CN101229131B - Novel type nanometer particle preparation capable of reducing gastroenteritic toxicity of camptothecin medicines - Google Patents
Novel type nanometer particle preparation capable of reducing gastroenteritic toxicity of camptothecin medicines Download PDFInfo
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Abstract
The invention belongs to the field of medical technology and relates to a novel nano-particle preparation for reducing the gastrointestinal toxicity of camptothecin derivatives. The preparation mainly consists of camptothecin derivatives treating effective doses, carrier matrix, excipents with the BCRP inhibitory effect and emulsifiers. The novel nano-particle preparation of camptothecin derivatives of the invention can decrease the metabolism yield by bile, reduce the irritation to the gastrointestinal tract by medicines and reduce the gastrointestinal toxicity by medicines.
Description
Technical field
The invention belongs to medical technical field, relate to novel nano microparticle formulation with reduction camptothecine gastrointestinal toxicity.
Background technology
Be used for the camptothecine (genus cytotoxic drug) of oncotherapy at present, have tangible anti-tumor activity, can prolong patient's life span, reduced mortality rate, stronger to digestive tract tumor, leukemia, bladder cancer isoreactivity.But be still the rate-limiting step that the patient obtains to cure by gastrointestinal toxicity such as the nausea,vomiting,diarrhea reaction that these treatments cause.Wherein as irinotecan (CPT-11), be a line medicine of advanced CRC treatment, CPT-11 and active metabolite SN-38, SN-38G eliminate approach in vivo mainly via bile excretion.When giving the CPT-11 of various dose to different patients, the accumulation excretion excursion of CPT-11, SN-38 and SN-38G is 25%～50% in its bile
[1]Medicine is many more at biliary excretion, and is strong more to the gastrointestinal zest.Its gastrointestinal reaction mainly shows as diarrhoea, and diarrhoea is 40% above 24 hours persons in the clinical practice, and diarrhoea surpasses 48 hours persons 20%, and acute diarrhea person 20%
[2]Gastrointestinal reaction is also comparatively common in the clinical observation of topotecan hydrochloride treatment small cell lung cancer, shows as nauseating (38%), vomiting (28%), diarrhoea (21%)
[3]In the clinical observation that hydroxy camptothecin treatment small cell lung cancer vertigo moves, nauseating, incidence of vomiting is 30%, and tardy property diarrhoea incidence rate is 39%
[4]These cytotoxic drugs usually can limit patient's therapeutic dose, the treatment persistent period to Normocellular damage in the gastrointestinal mucosa; make patient's treatment become complicated; and in kill cancer cell; also damage the normal cell in the gastrointestinal mucosa, caused the absorption of mucosa and barrier action normally not to bring into play.
Anti-tumor medicine often adopts the administering drug combinations mode at present, to realize the collaborative or summation action of medicine, reaches better therapeutic, but the also aggravation thereupon of its gastrointestinal tract toxicity.According to the literature, in hydroxy camptothecin associating calcium leucovorin, the clinical observation of fluorouracil in treatment digestive system tumor in late period, treatment group gastrointestinal side effect is more obvious, and wherein nauseating, vomiting reaches 55.56%, and the diarrhoea incidence rate is 5.56%
[5]Irinotecan associating 5-fluorouracil/calcium folinate treatment metastatic colorectal cancer patients, tardy property diarrhoea incidence rate is 85% (1～4 grade), wherein 3 grades to be 15%, 4 grade be 8%
[6]These gastrointestinal tract toxicities such as nausea,vomiting,diarrhea, stomachache etc. have influenced the intestinal absorption nutrient substance, make intestinal lack nutrient substance, the gastrointestinal tract effect increases the weight of and prolongs, and causes patient tolerability to reduce, and serious diarrhoea makes patient be prone to life danger because of dehydration or infections relating.Dosage and treatment persistent period that this has limited camptothecine greatly, curative effect of medication is descended.
The method that reduces the camptothecine gastrointestinal toxicity commonly used at present has: 1) cooperativing medicine-feeding.As giving metoclopramide half an hour before the chemotherapy, suppress the oblongata chemoreceptor trigger zone; Or Zofran 4～gmg vein injects, and prevents the release of the small intestinal 5-hydroxy tryptamine that caused by chemotherapeutic; Or preceding emesis, the tranquilizer given of chemotherapy; 2) strengthen diet nursing, drink and contain electrolytical beverage in a large number, give easy digestion, few oily light diet, have more meals a day but less food at each, allow the feed condiment in case of necessity, with stimulate appetite [3].These methods have reduced the gastrointestinal toxic reaction to a certain extent, but the quality of life these auxiliary treatment can influence patient treatment greatly when reducing gastrointestinal symptoms during influences patient's long-term treatment simultaneously.
