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CN109276719A - Composition containing orlistat nanoparticle and kinases inhibitor - Google Patents

Composition containing orlistat nanoparticle and kinases inhibitor Download PDF

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Publication number
CN109276719A
CN109276719A CN201811293207.7A CN201811293207A CN109276719A CN 109276719 A CN109276719 A CN 109276719A CN 201811293207 A CN201811293207 A CN 201811293207A CN 109276719 A CN109276719 A CN 109276719A
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CN
China
Prior art keywords
orlistat
nanoparticle
buddhist nun
kinases inhibitor
acid
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CN201811293207.7A
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Chinese (zh)
Inventor
向飞
杜志博
彭韪
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Zhongshan Wan Han Pharmaceutical Co Ltd
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Zhongshan Wan Han Pharmaceutical Co Ltd
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Priority to CN201811293207.7A priority Critical patent/CN109276719A/en
Publication of CN109276719A publication Critical patent/CN109276719A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

One aspect of the present invention provides a kind of composition containing orlistat nanoparticle and kinases inhibitor, it is characterized in that, the orlistat nanoparticle has orlistat and poly lactose hydroxyacetic acid, and the kinases inhibitor is selected from Imatinib, Gefitinib, Tarceva, Sutent, Sorafenib, Lapatinib, Dasatinib, nilotinib, training azoles pa Buddhist nun, Afatinib, bosutinib and gram azoles for one of Buddhist nun or the solvate of its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt.Extracorporeal bacteria inhibitor test as a result, it has been found that, composition provided by the present invention can to the various bacterias such as methicillin-resistant S staphylococcus generate collaboration bacteriostasis.

