CN114767684B - Pharmaceutical composition, itraconazole pellets, preparation method and itraconazole capsules - Google Patents
Pharmaceutical composition, itraconazole pellets, preparation method and itraconazole capsules Download PDFInfo
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- CN114767684B CN114767684B CN202210477958.4A CN202210477958A CN114767684B CN 114767684 B CN114767684 B CN 114767684B CN 202210477958 A CN202210477958 A CN 202210477958A CN 114767684 B CN114767684 B CN 114767684B
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- itraconazole
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- drug
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- 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 title claims abstract description 120
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 120
- 239000008188 pellet Substances 0.000 title claims abstract description 78
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 239000002775 capsule Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000284 extract Substances 0.000 claims abstract description 40
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 35
- 229940023019 aconite Drugs 0.000 claims abstract description 22
- 241000173529 Aconitum napellus Species 0.000 claims abstract description 19
- 240000004980 Rheum officinale Species 0.000 claims abstract description 12
- 235000008081 Rheum officinale Nutrition 0.000 claims abstract description 12
- 239000011248 coating agent Substances 0.000 claims description 79
- 238000000576 coating method Methods 0.000 claims description 79
- 239000006187 pill Substances 0.000 claims description 64
- 239000003814 drug Substances 0.000 claims description 55
- 229940079593 drug Drugs 0.000 claims description 42
- 239000010410 layer Substances 0.000 claims description 29
- 239000000463 material Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000314 lubricant Substances 0.000 claims description 21
- 239000011247 coating layer Substances 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 19
- 239000000725 suspension Substances 0.000 claims description 19
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 18
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 18
- 239000000853 adhesive Substances 0.000 claims description 16
- 230000001070 adhesive effect Effects 0.000 claims description 16
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 16
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 16
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 16
- 241000758794 Asarum Species 0.000 claims description 15
- 229930006000 Sucrose Natural products 0.000 claims description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 15
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
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- 229960003943 hypromellose Drugs 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
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- 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 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- 239000012738 dissolution medium Substances 0.000 description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
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- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- VWVRASTUFJRTHW-UHFFFAOYSA-N 2-[3-(azetidin-3-yloxy)-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound O=C(CN1C=C(C(OC2CNC2)=N1)C1=CN=C(NC2CC3=C(C2)C=CC=C3)N=C1)N1CCC2=C(C1)N=NN2 VWVRASTUFJRTHW-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
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- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/26—Aristolochiaceae (Birthwort family), e.g. heartleaf
- A61K36/268—Asarum (wild ginger)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
- A61K36/708—Rheum (rhubarb)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
- A61K36/714—Aconitum (monkshood)
-
- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- 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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, 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
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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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Mycology (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition, itraconazole pellets, a preparation method and itraconazole capsules. The pharmaceutical composition comprises itraconazole and a penetration enhancer, wherein the penetration enhancer contains rheum officinale extract and aconite extract. Due to the permeation promotion effect of the permeation enhancer, the pharmaceutical composition can ensure the bioavailability of the itraconazole and simultaneously obviously reduce the use amount of the itraconazole, thereby reducing the incidence or severity of untoward effects of the itraconazole.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition, itraconazole pellets, a preparation method and itraconazole capsules.
Background
Itraconazole, i.e., (±) -cis-4- [4- [4- [4- [ [2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-yl ] methoxy ] phenyl ] -1-piperazine ] phenyl ] -2, 4-dihydro-2- (1-methylpropyl) -3H-1,2, 4-triazol-3-one, is a triazole high-efficiency broad-spectrum antifungal agent, can be combined with fungal cytochrome P450 isozymes, and inhibits ergosterol synthesis. Itraconazole is effective against infections of dermatophytes, candida, cryptococcus neoformans, pityrosporum, aspergillus, histoplasmodium, paracoccidiomycosis brazil, sporomyces lanuginosus, chromomycosis, cladosporium, dermatitis blastomycosis and the like, and is mainly used for treating systemic infections caused by deep fungi, such as blastomycosis, histoplasmosis, coccidiosis, chromomycosis, sporotrichosis, coccidioidomycosis and the like. Can also be used for treating candidiasis and aspergillosis.
Itraconazole may cause serious adverse effects such as liver damage, congestive heart failure, nausea and other gastrointestinal reactions, hypokalemia and oedema during administration.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to reduce the occurrence rate of adverse reaction caused by itraconazole or reduce the degree of adverse reaction caused by itraconazole while ensuring the bioavailability of itraconazole, so as to provide a pharmaceutical composition, itraconazole pellets, a preparation method and itraconazole capsules.
