CN106166139A - A kind of compositions liposome of palmitoyl ascorbate and hydroxy camptothecin - Google Patents
A kind of compositions liposome of palmitoyl ascorbate and hydroxy camptothecin Download PDFInfo
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- CN106166139A CN106166139A CN201610294386.0A CN201610294386A CN106166139A CN 106166139 A CN106166139 A CN 106166139A CN 201610294386 A CN201610294386 A CN 201610294386A CN 106166139 A CN106166139 A CN 106166139A
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- acid
- hydroxy camptothecin
- cholesterol
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- 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
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Abstract
The present invention relates to a kind of compositions Liposomal formulation for drug administration by injection tumor, particularly relate to a kind of compound palm acyl acid ascorbyl ester and the compositions liposome of hydroxy camptothecin.By palmitoyl ascorbate is combined with hydroxy camptothecin, experiment in vivo and vitro all finds that it can be obviously enhanced the antitumor drug effect of hydroxy camptothecin, make hydroxy camptothecin just can play drug effect under extremely low dosage, it is administered through modes such as vein, tremulous pulse, muscle, subcutaneous, abdominal cavities, especially for the insertion administration such as intravenous injection or intratumor injection, improve effectiveness and the safety of hydroxy camptothecin clinical practice.The preparation method technique that the present invention uses is simple, with low cost, the liposomal particle size prepared is uniform, envelop rate is high, Release Performance is good, compared with the folk prescription liposome of palmitoyl ascorbate and hydroxy camptothecin, the extracorporeal suppression tumor cell growth of this complex and anti-tumor in vivo proliferative effect been significantly enhanced.
Description
Technical field
The present invention relates to a kind of compositions Liposomal formulation for drug administration by injection tumor, particularly relate to one
Compound palm acyl acid ascorbyl ester and the compositions liposome of hydroxy camptothecin.
Background technology
It is special that hydroxy camptothecin (Hydroxycamptothecine, HCPT, formula 1 be shown in chemical structural formula) belongs to cell cycle
Property medicine, mainly act on DNA synthesize the phase, HCPT is topoisomerase I specific inhibitor, by suppression DNA superhelix tie
Reconnection step in structure relaxation, causes strand and double-strand DNA cleavage, thus triggers the death of cell.This uniqueness
Mechanism of action makes HCPT be difficult to and other antineoplastic agents formation cross resistance, therefore, can merge with multi-medicament clinically
Medication, has preferable therapeutical effect to drug-resistant tumor.Be mainly used in clinically at present primary hepatocarcinoma, gastric cancer, incidence cancer,
The chemicotherapy of the malignant tumor such as gland originality epithelial cancer, leukemia, bladder cancer, toxic reaction is mainly manifested in urinary system, digestion
In the suppression of system and hemopoietic function, its toxicity is significantly lower than camptothecine, and particularly urinary system reaction is few, is the most easily connect
It is subject to.But this medicine has problems in that, the distribution half-life of intravenous only has 4.5min, elimination half-life to be 29min, needs repeatedly
It is administered or extends the period for the treatment of, causing dose-limiting toxicity, bone marrow depression and gastrointestinal toxicity to be consequently increased.Bolos intravenous administration
Being mainly distributed on gallbladder afterwards, it is unsatisfactory that cancer often sends out the histoorgan such as tissue distribution such as liver, lung, stomach.Use clinically
The water-soluble sodium salt of HCPT, active anticancer reduces by 90%, and toxic and side effects increases, poor stability, and pharmacologically active is greatly reduced, resistance
Hinder HCPT to give full play to antitumor action, limit clinical practice.Therefore, research HCPT novel form overcomes these problems very
Necessary.
The chemical structural formula of chemical structural formula 1. hydroxy camptothecin
Palmitoyl ascorbate (L-palmitoyl ascorbate, PA, formula 2 be shown in chemical structural formula) is ascorbic acid
A kind of fat-soluble derivant, due to the implantation of Palmic acid so that it is existing hydrophilic ascorbyl, have again the Petiolus Trachycarpi of oleophylic
Acyl ester, thus become a kind of excellent antioxidant.Compared with ascorbic acid, its stability is higher, possesses more preferable physics and chemistry
Character.After fat-soluble enhancing, palmityl ascorbic acid enters the ability of cell to be strengthened, and drug effect strengthens.Early-stage Study has shown that
Ascorbic acid can strengthen antitumor action and the safety of hydroxy camptothecin.Therefore its with ascorbic acid, hydroxy camptothecin or
Combinations thereof thing compares, and is administered through vein, tremulous pulse, muscle, subcutaneous, abdominal cavity etc., and particularly intratumor injection, insertion administration etc. is given
Prescription formula can be more significantly strengthen the antitumor action of hydroxy camptothecin and safety.And with ascorbic acid similarly,
Palmityl ascorbic acid optionally can play drug effect in tumor cell, and toxic and side effects is less.Additionally, hydrophobic characteristic
Make palmityl ascorbic acid be easier to by liposome entrapment, prepare the preferable liposome of slow release effect.
