CN110623927A - High-bioavailability nintedanib nano lipid carrier and preparation method thereof - Google Patents
High-bioavailability nintedanib nano lipid carrier and preparation method thereof Download PDFInfo
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 54
- 229960004378 nintedanib Drugs 0.000 title claims abstract description 53
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 28
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000010521 absorption reaction Methods 0.000 claims abstract description 6
- 239000000523 sample Substances 0.000 claims abstract description 6
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract description 5
- 239000003623 enhancer Substances 0.000 claims abstract description 3
- 239000005457 ice water Substances 0.000 claims abstract description 3
- 239000012071 phase Substances 0.000 claims description 14
- -1 poly-oleic glyceride Substances 0.000 claims description 13
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000003921 oil Substances 0.000 claims description 11
- 235000019198 oils Nutrition 0.000 claims description 11
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 claims description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 8
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 235000019438 castor oil Nutrition 0.000 claims description 5
- 125000005456 glyceride group Chemical group 0.000 claims description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 5
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 5
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229940093609 tricaprylin Drugs 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- 239000005639 Lauric acid Substances 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims description 3
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- 229960003511 macrogol Drugs 0.000 claims description 3
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 abstract description 4
- 239000002245 particle Substances 0.000 abstract description 4
- 238000011068 loading method Methods 0.000 abstract description 3
- 210000002490 intestinal epithelial cell Anatomy 0.000 abstract description 2
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- 230000000694 effects Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61K31/12—Ketones
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a high-bioavailability nintedanib nano lipid carrier and a preparation method thereof. The nano lipid carrier comprises nintedanib, a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer. The preparation scheme comprises the following steps: heating solid and liquid lipid in water bath at certain temperature, and stirring to melt. Adding surfactant, and stirring for 5 min. Adding nintedanib, and stirring for 1 hr to obtain oil phase containing medicine. Adding part or all of surfactant into water phase, preheating at the same temperature, and adding water phase into the above oil phase under stirring. And (5) after the probe is subjected to ultrasonic treatment, solidifying in ice-water bath to obtain the product. The Nintedanib nano lipid carrier prepared by the method has the advantages of simple scheme, no organic solvent, high drug loading rate, uniform particle size and particle size distribution, good stability, and capability of remarkably increasing the absorption of small intestinal epithelial cells to Nintedanib and effectively improving the in vivo bioavailability.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations and the technical field of biological medicines, in particular to a high-bioavailability nintedanib nano lipid carrier and a preparation method thereof.
Background
Idiopathic pulmonary interstitial fibrosis (IPF) is a group of diseases characterized by progressive dyspnea and deterioration of lung function, of unknown etiology. Currently, there is no definitive and effective treatment for IPF other than lung transplantation. Without lung transplantation, their 3-and 5-year mortality rates were 50% and 80%, respectively.
Nintedanib is a triple tyrosine kinase inhibitor and a growth factor antagonist, is used for treating idiopathic pulmonary fibrosis diseases which can only be treated by lung transplantation in the medical field at present, and is a new research result for treating IPF. The nintedanib is a p-gp substrate, has a first-pass effect, is poor in solubility in a small intestine environment and not easy to absorb, and therefore the bioavailability of the nintedanib is low and is only 4.7% in vivo. Therefore, the search for a new dosage form that can effectively promote the oral bioavailability of nintedanib has long been a problem that is desired to be solved.
The existing products of the nintedanib are soft capsules sold in the company of the German Boringer Vargohne, and the products are prepared into solid dispersions to improve the bioavailability of the nintedanib through domestic and foreign researches. The nanometer lipid carrier is a new generation of nanometer medicine carrying system developed on the basis of solid lipid nanometer particles, and consists of solid and liquid mixed lipid, a surfactant and a medicine. As a nano drug carrier, the nano drug carrier can change the membrane transport mechanism, enhance the permeability of the drug to a biological membrane, and is beneficial to the percutaneous or mucosal permeation and absorption of the drug and the exertion of the drug effect in cells. The nano lipid carrier has good biocompatibility, can control the release of the drug, avoids the degradation or leakage of the drug, has good targeting property, and can be used for various administration routes.
Disclosure of Invention
Aiming at solving the problem of low oral bioavailability of nintedanib, the invention provides a curcumin nano lipid carrier with high bioavailability and a preparation method thereof.
The invention is realized by the following technical scheme:
a high bioavailability Nintedanib nanometer lipid carrier is characterized in that the raw material drug is Nintedanib, and the auxiliary materials comprise a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer. Wherein the contents of the components in 10ml of the final preparation are as follows: 50-200mg of nintedanib, 500-1500mg of solid lipid material, 750mg of liquid lipid material and 1000mg of surfactant.