Description

Composition containing orlistat nanoparticle and kinases inhibitor
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the group containing kinases inhibitor Yu orlistat nanoparticle Close object.
Background technique
Infectious diseases is the major class disease caused by the microorganism infections such as bacterium, helminth, fungi or virus, can be passed through Various approach are directly or indirectly propagated between human body.It is posted including antibiotic, antiviral agent, antifungal with anti-although having at present A variety of anti-infectives such as infested medicine can be used for the treatment of infectious diseases, cause a disease in this disease still global range or lethal One of the main reason for.2010, there are about 15,000,000 to die of infectious diseases in the whole world.
First kinases inhibitor Imatinib listing in 2001 is used for the treatment of leukaemia, thus the tumor target pulled open To the prelude for the treatment of.To in October, 2018, FDA has had been approved by more than ten kinases inhibitors controlling for kinds cancer It treats.In recent years, application of the kinases inhibitors such as Imatinib in infectious diseases is more and more concerned, such as Sarah A.Stanley et al. is according to the report, Imatinib can inhibit big by the process for blocking mycobacterium to enter rat macrophage The duplication of tubercle bacillus in mouse model.In the prior art without other kinases inhibitors to infectious diseases therapeutic effect Data.The present inventor determines multiple protein kinase inhibitor to the antibacterial activity of various bacteriums in early-stage study, but big Part antibacterial activity does not reach IC50.
Orlistat is a kind of lipase inhibitor class loss of weight drug, also has inhibiting effect to fatty acid synthetase.And There is document prompt, fatty acid synthetase plays certain effect in the physiological regulating control of bacterium, however temporary nothing in the prior art Orlistat is used for antibacterial technical teaching, also combines without orlistat with kinases inhibitor and generates collaboration bacteriostasis Introduction, there are no orlistat nanoparticles to combine the introduction for generating collaboration bacteriostasis with kinases inhibitor.
Summary of the invention
The purpose of the present invention is to provide a kind of composition containing orlistat nanometer and kinases inhibitor, it is described Composition can generate the bacteriostasis of collaboration.
To achieve the goals above, one aspect of the present invention provides a kind of containing orlistat nanoparticle and protein kinase suppression The composition of preparation, which is characterized in that the orlistat nanoparticle contains orlistat and poly lactose hydroxyacetic acid (PLGA), the kinases inhibitor is selected from Imatinib (imatinib), Gefitinib (gefitinib), E Luo For Buddhist nun (erlotinib), Sutent (sunitinib), Sorafenib (sorafenib), Lapatinib (lapatinib), Dasatinib (dasatinib), nilotinib (nilotinib), training azoles pa Buddhist nun (pazopanib), Afatinib (afatinib), bosutinib (bosutinib) and gram azoles are for one of Buddhist nun (crizotinib) or its is pharmaceutically acceptable Salt or solvate or pharmaceutically acceptable salt solvate.
Kinases inhibitor of the present invention be selected from imatinib mesylate, Gefitinib, erlotinib Hydrochloride, Sunitinib malate, Sorafenib Tosylate, two tosilate monohydrate of Lapatinib, one water of Dasatinib Close object, hydrochloric acid nilotinib monohydrate, hydrochloric acid training azoles pa Buddhist nun, two maleic acid Afatinibs, bosutinib monohydrate with gram Azoles is for one of Buddhist nun.
Preferably, in composition of the present invention the molar ratio of orlistat and kinases inhibitor (0.01~ 100): between 1.
Preferably, the weight average molecular weight of poly lactose hydroxyacetic acid of the present invention is between 10000~200000.
Preferably, in poly lactose hydroxyacetic acid of the present invention the molar ratio of lactose and hydroxyacetic acid in 50:50~85: Between 15.
Preferably, the mass ratio of orlistat and poly lactose hydroxyacetic acid exists in orlistat nanoparticle of the present invention 1:(1~10) between.
Another aspect of the present invention provides the oral drug preparation containing composition as previously described, which is characterized in that described The dosage form of preparation be one of selected from tablet, capsule and granule.
Preferably, the oral solid formulation further contains diluent and lubricant.Wherein, dilution of the present invention Agent is more preferably pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, phosphoric acid One of hydrogen calcium and calcium phosphate；Lubricant of the present invention be more preferably sodium stearyl fumarate, stearic acid, magnesium stearate, Calcium stearate, paraffin oil, paraffin, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-leucine, the moon One in lauryl sulfate, magnesium laurylsulfate, polyethylene glycol, polyoxyl 40 stearate and Brij30 Kind.
Another aspect of the present invention provides a kind of foregoing composition and is preparing the drug for treating bacterium infection In application.
Preferably, the bacterium in application of the present invention is selected from MRSA, MRCNS, enterococcus faecalis, enterococcus faecium, pneumonia One of streptococcus, escherichia coli, Klebsiella Pneumoniae, pseudomonas aeruginosa.
The invention of bacteriostatic test result, the combination pair of orlistat nanoparticle and kinases inhibitor provided by the present invention MRSA, MRCNS, enterococcus faecalis, enterococcus faecium, streptococcus pneumonia, escherichia coli, Klebsiella Pneumoniae, pseudomonas aeruginosa In various bacteria generate collaboration bacteriostasis (CI < 1)
Specific embodiment
Below with reference to the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention, it is clear that retouched The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair The range of bright protection.
1. kinases inhibitor