In recent years studies show that the metabolism of camptothecine and discharge process are directly related with breast carcinoma drug-resistant protein (BCRP).BCRP is that a kind of ATP is in conjunction with box high-performance transport protein (genetic marker ABCG
2), at placental plasmodium trophoderm teleblem, small intestinal endothelium teleblem and liver-positions such as timid periosteum high expressed is arranged all.Camptothecine is the substrate of BCRP, and BCRP is closely related at the high bile excretion amount and the gastrointestinal toxicity thereof of liver-cholangiolar expression and camptothecine.Bibliographical information, the collaborative micromolecular inhibitor GF120918 that gives BCRP can increase the blood drug level of topotecan and improve oral administration biaavailability.This points out activity that we attempt suppressing BCRP for reducing camptothecine through the bile excretion amount, reduces the medicine gastrointestinal toxicity and has important value.Some BCRP micromolecular inhibitors of finding comprise methylsulfonyl imatinib, estrone, cyclosporin A, GF120918 etc. at present.But these inhibitor tend to produce targeted activity pharmacological effect in addition, or the inhibition BCRP activity of general, cause that uncertain systemic metabolism changes, and toxic and side effects is big, therefore is difficult to clinically promote the use of.
Traditional viewpoint thinks that pharmaceutic adjuvant should be inert, should not have any physiologically active.But along with the cross development of material science and pharmacy, in recent years, many new adjuvants with specific function continued to bring out.The new adjuvant that utilization has a specific function also had in recent years for the inhibiting research of BCRP and appeared in the newspapers.As Pluronic P85 and Tween 20
[7]Deng can producing inhibitory action to BCRP, these adjuvants have the less advantage of toxic and side effects when suppressing BCRP.But the adjuvant amount that this method need be used is often bigger, easily causes the BCRP inhibitory action of general, and prolonged application equally easily causes safety issue, does not possess the probability of extensive clinical practice substantially.
As fully visible, only suppress the gastrointestinal toxicity that BCRP is used for reducing camptothecine, be difficult to obtain ideal effect with coupling BCRP micromolecular inhibitor or functional adjuvant.
List of references:
[1]Lokiec?F，Canal?P，Gay?C，et?el.Pharmacokinetics?of?irinotecan?and?itsmetabolites?in?human?blood，bile，and?urine[J].Cancer?ChemotherPharmacol，1995，36：79～82.
[2] Qin Fengping, Ma Juan etc. irinotecan (CPT-11) treatment advanced CRC causes that diarrheal is observed and nursing [J]. Shandong medicine, 2002,42 (28): 58.
[3] Zhang Li, elegant China etc. fights. and topotecan hydrochloride is treated the clinical observation on the therapeutic effect [J] of 34 routine small cell lung canceres. Chinese treatment and prevention of tumour magazine, 2006,13 (4): 310～311.
[4] Sha Jianhua. the clinical observation [J] that hydroxy camptothecin treatment small cell lung cancer vertigo moves. institute of Mudanjiang Medical College newspaper, 2006,27 (3): 27～28.
[5] Liu Guozhu, Wang Ping etc. hydroxy camptothecin combination chemotherapy late gastric cancer short term effect is observed [J]. Binzhou Medical College's journal, 2006,29 (2): 108～109.
[6]Saltz?L?B，Cox?J?V，Blanke?C，et?al.Irinotecan?plus?fluorouracil?andleucovorin?for?metastatic?colorectal?cancer.Irinotecan?Study?Group[J].N?Engl?JMed.2000，343(13)：905-914.
[7]Tetsuo?Y，Hiroyuki?K，Mariko?M，et?al.Improvement?of?the?oral?drugabsorption?of?topotecan?through?the?inhibition?of?intestinal?xenobioticefflux?transporter，brest?cancer?resistance?protein，by?excipients[J].Drug?metabolism?and?disposition，2007，35：1142-1148.
Summary of the invention
An object of the present invention is to provide a kind of novel nano microparticle formulation that can reduce the camptothecine gastrointestinal toxicity that has.Said preparation can reduce medicine via biliary metabolism amount, reduces medicine to the gastrointestinal zest, improves clinical efficacy.
Another object of the present invention provides a kind of preparation method with the novel nano microparticle formulation that reduces the camptothecine gastrointestinal toxicity.
For achieving the above object, technical solution of the present invention provides a kind of novel nano microparticle formulation that reduces the camptothecine gastrointestinal toxicity that has, and its component comprises: camptothecine, the carrier matrix of treatment effective dose, have inhibiting adjuvant of BCRP and emulsifying agent.
The weight percent content of each component of above-mentioned novel nano microparticle formulation is as follows:
Camptothecine 0.01～10.0wt%
Carrier matrix 3.0～75.0wt%
Emulsifying agent 0.5～70.0wt%
Has the inhibiting adjuvant 0.1～30.0wt% of BCRP.
Preferably, the weight percent content of each component of above-mentioned novel nano microparticle formulation is as follows:
Camptothecine 0.01～10.0wt%
Carrier matrix 5.0～70.0wt%
Emulsifying agent 0.5～50.0wt%
Has the inhibiting adjuvant 0.5～27.5wt% of BCRP.
More preferably, the weight percent content of each component of above-mentioned novel nano microparticle formulation is as follows:
Camptothecine 0.05～10.0wt%
Carrier matrix 5.0～70.0wt%
Emulsifying agent 0.5～30.0wt%
Has the inhibiting adjuvant 1.0～20.0wt% of BCRP.
The inhibiting adjuvant of the described BCRP of having is substrate or the transcription inhibitor of BCRP, is selected from D-alpha-tocopherol and derivant thereof (comprising the VE succinic acid macrogol ester), Oleum menthae, Oleum Curcumae, Fel Anas domestica seed oil, limonene, the fragrant alkene of olive and the Rhizoma Atractylodis Macrocephalae oil one or more.