The chemical structural formula of chemical structural formula 2. vitamin C palmityl ester
Antitumor drug, also can injuring normal cell medicine while playing antitumor cell effect.One for the treatment of
Medicine orientation is key challenge is how to be transported to cancer cell and don't injuring normal cell.Liposome is targeting drug delivery system
A kind of novel form, this system is current pharmaceutics drug-supplying system up-to-date, the most promising.It can be by drug selectivity ground
It is transported to target spot position, plays therapeutical effect, the most do not affect the function of normal cell, tissue or organ simultaneously, thus reach to carry
High curative effect, the purpose of minimizing toxic and side effects.
At present, not yet there is the report of compound palm acyl acid ascorbyl ester/Hydroxycamptothecin liposome, it is contemplated that develop
The liposome of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin, to improve the targeting of hydroxy camptothecin, reduces its poison
Side effect, the antitumor action of application palmitoyl ascorbate improves curative effect.Meanwhile, preparation method of the present invention is fitted
Close Industry Promotion.
Summary of the invention
The solving the technical problem that of the present invention is to provide a kind of has good envelop rate, drug loading and stability；And
And centralized particle diameter, size distribution uniform compound palm acyl acid ascorbyl ester and the compositions liposome of hydroxy camptothecin.
For solving the technical problem of the present invention, adopt the following technical scheme that
The compositions liposome of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin of the present invention, including following each
Component: hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog.
And the weight part ratio between each component is as follows:
Hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog=0.006～0.3: 0.06
～60: 203.3～290: 96.7～9.67.
Preferably hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog=0.06～0.21
: 6～60: 203.3～273: 96.7～9.67.
Preferred hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog=0.06～
0.12: 6～24: 203.3～273: 96.7～27.
In compositions, each component is also selected from following weight portion:
The weight portion of hydroxy camptothecin is 0.006～0.06；0.006～0.12；0.006～0.21；0.006～0.3；
0.06～0.12；0.06～0.21；0.06～0.3；0.12～0.21,0.12～0.3,0.21～0.3,0.12；
The weight portion of ascorbyl palmitate is: 0.06～3；0.06～6；0.06～15；0.06～24；0.06～
60；3～6；3～15；3～24；3～60；6～15；6～24；6～60；15～24；15～60；24～60；24；
The weight portion of phospholipid substance is: 203.3～225；203.3～250；203.3～273；203.3～290；225
～250；225～273；225～290；250～275；250～290；275～290；
The weight portion of cholesterol analog is 96.7～75；96.7～50；96.7～27；96.7～9.67；75～50；75
～27；75～9.67；50～27；50～9.67；27～9.67；
Preferably phospholipid substance is selected from phosphatidylcholine class, phosphatidyl glycerol class, phosphatidyl-4 alcohols, phosphatidyl ethanol
Amine, sphingomyelin apoplexy due to endogenous wind at least one.
Preferably phospholipid substance is selected from strand or dichain phospholipids；
Preferably dichain phospholipids selected from DPPC (DPPC), tin dilaurate phosphatidylcholine (DLPC),
Two myristic acid phosphatidylcholines (DMPC), distearoyl phosphatidylcholine (DSPC), two Semen Myristicae acid phosphatidyl glycerols, two Laurels
Acid phosphatidyl glycerol, two palmitic acid phosphatidyl glycerols, DSPG, dilinoleic acid phosphatidylinositols, two Semen Myristicaes
Acid phosphatidic acid, tin dilaurate phosphatidic acid, two palmitic acid phosphatidic acid, distearyl acid phosphatidic acid, two oleic acid Phosphatidylserine,
Preferably strand phospholipid selected from single Palmic acid phosphatidylcholine (MPPC), mono laurate phosphatidylcholine (MLPC),
Single myristic acid phosphatidylcholine (MMPC), MSPC (MSPC), single Semen Myristicae acid phosphatidyl glycerol, single Laurel
Acid phosphatidyl glycerol, single palmitic acid phosphatidyl glycerol, monostearate phosphatidyl glycerol, single Semen Myristicae acid phosphatidic acid, mono laurate phosphorus
Fat acid, single palmitic acid phosphatidic acid, monostearate phosphatidic acid, single oleic acid Phosphatidylserine, single linoleic acid phosphatidylinositols,
Preferably phospholipid substance is further selected from soybean phospholipid, lecithin, cuorin, cephalin at least one.
Described cephalin can be naturally occurring or synthetic cephalin.
Preferred phospholipid substance is selected from two myristic acid phosphatidylcholines, DPPC, Semen sojae atricolor phosphorus
In fat, lecithin, cephalin, cuorin at least one.
