CN104031080B - Silica nodule being loaded with 10-hydroxycamptothecine and preparation method thereof - Google Patents
Silica nodule being loaded with 10-hydroxycamptothecine and preparation method thereof Download PDFInfo
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- CN104031080B CN104031080B CN201410280543.3A CN201410280543A CN104031080B CN 104031080 B CN104031080 B CN 104031080B CN 201410280543 A CN201410280543 A CN 201410280543A CN 104031080 B CN104031080 B CN 104031080B
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 title claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 93
- 239000000243 solution Substances 0.000 claims abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000002632 lipids Chemical class 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000005457 ice water Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000006228 supernatant Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 239000011259 mixed solution Substances 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 238000002390 rotary evaporation Methods 0.000 claims description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 9
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 5
- 239000011541 reaction mixture Substances 0.000 abstract 1
- 150000007524 organic acids Chemical class 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 description 1
- 0 *CCCON(*C*)OC* Chemical compound *CCCON(*C*)OC* 0.000 description 1
- 101100493710 Caenorhabditis elegans bath-40 gene Proteins 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- -1 amine salt Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of silica nodule being loaded with 10 hydroxy camptothecins and preparation method thereof, comprise the following steps: 10 hydroxy camptothecins are dissolved in the acid dichloromethane solution of pH=2～4；Siliceous lipid molecular in point 3～10 batches of acid dichloromethane solutions joining described 10 hydroxy camptothecins, is continued to ice-water bath condition and stirs 10～120 minutes, then remove the solvent in reaction mixture under the conditions of ice-water bath；To removing, the solution after solvent adds ethanol/water solution, water-bath 10～240 minutes under the conditions of 50～80 DEG C, then by ultrasonic for solution 1～20 minute；Mixed solution after ultrasonic is centrifuged, takes supernatant, then be loaded with the silica nodule of 10 hydroxy camptothecins described in supernatant lyophilizing i.e. being obtained.This silica nodule makes the envelop rate of 10 hydroxy camptothecins be at least up to 75%, and drug loading is at least up to 3%.
Description
Technical field
The present invention relates to pharmaceutical chemistry and therapeutics field, particularly relate to one and be loaded with 10-hydroxy-camptothecin
Silica nodule of alkali and preparation method thereof.
Background technology
Camptothecine (Camptothecin, CPT) is to extract, from China endemic plant Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae), the biology obtained
Alkali.In external activity screening in early days, camptothecine shows stronger anti-tumor activity, to multiple reality
Body tumor and leukemia have an obvious inhibitory action, but camptothecine poorly water-soluble, strong toxicity, therefore limit
Make its application on oncotherapy.Hsiang Y.H. in 1985 etc. find that camptothecine is opened up by suppression
Flutter isomerase I and play cytotoxic activity, attract attention again.
10-hydroxycamptothecine is the natural derivative of camptothecine, is the antineoplastic agent of China's extensively clinic
Thing, 10-hydroxycamptothecine molecular structural formula is as follows.
In 10-hydroxycamptothecine structure, the Alpha-hydroxy lactonic ring of Guan Bi is that it keeps the required of anti-tumor activity
Structure, but the facile hydrolysis open loop in human body of Alpha-hydroxy lactonic ring forms carboxylate structure, this open loop form
Carboxylate structure be easily combined with human albumin and make 10-hydroxycamptothecine forfeiture anti-tumor activity.More
Seriously, the sodium salt of open loop form has great poison to urinary system and digestive system after renal metabolism
Side effect.
Silica nodule is a kind of Novel siliceous lipoid plastid vesicle, can be used for carrying medicament, but by traditional
The silica nodule envelop rate that preparation method obtains is low (less than 70%), and drug loading is also less than 2%.
Summary of the invention
In view of this, it is an object of the invention to propose a kind of silica nodule being loaded with 10-hydroxycamptothecine and
Its preparation method, to improve envelop rate and the drug loading of silica nodule.
Based on above-mentioned purpose, the preparation method of the silica nodule being loaded with 10-hydroxycamptothecine that the present invention provides
Comprise the following steps:
10-hydroxycamptothecine is dissolved in the acid dichloromethane solution of pH=2～4；
Under the conditions of ice-water bath, divide 3～10 batches by siliceous lipid molecular and join described 10-hydroxycamptothecine
In acid dichloromethane solution, continue to ice-water bath condition and stir 10～120 minutes, then remove anti-
Answer the solvent in mixed solution；
To removing, the solution after solvent adds ethanol/water solution, under the conditions of 50～80 DEG C water-bath 10～
240 minutes, then by ultrasonic for solution 1～20 minute；
Mixed solution after ultrasonic is centrifuged, takes supernatant, then be loaded with described in supernatant lyophilizing is i.e. obtained
The silica nodule of 10-hydroxycamptothecine.
