CN112641756A - 一种泊沙康唑肠溶微丸及其制备方法 - Google Patents
一种泊沙康唑肠溶微丸及其制备方法 Download PDFInfo
- Publication number
- CN112641756A CN112641756A CN202011604246.1A CN202011604246A CN112641756A CN 112641756 A CN112641756 A CN 112641756A CN 202011604246 A CN202011604246 A CN 202011604246A CN 112641756 A CN112641756 A CN 112641756A
- Authority
- CN
- China
- Prior art keywords
- enteric
- posaconazole
- pellet
- mixture
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008188 pellet Substances 0.000 title claims abstract description 38
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 33
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 239000004014 plasticizer Substances 0.000 claims abstract description 10
- 239000000853 adhesive Substances 0.000 claims abstract description 7
- 230000001070 adhesive effect Effects 0.000 claims abstract description 7
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000002702 enteric coating Substances 0.000 claims abstract description 7
- 238000009505 enteric coating Methods 0.000 claims abstract description 7
- 239000002198 insoluble material Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 10
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 8
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 8
- ALOUNLDAKADEEB-UHFFFAOYSA-N dimethyl sebacate Chemical compound COC(=O)CCCCCCCCC(=O)OC ALOUNLDAKADEEB-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000005507 spraying Methods 0.000 claims description 8
- 229920000881 Modified starch Polymers 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 5
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 229940014772 dimethyl sebacate Drugs 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 238000005469 granulation Methods 0.000 claims description 4
- 230000003179 granulation Effects 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 claims description 4
- 239000001069 triethyl citrate Substances 0.000 claims description 4
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000013769 triethyl citrate Nutrition 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- LUJQXGBDWAGQHS-UHFFFAOYSA-N ethenyl acetate;phthalic acid Chemical compound CC(=O)OC=C.OC(=O)C1=CC=CC=C1C(O)=O LUJQXGBDWAGQHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 14
- 239000002662 enteric coated tablet Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; 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
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种泊沙康唑肠溶微丸及其制备方法，该微丸包括含药微丸和肠溶性包衣膜；含药微丸与肠溶性包衣膜的比例为90:10‑98:2；含药微丸包括以下质量配比的组分：泊沙康唑10％‑30％、稀释剂1％‑40％、崩解剂0％‑15％、粘合剂1％‑10％和pH调节剂1％‑5％；肠溶性包衣膜包括以下质量配比的组分：水不溶性材料30‑65％、肠溶性材料5％‑20％和增塑剂0.1％‑2％。本发明的制备工艺简单，采用的设备普及度高，节约能源，降低成本，适合工业化生产，极具市场开发前景；利用药物本身的溶解特点，达到肠溶片一样的疗效。