The solid lipid material comprises glycerol trilaurate, glycerol monostearate, glycerol monooleate and glycerol behenate, preferably one or more of glycerol monooleate and glycerol trilaurate vinegar.
The liquid lipid material comprises tricaprylin, caprylic/capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic/capric polyethylene glycol glyceride, the mass of the liquid lipid material is one half of that of solid lipid, and one or more of tricaprylin and caprylic/capric polyethylene glycol glyceride are preferably selected.
The surfactant comprises phospholipid, tween-80, poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85, and preferably one or more of tween-80, polyoxyethylene castor oil, poloxamer 188 or pluronic P85.
The invention also provides a preparation method of the nintedanib nano lipid carrier, which is characterized by comprising the following steps of:
the solid lipid material and the liquid lipid material are put in a water bath or an oil bath at the temperature of 10-40 ℃ higher than the melting point of the solid lipid material, and stirred at 600rpm/min until being melted.
Adding surfactant, and stirring for 5 min.
Adding nintedanib, and stirring for 1 hr to obtain oil phase containing medicine.
Adding 10-30% or all of surfactant into water phase, preheating at the same temperature, adding water phase into the oil phase obtained in the step (3) under stirring, and continuously stirring for 3 min.
Performing ultrasonic treatment on the probe for 5-15min under the power of 25-35%.
Curing in ice water bath for 5-10 min.
The temperature in step (1) is 30 ℃ higher than the solid lipid material.
The step (4) is to add 20% or all of the surfactant to the aqueous phase.
The power of the ultrasound in the step (5) is 30%.
The ultrasonic treatment time in the step (5) is 13 min.
The curing time in the step (6) is 6 min.
The average grain diameter of the nano lipid carrier is 10-200 nm.
The Nintedanib nano lipid carrier prepared by the method provided by the invention can obviously improve the in-vivo bioavailability of the Nintedanib and effectively improve the absorption of intestinal epithelial cells to the Nintedanib nano lipid carrier.
Drawings
Fig. 1 is a graph of blood drug concentration-time curve of nintedanib drug substance.
Fig. 2 is a blood concentration-time curve of the nintedanib nano lipid carrier.
Detailed description of the preferred embodiments
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the claims.
Example 1:
1250mg of glyceryl monooleate and 625mg of glyceryl tricaprylate are weighed into a small beaker, placed in a water bath at 67 ℃ and stirred at 600rpm/min until molten. Tween-80660 mg was added, and stirring was continued for 5 min. Adding 50mg of nintedanib, and stirring for 1h to obtain the oil phase containing the medicine. And taking a proper amount of distilled water, adding 225mg of Tween-80, and preheating at the same temperature to obtain a water phase. Slowly adding the water phase into the oil phase, and stirring for 3 min. Carrying out 30% power ultrasound for 13min, and carrying out ice bath curing for 6min to obtain the high-bioavailability nintedanib nano lipid carrier.
As a result: the particle size of the high bioavailability Nintedanib nano lipid carrier is 145.4 +/-3.1 nm. The encapsulation efficiency is 87.5 percent, and the drug loading rate is 5 mg/ml.
Example 2:
referring to the preparation method of example 1, except that the solid lipid material is selected from glycerol trilaurate, glycerol monostearate and glycerol behenate.
Table 1 effect of solid lipids on high bioavailability nintedanib lipid vehicle (n ═ 3)
Example 3:
referring to the preparation method of example 1, except that the liquid lipid material was selected from caprylic capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic capric polyglycol glyceride, respectively.
TABLE 2 Effect of liquid lipids on high bioavailability Nintedanib lipid vehicle (n ═ 3)
Example 4:
referring to the preparation method of example 1, except that the surfactant is one or more selected from poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85.
Table 3 effect of surfactants on high bioavailability nintedanib lipid vehicles (n ═ 3)
Example 5:
referring to the preparation method of example 1, except that the surfactants are preferably tween-80 and poloxamer 188 respectively, the ratio of tween-80 to poloxamer 188 is changed to 3: 1, 2: 1, 1: 2 and 1: 3 when the surfactants are used in combination.
Table 4 effect of surfactant ratio on high bioavailability nintedanib lipid carrier (n ═ 3)
Example 6
Referring to the preparation method of example 1, except that the mass of nintedanib was changed to 100mg, 150mg, and 200mg, respectively.