Alternatively, the structural formula of described siliceous lipid molecular is
It is preferred that described siliceous lipid molecular prepares by the following method:
By 1,3-olein is dissolved in dichloromethane, continuously add aminopropyl triethoxysilane and
1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, reacts 2～8 little under the conditions of 20～30 DEG C
Time；
Product rotary evaporation under vacuum is obtained thick product, and this thick product column chromatography purifies
After obtain described siliceous lipid molecular by rotary evaporation again.
Alternatively, the temperature of described ice-water bath is-2～10 DEG C.
Preferably, in described ethanol/water solution, the volume ratio of ethanol and water is 1:1～1:9.
It is preferred that the solvent of described dichloromethane solution is organic acid, regulate dichloromethane by organic acid
PH value.
Preferably, at least one during described organic acid can be acetic acid, formic acid and trichloroacetic acid.
The present invention also provides for a kind of silica nodule being loaded with 10-hydroxycamptothecine, described in be loaded with 10-hydroxyl
The silica nodule of camptothecine prepares according to said method.
Alternatively, the envelop rate of described silica nodule is more than or equal to 75%.
Preferably, the drug loading of described silica nodule is more than or equal to 3%.
From the above it can be seen that by the system of the silica nodule being loaded with 10-hydroxycamptothecine of the present invention
The silica nodule of what Preparation Method prepared be loaded with 10-hydroxycamptothecine can make the bag of 10-hydroxycamptothecine
Envelope rate is at least up to 75%, and drug loading is at least up to 3%.Therefore, it can be substantially reduced non-active ingredient
Consumption, 10-hydroxycamptothecine absorbance in vivo can be effectively improved simultaneously, and realize the slow of medicine
Release.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearer, below in conjunction with being embodied as
Example, the present invention is described in more detail.
The synthesis of the siliceous lipid molecular of embodiment 1
Adding 2.3 gram 1 in dry dichloromethane, 3-olein, after fully dissolving, under room temperature
Continuously add 1 gram of aminopropyl triethoxysilane and 5 grams of 1-(3-dimethylamino-propyl)-3-ethyl carbon two are sub-
Amine hydrochlorate, reaction system stirs 4 hours at 25 DEG C.Product is rotated under vacuum steaming
Sending out and obtain thick product, this thick product column chromatography obtains siliceous lipid by rotary evaporation again after purifying and divides
Son, productivity 50%.
1HNMR(400MHz,CDCl3,TMS,ppm):δ0.59(2H,t),0.85(6H,t),1.21(9H,t),
1.22-1.26(54H,m),1.489-1.64(6H,m),2.59(2H,t),3.19-3.30(2H,m),3.49-3.53
(2H,t),3.63-3.66(4H,t)3.68-3.86(6H,m),3.95-4.10(4H,t)6.40(1H,s)。
The synthesis of the siliceous lipid molecular of embodiment 2
Adding 3.4 gram 1 in dry dichloromethane, 3-olein, after fully dissolving, under room temperature
Continuously add 0.8 gram of aminopropyl triethoxysilane and 6.2 grams of 1-(3-dimethylamino-propyl)-3-ethyl carbon two
Inferior amine salt hydrochlorate, reaction system stirs 3.8 hours at 27.5 DEG C.By product under vacuum
Rotary evaporation obtains thick product, and this thick product column chromatography is obtained containing silicone grease by rotary evaporation after purifying again
Matter molecule, productivity 55%.
1HNMR(400MHz,CDCl3,TMS,ppm):δ0.59(2H,t),0.85(6H,t),1.21(9H,t),
1.22-1.26(54H,m),1.489-1.64(6H,m),2.59(2H,t),3.19-3.30(2H,m),3.49-3.53
(2H,t),3.63-3.66(4H,t)3.68-3.86(6H,m),3.95-4.10(4H,t)6.40(1H,s)。
The synthesis of the siliceous lipid molecular of embodiment 3
Adding 1.5 gram 1 in dry dichloromethane, 3-olein, after fully dissolving, under room temperature
Continuously add 0.78 gram of aminopropyl triethoxysilane and 4.4 grams of 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimmonium salt hydrochlorate, reaction system stirs 6 hours at 23 DEG C.Product is revolved under vacuum
Turning evaporation and obtain thick product, this thick product column chromatography obtains siliceous lipid by rotary evaporation after purifying again
Molecule, productivity 58.5%.
