
  • enteric-coated pellet preparation prepared in this example (approximately equivalent to 65mg of oxidazine fumarate), accurately weigh it, place it in a 25ml measuring bottle, add an appropriate amount of diluent (DMSO-methanol (1:4v/v) )) ultrasonication for 15min to dissolve oxidazine fumarate, let cool, dilute to volume with diluent, shake well, centrifuge at 12000rpm for 10min, and take the supernatant as the test solution. Precisely measure 1ml of the test solution and put it in a 100ml volumetric flask, dilute it to the mark with diluent, shake well, and use it as a control solution.
  • DMSO-methanol (1:4v/v) diluent
  • oxbitzine fumarate reference substance oxbitzine fumarate reference substance
  • impurity A reference substance impurity A reference substance
  • impurity C reference substance impurity C reference substance
  • TEC triethyl citrate
  • capsule T content is the enteric-coated pellet preparation of oxitrazine fumarate prepared in Example 1, 100 mg
  • R oxitrazine hydroxypropyl- ⁇ cyclodextrin inclusion complex solution
  • Preparation method of R drug add an appropriate amount of hydroxypropyl- ⁇ cyclodextrin into 100 mL of purified water to dissolve, and then add 1 g of oxidazine fumarate raw material drug into water, stir and dissolve to obtain 10 mg/mL inclusion compound. 10 servings, 10mL each)
  • Blood sample collection before administration (0h) and after administration at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h forelimb venous blood was collected from 3mL to 5mL of heparinized blood. in blood vessels.
  • the blood samples were centrifuged at 3000 r/min for 10 min within 15 min after collection to separate the plasma, and the plasma was transferred to a clean 2 mL EP tube to detect the content of oxidazine in the plasma.
  • the detection method of oxidazine in plasma is as follows:
  • the AUC 0- ⁇ of T drug (7977.234ug/L*h) was significantly higher than that of R drug (4182.582 ⁇ g/L*h), indicating that the enteric-coated micropill capsule prepared in Example 1 of the present invention has a stable release in vivo, and its bioavailability high.
  • the preparation provided by the present invention is an enteric-coated micro-pellet capsule, and is well absorbed in the duodenum, and the preparation needs to be released quickly after entering the intestinal tract.
  • enteric-coated materials whose dissolution pH is as close to the duodenal pH range as possible are selected as candidate materials.
  • Acrylic resin epoxy resin
  • HPMC-AS HPMC-AS
  • Opadry enteric 91 series PVAP
  • HPMCP HP-55
  • Cup 1 in group 1 can be completely dissolved, indicating that 5 mg of Eudragit L100-55 can be completely dissolved in 100 ml of release medium, but precipitation occurs in cup 2, and the amount of oxidazine fumarate measured in the solution is very small, which is reasonable It is inferred that they interact with each other, and the effect is strong.
  • groups 2, 3, and 4 also have different degrees of interaction, and the order of their strength is: Opadry (PVAP) > Acrylic resin (Udag L100-55) > HPMCP (HP-55) > HPMC- AS (LG). From the perspective of stability and formulation release risk, HPMC-AS is suitable for the enteric-coated pellet formulation of the present invention, followed by HPMCP.
  • the wetting agent ethanol concentration was designed to vary between 50% and 95% to prepare the pellets.
  • the optimal ethanol concentration was screened out with roundness and disintegration time as the inspection objects.
  • Table 7 the formulation and feeding were carried out, and the soft materials were manually prepared by using ethanol with concentrations of 75%, 60% and 50%, respectively, using an extrusion plate with a diameter of 0.9 mm and an extrusion speed of 30 rpm.
  • the pellets are prepared by adjusting the spheronization parameters according to the situation, and the prepared pellets are dried in a fluidized bed (the inlet air temperature and the material temperature are 35°C to 45°C) to obtain the plain pellets.
  • the roundness of the plain pills was observed, and the disintegration time was measured.
  • Table 7 The results are shown in Table 7.
  • Crospovidone (XL-10), Croscarmellose Sodium and Sodium Carboxymethyl Starch as the investigation objects, all use the conventional maximum dosage, and are used in combination with low-substituted hydroxypropyl cellulose to maintain the prescription
  • the dosage of other excipients remains unchanged, and the dosage of diluent is fine-tuned to make the drug loading of the pellets consistent.
  • 60% ethanol as a wetting agent, the soft material was manually prepared, the diameter of the extrusion plate was 0.9 mm, and the extrusion speed was 30 rpm.
  • the pellets are dried in a fluidized bed (the inlet air temperature is set at 45°C, and the material temperature is controlled at a temperature of 35°C to 45°C) to obtain plain pellets.
  • the fluidized bed air inlet fan rotates at 1200 rpm
  • the peristaltic pump rotates at 6-12 rpm
  • calculates the spraying speed of about 0.5-1.4 g/min and controls the atomization pressure of about 0.04Mpa to fully atomize the coating liquid
  • Material stability control is 3% weight gain at 35-45°C.
  • the fluidized bed air inlet fan rotates at 1200rpm
  • the peristaltic pump rotates at 6-12rpm
  • calculates the spraying speed of about 1.1g-1.7g/min and controls the atomization pressure of about 0.04Mpa to fully atomize
  • the temperature of the material is controlled to be 35°C to 45°C
  • the weight gain is 18% (theoretical feeding)
  • the coating recipe and process are the same.
  • the release and acid resistance were tested after the pellets were filled into capsules, and the results are shown in Table 8.
  • the barrier coating can prevent the API from interacting directly with the enteric coating material hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which affects the release and stability of the formulation. Only after the isolation coat completely wraps the drug-loaded pills and reaches a certain thickness, the direct contact or infiltration of API and HPMC-AS can be prevented. Incomplete or too thin coating of the isolation coat will lead to the interaction of API and HPMC-AS in the release medium in the case of local high concentrations, slowing down the release. The thicker the isolation coat (the greater the weight gain), the weaker the interaction, and HPMC itself also has the characteristics of non-ionic surface activity, which is beneficial to the release of the formulation. In addition, the acidity of the enteric coating material is the unstable factor (degradation) of the API, so the weight gain of the barrier coat is beneficial to the stability of the preparation-related substances.
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • the particle size of the plain pill is about 0.6-1.2mm, and the surface area is large. It needs a certain amount of coating to increase the weight to completely wrap the surface of the plain pill. According to the diameter of the plain pellets, the surface of the pellets can be completely covered by the isolation coat only when the coating weight gain is 6.8%. In this example, the weight gain was designed to be 7%, 15% and 19%, and the coating effect was investigated.