For this purpose, the invention provides a pharmaceutical composition comprising itraconazole and a permeation enhancer, wherein the permeation enhancer contains rhubarb extract and aconite extract.
Optionally, the content of the penetration enhancer is 1 to 10 parts by weight relative to 75 parts by weight of itraconazole;
optionally, the rheum officinale extract is a rheum officinale aqueous extract, the aconite extract is an aconite water extract, and the dosage ratio of rheum officinale to aconite is (0.5-1): (0.5-1).
Optionally, the penetration enhancer further comprises herba asari extract;
optionally, the asarum extract is an asarum water extract, and the dosage ratio of rheum officinale, aconite and asarum is (0.5-1): (0.5-1): (0.3-1).
Optionally, the penetration enhancer can be obtained by combining extracts of multiple medicinal materials, or can be obtained by extracting multiple medicinal materials after combining. For example, the extraction method of the medicinal material extract may include: taking medicinal materials (single medicinal materials or combination of medicinal materials), crushing, soaking in water for 2-6 h, boiling for 0.25-1 h, separating solid from liquid, taking liquid, drying at low temperature (30-60 ℃) and adding water with the water content of 10-15 mL relative to 1g of medicinal materials.
The invention also provides a pharmaceutical preparation, which comprises the pharmaceutical composition as described in any one of the above and pharmaceutically acceptable auxiliary components.
The invention also provides an itraconazole pellet, which contains the pharmaceutical composition of any one of the above components;
optionally, the itraconazole pellets comprise a pellet core, a drug-containing layer and a coating layer, wherein the drug-containing layer is coated on the surface of the pellet core, and the coating layer is coated on the surface of the drug-containing layer;
wherein the drug-containing layer contains itraconazole, and the drug-containing layer and/or the pill core contains the permeation enhancer;
optionally, the particle size of the pill core is 20-25 meshes.
Optionally, the drug-containing layer contains itraconazole and the permeation enhancer, and the pill core is a blank pill core;
optionally, the blank pellet core is selected from at least one of sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core and starch sucrose pellet core, and the content of the blank pellet core is 50-150 parts by weight relative to 75 parts by weight of itraconazole.
Optionally, the drug-containing layer contains itraconazole, the pill core is a pill-containing core, and the pill-containing core contains the permeation enhancer;
optionally, the pill core further comprises a first adhesive and a filler, wherein the content of the first adhesive is 40-60 parts by weight and the content of the filler is 40-60 parts by weight relative to 75 parts by weight of itraconazole;
optionally, the first binder is selected from at least one of sucrose, corn starch, crospovidone, and hypromellose; the filler is at least one selected from starch, microcrystalline cellulose and lactose.
Alternatively, the pill-containing core may be prepared by the following method: dissolving penetration enhancer and first binder in water, adding filler, and granulating with fluidized bed to obtain the pill core.
Optionally, the drug-containing layer further contains a second binder and a lubricant, wherein the content of the second binder is 180-220 parts by weight and the content of the lubricant is 25-45 parts by weight relative to 75 parts by weight of itraconazole;
the coating layer contains a coating material, and the content of the coating material is 20-30 parts by weight relative to 75 parts by weight of itraconazole;
optionally, the second binder is selected from hydroxypropyl methylcellulose and/or crospovidone;
optionally, the lubricant is selected from at least one of sodium dodecyl sulfate, talcum powder and magnesium stearate; preferably sodium dodecyl sulfate and talcum powder, the dosage ratio of the sodium dodecyl sulfate to the talcum powder is (15-25): (10-20);
optionally, the coating material is selected from at least one of polyethylene glycol 6000, hypromellose, hydroxypropyl cellulose, and acrylic resin.
The invention also provides a method for preparing the itraconazole pellets according to any one of the above steps, which comprises the following steps:
coating a drug-containing suspension on a pill core, and drying to obtain a pellet intermediate, wherein the drug-containing suspension contains itraconazole, and the drug-containing suspension and/or the pill core contains a penetration enhancer;
and (5) taking the coating liquid, coating the pellet intermediate product with a coating layer, and drying.
Optionally, the drug-containing suspension contains itraconazole and the permeation enhancer, and the pill core is a blank pill core;
optionally, the blank pellet core is selected from at least one of sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core and starch sucrose pellet core, and the content of the blank pellet core is 50-150 parts by weight relative to 75 parts by weight of itraconazole.
Optionally, the drug-containing suspension contains itraconazole, the pill core is a drug-containing pill core, and the permeation enhancer is contained in the drug-containing pill core;
optionally, the pill core further comprises a first adhesive and a filler, wherein the content of the first adhesive is 40-60 parts by weight and the content of the filler is 40-60 parts by weight relative to 75 parts by weight of itraconazole;
optionally, the first binder is selected from at least one of sucrose, corn starch, crospovidone, and hypromellose; the filler is at least one selected from starch, microcrystalline cellulose and lactose.
Optionally, the drug-containing suspension also contains a second binder and a lubricant, wherein the content of the second binder is 180-220 parts by weight and the content of the lubricant is 25-45 parts by weight relative to 75 parts by weight of itraconazole;
the coating liquid contains a coating material, and the content of the coating material is 20-30 parts by weight relative to 75 parts by weight of itraconazole;
optionally, the second binder is selected from hydroxypropyl methylcellulose and/or crospovidone;
optionally, the lubricant is at least one of sodium dodecyl sulfate, talcum powder and magnesium stearate; preferably sodium dodecyl sulfate and talcum powder, the dosage ratio of the sodium dodecyl sulfate to the talcum powder is (15-25): (10-20);
optionally, the coating material is at least one selected from polyethylene glycol 6000, hypromellose, hydroxypropyl cellulose, and acrylic resin.
The invention also provides an itraconazole capsule, which contains the pharmaceutical composition described in any one of the above, or the itraconazole pellets prepared by the method described in any one of the above.
The technical scheme of the invention has the following advantages:
1. the pharmaceutical composition provided by the invention comprises itraconazole and a penetration enhancer, and the rheum officinale extract and the aconite extract are used together to be used as the penetration enhancer of the itraconazole drug, so that the absorption of the itraconazole can be obviously promoted, and the pharmaceutical composition can ensure the bioavailability of the itraconazole and simultaneously obviously reduce the use amount of the itraconazole, thereby reducing the occurrence rate or the severity of untoward effects of the itraconazole.
2. The pharmaceutical composition provided by the invention contains the rheum officinale extract, the aconite extract and the asarum extract, and the rheum officinale, the aconite and the asarum are combined, so that the permeation promoter has the permeation promoting effect and the harmonizing effect on organisms, and is beneficial to further reducing the incidence or the severity of untoward effects of itraconazole.
3. The itraconazole pellets provided by the invention contain the permeation promoting agent, and the permeation promoting effect of the permeation promoting agent ensures the bioavailability of itraconazole and simultaneously obviously reduces the use amount of itraconazole, thereby reducing the incidence or severity of untoward effects of itraconazole.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing cumulative elution as plotted in Experimental example 1 of the present invention.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
The preparation method of the rheum officinale, aconite and asarum extract, which is related to the embodiment of the invention, comprises the following steps:
taking 40g of crude powder of crude rhubarb, radix aconiti carmichaeli and asarum herb, adding 500mL of water to soak for 4 hours, boiling for 0.5 hour, filtering, taking liquid and drying at low temperature (30-60 ℃) to obtain the radix et rhizoma rhei aconiti carmichaeli asarum herb extract.
The preparation method of the radix et rhizoma Rhei and radix aconiti lateralis preparata extract in the embodiment of the invention comprises the following steps:
taking 40g of crude powder of the crude drug composition of the raw rhubarb and the prepared aconite, adding 500mL of water to soak for 4 hours, boiling for 0.5 hour, filtering, taking liquid and drying at low temperature (30-60 ℃) to obtain the extract of the rhubarb and the aconite.
Example 1
The embodiment provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Coating a medicine-containing layer:
A. dissolving 20g of sodium dodecyl sulfate (lubricant) in 1000g of 95% ethanol, adding 200g of hydroxypropyl methylcellulose (second adhesive), and dispersing uniformly;
B. taking 75g of itraconazole and 6g of radix et rhizoma Rhei and radix aconiti lateralis extract (penetration enhancer) to disperse in the solution obtained in the step A, then adding 1500g of dichloromethane, stirring and dispersing uniformly, wherein the dosage ratio of raw rheum officinale to radix aconiti lateralis preparata for preparing the radix et rhizoma Rhei and radix aconiti lateralis preparata is 1:1, a step of;
C. 15g of talcum powder (lubricant) is taken and dispersed in 200g of 95% ethanol;
D. the solution obtained in the step C is added into the solution obtained in the step B after passing through a 325-mesh screen, and the mixture is stirred uniformly to obtain a drug-containing suspension;
E. taking 100g of an amylosucrase pill core (blank pill core), putting into a coating pot, heating, and coating by using the drug-containing suspension obtained in the step D until the coating is finished after the temperature of the pill core reaches 40 ℃;
F. drying the coating product obtained in the step E at 80 ℃ until the water content is less than 1%, thus obtaining a pellet intermediate.
(2) Coating layer coating:
a. 25g of polyethylene glycol 6000 (coating material) is dispersed in 100g of dichloromethane;
b. adding 80g of 95% ethanol into the solution obtained in the step a, and stirring until the polyethylene glycol 6000 is completely dissolved;
c. placing the pellet intermediate obtained in the operation (1) into a coating pot, heating, spraying the solution obtained in the step b into the coating pot after the temperature reaches 35 ℃ for coating until the coating is finished;
d. and (3) drying the coating product obtained in the step (c) at 80 ℃ until the water content is less than 1%, thus obtaining the itraconazole pellets.
The itraconazole micro-pill prepared in the embodiment consists of a pill core, a medicine-containing layer and a coating layer, wherein the medicine-containing layer is coated on the surface of the pill core, the coating layer is coated on the surface of the medicine-containing layer, the medicine-containing layer contains itraconazole, a penetration enhancer (radix et rhizoma Rhei and aconiti carmichaeli extract), a second adhesive (hydroxypropyl methylcellulose) and a lubricant (sodium dodecyl sulfate and talcum powder in a weight ratio of 20:15), the pill core is a blank pill core (starch sucrose pill core), and the coating layer contains a coating material (polyethylene glycol 6000). The content of the permeation enhancer was 6 parts by weight, the content of the second binder was 200 parts by weight, the content of the lubricant was 35 parts by weight, the content of the blank pellet core was 100 parts by weight, and the content of the coating material was 25 parts by weight, relative to 75 parts by weight of itraconazole.
Example 2
The embodiment provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Preparing a pill-containing core:
6g of radix et rhizoma Rhei aconiti extract (penetration enhancer) and 54g of sucrose (first adhesive) are taken and dissolved in water, 50g of starch (filler) is added, and then the mixture is granulated by a fluidized bed to obtain a pill-containing core with the particle size of 20-25 meshes, wherein the dosage ratio of raw rheum officinale to prepared radix aconiti lateralis is 1:1.
(2) Coating a medicine-containing layer:
A. dissolving 20g of sodium dodecyl sulfate (lubricant) in 1000g of 95% ethanol, adding 200g of hydroxypropyl methylcellulose (second adhesive), and dispersing uniformly;
B. taking and dispersing 75g of itraconazole in the solution obtained in the step A, then adding 1500g of dichloromethane, and stirring and dispersing uniformly;
C. 15g of talcum powder (lubricant) is taken and dispersed in 200g of 95% ethanol;
D. the solution obtained in the step C is added into the solution obtained in the step B after passing through a 325-mesh screen, and the mixture is stirred uniformly to obtain a drug-containing suspension;
E. putting the pill-containing core obtained in the operation (1) into a coating pot, heating, and coating by using the drug-containing suspension obtained in the step D until the coating is finished after the temperature of the pill core reaches 40 ℃;
F. drying the coating product obtained in the step E at 80 ℃ until the water content is less than 1%, thus obtaining a pellet intermediate.
(3) Coating layer coating:
a. 25g of polyethylene glycol 6000 (coating material) is dispersed in 100g of dichloromethane;
b. adding 80g of 95% ethanol into the solution obtained in the step a, and stirring until the polyethylene glycol 6000 is completely dissolved;
c. placing the pellet intermediate obtained in the operation (2) into a coating pot, heating, spraying the solution obtained in the step b into the coating pot after the temperature reaches 35 ℃ for coating until the coating is finished;
d. and (3) drying the coating product obtained in the step (c) at 80 ℃ until the water content is less than 1%, thus obtaining the itraconazole pellets.
The itraconazole micro-pill prepared in the embodiment consists of a pill core, a medicine-containing layer and a coating layer, wherein the medicine-containing layer is coated on the surface of the pill core, the coating layer is coated on the surface of the medicine-containing layer, the medicine-containing layer contains itraconazole, a second adhesive (hydroxypropyl methylcellulose) and a lubricant (sodium dodecyl sulfate and talcum powder in a weight ratio of 20:15), the pill core is a pill-containing core, the pill-containing core contains a penetration enhancer (radix et rhizoma Rhei and aconiti lateralis extract), a first adhesive (sucrose) and a filler (starch), and the coating layer contains a coating material (polyethylene glycol 6000). The content of the second binder was 200 parts by weight, the content of the lubricant was 35 parts by weight, the content of the permeation enhancer was 6 parts by weight, the content of the first binder was 54 parts by weight, the content of the filler was 50 parts by weight, and the content of the coating material was 25 parts by weight, relative to 75 parts by weight of itraconazole.
Example 3
The embodiment provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Coating a medicine-containing layer:
A. dissolving 20g of sodium dodecyl sulfate (lubricant) in 1000g of 95% ethanol, adding 200g of hydroxypropyl methylcellulose (second adhesive), and dispersing uniformly;
B. dispersing 75g of itraconazole and 6g of radix et rhizoma Rhei, radix aconiti lateralis preparata and herba asari extract (penetrating agent) in the solution obtained in the step A, adding 1500g of dichloromethane, stirring and dispersing uniformly, wherein the dosage ratio of raw radix et rhizoma Rhei, radix aconiti lateralis preparata and herba asari used in preparing the radix et rhizoma Rhei, radix aconiti lateralis preparata and herba asari is 1:1:0.6;
C. 15g of talcum powder (lubricant) is taken and dispersed in 200g of 95% ethanol;
D. the solution obtained in the step C is added into the solution obtained in the step B after passing through a 325-mesh screen, and the mixture is stirred uniformly to obtain a drug-containing suspension;
E. taking 100g of an amylosucrase pill core (blank pill core), putting into a coating pot, heating, and coating by using the drug-containing suspension obtained in the step D until the coating is finished after the temperature of the pill core reaches 40 ℃;
F. drying the coating product obtained in the step E at 80 ℃ until the water content is less than 1%, thus obtaining a pellet intermediate.
(2) Coating layer coating:
a. 25g of polyethylene glycol 6000 (coating material) is dispersed in 100g of dichloromethane;
b. adding 80g of 95% ethanol into the solution obtained in the step a, and stirring until the polyethylene glycol 6000 is completely dissolved;
c. placing the pellet intermediate obtained in the operation (1) into a coating pot, heating, spraying the solution obtained in the step b into the coating pot after the temperature reaches 35 ℃ for coating until the coating is finished;
d. and (3) drying the coating product obtained in the step (c) at 80 ℃ until the water content is less than 1%, thus obtaining the itraconazole pellets.
Example 4
The embodiment provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Preparing a pill-containing core:
6g of rhubarb-aconite asarum extract (penetrating agent) and 54g of sucrose (first adhesive) are taken and dissolved in water, 50g of starch (filler) is added, and then the mixture is granulated by a fluidized bed to obtain a pill-containing core with the particle size of 20-25 meshes, wherein the dosage ratio of raw rhubarb, prepared aconite and asarum used in preparing the rhubarb-aconite asarum extract is 1:1:0.6.
(2) Coating a medicine-containing layer:
A. dissolving 20g of sodium dodecyl sulfate (lubricant) in 1000g of 95% ethanol, adding 200g of hydroxypropyl methylcellulose (second adhesive), and dispersing uniformly;
B. taking and dispersing 75g of itraconazole in the solution obtained in the step A, then adding 1500g of dichloromethane, and stirring and dispersing uniformly;
C. 15g of talcum powder (lubricant) is taken and dispersed in 200g of 95% ethanol;
D. the solution obtained in the step C is added into the solution obtained in the step B after passing through a 325-mesh screen, and the mixture is stirred uniformly to obtain a drug-containing suspension;
E. putting the pill-containing core obtained in the operation (1) into a coating pot, heating, and coating by using the drug-containing suspension obtained in the step D until the coating is finished after the temperature of the pill core reaches 40 ℃;
F. drying the coating product obtained in the step E at 80 ℃ until the water content is less than 1%, thus obtaining a pellet intermediate.
(3) Coating layer coating:
a. 25g of polyethylene glycol 6000 (coating material) is dispersed in 100g of dichloromethane;
b. adding 80g of 95% ethanol into the solution obtained in the step a, and stirring until the polyethylene glycol 6000 is completely dissolved;
c. placing the pellet intermediate obtained in the operation (2) into a coating pot, heating, spraying the solution obtained in the step b into the coating pot after the temperature reaches 35 ℃ for coating until the coating is finished;
d. and (3) drying the coating product obtained in the step (c) at 80 ℃ until the water content is less than 1%, thus obtaining the itraconazole pellets.
Example 5
Itraconazole pellets were prepared according to the method of example 2, except that: the extract of radix et rhizoma Rhei and radix Aconiti lateralis Preparata used in this example has a dosage ratio of 0.5:1.
example 6
Itraconazole pellets were prepared according to the method of example 2, except that: the rhubarb and aconite extract used in this example is prepared by the following raw rhubarb and aconite processed by the method in a dosage ratio of 1:0.5.
example 7
Itraconazole pellets were prepared according to the method of example 4, except that: the radix et rhizoma Rhei, radix Aconiti lateralis Preparata and herba asari extract used in this example has a dosage ratio of 1:1:0.3.
example 8
Itraconazole pellets were prepared according to the method of example 4, except that: the radix et rhizoma Rhei, radix Aconiti lateralis Preparata and herba asari extract used in this example has a dosage ratio of 1:1:1.
example 9
Itraconazole pellets were prepared according to the method of example 4, except that: in this example, itraconazole was used in an amount of 75g, hydroxypropyl methylcellulose was used in an amount of 180g, sodium lauryl sulfate was used in an amount of 15g, talc was used in an amount of 10g, permeation enhancer (radix et rhizoma Rhei Fuzi herba asari extract) was used in an amount of 1g, sucrose was used in an amount of 40g, starch was used in an amount of 40g, and polyethylene glycol 6000 was used in an amount of 20g.
Example 10
Itraconazole pellets were prepared according to the method of example 4, except that: in this example, itraconazole was used in an amount of 75g, hydroxypropyl methylcellulose was used in an amount of 220g, sodium lauryl sulfate was used in an amount of 25g, talc was used in an amount of 20g, permeation enhancer (radix et rhizoma Rhei Fuzi herba asari extract) was used in an amount of 10g, sucrose was used in an amount of 60g, starch was used in an amount of 60g, and polyethylene glycol 6000 was used in an amount of 30g.
Comparative example
The comparative example provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Coating a medicine-containing layer:
A. dissolving 20g of sodium dodecyl sulfate in 1000g of 95% ethanol, adding 200g of hydroxypropyl methylcellulose (5 cps), and uniformly dispersing;
B. taking and dispersing 100g of itraconazole in the solution obtained in the step A, then adding 1500g of dichloromethane, and stirring and dispersing uniformly;
C. 15g of talcum powder is taken and dispersed in 200g of 95% ethanol;
D. the solution obtained in the step C is added into the solution obtained in the step B after passing through a 325-mesh screen, and the mixture is stirred uniformly to obtain a drug-containing suspension;
E. placing 100g of sucrose pill core into a coating pan, heating, and coating with the drug-containing suspension obtained in step D until the coating is completed after the temperature of the pill core reaches 40 ℃;
F. drying the coating product obtained in the step E at 80 ℃ until the water content is less than 1%, thus obtaining a pellet intermediate.
(2) Coating layer coating:
a. dispersing 6000 g of polyethylene glycol in 100g of dichloromethane;
b. adding 80g of 95% ethanol into the solution obtained in the step a, and stirring until the polyethylene glycol 6000 is completely dissolved;
c. placing the pellet intermediate obtained in the operation (1) into a coating pot, heating, spraying the solution obtained in the step b into the coating pot after the temperature reaches 35 ℃ for coating until the coating is finished;
d. and (3) drying the coating product obtained in the step (c) at 80 ℃ until the water content is less than 1%, thus obtaining the itraconazole pellets.
Experimental example 1
The experimental example is used for verifying the dissolution performance of the itraconazole pellets of the present invention:
(1) dissolution method
Taking itraconazole pellets prepared in examples 1-10, and filling into capsules, wherein the filling amount of each capsule is 440mg. The dissolution rate of each capsule was measured by a dissolution rate and release rate measurement method (second method of the fourth rule 0931 of the year of the pharmacopoeia 2020), in which 1000ml of a hydrochloric acid solution (9 ml of 37% concentrated hydrochloric acid diluted to 1000ml with water, pH 1.0) was used as a dissolution medium, the rotation speed was 75 revolutions per minute, and 10ml of the solution was taken at 5, 10, 15, 20, 30, 45, 60, 90, 120 minutes, respectively, filtered, and 10ml of the dissolution medium was timely replenished.
(2) Dissolution measurement
Preparing a test solution: the subsequent filtrate was measured precisely at 5ml and placed in a 25ml measuring flask, diluted to scale with methanol-eluting medium (5:95) to give the sample solution.
Preparing a reference substance solution: and (3) taking about 20mg of itraconazole reference substance, precisely weighing, placing into a 200ml measuring flask, adding 40ml of methanol, heating and shaking in a water bath at 40 ℃ to dissolve, cooling, diluting to a scale with a dissolution medium, shaking uniformly, precisely weighing 5ml, placing into a 25ml measuring flask, diluting to the scale with the dissolution medium, shaking uniformly, and taking as a reference substance solution.
And (3) measuring: the cumulative dissolution of each capsule at different times was calculated and a cumulative dissolution curve was drawn by measuring absorbance at a wavelength of 255nm according to ultraviolet-visible spectrophotometry (appendix IVA).
(3) Measurement results
The measurement results are shown in Table 1 and FIG. 1.
TABLE 1 cumulative dissolution rate (%)
| Capsule | 5min | 10min | 15min | 20min | 30min | 45min | 60min | 90min | 120min |
| Example 1 | 2 | 11 | 20 | 35 | 62 | 82 | 92 | 98 | 99 |
| Example 2 | 2 | 11 | 24 | 39 | 64 | 81 | 89 | 94 | 96 |
| Example 3 | 3 | 10 | 19 | 31 | 51 | 70 | 84 | 95 | 99 |
| Example 4 | 2 | 10 | 22 | 37 | 59 | 77 | 88 | 97 | 101 |
| Example 5 | 3 | 12 | 24 | 37 | 58 | 75 | 84 | 95 | 99 |
| Example 6 | 3 | 13 | 22 | 36 | 62 | 84 | 93 | 99 | 101 |
| Example 7 | 3 | 13 | 25 | 40 | 63 | 79 | 87 | 96 | 99 |
| Example 8 | 2 | 10 | 17 | 38 | 55 | 73 | 85 | 96 | 97 |
| Example 9 | 3 | 10 | 18 | 26 | 44 | 61 | 73 | 87 | 94 |
| Example 10 | 2 | 9 | 16 | 23 | 38 | 56 | 70 | 87 | 95 |
As can be seen from table 1 and fig. 1, the in vitro dissolution behavior of itraconazole pellets of examples 1-8 is relatively consistent, demonstrating that the adjustment of the preparation process and the adjustment of the permeation enhancer have no substantial effect on the in vitro dissolution of itraconazole, and therefore the product quality of each formulation is uniform and representative; for examples 9-10, the in vitro dissolution was somewhat slower, but still within the allowable range, because of the relatively large changes in the overall formulation.
Experimental example 2
The itraconazole pellets prepared in example 1, example 4 and comparative example were filled into capsules, and the filling amount of each capsule was 440mg. The 18 healthy male subjects were randomly divided into 3 groups of 6 persons each, each group was administered with one capsule per each period on an empty stomach (0.1 g/person), 240mL of warm water was administered, each subject was blood-drawn before (0 h) and after (0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 24, 48, 72h, respectively, and the itraconazole content in serum was measured by HPLC method, and the bioequivalence of the itraconazole pellets obtained in example 1 and example 4 and the itraconazole pellets obtained in comparative example was calculated, respectively, and the calculation results are shown in tables 2 and 3.
After a single administration, the number of people and symptoms of adverse reactions were counted, and the occurrence rate of adverse reactions was calculated, and the calculation results are shown in table 4.
Table 2 bioequivalence of itraconazole pellets of example 1 and itraconazole pellets of comparative example
| Equivalent parameters | Ratio of | Lower 90% confidence limit | Upper 90% confidence limit |
| Ln(Cmax) | 91.35 | 61.13 | 136.77 |
| Ln(AUClast) | 96.32 | 68.90 | 133.69 |
| Ln(AUCINF_obs) | 96.80 | 69.91 | 132.97 |
Table 3 bioequivalence of itraconazole pellets of example 4 and itraconazole pellets of comparative example
| Equivalent parameters | Ratio of | Lower 90% confidence limit | Upper 90% confidence limit |
| Ln(Cmax) | 105.18 | 88.59 | 124.30 |
| Ln(AUClast) | 107.08 | 86.48 | 131.60 |
| Ln(AUCINF_obs) | 105.85 | 84.33 | 133.86 |
TABLE 4 adverse reaction statistics table
As can be seen from tables 2 and 3, in the itraconazole pellets prepared in examples 1 and 4, although the content of itraconazole is only 75% of that of the comparative example, the bioavailability of itraconazole in the pellets obtained in examples 1 and 4 in vivo can be maintained at the same level as that of the comparative example due to the use of the permeation enhancer by compounding, i.e., the pellets obtained in examples 1 and 4 significantly reduce the amount of main itraconazole while obtaining the same level of bioavailability as that of the pellets obtained in comparative example, and the reduction of the main drug reduces the occurrence rate of adverse reaction of the drug and the damage degree of adverse reaction to the body.
As can be seen from table 4, in 18 healthy male subjects, no serious adverse reaction occurred after a single administration of itraconazole capsule, but a total of 7 cases of mild adverse reactions occurred. Wherein, the occurrence rate of adverse reaction is obviously reduced in the example 1 compared with the comparative example; compared with the example 1 and the comparative example, the example 4 has obviously reduced occurrence rate of adverse reaction and obviously lighter severity after adverse reaction, which indicates that the application of the rhubarb-aconite root asarum composition can promote drug permeation and has certain harmonizing effect on human body, and can further reduce the occurrence rate or severity of itraconazole adverse reaction.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (10)
1. A pharmaceutical composition, which is characterized by comprising itraconazole and a penetration enhancer, wherein the penetration enhancer contains rhubarb extract and aconite extract;
wherein the extraction method of the rheum officinale extract and the aconite extract comprises the following steps:
pulverizing the medicinal materials, soaking in water for 2-6 h, boiling for 0.25-1 h, separating solid from liquid, taking liquid, and drying at 30-60 ℃ with water content of 10-15 mL relative to 1g of medicinal materials.