Described camptothecine is selected from camptothecine, hydroxy camptothecin, deoxidation camptothecine, topotecan, Irinotecan, irinotecan, Bei Luo in the camptothecin derivatives such as health, lurtotecan, Rubitecan, 7-ethyl-camptothecin, 9-nitrocamptothecin, 7-ethyl-10-hydroxycamptothecine, 9-aminocamptothecin, 10-hydroxycamptothecine, 10-Methoxycamptothecine, 18-hydroxy camptothecin and 20-acetyl group camptothecine one or more.
Described carrier matrix is selected from one or more in solid-state lipid, oil for injection, phospholipid and the polymeric material.
Wherein, solid-state lipid is selected from following all kinds of one or more: the triacylglycerol class, as tripalmitin, glyceryl tristearate, glyceryl monostearate, Glyceryl Behenate, behenic acid list/pair/in the mixture with triglycerides thing one or more; Fatty acid is as in stearic acid, the Palmic acid one or more; The waxiness class is as in cetyl palmitate, the spermol cetylate one or more; Steroid is as cholesterol.Be preferably: tripalmitin, Glyceryl Behenate, glyceryl monostearate, stearic acid, cholesterol.
Wherein, oil for injection is selected from one or more in following: crude vegetal, as in soybean oil, Oleum Ricini, Oleum Arachidis hypogaeae semen, safflower oil, the olive oil one or more; Chain length is at C
8～C
10Between fatty glyceride (comprising MCT); Oleic acid; Linoleic acid; Isopropyl myristate; Vitamin E; Vitamin A; The vitamin esters.Be preferably: MCT, oleic acid, vitamin E, soybean oil, Oleum Ricini.
Wherein, phospholipid is selected from one or more in the PEG derivatization phospholipids such as lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, two Semen Myristicae phospholipid acid choline, two Semen Myristicae phosphatidyl glycerol, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidic acid, two Palmic acid phosphatidylcholines, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine and PEG derivatization phospholipid acyl serine.Be preferably: soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine.
Wherein, polymeric material is selected from one or more in glucosan, chitosan, polylactic acid, polylactic acid derivative, polybutylcyanoacrylate, polybutylcyanoacrylate derivant and the polyethylene glycol-(lactide-caprolactone).Be preferably: glucosan, chitosan, polylactic acid, polylactic acid derivative, polyethylene glycol-(lactide-caprolactone).
Described emulsifying agent is selected from one or more of following each apoplexy due to endogenous wind: phospholipid, as in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the hydrolecithin one or more; The smooth class of fatty acid Pyrusussuriensis is as in sorbester p18 (Span60), the sorbester p17 (Span80) one or more; Poly yamanashi esters is as in polysorbate60 (Tween60), the Tween 80 (Tween80) one or more; The poloxalkol class is as in poloxamer (Poloxamer) series/pluronic (Pluronic) series (comprising Poloxamer188, Poloxamer105, Pluronic P85) one or more; The polyoxyethylene fatty acid ester class is as Myrj 52 (Myrj52), Myrj 59 (Myrj59); The polyoxyethylene aliphatic alcohol ether class is as Brij30 (Brij30), Brij 50 (Brij50); The Polyethylene Glycol esters is as Polyethylene Glycol-12-hydroxy stearic acid ester (Solutol HS15).Be preferably: soybean lecithin, Ovum Gallus domesticus Flavus lecithin, Span60, Tween80, Poloxamer188 (PluronicF68), Pluronic P85, Solutol HS15.
Novel nano microparticle formulation with reduction camptothecine gastrointestinal toxicity provided by the invention further can also comprise 0～30wt%, is preferably the acceptable accessories of 0～15wt%.
Described acceptable accessories is selected from one or more in interfacial film stabilizing agent, antioxidant, osmotic pressure regulator, pH regulator agent, complexing of metal ion agent and the antiseptic.
Wherein, the interfacial film function of stabilizer is to form stable interfacial film packaging medicine and form nanoparticle, and it is selected from glycerol, propylene glycol, mannitol, oleic acid, enuatrol and the cholesterol one or more.
Because phospholipid, oil for injection are all easily oxidized, as required, also contain antioxidant in the Nanoparticulate formulations of the present invention, it is selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C and the vitamin E one or more.
As required, Nanoparticulate formulations of the present invention can add osmotic pressure regulator, and it is selected from sodium chloride, glucose, mannitol, propylene glycol and the glycerol one or more.
As required, Nanoparticulate formulations of the present invention can add the pH regulator agent, comprises all kinds of buffer salt system such as citric acid-sodium citrate, acetic acid-sodium acetate, phosphate agent etc., and NaOH solution, alkali and acid such as HCl.
As required, Nanoparticulate formulations of the present invention can add the complexing of metal ion agent, as in EDTA or the b diammonium disodium edta salt etc. one or more.
As required, Nanoparticulate formulations of the present invention can add antiseptic, as in benzalkonium bromide, benzalkonium chloride, parabens or the sorbic acid etc. one or more.