  • Hypromellose is selected as the isolation coat material
  • talcum powder is used as an anti-sticking agent (the dosage ratio is 4:1)
  • the rotational speed of the fluidized bed air inlet fan is controlled to be adjusted according to different batches, 1200 ⁇ 1800rpm, and the rotational speed of the peristaltic pump is 6 ⁇ 8.
  • the spraying speed is about 0.7 ⁇ 1.5g/min
  • the atomization pressure is controlled to be about 0.04 ⁇ 0.12Mpa to fully atomize the coating liquid
  • the material stability is controlled at 35 ⁇ 45°C.
  • the fluidized bed air inlet fan speed is 1200-1400rpm
  • the peristaltic pump speed is 6-12
  • the spray rate is about 0.8-1.3g/min
  • the atomization pressure is controlled at about 0.04-0.06Mpa.
  • Atomize the coating liquid the actual material temperature is controlled at 35°C to 42°C, and the weight gain is 18%. After the enteric-coated pellets were filled with capsules, the release and acid resistance were tested. The results are shown in Table 9.
  • Obitrazine fumarate is unstable in acidic conditions, and the enteric material is highly acidic, and the weight gain of the isolation coating affects the integrity and thickness of the isolation coating film.
  • the weight gain of the isolation coating is investigated, and the isolation coating that can effectively block the weight gain of oxidazine fumarate and enteric materials is screened out.
  • the main inspection items are content, related substances, acid resistance and release. The results are shown in Table 10.
  • the impurity C in the related substances of the barrier coat coating increased by 14.1% and 19.5%, and was not detected in 0 days.
  • the increase in the impurity C in March accelerated to 0.19%, and the growth rate was the same, and the stability was achieved. Require. Therefore, from the perspective of related substances, the isolation coat of 14.1% (according to 15% of the material) and above can effectively block the enteric coating and protect the oxbitzine fumarate.
  • the rotational speed of the fluidized bed air inlet fan is 1200 ⁇ 1400rpm
  • the rotational speed of the peristaltic pump is 6 ⁇ 12rpm
  • the spray rate is about 0.8 ⁇ 1.2g/min
  • the atomization pressure is controlled to be about 0.03 ⁇ 0.04Mpa to fully atomize the coating liquid.
  • the actual material temperature is controlled as 35°C ⁇ 40°C.
  • the acid resistance and release of enteric-coated pellets were tested, and the results are shown in Table 11.
  • the weight gain of the enteric coating is 18%, which can ensure that the release of the enteric-coated micro-pill capsules of oxynitzine fumarate reaches the development target;

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Abstract

一种富马酸奥比特嗪肠溶微丸，及其制备方法和其在制备用于预防和/或治疗抗肿瘤药物中的用途。

Description

富马酸奥比特嗪肠溶微丸及其制备方法和用途
本申请是以CN申请号为202010789585.5，申请日为2020年8月7日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本发明属于医药化工领域，具体地，涉及一种富马酸奥比特嗪肠溶微丸、其制备方法及其在制备用于预防和/或治疗抗肿瘤药物中的用途。