TABLE 5 Effect of drug loading on high bioavailability Nintedanib lipid vehicle (n ═ 3)
Example 7:
the pharmacokinetics comparison of the nintedanib nano lipid carrier and the nintedanib bulk drug:
SD rats (male, body weight 200-. Fasting was overnight before dosing, and water was freely available. The nintedanib nano lipid carrier obtained in example 1 and the nintedanib bulk drug suspension are taken as examples, and the same dose (30mg/kg) is respectively administered by intragastric administration. Respectively taking blood from orbital venous plexus at 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h after administration, placing in a centrifuge tube with heparin sodium, and centrifuging at 8000rpm/min to obtain plasma. 100 μ L of the obtained plasma was taken, 20 μ L of the internal standard solution (2.5 μ g/ml) was added, and vortexed and shaken for 3 min. Adding ethyl acetate 1ml, vortexing for 5min, centrifuging at 10000rpm/min for 10min, sucking supernatant nitrogen gas for drying, redissolving 100 μ L of mobile phase, vortexing for 5min, centrifuging at 12000rpm/min for 10min, taking supernatant, and injecting 10 μ L. The mass spectrum and chromatographic conditions are as follows by using UPLC-MS/MS analysis and determination:
conditions of Mass Spectrometry
An ion source: ESI source positive ionization mode; capillary pressure: 2.0 kV; ion source temperature: 100 ℃; desolvation temperature: 400 ℃; flow rate of desolventizing agent: 550L/h; taper hole air flow rate: 50L/h; the scanning mode is as follows: multiple reactive ion monitoring (MRM) mode. Mass spectral parameters for the determination of BIBF and IS are shown in Table 1.
TABLE 6 Mass Spectrometry parameters of DSF and IS
Chromatographic conditions
ACQUITYTM UPLC system (Waters Corp., Milford, MA, USA); phenomenex kinetex XB C18 column (50mm X21 mm, 2.6 μm; Phenomenex, Torrance, CA, USA); column temperature: 40 ℃; autosampler temperature: 4 ℃; sample introduction amount: 10 mu L of the solution; sample introduction mode: partial sample introduction (partial loop mode); mobile phase: acetonitrile (a) and water (containing 0.1% formic acid) (B) 70: 30.
Results plasma concentration-time of both formulationsThe curves are shown in fig. 1-2. The AUC is 901.606 ug/Lxh and 394.29 ug/Lxh respectively, and the relative bioavailability is calculated according to the AUC of the two preparationsT·DR/AUCR·DT×100%=(901.606*30)/(394.29*30)*100%=228.67%
Where AUC represents the area under the plasma concentration-time curve, the subscripts T and R represent the test formulation and the extravascularly administered reference formulation, respectively, and D represents the administered dose.
It can be seen that the bioavailability of the nintedanib nano lipid carrier can be more than twice of that of the nintedanib raw material drug, and the bioavailability of the nintedanib in vivo can be effectively improved.
Claims (10)
1. A high bioavailability Nintedanib nanometer lipid carrier is characterized in that the raw material drug is Nintedanib, and the auxiliary materials comprise a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer; wherein the contents of the components in 10ml of the final preparation are as follows: 50-200mg of nintedanib, 500-1500mg of solid lipid material, 750mg of liquid lipid material and 1000mg of surfactant.
2. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the solid lipid material comprises glycerol trilaurate, glycerol monostearate, glycerol monooleate and glycerol behenate, preferably one or more of glycerol monooleate and glycerol trilaurate vinegar.
3. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the liquid lipid material comprises tricaprylin, caprylic/capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic/capric polyethylene glycol glyceride, the mass of the liquid lipid material is one half of that of solid lipid, and one or more of tricaprylin and caprylic/capric polyethylene glycol glyceride are preferably selected.
4. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the surfactant comprises phospholipid, tween-80, poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85, and preferably one or more of tween-80, polyoxyethylene castor oil, poloxamer 188 or pluronic P85.
5. The nedanib nanoliposome carrier according to any one of claims 1-4, wherein the nanoliposome carrier is prepared by the following method:
(1) the solid lipid material and the liquid lipid material are put in a water bath or an oil bath at the temperature of 10-40 ℃ higher than the melting point of the solid lipid material, and are stirred at 600rpm/min until being melted;
(2) adding surfactant, and stirring for 5 min;
(3) adding nintedanib, and continuously stirring for 1h to obtain a drug-containing oil phase;
(4) adding 10-30% or all of surfactant into water phase, preheating at the same temperature, adding water phase into the oil phase obtained in the step (3) under stirring, and continuing stirring for 3 min;
(5) performing ultrasonic treatment on the probe for 5-15min under the power of 25-35%;
(6) curing in ice water bath for 5-10 min.
6. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the temperature in step (1) is 30 ℃ higher than the solid lipid material.
7. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the step (4) is to add 20% or all of the surfactant to the aqueous phase.
8. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the power of the ultrasound in the step (5) is 30%.
9. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the ultrasonic treatment time in the step (5) is 13 min.
10. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the curing time in the step (6) is 6 min.
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CN111973596B (en) * | 2020-06-15 | 2022-02-15 | 深圳市泰力生物医药有限公司 | Anti-pulmonary fibrosis composition with improved dissolution property |
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