Nanoparticulate formulations preparation method with reduction camptothecine gastrointestinal toxicity of the present invention can be divided into three kinds of technical schemes.
Scheme one: if carrier matrix contains solid-state lipid, the preparation method of product of the present invention is: with camptothecine, solid-state lipid material, oil for injection, emulsifying agent (fat-soluble), have the inhibiting adjuvant of BCRP and be dissolved in the organic solvent, remove organic solvent by methods such as decompression rotary evaporation or vacuum dryings then, and be heated to fusion, to constitute organic facies; Emulsifying agent (water solublity), acceptable accessories are dissolved in the water for injection, and heating in water bath is to constitute water; In water-bath, under stirring or the shear conditions described organic facies and water are mixed, with the preparation colostrum; Carry out ultrasonic or the high pressure homogenize processing to colostrum, make camptothecine nanoparticle 1 after the cooling.The camptothecine nanoparticle that makes can be carried out lyophilizing or spray dry-cure or sealing and be preserved.
Above-mentioned organic solvent is selected from dichloromethane, chloroform, acetone, ethanol and isopropyl alcohol.
Scheme two: if carrier matrix is phospholipid and/or cholesterol, the preparation method of product of the present invention is: with camptothecine, phospholipid, cholesterol, have the inhibiting adjuvant of BCRP and be dissolved in the organic solvent, the decompression rotary evaporation removes and desolvates, make solute form the layer of even lipid membrane at the bottle wall, add the aqueous solution aquation that contains emulsifying agent and pharmaceutically acceptable adjuvant, can form camptothecine nanoparticle 2 under high-speed stirred, high shear or the high pressure homogenize effect, above-mentioned nanoparticle can be carried out lyophilizing or spray dry-cure or sealing and be preserved.
Described organic solvent is with described in the technical scheme one.
Scheme three: if carrier matrix is a polymeric material, the preparation method of product of the present invention can be divided into two classes:
(1) water intaking insoluble polymer, camptothecine and have the inhibiting adjuvant of BCRP and add organic dissolution with solvents, under stirring or shear action, add the aqueous solution that contains emulsifying agent and pharmaceutically acceptable adjuvant, make into colostrum, carry out ultrasonic or the high pressure homogenize processing to colostrum, remove organic solvent in stirred in water bath or reduction vaporization, promptly get camptothecine nanoparticle 3-1.
(2) water intaking soluble polymer, acceptable accessories add the dissolving of injection water and (can add a small amount of organic solvent, adopt modes such as stirring), with camptothecine, have inhibiting adjuvant of BCRP and emulsifying agent organic solvent dissolution, and organic solvent is removed in rotary evaporation or water-bath, under stirring or shear action, add aqueous solutions of polymers, make into colostrum, carry out ultrasonic or the high pressure homogenize processing to colostrum, remove organic solvent in stirred in water bath or reduction vaporization, promptly get camptothecine nanoparticle 3-2.
Nanoparticle 3-1,3-2 can carry out lyophilizing or spray dry-cure or sealing and preserve.
The nanoparticle that obtains in above-mentioned three kinds of technical schemes can directly be used as preparation, also can further make other preparations.When lyophilized formulations was made in its lyophilizing, the lyophilizing proppant was selected from one or more in dextran, mannitol, lactose, sucrose and the trehalose; When it is spray dried to powder, sprays dried proppant and be selected from mannitol, lactose, starch, sucrose, polyvinylpyrrolidone (PVP) and the hydroxypropyl emthylcellulose (HPMC) one or more.
Nanoparticulate formulations beneficial effect with reduction camptothecine gastrointestinal toxicity provided by the invention shows as: 1. the present invention adds the adjuvant that specificity has inhibition BCRP effect.Camptothecine is wrapped in the nanoparticle, delivers to liver-biliary ductuli with dosage form, and its specific adjuvant can suppress the effect of BCRP in the local performance of liver-biliary ductuli, reduces medicine through biliary excretion.To have an inhibiting supplementary product consumption of BCRP less owing to adopt in the Nanoparticulate formulations, and high concentration acts on the part, therefore can not have side effects to normal internal organs.Can avoid because of the gastrointestinal side-effect therapy discontinued.2. the specificity adjuvant has the effect that suppresses BCRP in the Nanoparticulate formulations, is reducing medicine can improve camptothecine in the bile excretion amount bioavailability, increases the antitumor action of medicine.3. (the tumor tissues angiogenic growth is rapid for the EPR effect of Nanoparticulate formulations, adventitial cell lacks, the basement membrane distortion, lymph pipeline return-flow system is damaged), make microgranule can penetrate tumor vascular endothelial cell and enter tumor tissues, improve the concentration of chemotherapeutics in tumor cell, bring into play the drug effect of antitumor drug to greatest extent.
In a word, Nanoparticulate formulations provided by the invention contains the inhibiting adjuvant of specific b CRP, and this novel nano microparticle formulation has following advantage:
(1) contains the adjuvant that BCRP is played specific inhibitory effect in the Nanoparticulate formulations of the present invention, can suppress the effect of BCRP, reduce medicine, reduce the gastrointestinal toxicity of camptothecine through biliary excretion in high local concentrations.