背景技术
富马酸奥比特嗪，化学名为(4-苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼富马酸盐，化学结构式如下：
Figure PCTCN2021108360-appb-000001
文献WO2010102513A1报道了富马酸奥比特嗪及其衍生物的结构、制备方法和用途，该类化合物可特异性的激活肿瘤细胞内的procaspase-3为有活性的caspase-3，从而诱导肿瘤细胞凋亡。文献还进一步报道了该类化合物对多种癌症细胞株的生长有明显抑制作用，如对HL-60细胞、NCI-H460细胞、HepG2细胞、A549细胞等具有明显抑制作用。由于Procaspase-3在肿瘤细胞的表达显著高于正常细胞，因此富马酸奥比特嗪有望成为调节细胞凋亡信号转导通路的新型抗肿瘤药物。
发明内容
本申请的发明人对富马酸奥比特嗪的制剂处方、制剂工艺进行大量的实验研究，开发了一种富马酸奥比特嗪肠溶微丸制剂，该制剂所用的辅料与富马酸奥比特嗪的相容性好，该制剂稳定性佳、安全性高，在肠液中可以快速崩解、平稳释放，从而提高了富马酸奥比特嗪的生物利用度。该肠溶微丸采用挤出滚圆工艺制备含药微丸，有利于扩大微丸的载药量范围，方便根据临床需求调整微丸剂量规格，实现了工业化生产，同时耗时短，效果好。
本发明第一方面提供一种富马酸奥比特嗪肠溶微丸；本发明的第二方面提供一种含有所述肠溶微丸的胶囊或片剂；本发明的第三方面提供一种制备所述肠溶微丸的方法；本发明的第四方面提供了所述肠溶微丸或所述胶囊或片剂在制备用于预防和/或治 疗肿瘤的药物中的用途。本发明的第五方面提供所述肠溶微丸或所述胶囊或片剂，其用于预防和/或治疗肿瘤。本发明的第六方面提供一种治疗肿瘤的方法，包括给有需要的受试者施用治疗和/或预防有效量的所述肠溶微丸或所述胶囊或片剂。
具体地说，本发明第一方面提供了一种肠溶微丸，其包含a)含富马酸奥比特嗪的丸芯，b)隔离层和c)肠溶层。
在一些实施方案中，所述的丸芯还包含稀释剂、崩解剂和助溶剂。
在另一些实施方案中，所述的稀释剂选自微晶纤维素、乳糖、预胶化淀粉中的一种或多种。
在另一些实施方案中，所述的稀释剂为微晶纤维素。
在另一些实施方案中，所述的稀释剂为乳糖。
在另一些实施方案中，所述的稀释剂为预胶化淀粉。
在另一些实施方案中，所述的崩解剂为选自羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮中的一种或多种。
在另一些实施方案中，所述的助溶剂为选自聚乙烯吡咯烷酮、吐温-20、吐温-60、吐温-80、十二烷基硫酸钠等表面活性剂中的一种或多种。
在另一些实施方案中，所述的助溶剂为聚乙烯吡咯烷酮。
在另一些实施方案中，所述的助溶剂为吐温-20。
在另一些实施方案中，所述的助溶剂为吐温-60。
在另一些实施方案中，所述的助溶剂为吐温-80。
在另一些实施方案中，所述的助溶剂为十二烷基硫酸钠。
在另一些实施方案中，所述的助溶剂为聚乙烯吡咯烷酮和吐温-20的组合。
在一些实施方案中，所述的丸芯中稀释剂为选自微晶纤维素、乳糖和预胶化淀粉中的一种或多种；崩解剂为选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮中的一种或多种；助溶剂为选自聚乙烯吡咯烷酮、吐温-20、吐温-60、吐温-80、十二烷基硫酸钠中的一种或多种。
在另一些实施方案中，所述的崩解剂为：
羧甲基淀粉钠，
交联羧甲基纤维素钠，
交联聚维酮，
低取代羟丙基纤维素与羧甲基淀粉钠的组合，
低取代羟丙基纤维素与交联羧甲基纤维素钠的组合，或
低取代羟丙基纤维素与交联聚维酮的组合。
在另一些实施方案中，所述的崩解剂为：羧甲基淀粉钠。
在另一些实施方案中，所述的崩解剂为：交联羧甲基纤维素钠。
在另一些实施方案中，所述的崩解剂为：交联聚维酮。
在另一些实施方案中，所述的崩解剂为：低取代羟丙基纤维素与羧甲基淀粉钠的组合。
在另一些实施方案中，在低取代羟丙基纤维素与羧甲基淀粉钠的组合中，所述的低取代羟丙基纤维素与羧甲基淀粉钠的质量比例为0.1～3.5:1，例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1。
在另一些实施方案中，所述的崩解剂为：低取代羟丙基纤维素与交联羧甲基纤维素钠的组合。
在另一些实施方案中，在低取代羟丙基纤维素与交联羧甲基纤维素钠的组合中，所述的低取代羟丙基纤维素与交联羧甲基纤维素钠的质量比例为0.1～3.5:1，例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1。
在另一些实施方案中，所述的崩解剂为：低取代羟丙基纤维素与交联聚维酮的组合。
在另一些实施方案中，在低取代羟丙基纤维素与交联聚维酮的组合中，所述的低取代羟丙基纤维素与交联聚维酮的质量比例为0.1～3.5:1，例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1。
在另一些实施方案中，所述的丸芯包含：以重量份计的
Figure PCTCN2021108360-appb-000002
在另一些实施方案中，所述的丸芯包含：以重量份计的
Figure PCTCN2021108360-appb-000003
Figure PCTCN2021108360-appb-000004
在另一些实施方案中，所述的丸芯包含：以重量份计的
Figure PCTCN2021108360-appb-000005
在一些实施方案中，所述的隔离层中包含隔离材料，
可选地，所述隔离层还包括抗粘剂。
在一些实施方案中，所述隔离材料为选自羟丙甲基纤维素、羟丙基纤维素中的一种或两种。
在一些实施方案中，所述隔离材料为羟丙甲基纤维素。
在一些实施方案中，所述隔离材料为选自羟丙基纤维素。
在一些实施方案中，所述隔离材料为羟丙甲基纤维素和羟丙基纤维素的组合。
在一些实施方案中，所述的隔离层中的抗粘剂为滑石粉。
在一些实施方案中，所述的肠溶层中包含肠溶材料，
可选地，所述肠溶层还包括增塑剂和/或抗粘剂。
在一些实施方案中，所述肠溶材料为选自丙烯酸树脂、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙甲纤维素邻苯二甲酸酯、醋酸纤维素酞酸酯中的一种或多种。
在一些实施方案中，所述肠溶材料为丙烯酸树脂。
在一些实施方案中，所述肠溶材料为醋酸羟丙基甲基纤维素琥珀酸酯。
在一些实施方案中，所述肠溶材料为羟丙甲纤维素邻苯二甲酸酯。
在一些实施方案中，所述肠溶材料为醋酸纤维素酞酸酯中。
在一些实施方案中，所述增塑剂为柠檬酸三乙酯。
在一些实施方案中，所述肠溶层中的抗粘剂为滑石粉或单硬脂酸甘油酯或者二者的组合。
在一些实施方案中，所述肠溶层中的抗粘剂为滑石粉。