Most preferably phospholipid substance is selected from two myristic acid phosphatidylcholines, DPPC, Semen sojae atricolor phosphorus
In fat at least one.
Preferred cholesterol analog is selected from cholesterol, Cholesteryl hemisuccinate, sitosterol at least one.
Most preferably cholesterol analog is selected from cholesterol.
In a preferred embodiment of the invention, the mass parts ratio (or weight ratio) between each component is permissible
Selected from following scope combination in any:
Preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.06～
0.21: 6～24: 203.3～273: 96.7～27.
Preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.12: 6～
24: 203.3～273: 96.7～27.
Most preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.12:
15～24: 203.3～273: 96.7～27.
In compositions, each component is also selected from following weight portion:
The weight portion of hydroxy camptothecin is 0.06～0.12,0.06～0.21,0.12～0.21,0.12；
The weight portion of ascorbyl palmitate is: 6～15,6～24,15～24；
The weight portion of two myristic acid phosphatidylcholines is: 203.3～225；203.3～250；203.3～273；225～
250；225～273；250～275；
The weight portion of cholesterol is 96.7～75；96.7～50；96.7～27；75～50；75～27；50～27；
In above-mentioned preferred embodiment, the mass parts ratio (or weight ratio) between most preferred each component is selected from:
Most preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.12:
24∶203.3∶96.7。
Most preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.12:
24∶250∶50。
Most preferably hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.12:
24∶273∶27。
In a preferred embodiment of the invention, the mass parts ratio (or weight ratio) between each component is permissible
Selected from following scope combination in any:
Preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.06～0.21: 6～24:
203.3～273: 96.7～27.
More preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.12: 6～24: 203.3～
273: 96.7～27.
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.12: 15～24: 203.3
～273: 96.7～27.
In compositions, each component is also selected from following weight portion:
The weight portion of hydroxy camptothecin is 0.06～0.12,0.06～0.21,0.12～0.21,0.12；
The weight portion of ascorbyl palmitate is: 6～15,6～24,15～24；
The weight portion of soybean phospholipid is: 203.3～225；203.3～250；203.3～273；225～250；225～
273；250～275；
The weight portion of sitosterol is 96.7～75；96.7～50；96.7～27；75～50；75～27；50～27；
In above-mentioned preferred embodiment, the mass parts ratio (or weight ratio) between most preferred each component is selected from:
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.12: 24: 203.3:
96.7。
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.12: 24: 250: 50.
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.12: 24: 273: 27.
In a preferred embodiment of the invention, the mass parts ratio (or weight ratio) between each component is permissible
Selected from following scope combination in any:
Preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.06～0.12: 6～24: 203.3～273: 96.7～27.
More preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.12: 6～24: 203.3～273: 96.7～27.
Most preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.12: 15～24: 203.3～273: 96.7～27.
In compositions, each component is also selected from following weight portion:
The weight portion of hydroxy camptothecin is 0.06～0.12,0.06～0.21,0.12～0.21,0.12；
The weight portion of ascorbyl palmitate is: 6～15,6～24,15～24；
The weight portion of DPPC is: 203.3～225；203.3～250；203.3～273；225～
250；225～273；250～275；
The weight portion of Cholesteryl hemisuccinate is 96.7～75；96.7～50；96.7～27；75～50；75～27；50
～27；
In above-mentioned preferred embodiment, the mass parts ratio (or weight ratio) between most preferred each component is selected from:
Most preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.12: 24: 203.3: 96.7.
Most preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.12: 24: 250: 50.
Most preferably hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate
=0.12: 24: 273: 27.
In a preferred embodiment of the invention, the mass parts ratio (or weight ratio) between each component is permissible
Selected from following scope combination in any:
Preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.06～0.21: 6～24:
203.3～273: 96.7～27.
More preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.12: 6～24: 203.3～
273: 96.7～27.
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.12: 15～24: 203.3
～273: 96.7～27.
In compositions, each component is also selected from following weight portion:
The weight portion of hydroxy camptothecin is 0.06～0.12,0.06～0.21,0.12～0.21,0.12；
The weight portion of ascorbyl palmitate is: 6～15,6～24,15～24；
The weight portion of soybean phospholipid is: 203.3～225；203.3～250；203.3～273；225～250；225～
273；250～275；
The weight portion of cholesterol is 96.7～75；96.7～50；96.7～27；75～50；75～27；50～27；
In above-mentioned preferred embodiment, the mass parts ratio (or weight ratio) between most preferred each component is selected from:
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.12: 24: 203.3:
96.7。
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.12: 24: 250: 50.
Most preferably hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.12: 24: 273: 27.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin prepared by the present invention, particle diameter distribution collection
In, size distribution is uniform: particle diameter is 80-200nm, and envelop rate is more than 70%, the drug loading of hydroxy camptothecin be 0.005%～
5%, the drug loading of palmitoyl ascorbate is 0.1%～40%.