1HNMR(400MHz,CDCl3,TMS,ppm):δ0.59(2H,t),0.85(6H,t),1.21(9H,t),
1.22-1.26(54H,m),1.489-1.64(6H,m),2.59(2H,t),3.19-3.30(2H,m),3.49-3.53
(2H,t),3.63-3.66(4H,t)3.68-3.86(6H,m),3.95-4.10(4H,t)6.40(1H,s)。
The synthesis of the siliceous lipid molecular of embodiment 4
Adding 2 gram 1 in dry dichloromethane, 3-olein, after fully dissolving, under room temperature
Continuously add 1.2 grams of aminopropyl triethoxysilanes and 4 grams of 1-(3-dimethylamino-propyl)-3-ethyl carbon two are sub-
Amine hydrochlorate, reaction system stirs 2 hours at 28 DEG C.Product is rotated under vacuum steaming
Sending out and obtain thick product, this thick product column chromatography obtains siliceous lipid by rotary evaporation again after purifying and divides
Son, productivity 53.6%.
1HNMR(400MHz,CDCl3,TMS,ppm):δ0.59(2H,t),0.85(6H,t),1.21(9H,t),
1.22-1.26(54H,m),1.489-1.64(6H,m),2.59(2H,t),3.19-3.30(2H,m),3.49-3.53
(2H,t),3.63-3.66(4H,t)3.68-3.86(6H,m),3.95-4.10(4H,t)6.40(1H,s)。
Embodiment 5 preparation is loaded with the silica nodule of 10-hydroxycamptothecine
First in round-bottomed flask, 1 gram of 10-hydroxycamptothecine is dissolved in the acid dichloromethane of pH=3.6
In solution, then embodiment 1 will synthesize the 15 grams of siliceous lipid moleculars obtained under the conditions of ice-water bath
(5 DEG C) point 5 batches (3 grams/batches) join in the acid dichloromethane solution of 10-hydroxycamptothecine, and
Under the conditions of ice-water bath, (5 DEG C) stir 30 minutes.Wherein, the solvent of described dichloromethane solution is for having
Machine acid, by the pH value of organic acid regulation dichloromethane to 3.6.Alternatively, described organic acid can be
At least one in acetic acid, formic acid and trichloroacetic acid.
The slowest rotary evaporation, to remove the solvent in round-bottomed flask, then to round bottom
Flask adds 20 milliliter of 40% ethanol/water solution (volume ratio), round-bottomed flask is put into 65 DEG C of constant temperature
In shaking bath 60 minutes, then with Probe Ultrasonic Searching instrument by ultrasonic for the solution in round-bottomed flask 10 minutes.?
After, the mixed solution after ultrasonic is centrifuged 10 minutes under 10000 revs/min, takes supernatant, then will
Supernatant lyophilizing i.e. obtains the silica nodule of described 10-hydroxycamptothecine.
In gained silica nodule, the envelop rate of 10-hydroxycamptothecine reaches 75%, and drug loading reaches at least up to
3%.
Embodiment 6 preparation is loaded with the silica nodule of 10-hydroxycamptothecine
First in round-bottomed flask, 1.5 grams of 10-hydroxycamptothecines are dissolved in the acid dichloromethane of pH=2.5
In alkane solution, then embodiment 2 will synthesize the 20 grams of siliceous lipid moleculars obtained under the conditions of ice-water bath
(2 DEG C) point 4 batches (5 grams/batches) join in the acid dichloromethane solution of 10-hydroxycamptothecine, and
Under the conditions of ice-water bath, (2 DEG C) stir 50 minutes.Wherein, the solvent of described dichloromethane solution is for having
Machine acid, by the pH value of organic acid regulation dichloromethane to 2.5.Alternatively, described organic acid can be
At least one in acetic acid, formic acid and trichloroacetic acid.
The slowest rotary evaporation, to remove the solvent in round-bottomed flask, then to round bottom
Flask adds 40 milliliter of 55% ethanol/water solution (volume ratio), round-bottomed flask is put into 65 DEG C of constant temperature
In shaking bath 100 minutes, then with Probe Ultrasonic Searching instrument by ultrasonic for the solution in round-bottomed flask 12 minutes.?
After, the mixed solution after ultrasonic is centrifuged 15 minutes under 12000 revs/min, takes supernatant, then will
Supernatant lyophilizing i.e. obtains the silica nodule of described 10-hydroxycamptothecine.
In gained silica nodule, the envelop rate of 10-hydroxycamptothecine reaches 80%, and drug loading reaches at least up to
3.6%.