在一些实施方案中，所述肠溶层中的抗粘剂为单硬脂酸甘油酯。
在一些实施方案中，所述肠溶层中的抗粘剂为滑石粉和单硬脂酸甘油酯的组合。
在一些实施方案中，所述的肠溶微丸，其中a)含富马酸奥比特嗪的丸芯，b)隔离层和c)肠溶层的质量百分数如下：
a)丸芯     60％-78％；
b)隔离层   10％-20％，及
c)肠溶层   12％-20％。
在另一些实施方案中，所述的肠溶微丸，其中a)含富马酸奥比特嗪的丸芯，b)隔离层和c)肠溶层的质量百分数如下：
a)丸芯     62％-72％；
b)隔离层   14％-20％，及
c)肠溶层   14％-18％。
在一些实施方案中，所述的肠溶微丸，其中隔离层的重量为含富马酸奥比特嗪的丸芯的重量的10％-20％。
在一些实施方案中，所述的肠溶微丸，其中隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-20％。
在一些实施方案中，所述的肠溶微丸，其中隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-18％。
在一些实施方案中，所述的肠溶微丸，其中隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-16％。
在一些实施方案中，所述的肠溶微丸，其中肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的16％-26％。
在一些实施方案中，所述的肠溶微丸，其中肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的16％-20％。
在一些实施方案中，所述的肠溶微丸，其中肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的17％-20％。
在一些实施方案中，所述的肠溶微丸，其中肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的18％-20％。
在一些实施方案中，所述的肠溶微丸，其包含：以重量份计的
Figure PCTCN2021108360-appb-000006
在一些实施方案中，所述的肠溶微丸，其包含：以重量份计的
Figure PCTCN2021108360-appb-000007
在一些实施方案中，所述肠溶微丸粒径在0.3-1.5mm之间。
在一些实施方案中，所述的肠溶微丸，其中所述的富马酸奥比特嗪为无定形、晶型A或晶型B。
在一些实施方案中，所述的肠溶微丸中的富马酸奥比特嗪颗粒粒径D90小于或等于50μm。
在另一些实施方案中，所述的肠溶微丸中的富马酸奥比特嗪颗粒粒径D90小于或等于30μm。
本发明的第二方面提供一种胶囊或片剂，由本发明前述任一项所述的肠溶微丸罐装胶囊而成或压片而成。
在另一些实施方案中，所述胶囊或片剂中的富马酸奥比特嗪的含量为0-200mg。
在另一些实施方案中，所述胶囊或片剂中的富马酸奥比特嗪的含量为5mg、10mg、25mg、50mg、100mg或200mg。
本发明第三方面提供了一种肠溶微丸的制备方法，其包含以下步骤：
a)将富马酸奥比特嗪与稀释剂、崩解剂混合，得到预混物；
b)将预混物与助溶剂溶液混合，制得软材，其中所述助溶剂溶液是将助溶剂与浓度为50％～70％(优选为55％～65％，例如60％)的乙醇水溶液混合后得到；
c)使制得的软材经过挤出滚圆制丸，干燥；
d)包隔离衣；
e)包肠溶衣。
本发明的第四方面提供了所述肠溶微丸或所述胶囊或片剂在制备用于预防和/或治疗肿瘤的药物中的用途。
本发明的第五方面提供所述肠溶微丸或所述胶囊或片剂，其用于预防和/或治疗肿瘤。
本发明的第六方面提供一种治疗肿瘤的方法，包括给有需要的受试者施用治疗和/或预防有效量的所述肠溶微丸或所述胶囊或片剂。
在某些实施方案中，所述肿瘤为急性早幼粒细胞白血病、大细胞肺癌、肝癌或非小细胞肺癌。
发明详述
在更详细地描述本发明之前，应理解，本发明不限于本文中描述的特定实施方式，因为这样的实施方式可以变化。还应理解，本文中使用的术语仅用于描述特定实施方式的目的，并且术语不用于限制。除非另有规定，本文使用的所有技术和科学术语具有本领域技术人员普遍理解的相同含义。本文参照的所有出版物和专利均通过引用将其全部内容并入本文。
术语“质量百分比”、“重量百分比”或“以重量计的百分比”或“wt％”定义为制剂中单个组分的重量除以制剂所有组分的总重量然后乘以100％。本发明中“％”，除另有说明外均指质量百分比。
在本发明的上文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字 均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
术语“D 90”是指一个样品的累计粒度分布数达到90％时所对应的粒径。它的物理意义是粒径小于它的的颗粒占90％，例如“D 90小于或等于50μm”表示“粒径不大于50μm的颗粒占90％”。
术语“AUC 0-∞”是指外推至无穷大时的浓度时间曲线下面积(AUC)或到最后一次测定时间点的AUC+(最后测定浓度/消除速度常数)。
术语“C max”定义为所测得的活性成分的最大血浆浓度。
本发明所提供的制剂可单独给予患者，也可与其他活性制剂共同给予或联合给药。术语“共同给予”和“联合”包括在没有具体时限的情况下同时或顺序给予两种或多种治疗剂。在一个实施方案中，试剂同时存在于细胞中或个体体内，或者同时发挥生物或治疗效果。在一个实施方案中，各治疗剂在同一组合物或单位剂型中。在其他实施方案中，各治疗剂在不同的组合物或单位剂型中。在某些实施方案中，在给予第二治疗剂之前(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周前)、同时或之后(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周后)给予第一种试剂。
术语“稀释剂”包括但不限于微晶纤维素、乳糖、可压缩糖、右旋糖、甘露糖醇、糊精、麦芽糊精、山梨糖醇、木糖醇、氯化钠、碳酸钙、碳酸镁、磷酸钙、硫酸钙、氧化镁、高岭土、粉状纤维素、预胶化淀粉、淀粉、硫酸钡、三硅酸镁、氢氧化铝及其组合。在一些实施例中，本发明所述稀释剂至少包括微晶纤维素。在另一些实施例中，本发明所述稀释剂包括微晶纤维素和选自甘露醇、乳糖、一水乳糖、预胶化淀粉、山梨醇、磷酸氢钙、淀粉、蔗糖中的一种或多种。
术语“崩解剂”包含但不限于玉米淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、微晶纤维素、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮(交联聚维酮，PVP)、海藻酸、海藻酸钠和瓜尔胶等。