Preferably prescription is: particle diameter: 100～200nm, envelop rate: ＞ 85%, the drug loading of palmitoyl ascorbate:
1%～20%
Present invention also offers the compositions liposome preparing above-mentioned compound palm acyl acid ascorbyl ester/hydroxy camptothecin
Technical scheme, the program includes two kinds of preparation methoies:
Method one comprises the steps:
A, the palmitoyl ascorbate of recipe quantity, hydroxy camptothecin, phospholipid substance, cholesterol analog are dissolved in
In organic solvent；
B, evaporating organic solvent, prepare uniform lipid membrane in bottle wall；
C, be dried；
D, add distilled water, use and ultrasonic lipid membrane is washed down；
Probe Ultrasonic Searching under E, low temperature, to obtain final product.
In step A, preferred organic solvent can be dichloromethane, chloroform, acetone, ethanol, ether, oxolane.
Preferred solvent is selected from dichloromethane, chloroform, acetone；Most preferably organic solvent is selected from chloroform.
In step B, evaporating organic solvent preferably employs the mode of rotating pressure-decreasing；When preferably rotating pressure-decreasing evaporates
Temperature is selected from 30 DEG C～80 DEG C；Preferably temperature is selected from 50 DEG C～75 DEG C；Preferred temperature is selected from 65 DEG C～75 DEG C；Most preferably
Temperature be 70 DEG C；
In step C, the mode being dried: preferably employ vacuum drying；The temperature being dried is set as 30 DEG C～90 DEG C；Temperature is selected
From 40 DEG C～90 DEG C；Preferably temperature is selected from 50 DEG C～85 DEG C；Preferred temperature is selected from 70 DEG C～80 DEG C；Most preferably temperature
It it is 75 DEG C；
In step E, Probe Ultrasonic Searching intensity and duration are set as 30%～90%, 10s～50s, and ultrasonic 1～7s stops 1s, follows
Ring number of times is 1～8 time.
Method two comprises the steps::
A, the preparation aqueous phase containing surfactant, and heat；
B, hydroxy camptothecin, cholesterol, phospholipid are dissolved in organic solvent, as oil phase；
C, aqueous phase stir during be slowly added dropwise oil phase；
D, drip complete being placed in vacuum drying oven organic solvent is volatilized；
Probe Ultrasonic Searching under E, ice-water bath, to obtain final product.
In step A, described surfactant is selected from Polyethylene Glycol-lithium 12-hydroxy stearate, Pluronic/Lutrol F 44, pool
Luo Shamu 188, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, tween 20, Tween-40, Tween-60, tween-
80, one or more materials in tween 85, Arlacel-80, dexycholate, cholate, deoxycholic acid, cholic acid, cholyltaurine salt
Material mixing, surfactant concentration is 0.01%～10%；
In step A, preferred mode of heating is heating in water bath, and the temperature of heating is preferably 30 DEG C～80 DEG C；
In step B, the organic solvent of choosing can be dichloromethane, chloroform, acetone, ethanol, ether, oxolane.More
Preferably solvent is selected from dichloromethane, chloroform, acetone；Most preferably organic solvent is selected from chloroform.
In step C, oil phase is 1: 1～20 with the volume ratio of aqueous phase, and oil phase rate of addition is 0.1mL/min～5mL/min；
During magnetic agitation, mixing speed is 100rpm～5000rpm, and temperature is set as 10 DEG C～80 DEG C；
In step D, the mode being dried: preferably employ vacuum drying；The temperature being dried is set as 30 DEG C～90 DEG C；Temperature is selected
From 40 DEG C～90 DEG C；Preferably temperature is selected from 50 DEG C～85 DEG C；Preferred temperature is selected from 70 DEG C～80 DEG C；Most preferably temperature
It it is 75 DEG C；
In step E, Probe Ultrasonic Searching intensity and duration are set as 30%～100%, 10s～60s, and ultrasonic 1～10s stops 1s,
Cycle-index is 1～10 time.
Third aspect present invention provides the compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin in system
Application in standby antitumor drug.
Described tumor selected from melanoma, gastric cancer, pulmonary carcinoma, breast carcinoma, renal carcinoma, hepatocarcinoma, oral cavity epidermal carcinoma, cervical cancer,
Ovarian cancer, cancer of pancreas, carcinoma of prostate, colon cancer, bladder cancer, cerebroma, the esophageal carcinoma.
Advantageous Effects
The compositions liposome of the compound palm acyl acid ascorbyl ester/hydroxy camptothecin of the present invention has good encapsulating
Rate, drug loading and stability.
The compositions liposome of the compound palm acyl acid ascorbyl ester/hydroxy camptothecin of the present invention and palmityl ascorbic acid
The folk prescription liposome of ester folk prescription liposome and hydroxy camptothecin is compared, and drug effect is remarkably reinforced, and can significantly improve hydroxy camptothecin
Antitumous effect, and toxicity reduces, and safety is high.Improve the safety and efficacy of hydroxy camptothecin clinical application, tool
There is important actual application prospect.