(2) it is less that Nanoparticulate formulations employing of the present invention has the inhibiting supplementary product consumption of BCRP, and nanoparticle can deliver to tumor or liver-biliary ductuli by integral form, can avoid causing the BCRP inhibitory action of general the inhibiting while and, improve safety in performance the toxicity of other histoorgan.
(3) Nanoparticulate formulations of the present invention can solve the poorly water-soluble that most of camptothecines exist, defectives such as physicochemical property instability.And by EPR (Enhance Permeabilityand Retention) effect tumor tissues is produced passive targeting, improve the drug effect of oncotherapy.
(4) with respect to not adding the common nanoparticle that suppresses the BCRP adjuvant; Nanoparticulate formulations of the present invention is when having common nanoparticle slow releasing pharmaceutical, slowly metabolism, improving bioavailability; utilize the inhibitory action of specificity adjuvant for BCRP; autotelic minimizing medicine reduces the gastrointestinal toxicity of camptothecine through biliary excretion.
Description of drawings
Fig. 1 is that alkyl camptothecine injection and the embodiment of the invention 1 Nanoparticulate formulations are through the bile metabolic map.
Fig. 2 is that irinotecan injection (CPT-11) and the embodiment of the invention 3 Nanoparticulate formulations are through the bile metabolic map.
Fig. 3 is that irinotecan injection (CPT-11) and the embodiment of the invention 5 Nanoparticulate formulations are through the bile metabolic map.
Fig. 4 be BCRP micromolecular inhibitor cyclosporin A and the embodiment of the invention 2 Nanoparticulate formulations to hydroxy camptothecin through the metabolic influence of bile.
Fig. 5 is not for adding in the nano particle preparations of BCRP inhibitor and the embodiment of the invention 6 Nanoparticulate formulations hydroxy camptothecin through biliary accumulation metabolism amount.
The specific embodiment
Preparation embodiment
Preparation method: the fragrant alkene of hydroxy camptothecin, glyceryl monostearate, MCT (MCT), soybean phospholipid, olive of getting recipe quantity adds an amount of dissolve with ethanol, rotation evaporate to dryness organic solvent, and vacuum drying, 80 ℃ of heating for dissolving are as oil phase.Enuatrol is dissolved in the water for injection, is heated to 80 ℃ as water.Under 80 ℃ of stirrings, water is splashed into oil phase while hot, logical N
2Prepare colostrum in high-shear homogenizing machine under the condition, 80 ℃ of logical N
2High pressure homogenize is handled under the condition, makes the hydroxycamptothecin nano microgranule after the cooling, and lyophilizing after the packing promptly gets hydroxycamptothecin nano microgranule lyophilized formulations.
Mean diameter (Particle size)=112.4 ± 31.1nm; Polydispersity coefficient (PI)=0.114
Preparation method: take by weighing hydroxy camptothecin, limonene, soybean phospholipid and stearic acid by recipe quantity, under logical condition of nitrogen gas, be heated to (80 ± 5) ℃, under stirring condition, add the aqueous solution that uniform temp contains glycerol and Poloxamer-188 then, make thick breast; 4114MPa pressure stimulating milk secretion is spared 5 times on the high pressure dispersing emulsification machine under (80 ± 5) ℃ logical condition of nitrogen gas, and after the inflated with nitrogen packing, cooling forms the hydroxycamptothecin nano microgranule rapidly, and lyophilizing after the packing promptly gets hydroxycamptothecin nano microgranule lyophilized formulations.
Particle?size＝201.0±15.9nm；PI＝0.102
Preparation method: the CPT-11, glyceryl monostearate, Oleum Curcumae, Tween80, the Ovum Gallus domesticus Flavus lecithin that take by weighing recipe quantity add an amount of dissolve with ethanol, and the rotation evaporate to dryness is removed organic solvent, vacuum drying, and 80 ℃ of heating for dissolving are as oil phase.Enuatrol is dissolved in the water for injection, is heated to 80 ℃ as water.Under 80 ℃ of stirrings, water is splashed into oil phase, logical N
2Prepare colostrum in high-shear homogenizing machine under the condition, 80 ℃ of logical N
2High pressure homogenize is handled under the condition, makes the irinotecan nanoparticle after the cooling, lyophilizing after the packing, and 4 ℃ of storages promptly get irinotecan nanoparticle lyophilized formulations.
Particle?size＝123.6±21.0nm；PI＝0.124
Preparation method: accurately take by weighing 9-nitrocamptothecin, soybean phospholipid, the cholesterol of recipe quantity, add the chloroform-methanol mixed solvent (2: 1, V/V) an amount of, it dissolved fully and be transferred in the eggplant-shape bottle.25 ℃ of water bath with thermostatic control reduction vaporizations are removed organic solvent, make medicine and lipid form homogeneous film on the bottle wall.Eggplant-shape bottle is put the interior vacuum drying of vacuum drying oven and is spent the night, and adds a certain amount of 0.05mol/L phosphate buffer (pH=5.5) that contains the VE succinic acid macrogol ester, and 55 ℃ of water-baths come off lipid film, get light yellow suspension; Ice bath is the ultrasonic 5s of probe down, and intermittently 3s repeats power 160W 60 times; Crossing the aperture is 0.45 μ m microporous filter membrane, gets 9-nitrocamptothecin nanoparticle, and lyophilizing after the packing promptly gets 9-nitrocamptothecin nanoparticle lyophilized formulations.