Embodiment 7 preparation is loaded with the silica nodule of 10-hydroxycamptothecine
First in round-bottomed flask, 0.8 gram of 10-hydroxycamptothecine is dissolved in the acid dichloromethane of pH=4
In solution, then embodiment 3 will synthesize the 10 grams of siliceous lipid moleculars obtained under the conditions of ice-water bath
(8 DEG C) point 2 batches (5 grams/batches) join in the acid dichloromethane solution of 10-hydroxycamptothecine, and
Under the conditions of ice-water bath, (8 DEG C) stir 100 minutes.Wherein, the solvent of described dichloromethane solution is for having
Machine acid, by the pH value of organic acid regulation dichloromethane to 4.Alternatively, described organic acid can be second
At least one in acid, formic acid and trichloroacetic acid.
The slowest rotary evaporation, to remove the solvent in round-bottomed flask, then to round bottom
Flask adds 50 milliliter of 10% ethanol/water solution (volume ratio), round-bottomed flask is put into 78 DEG C of constant temperature
In shaking bath 80 minutes, then with Probe Ultrasonic Searching instrument by ultrasonic for the solution in round-bottomed flask 5 minutes.?
After, the mixed solution after ultrasonic is centrifuged 20 minutes under 9000 revs/min, takes supernatant, then by upper
Clear liquid lyophilizing i.e. obtains the silica nodule of described 10-hydroxycamptothecine.
In gained silica nodule, the envelop rate of 10-hydroxycamptothecine reaches 82%, and drug loading reaches at least up to
4%.
Embodiment 8 preparation is loaded with the silica nodule of 10-hydroxycamptothecine
First in round-bottomed flask, 3 grams of 10-hydroxycamptothecines are dissolved in the acid dichloromethane of pH=3.6
In solution, then embodiment 4 will synthesize the 18 grams of siliceous lipid moleculars obtained under the conditions of ice-water bath
(-1 DEG C) point 3 batches (6 grams/batches) join in the acid dichloromethane solution of 10-hydroxycamptothecine, and
Under the conditions of ice-water bath, (-1 DEG C) stirs 15 minutes.Wherein, the solvent of described dichloromethane solution is for having
Machine acid, by the pH value of organic acid regulation dichloromethane to 3.6.Alternatively, described organic acid can be
At least one in acetic acid, formic acid and trichloroacetic acid.
The slowest rotary evaporation, to remove the solvent in round-bottomed flask, then to round bottom
Flask adds 36 milliliter of 80% ethanol/water solution (volume ratio), round-bottomed flask is put into 50 DEG C of constant temperature
In shaking bath 40 minutes, then with Probe Ultrasonic Searching instrument by ultrasonic for the solution in round-bottomed flask 10 minutes.?
After, by under the mixed solution 15000 revs/min after ultrasonic centrifugal 8 minutes, take supernatant, then by supernatant
Liquid lyophilizing i.e. obtains the silica nodule of described 10-hydroxycamptothecine.
In gained silica nodule, the envelop rate of 10-hydroxycamptothecine reaches 78%, and drug loading reaches at least up to
4.5%.
It is loaded with the plasma pharmacokinetics of the silica nodule of 10-hydroxycamptothecine:
Male mice fasting, freely drink water 12 hours, by the dosage of 80mg/kg10-hydroxy camptothecin
(silica nodule is calculated by the amount of 10-hydroxycamptothecine contained therein) gastric infusion.After administration respectively at
0.17,0.33,0.67,1,1.5,2,4,8,12,24 hours, cardiac acquisition blood was in heparinization
In anticoagulant centrifuge tube, 4000r/min is centrifuged 30min, draws upper plasma, and RP-HPLC method measures raw
The content of HCPT in thing sample, the data obtained pharmacokinetics program analyzes (being shown in Table 1).
Compared with being directly administered with 10-hydroxycamptothecine, the silica nodule peak concentration of drug of load 10-hydroxycamptothecine
Relatively low, there is longer peak time and half-life and mean residence time, area under the drug-time curve
Improve about 400%, show that the silica nodule loading 10-hydroxycamptothecine can be effectively improved 10-hydroxyl
The body absorption of camptothecine, and realize the slow release of medicine.
Table 1 single dose gastric infusion 10-hydroxycamptothecine and load 10-hydroxycamptothecine silica nodule medicine generation
Thank to kinetic parameter
As can be seen here, prepared by the preparation method of the silica nodule being loaded with 10-hydroxycamptothecine of the present invention
The silica nodule being loaded with 10-hydroxycamptothecine obtained can make the envelop rate of 10-hydroxycamptothecine at least up to
To 75%, drug loading is at least up to 3%.Therefore, it can be substantially reduced the consumption of non-active ingredient, with
Time can be effectively improved 10-hydroxycamptothecine absorbance in vivo, and realize the slow release of medicine.
Those of ordinary skill in the field are it is understood that the foregoing is only the specific embodiment of the present invention
, be not limited to the present invention, all within the spirit and principles in the present invention, that is done any repaiies
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (8)
1. the preparation method of the silica nodule being loaded with 10-hydroxycamptothecine, it is characterised in that include
Following steps:
10-hydroxycamptothecine is dissolved in the acid dichloromethane solution of pH=2～4；
Under the conditions of ice-water bath, divide 3～10 batches by siliceous lipid molecular and join described 10-hydroxycamptothecine
In acid dichloromethane solution, continue to ice-water bath condition and stir 10～120 minutes, then remove anti-
Answer the solvent in mixed solution；
To removing, the solution after solvent adds ethanol/water solution, under the conditions of 50～80 DEG C water-bath 10～
240 minutes, then by ultrasonic for solution 1～20 minute；
Mixed solution after ultrasonic is centrifuged, takes supernatant, then be loaded with described in supernatant lyophilizing is i.e. obtained
The silica nodule of 10-hydroxycamptothecine；
Wherein, the structural formula of described siliceous lipid molecular is
The preparation method of the silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 1,
It is characterized in that, described siliceous lipid molecular prepares by the following method:
By 1,3-olein is dissolved in dichloromethane, continuously add aminopropyl triethoxysilane and
1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, reacts 2～8 little under the conditions of 20～30 DEG C
Time；
Product rotary evaporation under vacuum is obtained thick product, and this thick product column chromatography purifies
After obtain described siliceous lipid molecular by rotary evaporation again.
The preparation method of the silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 1,
It is characterized in that, the temperature of described ice-water bath is-2～10 DEG C.
The preparation method of the silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 1,
It is characterized in that, in described ethanol/water solution, ethanol is 1:1～1:9 with the volume ratio of water.
The preparation method of the silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 1,
It is characterized in that, the solvent of described dichloromethane solution is at least in acetic acid, formic acid and trichloroacetic acid
Kind.
6. the silica nodule being loaded with 10-hydroxycamptothecine, it is characterised in that described in be loaded with 10-hydroxyl
The silica nodule of base camptothecine is according to being loaded with 10-hydroxy-camptothecin described in any one in Claims 1 to 5
The preparation method of the silica nodule of alkali prepares.
The silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 6, its feature exists
In, the envelop rate of described silica nodule is more than or equal to 75%.
The silica nodule being loaded with 10-hydroxycamptothecine the most according to claim 6, its feature exists
In, the drug loading of described silica nodule is more than or equal to 3%.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410280543.3A CN104031080B (en) | 2014-06-20 | 2014-06-20 | Silica nodule being loaded with 10-hydroxycamptothecine and preparation method thereof |
| PCT/CN2015/077477 WO2015192692A1 (en) | 2014-06-20 | 2015-04-27 | 10-hydroxycamptothecin-loaded silica body and preparation method therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410280543.3A CN104031080B (en) | 2014-06-20 | 2014-06-20 | Silica nodule being loaded with 10-hydroxycamptothecine and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
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| CN104031080A CN104031080A (en) | 2014-09-10 |
| CN104031080B true CN104031080B (en) | 2016-07-13 |
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| CN201410280543.3A Expired - Fee Related CN104031080B (en) | 2014-06-20 | 2014-06-20 | Silica nodule being loaded with 10-hydroxycamptothecine and preparation method thereof |
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| WO (1) | WO2015192692A1 (en) |
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| CN1289088C (en) * | 2004-03-15 | 2006-12-13 | 重庆科美纳米生物技术有限公司 | Method for improving liposome enveloping rate of camptothecine or its derivatives |
| ES2562052T3 (en) * | 2004-06-18 | 2016-03-02 | Kabushiki Kaisha Yakult Honsha | Liposomal preparation containing camptothecin slightly soluble in water |
| WO2011006453A1 (en) * | 2009-07-17 | 2011-01-20 | 哈尔滨工业大学 | Compound lipid based on pentaerythritol, intermediates, preparation method and use thereof |
| CN102670509B (en) * | 2011-03-08 | 2016-10-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Liposomal formulation containing slightly solubility camptothecine and preparation method thereof |
| CN103585132B (en) * | 2012-10-24 | 2015-07-22 | 中山大学 | Preparation method of paclitaxel silicon plastid microcapsule |
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| CN104031080A (en) | 2014-09-10 |
| WO2015192692A1 (en) | 2015-12-23 |
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