The compositions method for preparing lipidosome of the compound palm acyl acid ascorbyl ester/hydroxy camptothecin of the present invention has technique
Easy, preparation cost is low, technique favorable reproducibility, experiment prescription and technique are scalable to the features such as production application, thus to industry
The application changed has directive significance.
Accompanying drawing illustrates:
Fig. 1. the pharmacy in vitro after hydroxy camptothecin acts solely on MCF-7 and share with variable concentrations PA is tested.
Fig. 2. the pharmacy in vitro after hydroxy camptothecin acts solely on HepG-II and share with variable concentrations PA is tested.
Fig. 3. the pharmacy in vitro after hydroxy camptothecin acts solely on A549 and share with variable concentrations PA is tested.
Fig. 4. the pharmacy in vitro after hydroxy camptothecin acts solely on SGC-7901 and share with variable concentrations PA is tested.
Fig. 5. the pharmacy in vitro after hydroxy camptothecin acts solely on BxPC-3 and share with variable concentrations PA is tested.
Fig. 6. the pharmacy in vitro after hydroxy camptothecin acts solely on Hela and share with variable concentrations PA is tested.
Fig. 7. it is converted into hydroxy-camptothecin aqueous slkali group and liposome group blood concentration-time in rat body after same dosage
Curve.
Detailed description of the invention
Embodiment 1: the compositions liposome formula of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin and preparation thereof
As follows:
Experimental technique: the liposome preparation technology of described compound palm acyl acid ascorbyl ester/hydroxy camptothecin is: by hydroxyl
Base camptothecine, palmitoyl ascorbate, two myristic acid phosphatidylcholines, cholesterol are dissolved in chloroform, and vortex is extremely
Add after being completely dissolved in 500mL eggplant type flask, 70 DEG C of rotating pressure-decreasing evaporating organic solvent, prepare uniform in bottle wall
Lipid membrane, is placed in after being dried overnight at 75 DEG C in vacuum drying oven, add distilled water, ultrasonic lipid membrane is washed lower after, ice
Probe Ultrasonic Searching 2 circulation under water-bath (30%, 20s, ultrasonic 1s stops 1s), to obtain final product.
Liposome evaluation methodology:
The mensuration of the particle diameter of liposome: use laser granulometry to measure.
The compound recipe liposome of envelop rate and the mensuration of drug loading: 0.3mL crosses sephadex column, with normal saline for washing
De-liquid, after the most free medicine and liposome, collects liposome components, is measured with HPLC after methanol breakdown of emulsion constant volume,
Calculate compound recipe concentration of liposomes C1.Separately take 0.3mL compound recipe liposome methanol constant volume to identical with liposome components after upper prop
Volume, then sample introduction calculate total concentration C after compound recipe liposome breakdown of emulsion0.According to below equation computational envelope rate
(Encapsulation Efficiency, EE%) and drug loading (Drug Loading Efficiency, DLE%):
Experimental result:
The experimental result of table 1. embodiment 1
Hydroxy camptothecin: HCPT, palmitoyl ascorbate: PA, two myristic acid phosphatidylcholine: DMPC, cholesterol:
CHOL preparation evaluation standard: particle diameter: 100～200nm, envelop rate: ＞ 85%, drug loading: 1%～20% is qualified preparation
Embodiment 2: the compositions liposome formula of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin and preparation thereof
As follows:
Experimental technique: the liposome preparation technology of described compound palm acyl acid ascorbyl ester/hydroxy camptothecin is: by hydroxyl
Base camptothecine, palmitoyl ascorbate, soybean phospholipid, sitosterol are dissolved in chloroform, and vortex adds after being completely dissolved
Enter in 500mL eggplant type flask, 60 DEG C of rotating pressure-decreasing evaporating organic solvent, in bottle wall, prepare uniform lipid membrane, put
After being dried overnight at 35 DEG C in vacuum drying oven, add distilled water, ultrasonic lipid membrane is washed lower after, under ice-water bath, probe is super
Sound 4 circulation (80%, 50s, ultrasonic 1s stops 1s), to obtain final product.
Experimental result:
The experimental result of table 2. embodiment 2
Hydroxy camptothecin: HCPT, palmitoyl ascorbate: PA
Preparation evaluation standard: particle diameter: 100～200nm, envelop rate: ＞ 85%, drug loading: 1%～20% is qualified preparation
Embodiment 3: the compositions liposome formula of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin and preparation thereof
As follows:
Experimental technique: the liposome preparation technology of described compound palm acyl acid ascorbyl ester/hydroxy camptothecin is: preparation
The poloxamer aqueous phase of 0.5%, 65 DEG C of heating in water bath, by solid to hydroxy camptothecin, palmitoyl ascorbate, soybean phospholipid, gallbladder
Alcohol is dissolved in dichloromethane alcohol mixed solvent, for oil phase, is slowly added dropwise oil phase, drips complete during aqueous phase stirs
It is placed in vacuum drying oven and is dried at 40 DEG C, organic solvent is volatilized, Probe Ultrasonic Searching 6 circulation under ice-water bath (30%, 60s,
Ultrasonic 1s stops 1s), to obtain final product.