Particle?size＝91.7±21.3nm；PI＝0.176
Embodiment 5:
Preparation method: CPT-11, lecithin, cholesterol, the Fel Anas domestica seed oil of getting recipe quantity are put in the round-bottomed flask, add ethanol, make said mixture be dissolved into clear and bright solution fully, put water bath with thermostatic control drying under reduced pressure film forming, add the aqueous solution dissolving film that contains mannitol, use the Ultrasound Instrument Ultrasonic Pulverization, get the CPT-11 nanoparticle.Lyophilizing after the packing promptly gets CPT-11 nanoparticle lyophilized formulations.
Particle?size＝86.7±15.6nm；PI＝0.211
Preparation method: take by weighing glucosan, Poloxamer-188 is soluble in water, regulating pH value with 1MNaOH solution is 9.32, this aqueous solution is slowly injected the acetone that contains Rhizoma Atractylodis Macrocephalae oil, magnetic agitation, 70 ℃ of heating in water bath.Take by weighing 10-hydroxycamptothecine in water, dripping NaOH solution adjusting pH value is 9.5.This liquid is added in the above-mentioned aqueous solution, is 6.84 with concentration for the HCl adjust pH, solution colour shoals, as seen a large amount of tiny muddy generations with mixed liquor sonic oscillation 5min, are statically placed in 24h under the room temperature, the centrifugal 15min of high speed 2000rpm, abandoning supernatant adds water recently distilled washing 2 times, gets 10-hydroxycamptothecine glucosan nanoparticle.Sealing is preserved after the packing, promptly gets 10-hydroxycamptothecine nanoparticle mixed suspension preparation.
Particle?size＝223.5±32.1nm；PI＝0.225
Embodiment 7
Preparation method: 7-ethyl-10-hydroxycamptothecine, polylactic acid, Oleum menthae are dissolved in chloroform-ethanol solution, 50 ℃ of rotary evaporations, on the bottle wall, obtain exsiccant thin polymer film, place 60 ℃ of water-baths to be preheated to transparent glue this thin polymer film, add some pieces of 60 ℃ of waters for injection that contain Solutol HS15 and beades, 60 ℃ of dispersed with stirring suspendible 30min, ultrasonic 10min, form medicine carrying submicron dispersion liquid, cross the microporous filter membrane of 0.45 μ m, remove the not drug crystallization and the polymer poly collective of parcel.Promptly get 7-ethyl-10-hydroxycamptothecine Nanoparticulate formulations.With mannitol is that the spray-dried back packing of proppant is preserved, and can further make 7-ethyl-10-hydroxycamptothecine nanoparticle spray dry preparation.
Particle?size＝201.2±21.4nm；PI＝0.204
Embodiment 8
Preparation method: get camptothecine and Polyethylene Glycol (5000)-poly-(lactide-caprolactone) polymer, the volume ratio that Oleum Curcumae is dissolved in oxolane and dimethyl sulfoxine is in 4/1 the mixed solvent, fully pour in the Dropping funnel after the dissolving, slowly splash in the water of Tween60 (rate of addition be 6～10 seconds/drip), after dripping off, continue to stir 2h (600～800 rev/mins), pour in the bag filter, dialysis 24h, every 1h, 2h, 2h, 3h, 4h, 6h, 12h changes water, sample filtering after the dialysis, free camptothecine is removed in the filtrate centrifugalize, the product that obtains is used aqueous dispersion again, promptly gets camptothecine polyethylene glycol-(lactide-caprolactone) Nanoparticulate formulations.With sucrose is that the spray-dried back packing of proppant is preserved, and can further make camptothecine nanoparticle spray dry preparation.
Pharmacology embodiment
Medicine bile metabolism research:
(1) get SD rat random packet, 3 every group, the anesthesia of lumbar injection 20% urethane, scratch the about 1cm of abdominal part flesh layer under along ventrimeson in xiphoid-process and do cystic duct cannula, respectively tail vein injection embodiment 1,3,5 Nanoparticulate formulations, alkyl camptothecine injection, CPT-11 injection.And the Preset Time section is collected bile after administration, and bile sample HPLC is after treatment measured.
Hydroxy camptothecin (HCPT) is measured chromatographic condition: chromatographic column: octadecyl silane post (150 * 4.6mm, 5 μ m); Mobile phase: methanol-0.05M Ammoniom-Acetate (glacial acetic acid is regulated pH 6.0) (45: 55); Detect wavelength: 382nm; Flow velocity: 1.0ml/min.
CPT-11 measures chromatographic condition: octadecyl silane post (150 * 4.6mm, 5 μ m); Mobile phase: acetonitrile-0.05M potassium dihydrogen phosphate contains 0.01M perfluoroetane sulfonic acid sodium solution (phosphoric acid is regulated pH3.0) (22: 78); Detect wavelength: 370nm; Flow velocity: 1.0ml/min.
The results are shown in Figure 1-3.The result shows that embodiment 1,3, and 5 Nanoparticulate formulations have significantly reduced camptothecine through biliary metabolism amount, provides the foundation for preparation reduces the camptothecine gastrointestinal toxicity.
(2) investigation BCRP micromolecular inhibitor cyclosporin A (CsA) reaches to add and has the nanoparticle of BCRP inhibitory action adjuvant to the metabolic influence of medicine bile.
Get SD rat random packet, 3 every group, behind the cystic duct cannula respectively through tail vein injection HCPT injection, the HCPT injection that contains CsA, embodiment 2 nanoparticles; Do not add among embodiment 6 nanoparticles and the embodiment 6 and have the nanoparticle of BCRP inhibitory action adjuvant (Rhizoma Atractylodis Macrocephalae oil).And the Preset Time section is collected bile after administration, and bile sample is measured down by above-mentioned HPLC chromatographic condition after treatment.
The results are shown in Figure 4-5.The result shows that CsA can reduce HCPT through biliary excretion owing to suppressed the activity of BCRP; Adding has the nanoparticle of BCRP inhibitory action adjuvant owing to can change the tissue distribution of medicine to a certain extent, has and slows down the effect of HCPT through bile metabolism amount.And Nanoparticulate formulations of the present invention (as embodiment 2,6 nanoparticles) can significantly reduce medicine through biliary metabolism amount on the two basis, has improved the effect of preparation reduction camptothecine gastrointestinal toxicity greatly.
Medicine is to the influence of mice gastrointestinal peristalsis function: investigate the influence of Nanoparticulate formulations of the present invention to the diarrhea of mouse effect with the gastrointestinal peristalsis functional experiment.Get KM mice random packet, every group 6, every other day tail vein injection embodiment 1,3,5 Nanoparticulate formulations, hydroxy camptothecin (HPCT) injection, CPT-11 injection and normal saline, successive administration five times, and in last tail vein injection after 10 minutes, per os pours into methylene blue solution 0.2ml, after 30 minutes, put to death mice, open the abdominal cavity, intestinal tube is gently pulled into straight line, measure intestinal tube total length and methylene blue movable length from pylorus, calculate and move than (moving ratio=methylene blue movable length/intestinal tube total length).The results are shown in Table 1-2.
Table 1HCPT injection and Nanoparticulate formulations of the present invention are to the influence of mice gastrointestinal peristalsis
＊P＜0.05
Table 2CPT-11 injection and Nanoparticulate formulations of the present invention are to the influence of mice gastrointestinal peristalsis
＊P＜0.05。
The result shows that alkyl camptothecine injection and CPT-11 injection have significantly increased the gastrointestinal peristalsis speed of mice, causes the diarrhea of mouse rate and improves, and gastrointestinal side-effect is obvious.Embodiment 1,3, and gastrointestinal peristalsis speed of 5 Nanoparticulate formulations mice after the tail vein injection administration and negative control group (normal saline) there was no significant difference can obviously reduce the gastrointestinal side-effect of camptothecine.
Claims (10)
1. have the Nanoparticulate formulations that reduces the camptothecine gastrointestinal toxicity, its component comprises: camptothecine, the carrier matrix of treatment effective dose, have inhibiting adjuvant of BCRP and emulsifying agent;
The inhibiting adjuvant of the described BCRP of having is selected from one or more in Oleum menthae, Oleum Curcumae, Fel Anas domestica seed oil, limonene, the fragrant alkene of olive and the Rhizoma Atractylodis Macrocephalae oil;
Wherein, the weight percent content of each component is as follows:
Camptothecine 0.01～10.0wt%
Carrier matrix 3.0～75.0wt%
Emulsifying agent 0.5～70.0wt%
Has the inhibiting adjuvant 0.1～30.0wt% of BCRP;
Described camptothecine is selected from camptothecine, hydroxy camptothecin, deoxidation camptothecine, topotecan, Irinotecan, irinotecan, Bei Luo in health, lurtotecan, Rubitecan, 7-ethyl-camptothecin, 9-nitrocamptothecin, 7-ethyl-10-hydroxycamptothecine, 9-aminocamptothecin, 10-hydroxycamptothecine, 10-Methoxycamptothecine, 18-hydroxy camptothecin and the 20-acetyl group camptothecine one or more.
2. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 1 is characterized in that the weight percent content of each component is as follows:
Camptothecine 0.01～10.0wt%
Carrier matrix 5.0～70.0wt%
Emulsifying agent 0.5～50.0wt%
Has the inhibiting adjuvant 0.5～27.5wt% of BCRP.
3. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 2 is characterized in that the weight percent content of each component is as follows:
Camptothecine 0.05～10.0wt%
Carrier matrix 5.0～70.0wt%
Emulsifying agent 0.5～30.0wt%
Has the inhibiting adjuvant 1.0～20.0wt% of BCRP.
4. according to the described Nanoparticulate formulations of one of claim 1～3, it is characterized in that described carrier matrix is selected from one or more in solid-state lipid, oil for injection, phospholipid and the polymeric material with reduction camptothecine gastrointestinal toxicity;
Described solid-state lipid is selected from one or more in triacylglycerol class, fatty acid, waxiness class and the steroid; Wherein: the triacylglycerol class be selected from tripalmitin, glyceryl tristearate, glyceryl monostearate, Glyceryl Behenate and behenic acid list/pair/in the mixture with triglycerides thing one or more; Fatty acid is selected from one or more in stearic acid and the Palmic acid; The waxiness class is selected from one or more in cetyl palmitate and the spermol cetylate; Steroid is selected from cholesterol;
Described oil for injection is selected from crude vegetal, chain length at C
8～C
10Between fatty glyceride, oleic acid, linoleic acid, isopropyl myristate, vitamin E, vitamin A and vitamin esters in one or more; Wherein crude vegetal is selected from one or more in soybean oil, Oleum Ricini, Oleum Arachidis hypogaeae semen, safflower oil and the olive oil;
Described phospholipid is selected from one or more in lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, two Semen Myristicae phospholipid acid choline, two Semen Myristicae phosphatidyl glycerol, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidic acid, two Palmic acid phosphatidylcholines, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine and the PEG derivatization phospholipid acyl serine;
Described polymeric material is selected from one or more in glucosan, chitosan, polylactic acid, polybutylcyanoacrylate, polybutylcyanoacrylate derivant and the polyethylene glycol-(lactide-caprolactone).
5. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 4, it is characterized in that described solid-state lipid is selected from one or more in tripalmitin, Glyceryl Behenate, glyceryl monostearate, stearic acid and the cholesterol;
Described oil for injection is selected from one or more in MCT, oleic acid, vitamin E, soybean oil and the Oleum Ricini;
Described phospholipid is selected from one or more in soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, PHOSPHATIDYL ETHANOLAMINE and the PEG derivatization phospholipid acyl ethanolamine;
Described polymeric material is selected from one or more in glucosan, chitosan, polylactic acid and the polyethylene glycol-(lactide-caprolactone).
6. according to the described Nanoparticulate formulations of one of claim 1～3 with reduction camptothecine gastrointestinal toxicity, it is characterized in that described emulsifying agent is selected from one or more of phospholipid, the smooth class of fatty acid Pyrusussuriensis, poly yamanashi esters, poloxalkol class, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class and macrogol ester apoplexy due to endogenous wind; Wherein phospholipid is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin and the hydrolecithin; The smooth class of fatty acid Pyrusussuriensis is selected from one or more in sorbester p18 and the sorbester p17; Poly yamanashi esters is selected from one or more in polysorbate60 and the Tween 80; The poloxalkol class is selected from one or more in the poloxamer series of poloxamer 188, poloxamer 105, pluronic P85; The polyoxyethylene fatty acid ester class is selected from one or more in Myrj 52 and the Myrj 59; The polyoxyethylene aliphatic alcohol ether class is selected from one or more in Brij30 and the Brij 50; The Polyethylene Glycol esters is selected from Polyethylene Glycol-12-hydroxy stearic acid ester.
7. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 6, it is characterized in that described emulsifying agent is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, sorbester p18, Tween 80, poloxamer 188, pluronic P85 and Polyethylene Glycol-12-hydroxy stearic acid ester.
8. according to the described Nanoparticulate formulations of one of claim 1～3, it is characterized in that, can also comprise the acceptable accessories of 0～30wt% with reduction camptothecine gastrointestinal toxicity; Wherein said acceptable accessories is selected from one or more in interfacial film stabilizing agent, antioxidant, osmotic pressure regulator, pH regulator agent, complexing of metal ion agent and the antiseptic.
9. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 8 is characterized in that the weight percent content of the acceptable accessories that comprises is 0～15wt%.
10. the Nanoparticulate formulations with reduction camptothecine gastrointestinal toxicity according to claim 8, it is characterized in that wherein said interfacial film stabilizing agent is selected from one or more in glycerol, propylene glycol, mannitol, oleic acid, enuatrol and the cholesterol;
Described antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C and the vitamin E;
Described osmotic pressure regulator is selected from one or more in sodium chloride, glucose, mannitol, propylene glycol and the glycerol;
Described pH regulator agent is selected from: citric acid-sodium citrate, acetic acid-sodium acetate, phosphate-buffered salt system, NaOH solution and HCl solution;
Described complexing of metal ion agent is selected from one or more in EDTA and the b diammonium disodium edta salt;
Described antiseptic is selected from one or more in benzalkonium bromide, benzalkonium chloride, parabens and the sorbic acid.
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| US20150119388A1 (en) * | 2012-06-15 | 2015-04-30 | The Children's Hospital Philadelphia | Novel pro- and codrug derivatives for nanoparticle delivery of select anticancer agents formed using rapidly cleavable phenolic ester bridges |
| CN102988366B (en) * | 2012-12-31 | 2014-07-02 | 成都中医药大学 | Use and nasal administration medicine of hydroxycamptothecine |
| CN103735504B (en) * | 2013-12-10 | 2016-06-29 | 国家纳米科学中心 | A kind of irinotecan nanometer fat bundle preparation and preparation method thereof |
| ES2680444T3 (en) * | 2014-01-17 | 2018-09-07 | Oncoral Pharma Aps | Solid oral dosage form of irinotecan for cancer treatment |
| CN106214672B (en) * | 2016-07-19 | 2019-07-09 | 华中科技大学 | A kind of naringenin nano-composition and its preparation method and application |
| CN109288795A (en) * | 2018-12-10 | 2019-02-01 | 佛山科学技术学院 | A kind of preparation method of nano liposomes |
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| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
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| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
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