Description
技术领域
本发明涉及医药技术领域，特别涉及一种泊沙康唑肠溶微丸及其制备方法。
背景技术
泊沙康唑是由伊曲康唑衍生而来，是一种广谱的三唑类抗真菌药，用于难治性疾病或其他药物耐药所引起的真菌感染(如曲霉菌病、结核菌病和镰刀菌病等)，该药由美国Schering-Plough公司研制上市，是一种新的化学分子实体，是第一个被FDA批准的用于预防由侵袭性曲霉菌引起病变的抗菌药物.
泊沙康唑为弱碱性药物，其在在胃酸性环境中溶解度较高，溶解度约为0.8mg/mL，在pH5-7的缓冲盐溶液中溶解度＜0.001mg/mL。表明泊沙康唑到达肠道时，溶解后的泊沙康唑会沉淀，而泊沙康唑的主要吸收部位位于小肠，这就泊沙康唑生物利用率低的主要原因。由于泊沙康唑的蛋白结合率高达98％～99％，因此保证泊沙康唑溶解后的药物被吸收就能达到提高生物利用度目的。又由于市售肠溶片(Noxafil)采用了固体分散体技术，设备成本较高，设备目前相对通用性低；而市售另一种剂型为口服混悬液，该剂型携带和服用不方便，且有文献报道个体差异较大。
发明内容
本发明的目的是提供一种泊沙康唑肠溶微丸及其制备方法，解决上述现有技术问题中的一个或者多个。
本发明提供的一种泊沙康唑肠溶微丸，其包括含药微丸和肠溶性包衣膜；所述含药微丸与肠溶性包衣膜的比例为90:10-98:2；所述含药微丸包括以下质量配比的组分：泊沙康唑10％-30％、稀释剂1％-40％、崩解剂0％-15％、粘合剂1％-10％和pH调节剂1％-5％；所述肠溶性包衣膜包括以下质量配比的组分：水不溶性材料30-65％、肠溶性材料5％-20％和增塑剂0.1％-2％。
在某些实施方式中，稀释剂选自淀粉、乳糖、糊精、预胶化淀粉、微晶纤维素、甘露醇或其混合物。
在某些实施方式中，崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、预胶化淀粉或其混合物。
在某些实施方式中，粘合剂选自淀粉、预胶化淀粉、甲基纤维素、羟丙基纤维素、羟丙甲纤维素、聚维酮或其混合物。
在某些实施方式中，pH调节剂选自柠檬酸、氨基酸类、硬脂酸或其混合物。
在某些实施方式中，肠溶性材料选自邻苯二甲酸醋酸纤维素(CAP)、聚乙烯邻苯二醋酸酯(PVAP)、甲基丙烯酸-甲基丙烯酸酯共聚物、醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素酞酸酯或其混合物。
在某些实施方式中，增塑剂选自柠檬酸三乙酯(TEC)、柠檬酸三丁酯(TBC)、乙酰柠檬酸三乙酯(ATEC)、癸二酸二甲酯(DMS)、癸二酸二丁酯(DBS)、邻苯二甲酸二丁酯(DBP)或其混合物。
在某些实施方式中，不溶性包衣材料包括但不限于乙基纤维素。
本发明还公开了一种泊沙康唑肠溶微丸的制备方法，其特征在于，包括以下步骤：
1)将泊沙康唑、稀释剂、崩解剂过筛网，并混合均匀；
2)配制粘合剂溶液；
3)将步骤1)中物料转移至流化床中，采用步骤2)制备的溶液作为粘合剂，侧喷制粒，干燥；
4)配制包衣溶液，将水不溶性材料溶于溶剂中，加入肠溶性材料、增塑剂搅拌至分散均匀；
5)将步骤3)的物料转移至流化床中，采用步骤4)制备的混悬液进行底喷包衣；
6)干燥收集微丸。
崩解剂是指能促使药物在胃肠道中迅速崩解成小粒子的辅料，由于药物被制成微丸后，孔隙率很小，结合力很强，即使原先在水中易溶解的药物被制成微丸后，其在水中溶解或者崩解也需要一定的时间。因此，微丸中难溶性药物的溶出速度成为体内药物吸收速度的限制因素，而微丸的崩解速度直接影响药物的溶出。
助流剂是指制备微丸时为了能够顺利加料和出丸，并减少黏冲及降低颗粒与颗粒、微丸与模孔壁之间的摩擦力，使片面光滑美观，在制备中加入的一种药物制剂。
与现有技术相比，本发明的有益效果是：本发明的制备工艺简单，采用的设备普及度高，节约能源，降低成本，适合工业化生产，极具市场开发前景；利用药物本身的溶解特点，达到肠溶片一样的疗效。
附图说明
图1是本发明实施例1制备的产品与市售产品的溶出曲线图；
图2是本发明实施例1制备的产品与市售产品的溶出曲线图；
图3是本发明实施例1、2制备的产品与市售产品的溶出曲线图。
具体实施方式
下面通过实施方式对本发明进行进一步详细的说明。
实施例1
处方：(制备1000粒微丸)
制备方法：
1)将泊沙康唑、微晶纤维素、乳糖交联羧甲基纤维素钠过80目筛网；
2)将羟丙甲基纤维素K4M配制1.5％水溶液；
3)将步骤1)中的物料转移至流化床中，采用步骤2)中的溶液作为粘合剂，侧喷制粒，干燥；
4)配制包衣溶液，将乙基纤维素分散于纯化水中，配成15％的水分散体，加入肠溶性材料、增塑剂搅拌至分散均匀；
5)将步骤3)中的物料转移至流化床中，采用步骤4)中制备的混悬液进行底喷包衣；
6)干燥收集微丸。
实施例2
处方：(制备1000粒微丸)
制备方法：
1)将泊沙康唑、微晶纤维素、乳糖交联羧甲基纤维素钠过80目筛网；
2)将羟丙甲基纤维素K4M配制2.0％水溶液；
3)将步骤1)中的物料转移至流化床中，采用步骤2)中溶液作为粘合剂，侧喷制粒，干燥；
4)配制包衣溶液，将乙基纤维素分散于纯化水中，配成20％的水分散体，加入肠溶材料、增塑剂搅拌至分散均匀；
5)将步骤3)中物料中物料转移至流化床中，采用步骤4)中制备的混悬液进行底喷包衣；
6)干燥收集微丸。
根据实施例1制得的微丸(简称示例1)，使用中国药典2015版，第二法，桨法，在75rpm和0.01N HCl中溶出2h后取样测定溶出量，加250mL磷酸盐(含吐温)调节pH至6.8，继续溶出60min，分别于10、15、20、30、45、50、60min中取样绘制其溶出曲线，并与市售产品(诺科飞)的溶出曲线对比，该溶出曲线对比如图1所示。
根据实施例1制得的微丸(简称示例1)，实施例2制得的微丸(简称示例2)，使用中国药典2015版，第二法，桨法，在100rpm 0.1N HCl(分别含0％和40％乙醇)中溶出2h，每隔15min取样，绘制其溶出曲线，并与市售产品(诺科飞)的溶出曲线对比，该溶出曲线对比如图2和图3所示。
图1至图3的结果表明，按照本发明所述制备方法制备得到的泊沙康唑肠溶微丸，与市售产品相比，在体外溶出曲线基本一致，证明本发明所得产品与市售产品的体内疗效具有一致性。