Experimental result:
The experimental result of table 3. embodiment 3
Hydroxy camptothecin: HCPT, palmitoyl ascorbate: PA, DPPC: DMPC, cholesterol half
Succinate: CHOL
Preparation evaluation standard: particle diameter: 100～200nm, envelop rate: ＞ 85%, drug loading: 1%～20% is qualified preparation
Embodiment 4: the compositions liposome formula of a kind of compound palm acyl acid ascorbyl ester/hydroxy camptothecin and preparation thereof
As follows:
Experimental technique: the liposome preparation technology of described compound palm acyl acid ascorbyl ester/hydroxy camptothecin is: preparation
The poloxamer aqueous phase of 0.5%, 65 DEG C of heating in water bath, by solid to hydroxy camptothecin, palmitoyl ascorbate, soybean phospholipid, gallbladder
Alcohol is dissolved in dichloromethane alcohol mixed solvent, for oil phase, is slowly added dropwise oil phase, drips complete during aqueous phase stirs
It is placed in vacuum drying oven and is dried at 40 DEG C, organic solvent is volatilized, Probe Ultrasonic Searching 2 circulation under ice-water bath (50%, 60s,
Ultrasonic 1s stops 1s), to obtain final product.
Experimental result:
The experimental result of table 4. embodiment 4
Hydroxy camptothecin: HCPT, palmitoyl ascorbate: PA, cholesterol: CHOL
Preparation evaluation standard: particle diameter: 100～200nm, envelop rate: ＞ 85%, drug loading: 1%～20% is qualified preparation
Pharmacological evaluation
Experimental example 1: palmitoyl ascorbate and hydroxy camptothecin share the effect to tumor cell
Mtt assay measures activity of tumor cells
The cell strain of exponential phase is after 0.25% trypsinization, with the RPMI1640 culture fluid containing 10% hyclone
It is made into single cell suspension, with 3 × 103The density of individual/mL is inoculated in 96 orifice plates, and every hole adds 100 μ L cell suspension, is placed in 37
DEG C, 5%CO2Cultivating 24h in incubator in aseptic culture case, after cell is the most adherent, remove original culture fluid, every hole adds
Enter the hydroxy-camptothecin aqueous slkali 50 μ L of the variable concentrations prepared with culture fluid, add with the variable concentrations palm fibre configured with culture fluid
Palmitic acid acyl acid ascorbyl ester 50 μ L.Matched group adds the culture fluid containing 0.1%DMSO, cultivates 72h for 37 DEG C.Cultivation is inhaled after terminating and is abandoned medicine
Liquid, every hole adds PBS 100 μ L and washes away the medicinal liquid of residual, and every hole adds the MTT working solution culture fluid 100 μ L Han 10%5mg/mL,
37 DEG C are continued to cultivate 4h.Supernatant is abandoned in suction, and every hole adds 150 μ L DMSO, and 10min is with abundant dissolving crystallized thing, at enzyme mark in vibration
Measure OD value under instrument 570nm, give the suppression ratio of tumor cell after hydroxy camptothecin by following equation calculating, and use SPSS number
According to processing computed in software half-inhibition concentration (IC50)。
According to the suppression ratio of each acute drug, apply SPSS statistical analysis software calculation of half inhibitory concentration IC50, and foundation
IC50The palmitoyl ascorbate calculating hydroxy camptothecin and variable concentrations share rear IC50Reduce multiple.
PA improves the determination methods of the Chemotherapy of medicine A
IR (A+PA) ＞ IR (A), represents that the existence of PA improves the Chemotherapy of medicine A, and prime marks is▲。
Synergism determination methods
By following computational methods, synergism is judged:
, between medicine, there is synergism in IR (A+B) ＞ IR (A)+IR (B)-IR (A) × IR (B)；
IR (A+B)=IR (A)+IR (B)-IR (A) × IR (B), simply simple superposition effect between medicine；
, between medicine, there is antagonism in IR (A+B) ＜ IR (A)+IR (B)-IR (A) × IR (B)；
Wherein IR (A+B), IR (A), IR (B) the most corresponding medicine AB combination, life when A independent role and B independent role
Long suppression ratio.
The result of IR (A)+IR (B)-IR (A) × IR (B) is shown as predictive value, and as associated with AB, suppression ratio { IR (A+B) } is big
In predictive value, then it represents that share and there is synergism.Prime marks▲▲For having synergism.If suppression ratio is negative value person's note
It is 0.