术语“助溶剂”包含但不限于苯甲酸钠、枸橼酸、乳酸钙、乙醇、异辛醇、聚乙烯吡咯烷酮、吐温-20、吐温-60、吐温-80、十二烷基硫酸钠等。
本发明的有益效果
本发明提供的富马酸奥比特嗪的肠溶微丸制剂，所选用的辅料与富马酸奥比特嗪的相容性好，制剂稳定性佳、安全性高，在肠液中可以快速崩解、平稳释放，从而提高了富马酸奥比特嗪的生物利用度。
该肠溶微丸采用挤出滚圆工艺制备含药微丸，有利于扩大微丸的载药量范围，方便根据临床需求调整微丸剂量规格，实现了工业化生产，同时耗时短，效果好。
附图说明
图1比格犬单次给药奥比特嗪的浓度-时间曲线(C-T曲线)
具体实施方式
下面结合本发明的具体实施例来进一步说明本发明的实质性内容，应理解，以下实施例仅用于说明本发明，但并不以此来限定本发明的保护范围。下面实施例中未注明具体条件者，按照常规条件或制造商建议的进行。所用原料未注明生产厂商者，均为可以通过市购获得的常规产品。
虽然以下实施例中所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，如果未特别说明，下面实施例中所用的材料和操作方法是本领域公知的。
以下实施例中：rpm指转/分钟；RRT指相对保留时间；min指分钟；ND即未检出；DCPA指无水磷酸氢钙；MCC PH200为微晶纤维素PH200；SDS指十二烷基硫酸钠；HPMC-AS指醋酸羟丙基甲基纤维素琥珀酸酯；HPMCP指羟丙甲纤维素邻苯二甲酸酯；API指富马酸奥比特嗪；SD表示标准差。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。富马酸奥比特嗪购自东莞市长安东阳光药物研发有限公司，微晶纤维素购自日本旭化成，羧甲基淀粉钠购自安徽山河辅料股份有限公司，低取代羟丙基纤维素购自安徽山河辅料股份有限公司，吐温20/吐温80购自南京威尔化工，聚乙烯吡咯烷酮(k30)购自亚什兰，预胶化淀粉购自罗盖特，羟丙甲基纤维素(E3)购自安徽山河辅料股份有限公司，滑石粉购自广西龙胜华美滑石开发有限公司，醋酸羟丙基甲基纤维素琥珀酸酯(LG)购自亚什兰/日本信越，柠檬酸三乙酯购自蚌埠丰源涂山制药有限公司，单硬脂酸甘油酯购自湖南尔康制药。
实施例1：肠溶微丸制剂的制备及稳定性测试
表1：处方列表
Figure PCTCN2021108360-appb-000008
1.肠溶微丸制剂的制备
第一，预处理：富马酸奥比特嗪原料药经过YK-60设备摇摆式颗粒机(长沙益制药机械有限公司)，过24目筛，预处理备用；
第二，混合制软材：称取经预处理的原料药1125.10g、微晶纤维素625.12g、羧甲基淀粉钠200.20g、低取代羟丙基纤维素350.32g加入到湿法制粒机(深圳信宜特科技有限公司)中，在搅拌桨转速1～3rps，切割刀转速10～40rps的条件下，混合5分钟。加入聚乙烯吡咯烷酮(k30)75.12g、吐温20 125.37g的乙醇(60％，900ml)溶液，设置搅拌桨转速1～3rps，切割刀转速20～60rps，加完停止搅拌和切割。
第三，挤出滚圆：将第二步制备的软材采用挤出滚圆机(深圳信宜特科技有限公司)通过0.3～1.5mm的孔板挤出，然后采用先高速(600～1600rpm)后低速(100～500rpm)的方式进行滚圆，高速滚圆时间和低速滚圆时间根据具体情况调整，滚圆过程中可喷加适量60％～95％乙醇，帮助微丸成型。
第四，干燥：将滚圆制备得到的微丸(湿料)采用流化床(深圳信宜特科技有限公司)进行干燥，进风温度45℃，物料温度控制35～45℃，干燥时间约30min。
第五，包隔离衣
包衣液配制：将处方量约1/2的纯化水加热至约60℃，搅拌成旋涡状缓慢加入羟丙 甲基纤维素241.12g分散后，加入剩下的纯化水(室温)，搅拌至溶液澄清，再加入滑石粉搅拌30min备用。
包衣：将素丸投入流化床，设置风机转速1750～2000rpm，设置进风温度40～50℃，可根据实际情况调节，对微丸预热，控制物料温度37～39℃后开启雾化压力0.13～0.18Mpa，开启蠕动泵开始喷液，喷液速度由慢加快，蠕动泵转速控制8～12rpm(管内径5mm)，注意监测包衣过程物料温度及流化状态，可根据实际情况调整参数，防止微丸粘连。
第六，包肠溶衣
包衣液配制：将称好的无水乙醇搅拌成旋涡状缓慢加入醋酸羟丙甲基纤维素琥珀酸酯227.02g溶胀后，缓慢加入纯化水(冷水)，搅拌至溶液澄清，再依次加入滑石粉、柠檬酸三乙酯和单硬脂酸甘油酯，搅拌30min备用；
包衣：将隔离衣丸投入流化床(深圳信宜特科技有限公司)，设置风机转速1850～2200rpm，进风温度42～49℃，对微丸预热，控制物料温度36～41℃后开启雾化压力0.11～0.18Mpa，开启蠕动泵开始喷液，喷液速度由慢加快，蠕动泵转速控制8～12rpm(管内径5mm)，注意监测包衣过程物料温度及流化状态，可根据实际情况调整参数，防止微丸粘连。
第七，胶囊填充
根据肠溶微丸含量确定胶囊装量后进行胶囊填充。装量：理论值±5％，装量差异：±7.5％。
2.稳定性考察
稳定性考察方法：40±2℃，75±5％RH条件下，在第0月、1月、2月、3月取样检测有关物质，耐酸力和释放度。具体检测方法如下：
2.1有关物质
取本实施例制备的肠溶微丸制剂适量(约相当于富马酸奥比特嗪65mg)，精密称定，置于25ml量瓶中，加适量稀释液(DMSO-甲醇(1:4v/v))超声15min使富马酸奥比特嗪溶解，放冷，用稀释液定容至刻度，摇匀，12000rpm离心10min，取上清液作为供试品溶液。精密量取供试品溶液1ml放至100ml量瓶中，用稀释液稀释至刻度，摇匀，作为对照溶液。另分别称取富马酸奥比特嗪对照品、杂质A对照品、杂质C对照品及柠檬酸三乙酯(TEC)适量，用稀释液稀释制成每1ml各约含富马酸奥比特嗪、杂质A、杂质C及柠檬酸三乙酯25μg的混合溶液。
照高效液相色谱法(中国药典2015年版四部通则0512)测定，用十八烷基硅烷键合 硅胶为填充剂(推荐色谱柱：YMC-PACK Pro C18,4.6mm×100mm,3μm)；以甲醇-乙腈(1:3)为流动相B，pH2.2的高氯酸盐缓冲溶液(称取高氯酸钠7.0g，加水1000ml使溶解，用高氯酸调节pH值至2.2，滤过)-流动相B(82:18)为流动相A；按下表2进行梯度洗脱；柱温按下表3进行梯度控制；检测波长为210nm；流速为每分钟1.0ml。
表2流动相梯度详情表
时间(分钟) 流动相A(％) 流动相B(％)
0 100 0
4 100 0
10 81 19
25 65 35
35 17 83
44 17 83
60 100 100
表3柱温梯度详情表
Figure PCTCN2021108360-appb-000009
取混合溶液3μl注入液相色谱仪，记录色谱图，出峰顺序为：富马酸、杂质A、柠檬酸三乙酯、奥比特嗪和杂质C。另取对照溶液3μl，注入液相色谱仪，调整检测灵敏度，使奥比特嗪的峰高约为满量程的20％～30％。精密量取空白溶液和供试品溶液各3μl注入液相色谱仪，记录色谱图，供试品溶液的色谱图中如有杂质峰，扣除空白溶液的色谱峰及混合溶液中的富马酸色谱峰、柠檬酸三乙酯色谱峰及杂质C色谱峰，乘以校正因子后，杂质A(RRT约为0.22，校正因子(1.88)法计算)峰面积不得大于对照溶液主峰面积0.5倍(0.5％)，其他单个杂质峰面积不得大于对照溶液主峰面积的0.2倍(0.20％)。供试品溶液色谱图中任何小于对照溶液主峰面积0.05倍(0.05％)的峰可忽略不计。
2.2释放度
取本实施例制备的肠溶微丸制剂，按照溶出度与释放度测定法(中国药典2015年版 四部通则0931第一法方法2)测定，以盐酸溶液(9→1000)900ml为溶出介质，转速为每分钟100转，依法操作，经120分钟，立即将转篮升出液面，将盐酸溶液弃去，立即加入预热至37℃的磷酸盐缓冲液(取磷酸二氢钾68.05g，加1mol/L氢氧化钠152ml，用水稀释至10 000ml，摇匀，pH值应为6.0)900ml，继续依法操作，经45分钟时，取溶液滤过，作为供试品溶液。另精密称取富马酸奥比特嗪对照品10mg，置100ml量瓶中，加乙醇溶解并稀释至刻度，摇匀，作为对照品溶液。取供试品溶液和对照品溶液，照含量测定项下的方法测定，计算每粒的溶出量。
2.3耐酸力
取本实施例制备的肠溶微丸制剂作为供试品，照溶出度与释放度测定法(通则0931第一法)，以盐酸溶液(9→1000)900ml为溶出介质，转速为每分钟100转，依法操作，经120分钟，取出供试品，用水洗净表面盐酸溶液，用适量无水乙醇转移至置100ml量瓶，超声15分钟使富马酸奥比特嗪溶解，放冷，用无水乙醇稀释至刻度，摇匀，滤过(或离心)，取滤液(或上清液)1ml，至10ml量瓶中，用无水乙醇定容至刻度，摇匀，作为供试品溶液，照含量测定项下的方法测定，计算每粒的含量。每粒溶出量均不大于标示量的10％。
稳定性测试结果如表4所示：
表4制剂稳定性考察结果
Figure PCTCN2021108360-appb-000010
Figure PCTCN2021108360-appb-000011
结论：从以上表格数据可以看出，经过三个月的加速实验后，1)测的杂质仅有奥比特嗪降解杂质1，且含量非常低，说明了该肠溶微丸制剂具有很好的稳定性及药物安全性；2)肠溶微丸胶囊耐酸力和释放度在加速3月均未发生显著变化，更进一步说明了该制剂的稳定性。
实施例2药代动力学实验
采用两周期交叉，自身对照实验设计，将8只比格犬分为两组，每组4只。每周期分别给予胶囊T(内容物为实施例1制备的富马酸奥比特嗪肠溶微丸制剂，100mg)或R(奥比特嗪羟丙基-β环糊精包合物溶液)10mL(100mg)。给药前禁食12h，给药前及给药后4h内控制饮水。给药后5h统一进食，洗脱期为7天。(注：R药制备方法：将适量羟丙基-β环糊精加入100mL纯化水中溶解，再将富马酸奥比特嗪原料药1g加入水中，搅拌溶解得到10mg/mL的包合物，分装成10份，每份10mL)
血样采集：给药前(0h)及给药后于0.25，0.5，0.75，1，1.25，1.5，2，3，4，6，8，10，12，24h前肢静脉采血3mL至5mL肝素化采血管中。血样采集后15min内在3000r/min条件下离心10min，分离血浆，血浆转移至洁净2mL EP管中，检测血浆中奥比特嗪含量。
血浆中奥比特嗪检测方法如下：
Figure PCTCN2021108360-appb-000012
Figure PCTCN2021108360-appb-000013
计算在比格犬体内单次给药后各个时间点血浆中的奥比特嗪浓度测定数据、每一时间点的平均浓度(Mean)，分别提供每只比格犬单次给药奥比特嗪的浓度-时间曲线(C-T曲线)、平均C-T曲线以及C-T曲线各个时间点的标准差。结果如表5和图1所示。
表5：比格犬单次口服两种制剂后的药动学参数
Figure PCTCN2021108360-appb-000014
结果分析：
(1)T药在比格犬体内其血药浓度达峰时间T max＝1.563h比R药达峰时间(T max＝0.906)晚。T药的AUC 0-∞(7977.234ug/L*h)明显高于R药(4182.582μg/L*h)，说明本发明实施例1制备的肠溶微丸胶囊体内释放平稳，且生物利用度高。
(2)T药在比格犬体内血药浓度峰值C max(1288.408μg/L)与R药无明显差异。该数据说明奥比特嗪肠溶微丸制剂在提高生物利用度(有效性)的同时，主药毒性未增加，同时保证了用药安全性。
实施例3肠溶材料相容性实验
本实施例考察肠溶材料与富马酸奥比特嗪的相容性。本发明提供的制剂为肠溶微丸胶 囊，且在十二指肠吸收好，制剂需要在进入肠道后快速释放。肠溶材料酸性越强，溶解pH越低，在碱性条件溶解性越好，对释放越有利。但是同时，肠溶酸性越强对本发明的肠溶微丸制剂的稳定性越不利，需要隔离包衣的厚度越大。因此，要保证肠溶材料能在较低pH条件溶解的同时，应尽量降低对制剂稳定性影响的风险。
本实施例选择溶解pH尽量接近十二指肠pH范围的肠溶材料作为候选材料。丙烯酸树脂(尤特奇L100-55)、HPMC-AS(LG)、欧巴代(肠溶型91系列PVAP)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(HP-55)，其均能在pH≥5.5时溶解，符合上述要求。
实验方法：称取约5mg肠溶材料2份，API富马酸奥比特嗪1份，将其中1份肠溶材料置于烧杯①中，另1份置于烧杯②中，将配置好的pH＝6.0的磷酸缓冲盐介质各100ml同时加入两个烧杯之中，并将两烧杯同时放入37℃水浴锅内，同时搅拌，待肠溶材料溶解后在杯②中加入原料药API并观察现象，取杯②样检测API浓度，计算其溶解量及相互作用量占总量比例。结果如表6所示。
表6肠溶材料与富马酸奥比特嗪相容性试验结果
Figure PCTCN2021108360-appb-000015
结果分析：
组1中杯①能完全溶解说明5mg尤特奇L100-55可以完全溶解于100ml释放介质，但是杯②中却产生沉淀，且溶液中测到的富马酸奥比特嗪量极少，可合理推断其发生了相互作用，且作用较强。同理可知组2、3、4也存在不同程度的相互作用，其强弱顺序为： 欧巴代(PVAP)＞丙烯酸树脂(尤特奇L100-55)＞HPMCP(HP-55)＞HPMC-AS(LG)。从稳定性和制剂释放风险角度评估，HPMC-AS适用于本发明的肠溶微丸制剂，HPMCP次之。
实施例4润湿剂乙醇浓度的筛选
设计润湿剂乙醇浓度在50％～95％之间变化，来制备微丸。以圆整度、崩解时间为考察对象筛选出较优乙醇浓度。按照表7进行处方投料，分别使用浓度为75％，60％和50％乙醇手动制取软材，使用孔径0.9mm挤出板，挤出速度30rpm，挤出物料在滚圆转盘中滚圆，根据物料情况调整滚圆参数制备微丸，制备好的微丸使用流化床进行干燥(进风温度物料温度35℃～45℃)制得素丸。观察素丸的圆整度，并测定崩解时间，结果如表7所示。