本发明的制备工艺简单，采用的设备普及度高，节约能源，降低成本，适合工业化生产，极具市场开发前景；利用药物本身的溶解特点，达到肠溶片一样的疗效。
以上表述仅为本发明的优选方式，应当指出，对本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些也应视为发明的保护范围之内。
Claims (9)
1.一种泊沙康唑肠溶微丸，其特征在于，包括含药微丸和肠溶性包衣膜；所述含药微丸与肠溶性包衣膜的比例为90:10-98:2；所述含药微丸包括以下质量配比的组分：泊沙康唑10％-30％、稀释剂1％-40％、崩解剂0％-15％、粘合剂1％-10％和pH调节剂1％-5％；所述肠溶性包衣膜包括以下质量配比的组分：水不溶性材料30-65％、肠溶性材料5％-20％和增塑剂0.1％-2％。
2.根据权利要求1所述的一种泊沙康唑肠溶微丸，其特征在于，所述稀释剂选自淀粉、乳糖、糊精、预胶化淀粉、微晶纤维素、甘露醇或其混合物。
3.根据权利要求2所述的一种泊沙康唑肠溶微丸，其特征在于，所述崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、预胶化淀粉或其混合物。
4.根据权利要求3所述的一种泊沙康唑肠溶微丸，其特征在于，所述粘合剂选自淀粉、预胶化淀粉、甲基纤维素、羟丙基纤维素、羟丙甲纤维素、聚维酮或其混合物。
5.根据权利要求4所述的一种泊沙康唑肠溶微丸，其特征在于，所述pH调节剂选自柠檬酸、氨基酸类、硬脂酸或其混合物。
6.根据权利要求5所述的一种泊沙康唑肠溶微丸，其特征在于，所述肠溶性材料选自邻苯二甲酸醋酸纤维素(CAP)、聚乙烯邻苯二醋酸酯(PVAP)、甲基丙烯酸-甲基丙烯酸酯共聚物、醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素酞酸酯或其混合物。
7.根据权利要求6所述的一种泊沙康唑肠溶微丸，其特征在于，所述增塑剂选自柠檬酸三乙酯(TEC)、柠檬酸三丁酯(TBC)、乙酰柠檬酸三乙酯(ATEC)、癸二酸二甲酯(DMS)、癸二酸二丁酯(DBS)、邻苯二甲酸二丁酯(DBP)或其混合物。
8.根据权利要求7所述的一种泊沙康唑肠溶微丸，其特征在于，所述不溶性包衣材料包括但不限于乙基纤维素。
9.根据权利要求8所述一种泊沙康唑肠溶微丸的制备方法，其特征在于，包括以下步骤：
1)将泊沙康唑、稀释剂、崩解剂过筛网，并混合均匀；
2)配制粘合剂溶液；
3)将步骤1)中物料转移至流化床中，采用步骤2)制备的溶液作为粘合剂，侧喷制粒，干燥；
4)配制包衣溶液，将水不溶性材料溶于溶剂中，加入肠溶性材料、增塑剂搅拌至分散均匀；
5)将步骤3)的物料转移至流化床中，采用步骤4)制备的混悬液进行底喷包衣；
6)干燥收集微丸。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011604246.1A CN112641756B (zh) | 2020-12-29 | 2020-12-29 | 一种泊沙康唑肠溶微丸及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011604246.1A CN112641756B (zh) | 2020-12-29 | 2020-12-29 | 一种泊沙康唑肠溶微丸及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112641756A true CN112641756A (zh) | 2021-04-13 |
| CN112641756B CN112641756B (zh) | 2022-08-19 |
Family
ID=75363979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011604246.1A Active CN112641756B (zh) | 2020-12-29 | 2020-12-29 | 一种泊沙康唑肠溶微丸及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112641756B (zh) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1853634A (zh) * | 2005-03-17 | 2006-11-01 | 参天堂制药株式会社 | 用于口服给药的、含有伊曲康唑的组合物 |
| CN101057837A (zh) * | 2006-04-20 | 2007-10-24 | 朱志宏 | 一种右旋酮洛芬肠溶微丸及制备方法 |
| CN103845292A (zh) * | 2012-11-29 | 2014-06-11 | 正大天晴药业集团股份有限公司 | 泊沙康唑微丸及其制备方法 |
| CN104971045A (zh) * | 2014-04-11 | 2015-10-14 | 上海宣泰医药科技有限公司 | 泊沙康唑药物组合物及其制备方法和药物制剂 |
| EP3342399A1 (en) * | 2016-12-31 | 2018-07-04 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions comprising posaconazole and manufacturing method |
| CN110960499A (zh) * | 2019-12-31 | 2020-04-07 | 卓和药业集团有限公司 | 一种泊沙康唑胃漂浮片及其制备方法 |
-
2020
- 2020-12-29 CN CN202011604246.1A patent/CN112641756B/zh active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1853634A (zh) * | 2005-03-17 | 2006-11-01 | 参天堂制药株式会社 | 用于口服给药的、含有伊曲康唑的组合物 |
| CN101057837A (zh) * | 2006-04-20 | 2007-10-24 | 朱志宏 | 一种右旋酮洛芬肠溶微丸及制备方法 |