Above-mentioned cell strain is selected from: MCF-7 cell strainHJ2mm, human hepatoma cell strain HepG-II, human lung carcinoma cell line
A549, human stomach cancer cell line SGC-7901, people pancreas adenocarcinoma cell strain BxPC-3, human cervical carcinoma cell lines Hela in situ.
PA share hydroxy camptothecin and the exercising result of MCF-7 cell strainHJ2mm is shown in Table 1-1, table 1-2 and Fig. 1.
PA share hydroxy camptothecin and the exercising result of human hepatoma cell strain HepG-II is shown in Table 2-1, table 2-2 and Fig. 2.
PA share hydroxy camptothecin and the exercising result of human lung carcinoma cell line A549 is shown in Table 3-1, table 3-2 and Fig. 3.
PA share hydroxy camptothecin and the exercising result of human stomach cancer cell line SGC-7901 is shown in Table 4-1, table 4-2 and Fig. 4.
PA share hydroxy camptothecin the exercising result of people in situ pancreas adenocarcinoma cell strain BxPC-3 is shown in Table 5-1, table 5-2 and
Fig. 5.
PA share hydroxy camptothecin and the exercising result of human cervical carcinoma cell lines Hela is shown in Table 6-1, table 6-2 and Fig. 6.
Table 1-1.PA share the hydroxy camptothecin exercising result to MCF-7
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 1-2. hydroxy camptothecin independent role MCF-7 and the IC after share with variable concentrations PA50Value and drug effect increase again
Number
Note: "▲" represent that PA can improve chemotherapeutic effect
Table 2-1.PA share the hydroxy camptothecin exercising result to HepG-II
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 2-2. hydroxy camptothecin independent role HepG-II and the IC after share with variable concentrations PA50Value and drug effect increase
Multiple
Note: "▲" represent that PA can improve chemotherapeutic effect
Table 3-1.PA share the hydroxy camptothecin exercising result to A549
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 3-2. hydroxy camptothecin independent role A549 and the IC after share with variable concentrations PA50Value and drug effect increase multiple
Note: "▲" represent that PA can improve chemotherapeutic effect
Table 4-1.PA share the hydroxy camptothecin exercising result to SGC-7901
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 4-2. hydroxy camptothecin independent role SGC-7901 and the IC after share with variable concentrations PA50Value and drug effect increase
Multiple
Note: "▲" represent that PA can improve chemotherapeutic effect
Table 5-1.PA share the hydroxy camptothecin exercising result to BxPC-3
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 5-2. hydroxy camptothecin independent role BxPC-3 and the IC after share with variable concentrations PA50Value and drug effect increase again
Number
Note: "▲" represent that PA can improve chemotherapeutic effect
Table 6-1.PA share the hydroxy camptothecin exercising result to Hela
Note: "▲▲" represent that there is synergism；“▲" represent that PA can improve chemotherapeutic effect
Table 6-2. hydroxy camptothecin independent role Hela and the IC after share with variable concentrations PA50Value and drug effect increase multiple
Note: "▲" represent that PA can improve chemotherapeutic effect
Pharmacokinetic experiments
Experimental example 1: the liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin moves with the medicine of hydroxy-camptothecin aqueous slkali
Learn Nature comparison
Taking rat 6, be randomly divided into two groups by body weight, often three rats of group, give 0.5mg/ by 2mg/kg dosage intravenous
ML hydroxy-camptothecin aqueous slkali (rat numbered No.1, No.2, No.3), 0.32mg/kg dosage intravenous give compound palm acyl and resist
Bad hematic acid ester/Hydroxycamptothecin liposome (wherein Concentration of Hydroxycamptothecinein is 0.08mg/mL, the numbered No.4 of rat, No.5,
No.6), after being administered precontract 0.25h and being administered, 0.083h, 0.25h, 0.5h, 0.75h, 1h, 2h, 4h, 8h, 12h take blood,
About 200 μ L, in heparinised tubes, are centrifuged 5min in 8000rpm, isolate blood plasma, preserve for test in-80 DEG C.
Table 1. rat intravenous gives the blood drug level (μ g/L) after 2mg/kg hydroxy-camptothecin aqueous slkali
Table 2. rat intravenous gives the pharmacokinetic parameter after 2mg/kg hydroxy-camptothecin aqueous slkali in rat body
The blood medicine that table 3. rat intravenous gives after 2mg/kg compound palm acyl acid ascorbyl ester/Hydroxycamptothecin liposome is dense
Degree (μ g/L)
Table 4. rat intravenous gives after 2mg/kg compound palm acyl acid ascorbyl ester/Hydroxycamptothecin liposome in rat body
Pharmacokinetic parameter
Experimental result: be shown in Table 1-4 and Fig. 7, from hydroxy-camptothecin aqueous slkali group and the blood concentration-time curve of liposome group
It can be seen that liposome slow down drug release in figure, extend the action time of medicine, enhance drug effect.