表7乙醇浓度筛选结果
Figure PCTCN2021108360-appb-000016
结果表明：当乙醇浓度为60％时，微丸圆整度较好，微丸崩解速度快(30s)。在保证圆整度的前提下，为使素丸快速崩解，保证快速释放，选择60％乙醇浓度作为润湿剂。
实施例5崩解剂的筛选
选择交联聚维酮(XL-10)、交联羧甲基纤维素钠和羧甲基淀粉钠为考察对象，均使 用常规最大用量，且与低取代羟丙基纤维素联合使用，保持处方中其他辅料用量不变，微调稀释剂用量使得微丸载药量一致。使用60％的乙醇作为润湿剂，手动制取软材，挤出板孔径0.9mm，挤出速度30rpm，将挤出物料在滚圆转盘中滚圆，根据物料形状调整滚圆参数制备微丸，制备好的微丸使用流化床进行干燥(进风温度设置45℃，物料温度控制温度35℃～45℃)制得素丸。然后使用HPMC进行隔离衣包衣，流化床进风风机转速1200rpm，蠕动泵转速6～12rpm，计算喷液速约0.5～1.4g/min，控制雾化压约0.04Mpa充分雾化包衣液，物料稳定控制为35～45℃增重3％。再使用HPMC-AS进行肠溶衣包衣，流化床进风风机转速1200rpm，蠕动泵转速6～12rpm，计算喷液速约1.1g～1.7g/min，控制雾化压约0.04Mpa充分雾化包衣液，物料温度控制为35℃～45℃，增重18％(理论投料)，包衣处方和工艺相同。将微丸填充胶囊后测试释放和耐酸力，结果如表8所示。
表8崩解剂的筛选结果
Figure PCTCN2021108360-appb-000017
Figure PCTCN2021108360-appb-000018
结果显示，处方比例均为常规最大用量(交联聚维酮10％(单位处方量22.22mg)、羧甲基淀粉钠8％(单位处方量17.78mg)，交联羧甲基纤维素钠6％(单位处方量13.33mg)，微丸释放效果从高到低依次为羧甲基淀粉钠(立崩)、交联羧甲基纤维素钠和交联聚维酮(XL-10)，使用羧甲基淀粉钠(立崩)作为崩解剂时，其膨胀力最大，肠溶微丸微丸崩解最好，释放最快。故选定羧甲基淀粉钠(立崩)作为本品崩解剂。为此，确定C20161108批处方为素丸目标处方。
实施例9隔离包衣增重对肠溶微丸释放和稳定性的影响
隔离包衣能够防止API与肠溶衣材醋酸羟丙甲基纤维素琥珀酸酯(HPMC-AS)直接接触产生相互作用，影响制剂释放和稳定性。只有隔离衣完全包裹载药素丸且达到一定的厚度后才能防止API和HPMC-AS直接接触或渗透后接触。若隔离衣包裹不完整或太薄将导致在释放介质中API和HPMC-AS在局部高浓度情况接触而相互作用，减缓释放。隔离衣越厚(增重越大)，这种相互作用越弱，且HPMC本身还具有非离子型表活的特性，对制剂释放有利。另外，肠溶衣材料的酸性特点，是API的不稳定因素(降解)，故隔离衣增重对制剂有关物质稳定性有利。
素丸粒径约0.6～1.2mm，表面积大，需要一定的包衣增重才能将素丸的表面完全包裹起来。根据素丸的直径计算得到包衣增重为6.8％时才能保证微丸表面完全被隔离衣覆盖。本实施例设计增重为7％、15％和19％，对包衣效果进行考察。选用羟丙甲基纤维素作为隔离衣材料，滑石粉为抗粘剂(用量比为4:1)，控制流化床进风风机转速根据批量不同而调整，1200～1800rpm，蠕动泵转速6～8，计算得喷液速约0.7～1.5g/min，控制雾化压约 0.04～0.12Mpa充分雾化包衣液，物料稳定控制为35～45℃。选用醋酸羟丙甲基纤维素琥珀酸酯(HPMC-AS)作为肠溶材料、滑石粉为抗粘剂，柠檬酸三乙酯为增塑剂、单硬脂酸甘油酯为抗静电材料，用量比(11.4:3.8:2.8:0.4)，流化床进风风机转速1200～1400rpm，蠕动泵转速6～12，喷液速约0.8～1.3g/min，控制雾化压约0.04～0.06Mpa充分雾化包衣液，实际物料温度控制为35℃～42℃，增重18％。肠溶微丸填充胶囊后测试释放，耐酸力，结果如表9所示。
表9隔离包衣增重对肠溶微丸释放影响
Figure PCTCN2021108360-appb-000019
Figure PCTCN2021108360-appb-000020
富马酸奥比特嗪在酸性条件不稳定，肠溶材料酸性较强，隔离包衣增重影响隔离衣膜完整性及厚度。本实施例对隔离包衣增重进行考察，筛选出能有效阻隔富马酸奥比特嗪和肠溶材料的隔离包衣增重，主要考察项目为含量、有关物质、耐酸力和释放。结果详见表10。
表10隔离包衣增重对肠溶微丸释放影响
Figure PCTCN2021108360-appb-000021
Figure PCTCN2021108360-appb-000022
结果表明：
(1)隔离衣包衣增重6.5％时，加速实验肠溶微丸胶囊释放变慢严重。主要原因为增重为6.5％时，隔离衣能完全包裹素丸，故0天质量合格，但次增重下隔离衣厚度不够，在放置过程中分子运动可导致API或肠溶材料均渗透过隔离衣而相互接触，相互作用导致释放下降。当隔离衣包衣增重增加至14.1％和19.5％时，肠溶微丸胶囊耐酸力和释放度在加速3月均未发生显著变化，相对较稳定。说明虽然前期实验表明当包衣增重6.5％时，制剂0天释放度达到了开发目标，但是从稳定性角度考虑，隔离衣的包衣增重应不小于14.1％。
(2)隔离衣包衣增重14.1％和19.5％肠溶微丸胶囊有关物质中杂C均有增长，0天未检出，加速3月杂质C增长为0.19％，增长幅度相同,达到稳定性要求。故从有关物质的角度考虑，隔离衣14.1％(投料按照15％)及以上即可以有效阻隔肠溶衣，保护富马酸奥比特嗪。
实施例10肠溶衣增重考察
当素丸的圆整度、粒径分布相同时，包衣增重越大，包衣层越厚，耐酸力越强；肠溶膜越厚溶解越慢，肠溶微丸胶囊释放随之变慢。为了在保证耐酸力合格的情况下，尽量选择低的包衣增重使其既能保证释放，又能保证制剂稳定性。本实施例设计了肠溶衣包衣增重分别为18％、22％、26％的三个实验，对相同的处方工艺制备的隔离衣微丸进行包衣。流化床进风风机转速1200～1400rpm，蠕动泵转速6～12rpm，喷液速约0.8～1.2g/min，控制雾化压约0.03～0.04Mpa充分雾化包衣液，实际物料温度控制为35℃～40℃。检测肠溶微丸胶囊耐酸力和释放，结果详见表11。
表11肠溶包衣增重对制剂耐酸和释放的影响
Figure PCTCN2021108360-appb-000023
注：因肠溶包衣增重18％时已能保证耐酸力，故未检测22％，26％时耐酸力。
结果表明：
(1)肠溶包衣增重18％，能保证富马酸奥比特嗪肠溶微丸胶囊释放达到开发目标；
(2)当肠溶增重从18％增加至26％时，肠溶微丸胶囊释放速率变慢，说明肠溶包衣不宜过高，否则不利于制剂释放。综合耐酸力，肠溶包衣18％为最佳。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (25)

  1. 一种肠溶微丸，其包含a)含富马酸奥比特嗪的丸芯，b)隔离层和c)肠溶层。
  2. 根据权利要求1所述的肠溶微丸，其中所述的丸芯包含稀释剂、崩解剂和助溶剂。
  3. 根据权利要求1-2任一项所述的肠溶微丸，其中所述的稀释剂为选自微晶纤维素、乳糖、预胶化淀粉中的一种或多种。
  4. 根据权利要求1-3任一项所述的肠溶微丸，所述的崩解剂为选自羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮中的一种或多种。
  5. 根据权利要求1-4任一项所述的肠溶微丸，其中所述的助溶剂为选自聚乙烯吡咯烷酮、吐温-20、吐温-60、吐温-80、十二烷基硫酸钠中的一种或多种。
  6. 根据权利要求1-5任一项所述的肠溶微丸，其中所述的丸芯中：稀释剂为选自微晶纤维素、乳糖和预胶化淀粉中的一种或多种；崩解剂为选自低取代羟丙基纤维素、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮中的一种或多种；助溶剂为选自聚乙烯吡咯烷酮、吐温-20、吐温-60、吐温-80、十二烷基硫酸钠中的一种或多种。
  7. 根据权利要求1-6任一项所述的肠溶微丸，其中所述的崩解剂为：
    羧甲基淀粉钠，
    交联羧甲基纤维素钠，
    交联聚维酮，
    低取代羟丙基纤维素与羧甲基淀粉钠的组合，
    低取代羟丙基纤维素与交联羧甲基纤维素钠的组合，或
    低取代羟丙基纤维素与交联聚维酮的组合。
  8. 根据权利要求7所述的肠溶微丸，其中所述的低取代羟丙基纤维素与羧甲基淀粉钠的质量比例为0.1～3.5:1(例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1)，
    低取代羟丙基纤维素与交联羧甲基纤维素钠的质量比例为0.1～3.5:1(例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1)，
    低取代羟丙基纤维素与交联聚维酮的质量比例为0.1～3.5:1(例如0.5:1、1:1、1.4:1、1.5:1、1.75:1、2:1、2.3:1、2.5:1或3:1)。
  9. 根据权利要求1-8任一项所述的肠溶微丸，其中所述的丸芯包含：以重量份计 的
    Figure PCTCN2021108360-appb-100001
  10. 根据权利要求1-9任一项所述的肠溶微丸，其中所述的隔离层中包含隔离材料，
    可选地，所述隔离层还包括抗粘剂，
    优选地，所述隔离材料为选自羟丙甲基纤维素、羟丙基纤维素中的一种或两种，
    优选地，所述的抗粘剂为滑石粉。
  11. 根据权利要求1-10任一项所述的肠溶微丸，其中所述的肠溶层中包含肠溶材料，
    可选地，所述肠溶层还包含增塑剂和/或抗粘剂，
    优选地，所述肠溶材料为选自丙烯酸树脂、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙甲纤维素邻苯二甲酸酯、醋酸纤维素酞酸酯中的一种或多种，
    优选地，所述增塑剂为柠檬酸三乙酯，
    优选地，所述抗粘剂为滑石粉或单硬脂酸甘油酯或者二者的组合。
  12. 根据权利要求1-11任一项所述的肠溶微丸，其中隔离层的重量为含富马酸奥比特嗪的丸芯的重量的10％-20％；
    优选地，隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-20％；
    优选地，隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-18％；
    优选地，隔离层的重量为含富马酸奥比特嗪的丸芯的重量的14％-16％。
  13. 根据权利要求1-12任一项所述的肠溶微丸，其中肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的16％-26％；
    优选地，肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的16％-20％；
    优选地，肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的17％-20％；
    优选地，肠溶层的重量为含富马酸奥比特嗪的丸芯的重量的18％-20％。
  14. 根据权利要求1-13任一项所述的肠溶微丸，其包含：以重量份计的
    Figure PCTCN2021108360-appb-100002
    Figure PCTCN2021108360-appb-100003
  15. 根据权利要求1-14任一项所述的肠溶微丸，其中所述肠溶微丸粒径在0.3-1.5mm之间。
  16. 根据权利要求1-15任一项所述的肠溶微丸，其中所述的富马酸奥比特嗪为无定形、晶型A或晶型B。
  17. 根据权利要求1-16任一项所述的肠溶微丸，其中所述的富马酸奥比特嗪颗粒粒径D90小于或等于50μm。
  18. 根据权利要求1-17任一项所述的肠溶微丸，其中所述的富马酸奥比特嗪颗粒粒径D90小于或等于30μm。
  19. 一种胶囊或片剂，由权利要求1-18任一项所述的肠溶微丸罐装胶囊而成或压片而成。
  20. 权利要求19所述胶囊或片剂，其中的富马酸奥比特嗪的含量为5-200mg。
  21. 权利要求19或20所述胶囊或片剂，其中的富马酸奥比特嗪的含量为5mg、10mg、25mg、50mg、100mg或200mg。
  22. 权利要求1-18任一项所述的肠溶微丸的制备方法，包括以下步骤：
    a,将富马酸奥比特嗪与稀释剂、崩解剂混合，得到预混物；
    b,将预混物与助溶剂溶液混合，制得软材，其中所述助溶剂溶液是将助溶剂与浓度为50％～70％的乙醇水溶液混合后得到；
    c,使制得的软材经过挤出滚圆制丸，干燥；
    d,包隔离衣；
    e,包肠溶衣。
  23. 权利要求1-18所述的肠溶微丸或权利要求19-21任一项所述的胶囊或片剂在制备用于预防和/或治疗肿瘤的药物中的用途。
  24. 权利要求1-18所述的肠溶微丸或权利要求19-21任一项所述的胶囊或片剂，其用于预防和/或治疗肿瘤。
  25. 一种治疗肿瘤的方法，包括给有需要的受试者施用治疗和/或预防有效量的权利要求1-18所述的肠溶微丸或权利要求19-21任一项所述的胶囊或片剂。
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CN111743876B (zh) 2022-05-10
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