| CN103845292A (zh) * | 2012-11-29 | 2014-06-11 | 正大天晴药业集团股份有限公司 | 泊沙康唑微丸及其制备方法 |
| CN104971045A (zh) * | 2014-04-11 | 2015-10-14 | 上海宣泰医药科技有限公司 | 泊沙康唑药物组合物及其制备方法和药物制剂 |
| EP3342399A1 (en) * | 2016-12-31 | 2018-07-04 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions comprising posaconazole and manufacturing method |
| CN110960499A (zh) * | 2019-12-31 | 2020-04-07 | 卓和药业集团有限公司 | 一种泊沙康唑胃漂浮片及其制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| JAMES C. DINUNZIO ET AL.: "Amorphous Compositions Using Concentration Enhancing Polymers for Improved Bioavailability of Itraconazole", 《MOLECULAR PHARMACEUTICS》 * |
| 奚念朱主编: "《药物动力学》", 30 April 1992 * |
| 赖颖强等: "泊沙康唑肠溶片的制备及Beagle犬体内药动学初探", 《中国医院药学杂志》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112641756B (zh) | 2022-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2005320609B2 (en) | Matrix type sustained-release preparation containing basic drug or salt thereof, and method for manufacturing the same | |
| EP1898886B1 (en) | Novel sustained release dosage form | |
| WO2011111818A1 (ja) | モサプリドまたはその塩を含む徐放型医薬組成物 | |
| WO2001035958A1 (en) | Carvedilol methanesulfonate | |
| SK285152B6 (sk) | Enterický potiahnutý farmaceutický prostriedok a spôsob jeho prípravy | |
| KR20110117199A (ko) | 유기 화합물의 생약 제제 | |
| US20060159753A1 (en) | Matrix type sustained-release preparation containing basic drug or salt thereof | |
| TW201545745A (zh) | 阿利沙坦酯固體分散體及藥物組合物 | |
| JP7021108B2 (ja) | ニコチンアミドの経口薬学的組成物 | |
| US20110086102A1 (en) | Delayed release compositions | |
| US11576917B2 (en) | Pharmaceutical compositions comprising Ibrutinib | |
| TW201542212A (zh) | 包括恩曲他濱、泰諾福韋、地瑞那韋與利托那韋的單位劑量形式以及包括地瑞那韋與利托那韋的單體錠劑 | |
| US20070196399A1 (en) | Enteric-coated preparation covered with enteric coating material for site-specific delivery of drug to site within the small intestine | |
| CN112641756B (zh) | 一种泊沙康唑肠溶微丸及其制备方法 | |
| CN114096530A (zh) | 一种复合物的药物组合物及其制备方法 | |
| EP3796908B1 (en) | Controlled release propiverine formulations | |
| WO2019237446A1 (zh) | 一种曲美他嗪缓释片及其制备方法 | |
| KR102104507B1 (ko) | 팔미토일-l-프롤릴-l-프롤릴-글리실-l-타이로신 나트륨을 포함하는 약제학적 제제 및 이의 제조방법 | |
| TW202143959A (zh) | 一種非布司他片 | |
| KR20160127405A (ko) | 리바스티그민 함유 서방출 의약조성물 | |
| CN111617257A (zh) | 一种阿比特龙或其衍生物药物组合物及其应用 | |
| CN111888339B (zh) | 盐酸二甲双胍肠溶片及其制备方法 | |
| CN112533608B (zh) | 包含1,3,5-三嗪衍生物或其盐的固体药物组合物 | |
| CN115463104A (zh) | 一种含有ebtp的片剂及其制备方法 | |
| WO2023038600A1 (en) | A capsule formulation comprising macitentan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd. Address before: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant before: Zhuohe Pharmaceutical Group Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |