CN116077462A - Aprepitant pellet, preparation method thereof and preparation containing aprepitant pellet - Google Patents
Aprepitant pellet, preparation method thereof and preparation containing aprepitant pellet Download PDFInfo
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- CN116077462A CN116077462A CN202211538132.0A CN202211538132A CN116077462A CN 116077462 A CN116077462 A CN 116077462A CN 202211538132 A CN202211538132 A CN 202211538132A CN 116077462 A CN116077462 A CN 116077462A
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- aprepitant
- pellet
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- medicine
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- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 title claims abstract description 80
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 80
- 239000008188 pellet Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 39
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 16
- -1 fatty alcohol sulfate Chemical class 0.000 claims abstract description 15
- 239000004094 surface-active agent Substances 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002775 capsule Substances 0.000 claims description 12
- 239000003995 emulsifying agent Substances 0.000 claims description 11
- 239000000375 suspending agent Substances 0.000 claims description 11
- 239000002562 thickening agent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000006187 pill Substances 0.000 claims description 9
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 7
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 claims description 7
- 238000000227 grinding Methods 0.000 claims description 6
- 238000001238 wet grinding Methods 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 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 4
- 238000002156 mixing Methods 0.000 claims description 4
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 32
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000008859 change Effects 0.000 abstract description 2
- 238000011835 investigation Methods 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 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 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 102100024304 Protachykinin-1 Human genes 0.000 description 3
- 238000005054 agglomeration Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 2
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- 108010040722 Neurokinin-2 Receptors Proteins 0.000 description 1
- 108010040716 Neurokinin-3 Receptors Proteins 0.000 description 1
- 102000002003 Neurokinin-3 Receptors Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 102100037342 Substance-K receptor Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000001094 effect on targets Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- A61K9/5073—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
- A61K9/5078—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 with drug-free core
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicines, in particular to aprepitant pellets, a preparation method thereof and a preparation containing the aprepitant pellets. The aprepitant pellets sequentially comprise a blank pellet core and an intermediate layer from inside to outside; the middle layer contains a drug and a first auxiliary material; the medicine is aprepitant and/or pharmaceutically acceptable salts of aprepitant; the average particle size of the medicine is 230-370nm. The invention controls the granularity of the raw materials in more detail, and the higher fatty alcohol sulfate surfactant is added to ensure the bioavailability of the product; meanwhile, the dissolution curve in the stability investigation period can be ensured not to change, and the good stability of the product is ensured.
Description
Technical Field
The invention relates to the field of medicines, in particular to aprepitant pellets, a preparation method thereof and a preparation containing the aprepitant pellets.
Background
Aprepitant, chemical name 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ]]Ethoxy group]-3- (4-fluorophenyl) -4-morpholinyl]Methyl group]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one of formula C 23 H 21 F 7 N 4 O 3 Structural formula:
aprepitant is the first neurokinin-1 (NK-1) receptor blocker approved by the FDA in 2003 in the united states to block the action of substance P by binding to NK-1 receptors, which are mainly present in the central nervous system and its periphery. Aprepitant can pass through the blood brain barrier, occupy NK-1 receptors in the brain, have selectivity and high affinity, and have very low affinity for NK-2 and NK-3 receptors. Meanwhile, the affinity effect on targets (such as dopamine receptors and 5-HT receptors) of other medicaments for treating chemotherapy-induced nausea and vomiting symptoms is low, and the effect of reducing nausea and vomiting is superior to that of other medicaments.
Aprepitant is a white or off-white powder that is practically insoluble in water. As aprepitant is almost insoluble in water and has low bioavailability, oral capsules of nanocrystalline microspheres have been developed.
The dissolution and bioavailability of aprepitant remain to be improved.
Disclosure of Invention
The aprepitant and the grinding medium are ground to nanometer level in a wet grinding mode, so that the solubility in water is improved, and the bioavailability is improved. However, the present inventors have found that too much grinding to reduce the particle size also increases the agglomeration phenomenon of the drug substance, and the dissolution of the preparation cannot be effectively improved, but may be reduced. Based on a large number of experiments, the inventor discovers that the reasonable range of the particle size of the aprepitant bulk drug can ensure the dissolution curve of the product. In addition, the formulation capsules have a tendency to slow down the dissolution profile during stability, and the sample pellets during stability have an agglomeration phenomenon during dissolution, slowing down dissolution. The addition of conventional magnesium stearate or talc lubricants will slightly improve agglomeration but will also affect the dissolution profile of the product due to the hydrophobicity of conventional lubricants. There is therefore also a need for aprepitant formulations (e.g. capsules or tablets) which maintain the dissolution profile during product stability.