2. The pharmaceutical composition according to claim 1, wherein the penetration enhancer is contained in an amount of 1 to 10 parts by weight relative to 75 parts by weight of itraconazole; the dosage ratio of the rhubarb to the aconite is (0.5-1): (0.5-1).
3. The pharmaceutical composition according to claim 2, wherein the permeation enhancer further comprises asarum extract; the dosage ratio of rhubarb, aconite and asarum is (0.5-1): (0.5-1): (0.3-1);
wherein the extraction method of the asarum extract comprises the following steps:
pulverizing the medicinal materials, soaking in water for 2-6 h, boiling for 0.25-1 h, separating solid from liquid, taking liquid, and drying at 30-60 ℃ with water content of 10-15 mL relative to 1g of medicinal materials.
4. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-3 and a pharmaceutically acceptable auxiliary ingredient.
5. An itraconazole pellet, characterized in that the itraconazole pellet contains the pharmaceutical composition according to any one of claims 1 to 3;
the itraconazole pellets comprise a pellet core, a drug-containing layer and a coating layer, wherein the drug-containing layer is coated on the surface of the pellet core, and the coating layer is coated on the surface of the drug-containing layer;
wherein the drug-containing layer contains itraconazole, and the drug-containing layer and/or the pill core contains the permeation enhancer;
the particle size of the pill core is 20-25 meshes.
6. The itraconazole micro-pill according to claim 5, wherein said drug-containing layer contains itraconazole and said permeation enhancer, and said pill core is a blank pill core;
the blank pill core is at least one selected from a sucrose pill core, a microcrystalline cellulose pill core, a starch pill core and an amylosucrose pill core, and the content of the blank pill core is 50-150 parts by weight relative to 75 parts by weight of itraconazole.
7. The itraconazole micro-pill according to claim 5, wherein said drug-containing layer contains itraconazole, said pill core is a pill-containing core, and said permeation enhancer is contained in said pill-containing core;
the pill-containing core also comprises a first adhesive and a filler, wherein the content of the first adhesive is 40-60 parts by weight and the content of the filler is 40-60 parts by weight relative to 75 parts by weight of itraconazole;
the first adhesive is selected from at least one of sucrose, corn starch, crospovidone and hypromellose; the filler is at least one selected from starch, microcrystalline cellulose and lactose.
8. The itraconazole pellets according to any one of claims 5-7, wherein said drug-containing layer further comprises a second binder and a lubricant, wherein the content of said second binder is 180-220 parts by weight and the content of said lubricant is 25-45 parts by weight with respect to 75 parts by weight of itraconazole;
the coating layer contains a coating material, and the content of the coating material is 20-30 parts by weight relative to 75 parts by weight of itraconazole;
the second binder is selected from hydroxypropyl methylcellulose and/or crospovidone;
the lubricant is at least one of sodium dodecyl sulfate, talcum powder and magnesium stearate; preferably sodium dodecyl sulfate and talcum powder, the dosage ratio of the sodium dodecyl sulfate to the talcum powder is (15-25): (10-20);
the coating material is at least one selected from polyethylene glycol 6000, hypromellose, hydroxypropyl cellulose and acrylic resin.
9. A process for the preparation of itraconazole pellets according to any one of claims 5-8, characterized by comprising the following operations:
coating a drug-containing suspension on a pill core, and drying to obtain a pellet intermediate, wherein the drug-containing suspension contains itraconazole, and the drug-containing suspension and/or the pill core contains a penetration enhancer;
and (5) taking the coating liquid, coating the pellet intermediate product with a coating layer, and drying.
10. An itraconazole capsule containing the pharmaceutical composition according to any one of claims 1-3, or the itraconazole pellets according to any one of claims 5-8, or the itraconazole pellets prepared by the method of claim 9.
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| CN102309488A (en) * | 2010-07-02 | 2012-01-11 | 北京京卫燕康药物研究所有限公司 | Itraconazole medicinal composition and preparation method thereof |
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| Title |
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| 林慧川 ; .中西医结合治疗重症哮喘并发真菌感染疗效观察.现代中西医结合杂志.2007,(第28期),4163. * |
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