Claims (12)
1. the compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin, it is characterised in that include following each
Component: hydroxy camptothecin, palmitoyl ascorbate, phospholipid substance and cholesterol analog；And the weight between each component
Amount part ratio is as follows:
Hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog=0.006～0.3: 0.06～60:
203.3～290: 96.7～9.67.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 1, its feature exists
In, hydroxy camptothecin: palmitoyl ascorbate: phospholipid substance: cholesterol analog=0.06～0.12: 6～24:
203.3～273: 96.7～27.
3. according to the compositions lipid of the compound palm acyl acid ascorbyl ester/hydroxy camptothecin any one of claim 1 or 2
Body, it is characterised in that described phospholipid substance is selected from phosphatidylcholine class, phosphatidyl glycerol class, phosphatidyl-4 alcohols, phosphorus
Acyl ethanolamines, Phosphatidylserine, sphingomyelin apoplexy due to endogenous wind at least one；
Described cholesterol analog is selected from cholesterol, Cholesteryl hemisuccinate, sitosterol at least one.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, described phospholipid
Class material is selected from strand or dichain phospholipids.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 4, described double-strand
Phospholipid is selected from DPPC (DPPC), tin dilaurate phosphatidylcholine (DLPC), two myristic acid phosphatidyl gallbladders
Alkali (DMPC), distearoyl phosphatidylcholine (DSPC), two Semen Myristicae acid phosphatidyl glycerols, tin dilaurate phosphatidyl glycerol, two soft
Fat acid phosphatidyl glycerol, DSPG, dilinoleic acid phosphatidylinositols, two Semen Myristicae acid phosphatidic acid, tin dilaurate
Phosphatidic acid, two palmitic acid phosphatidic acid, distearyl acid phosphatidic acid, two oleic acid Phosphatidylserine；
Described strand phospholipid is selected from single Palmic acid phosphatidylcholine (MPPC), mono laurate phosphatidylcholine (MLPC), single meat
Myristic acid phosphatidylcholine (MMPC), MSPC (MSPC), single Semen Myristicae acid phosphatidyl glycerol, mono laurate phosphorus
Phosphatidyl glycerol, single palmitic acid phosphatidyl glycerol, monostearate phosphatidyl glycerol, single Semen Myristicae acid phosphatidic acid, mono laurate phosphatidic acid,
Single palmitic acid phosphatidic acid, monostearate phosphatidic acid, single oleic acid Phosphatidylserine, single linoleic acid phosphatidylinositols.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, described phospholipid
Class material is selected from two myristic acid phosphatidylcholines, DPPC, soybean phospholipid, lecithin, cephalin, heart phosphorus
In fat at least one；
Described cholesterol analog is selected from cholesterol.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, its feature exists
In, including following each component: hydroxy camptothecin, ascorbyl palmitate, two myristic acid phosphatidylcholine and cholesterol；And
And weight part ratio between each component is as follows:
Hydroxy camptothecin: ascorbyl palmitate: two myristic acid phosphatidylcholines: cholesterol=0.06～0.21: 6～24
: 203.3～273: 96.7～27.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, its feature exists
In, including following each component: hydroxy camptothecin, ascorbyl palmitate, soybean phospholipid and sitosterol；And between each component
Weight part ratio as follows:
Hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: sitosterol=0.06～0.21: 6～24: 203.3～273:
96.7～27.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, its feature exists
In, including following each component: hydroxy camptothecin: ascorbyl palmitate: DPPC: cholesterol half succinum
Acid esters: and weight part ratio between each component is as follows:
Hydroxy camptothecin: ascorbyl palmitate: DPPC: Cholesteryl hemisuccinate=0.06～
0.12: 6～24: 203.3～273: 96.7～27.
The compositions liposome of compound palm acyl acid ascorbyl ester/hydroxy camptothecin the most according to claim 3, its feature exists
In, including following each component: hydroxy camptothecin, ascorbyl palmitate, soybean phospholipid and cholesterol；And between each component
Weight part ratio as follows:
Hydroxy camptothecin: ascorbyl palmitate: soybean phospholipid: cholesterol=0.06～0.21: 6～24: 203.3～273:
96.7～27.
The compositions liposome of the compound palm acyl acid ascorbyl ester/hydroxy camptothecin of 11. any one of claim 1-10 is in system
Application in standby antitumor drug.
12. application according to claim 11, it is characterised in that: described tumor is selected from melanoma, gastric cancer, pulmonary carcinoma, mammary gland
Cancer, renal carcinoma, hepatocarcinoma, oral cavity epidermal carcinoma, cervical cancer, ovarian cancer, cancer of pancreas, carcinoma of prostate, colon cancer, bladder cancer, cerebroma, esophagus
Cancer.
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