The present invention aims to solve, at least to some extent, one of the technical problems in the prior art, or at least to provide a commercial choice.
The invention firstly provides aprepitant micropills which have better dissolution and bioavailability.
An aprepitant pellet which sequentially comprises a blank pellet core and an intermediate layer from inside to outside; the middle layer contains a drug and a first auxiliary material; the medicine is aprepitant and/or pharmaceutically acceptable salts of aprepitant; the average particle size of the medicine is 230-370nm.
The aprepitant raw material medicine is almost insoluble in water, and although the average particle size of the raw material medicine is reduced by adopting a wet grinding mode, the bioavailability is improved, excessive grinding until the average particle size of the raw material medicine is smaller also slows down the dissolution curve, and the bioavailability of a preparation product is influenced. The invention controls the average grain diameter of the raw materials in more detail, ensures the good dissolution curve condition of the product, and can better control the quality of the product.
According to the embodiment of the invention, the average particle size of the medicine is 235-369nm.
According to the embodiment of the invention, the average particle size of the medicine is 260-300nm.
In some embodiments of the invention, the average particle size of the drug is 230nm, 235nm, 260nm, 287nm, 300nm, 369nm, or 370nm; preferably 287nm.
According to the embodiment of the invention, the blank pill core is selected from a sucrose pill core or a microcrystalline cellulose pill core, and the particle size is 0.5-0.7mm.
According to the embodiment of the invention, the first auxiliary material comprises one or more of a suspending agent, an emulsifying agent and a thickening agent. In some embodiments, the first auxiliary material is composed of a suspending agent, an emulsifying agent and a thickening agent.
According to the embodiment of the invention, the suspending agent is selected from one or more of hypromellose, hydroxypropyl cellulose and povidone.
According to an embodiment of the present invention, the emulsifier is sodium dodecyl sulfate.
According to an embodiment of the present invention, the thickener is selected from one or more of sucrose, sorbitol, dextrin.
According to the embodiment of the invention, in the aprepitant micro-pill, the weight ratio of the blank pill core to the middle layer is (15-25): (67-90), or alternatively (15-25): (52-85); in some embodiments 20:80.
According to the embodiment of the invention, in the aprepitant pellet, the weight ratio of the suspending agent, the emulsifying agent and the thickening agent in the middle layer is (7-10): 0.1-0.2): 30-40, and optionally 9.6:0.2:35.
According to the embodiment of the invention, the aprepitant pellet further comprises an outer layer, namely the outer layer is outside the middle layer; the outer layer is a surfactant of higher fatty alcohol sulfate, and can be specifically selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate, preferably sodium octadecyl sulfate.
The research shows that aprepitant has a tendency of slowing down the dissolution curve during the stability period, the common magnesium stearate and talcum powder lubricant have certain hydrophobicity, the dissolution curve condition of the product cannot be improved after the magnesium stearate and talcum powder lubricant are added, the dissolution curve condition can be improved by adding the surfactant of higher fatty alcohol sulfate, wherein the sodium stearyl sulfate is optimal, the dissolution curve of the product cannot be changed during the stability period, and the good stability of the product is ensured. Namely, the dissolution rate during the stability of the product can be ensured by taking the surfactant of the higher fatty alcohol sulfate as the outer layer, and the bioavailability can be further improved.
According to an embodiment of the invention, the surfactant of the higher fatty alcohol sulphate is micronised, for example with a D90 < 75 μm.
According to the embodiment of the invention, the content of the surfactant of the higher fatty alcohol sulfate is 0.1-0.3wt%, optionally 0.2wt%, based on the total weight of the aprepitant pellets.
According to an embodiment of the present invention, the aprepitant pellet contains: 15 to 25 weight percent of blank pill core, 30 to 40 weight percent of aprepitant, 7 to 10 weight percent of suspending agent, 0.1 to 0.2 weight percent of emulsifying agent, 30 to 40 weight percent of thickening agent and 0.1 to 0.3 weight percent of surfactant of higher fatty alcohol sulfate.
According to the embodiment of the invention, the aprepitant pellets comprise the following components in parts by weight:
aprepitant pellets:
15-25 parts of blank pill cores;
an intermediate layer, comprising:
30-40 parts of aprepitant and/or a pharmaceutically acceptable salt of aprepitant;
7-10 parts of suspending agent;
0.1-0.2 part of emulsifying agent;
30-40 parts of a thickening agent;
in some embodiments, the method further comprises:
and the outer layer is 0.1-0.3 part of higher fatty alcohol sulfate surfactant.
The invention also provides a preparation method of the aprepitant pellets, which comprises the following steps:
1) Wet grinding the medicine, the suspending agent and the emulsifying agent in the presence of water until the average grain diameter of the medicine is 230-370nm; the medicine is aprepitant and/or pharmaceutically acceptable salts of aprepitant;
2) Adding a thickener into the grinding liquid to prepare an aqueous dispersion;
3) Coating the water dispersion on a blank pellet core to prepare the drug-loaded pellets.
In some embodiments, the solids content of the aqueous dispersion is 15-25%, alternatively 20%.
In some embodiments, aprepitant pellets are prepared using a fluidized bed, bottom spray coating process.
In some embodiments, the preparation method of the aprepitant pellets further comprises the following steps:
4) And adding the surfactant of the higher fatty alcohol sulfate into the drug-loaded pellets, uniformly mixing, and preparing an outer layer to obtain the aprepitant pellets. I.e. the surfactant of the higher fatty alcohol sulphate is added at the time of total mixing of the pellets.
The invention also provides an aprepitant preparation which comprises the aprepitant pellet. The aprepitant preparation comprises a tablet, a capsule, a dry suspension or a pill, and can be prepared by adopting a conventional method in the field. As a preferred embodiment, the aprepitant formulation is a capsule.
The invention controls the granularity of the raw materials in more detail, and ensures the dissolution curve and bioavailability of the product. The invention also ensures that the dissolution profile during stability is unchanged.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase by regular vendors without the manufacturer's attention.
Examples 1-5 aprepitant pellets were formulated as follows (g):
the preparation method of the aprepitant pellets of examples 1-5 is as follows:
(1) Weighing a proper amount of purified water, adding hydroxypropyl cellulose and sodium dodecyl sulfate, stirring and dissolving completely, adding aprepitant, stirring and dispersing uniformly to prepare a solution;
(2) Wet grinding the solution; adding sucrose into the grinding liquid to prepare an aqueous dispersion with the solid content of 20%;
(3) The water dispersion is coated on the microcrystalline cellulose pellet core by adopting a fluidized bed bottom spray coating process to prepare the drug-loaded pellet (which can be used as aprepitant pellet).
The aprepitant pellets of examples 1-5 are only different in that the preparation method step (2) is ground until the average particle sizes of the raw materials are different, and specifically comprises the following steps:
| example 1 | Example 2 | Example 3 | Example 4 | Example 5 | |
| Average particle diameter nm | 653 | 369 | 287 | 235 | 152 |
The drug-loaded pellets of examples 1-5 are respectively filled into gelatin capsule shells to prepare aprepitant capsules.
Experiment 1
The dissolution profile in 2.2% SDS medium (see dissolution test method in JX2050137 standard) was measured for the aprepitant capsules of examples 1-5 and R027651 batches of the as-ground formulation (manufacturer: merck Sharp & Dohme Ltd.) and the results are shown in Table 1.
TABLE 1 dissolution profile results for examples 1-5
Conclusion: in the embodiment 1, the average particle diameter of the raw material medicine is controlled to be larger, the control range of the raw material medicine is smaller, and the dissolution of the preparation with smaller or larger raw material medicine is slower. Examples 2-4 the average particle size of the drug substance was controlled in a suitable range, and the dissolution profile of the prepared formulation was similar to that of the original formulation.
Description: f2 is a similarity factor (f 2) method in a non-model dependent method, and when the values of the similarity factors (f 2) of the two dissolution curves are not less than 50, the dissolution curves are considered to be similar, and when the values are less than 50, the dissolution curves are not similar.
Examples 6-10 aprepitant pellets comprise the aprepitant drug-loaded pellets prepared in example 3 and an outer layer, and the preparation method comprises the steps of taking the aprepitant drug-loaded pellets in example 3, adding an outer layer material, and uniformly mixing.
Examples 6-10 aprepitant pellets were formulated as follows:
| aprepitant drug-loaded pellets (example 3) | 998g |
| An outer layer | 2g |
Examples 6-10 aprepitant pellets differ only in the material of the outer layer, and are specifically as follows:
| example 6 | Example 7 | Example 8 | Example 9 | Example 10 | |
| Outer layer material | Magnesium stearate | Talc powder | Sodium dodecyl sulfate | Sodium hexadecyl sulfate | Sodium octadecyl sulfate |
Wherein, the sodium dodecyl sulfate, the sodium hexadecyl sulfate and the sodium octadecyl sulfate are micronized, and D90 is controlled to be less than 75 mu m.
The aprepitant pellets of examples 6-10 were filled into gelatin capsule shells, respectively, to prepare aprepitant capsules.
Experiment 2
The aprepitant capsules prepared in examples 3, 6, 7, 8, 9 and 10 were placed at 40±2 ℃ and 75%rh±5%, and dissolution curves were measured at 0 month, 3 month and 6 month of placement, respectively, and the results are shown in table 2.
TABLE 2 stability dissolution profile results for example 3, examples 6-10
The pellets of the capsules of example 3 do not contain an outer layer, the pellets of the capsules of examples 6-8 are respectively added with magnesium stearate, talcum powder and micronized sodium dodecyl sulfate, the dissolution curve tends to be slow in the stability process under the conditions of 40 ℃ +/-2 ℃ and 75%RH+/-5%, but the trend is smaller, the dissolution of samples added with sodium hexadecyl sulfate and sodium octadecyl sulfate is better, the dissolution of the samples added with sodium octadecyl sulfate is optimal, and the dissolution curve does not change during the stability.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (10)
1. The aprepitant micropill is characterized by comprising a blank pellet core and an intermediate layer from inside to outside in sequence; the middle layer contains a drug and a first auxiliary material; the medicine is aprepitant and/or pharmaceutically acceptable salts of aprepitant; the average particle size of the medicine is 230-370nm.
2. Aprepitant pellet according to claim 1, wherein the drug has an average particle size of 260-300nm, optionally 287nm.
3. Aprepitant pellet according to claim 1 or 2, wherein the first auxiliary material comprises one or more of a suspending agent, an emulsifying agent and a thickening agent;
optionally, the suspending agent is selected from one or more of hypromellose, hyprolose and povidone;
optionally, the emulsifier is sodium dodecyl sulfate;
optionally, the thickener is selected from one or more of sucrose, sorbitol, and dextrin.
4. Aprepitant pellet according to any one of claims 1-3, wherein the weight ratio of suspending agent, emulsifying agent and thickening agent in the middle layer is (7-10): (0.1-0.2): (30-40), optionally 9.6:0.2:35.
5. Aprepitant pellet according to any one of claims 1-4, wherein the weight ratio of empty pellet core to intermediate layer in the aprepitant pellet is (15-25): (67-90), or alternatively (15-25): (52-85).
6. Aprepitant pellet according to any one of claims 1-5, wherein the aprepitant pellet further comprises an outer layer; the outer layer is a surfactant of higher fatty alcohol sulfate; optionally, the surfactant of the higher fatty alcohol sulfate is selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate.
7. Aprepitant pellet according to claim 6, wherein the content of the surfactant of higher fatty alcohol sulphate is 0.1-0.3wt%, optionally 0.2wt%, based on the total weight of the aprepitant pellet.
8. A method for preparing aprepitant pellets, which is characterized by comprising the following steps:
1) Wet grinding the medicine, the suspending agent and the emulsifying agent in the presence of water until the average grain diameter of the medicine is 230-370nm; the medicine is aprepitant and/or pharmaceutically acceptable salts of aprepitant;
2) Adding a thickener into the grinding liquid to prepare an aqueous dispersion;
3) Coating the water dispersion on a blank pellet core to prepare the drug-loaded pellets.
9. The method of preparation of claim 8, further comprising the steps of:
4) And adding the surfactant of the higher fatty alcohol sulfate into the drug-loaded pellets, uniformly mixing, and preparing an outer layer.
10. Aprepitant formulation, characterized by comprising aprepitant pellets according to any one of claims 1-7; optionally, the aprepitant formulation comprises a tablet, a capsule, a dry suspension or a pill.
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Citations (3)
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| CN1617712A (en) * | 2001-12-10 | 2005-05-18 | 麦克公司 | Pharmaceutical nanoparticulate composition of a tachykinin receptor antagonist |
| CN103097379A (en) * | 2010-06-18 | 2013-05-08 | 成药技术Ip控股（泽西）有限公司 | Nanostructured aprepitant compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| CN110787125A (en) * | 2018-08-02 | 2020-02-14 | 北京化工大学 | Aprepitant nano preparation and preparation method thereof |
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| CN1617712A (en) * | 2001-12-10 | 2005-05-18 | 麦克公司 | Pharmaceutical nanoparticulate composition of a tachykinin receptor antagonist |
| CN103097379A (en) * | 2010-06-18 | 2013-05-08 | 成药技术Ip控股（泽西）有限公司 | Nanostructured aprepitant compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| CN110787125A (en) * | 2018-08-02 | 2020-02-14 | 北京化工大学 | Aprepitant nano preparation and preparation method thereof |
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