The present invention provides a kind of composition containing orlistat nanoparticle and kinases inhibitor, wherein described Kinases inhibitor be drug under ATC classification L01XE, and obtained U.S. FDA and China CFDA and ratified to be used for The treatment of tumour.
Specifically, kinases inhibitor of the present invention is selected from Imatinib (imatinib), Gefitinib (gefitinib), Tarceva (erlotinib), Sutent (sunitinib), Sorafenib (sorafenib), La Pa For Buddhist nun (lapatinib), Dasatinib (dasatinib), nilotinib (nilotinib), training azoles pa Buddhist nun (pazopanib), Afatinib (afatinib), bosutinib (bosutinib) and gram azoles are for one of Buddhist nun (crizotinib) or its pharmacy The solvate of upper acceptable salt or solvate or pharmaceutically acceptable salt；Preferably, albumen of the present invention swashs Enzyme inhibitor is selected from imatinib mesylate, Gefitinib, erlotinib Hydrochloride, Sunitinib malate, p-methyl benzenesulfonic acid Sorafenib, two tosilate monohydrate of Lapatinib, Dasatinib monohydrate, hydrochloric acid nilotinib one are hydrated Object, hydrochloric acid training azoles pa Buddhist nun, two maleic acid Afatinibs, bosutinib monohydrate and gram azoles are for one of Buddhist nun.
2. nanoparticulate carriers
Orlistat nanometer has been prepared as carrier using poly lactose hydroxyacetic acid in the present invention.The poly lactose hydroxyl Guanidine-acetic acid (abbreviation PLGA) is one of carrier well known to those of ordinary skill in the art.
PLGA used in the present invention is commercially available carrier, by supplier according to the present invention people requirement provide have spy Determine parameter (such as weight average molecular weight, lactic acid: glycolic acid molar ratio) to be prepared, preparation method is ordinary skill people Method known to member.
3. preparation and the structural characterization of nanoparticle
The Ao Lisi has been prepared using solvent evaporation method well known to those of ordinary skill in the art in the present invention His nanoparticle, preparation method are as described below:
The PLGA for taking various characteristic parameters is dissolved in the in the mixed solvent of 0.5mL acetone Yu 0.5mL methylene chloride, is configured to Carrier total concentration is the oil phase substrate of 20mg/mL.Quantitative orlistat is taken, is scattered in it in oil phase substrate, then at 300W Lower ultrasonic 30 seconds, gained lotion was added into 2mL 3% (w/v) polyvinyl alcohol, under 300W ultrasound 100 seconds to get emulsion Lotion.Emulsion lotion is added into 20mL 0.5% (w/v) polyvinyl alcohol under stiring, vacuum distillation removes remaining acetone With chloroform to get.
The present invention is determined the partial size of preparation-obtained nanoparticle using scanning electron microscope, specific table The average grain diameter of the nanoparticle of 1~table 4 is 115nm ± 79nm.
The present invention determines the encapsulation rate of preparation-obtained nanoparticle using dialysis, specifically, 1~table of table 4 is received The encapsulation rate of the grain of rice is between 85.32%~96.13%.
4. factors influencing
The present invention has investigated following factor to orlistat nanoparticle and kinases inhibitor using orthogonal experiment The influence of the collaboration bacteriostasis of combination.
I, the type of kinases inhibitor and its molar ratio with orlistat
II, the molecular weight of PLGA
III, in PLGA structure lactic acid and hydroxyacetic acid molar ratio
IV, in nanoparticle orlistat and PLGA mass ratio
The evaluation method of 4.1 collaboration bacteriostasis
Measured respectively using filter paper enzyme orlistat nanoparticle, kinases inhibitor and orlistat nanoparticle with Bacteriostatic activity of the combined system of kinases inhibitor to various bacteria.Specifically, being drawn with liquid-transfering gun prepared Bacterial suspension (1 × 105/ mL, preparation method: will be activated on slant tube culture medium for examination strain [37 ± 1 DEG C, 3 It], it recycles oese to beat easily a small amount of lawn from inclined-plane, is respectively added to be contained with the conical flask of 50mL sterile saline In), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.Sterilizing filter paper piece is taken, lets off 6 kinds of concentration respectively 1h is impregnated in the tested material methanol solution of gradient, the 6mm circular filter paper piece impregnated is attached on the above-mentioned plate containing bacterium made, Each culture dish (diameter 90mm) sticks the filter papers of 3 dipped same mass concentration tested material methanol solutions, and (filter paper is most Amount interval is identical), using 50% methanol solution as blank control.Processed plate containing bacterium is placed in 37 DEG C of insulating boxs and is cultivated For 24 hours, colony diameter is measured using crossing method, and calculates inhibiting rate (IR) according to following formula.
It is mapped with logarithm of the inhibiting rate (IR) to drug concentration (μM), and carries out linear regression with Excel, according to recurrence Equation extrapolates the concentration of orlistat nanoparticle and kinases inhibitor when generating 30% inhibition, respectively IC30(A)With IC30(B)Value.For drug combination, then with inhibiting rate (IR) to the concentration (Yi Aolisi of orlistat nanoparticle in drug combination He counts) logarithm (log (c)) mapping, and linear regression is carried out with Excel, when extrapolating 30% inhibition according to regression equation Orlistat nanoparticle concentration in combined system, i.e. IC30(mixA), further according to orlistat nanoparticle and albumen in combined system The molar ratio of kinase inhibitor, when extrapolating 30% inhibition in combined system kinases inhibitor concentration, i.e. IC30(mixB)。
Calculating orlistat nanoparticle according to the following formula and combining with protein kinase enzyme inhibitor inhibits the joint of various bacteriums to use Medicine index CI.
As CI < 1, synergistic effect is indicated, and the smaller representative synergistic effect of CI is stronger.The results are shown in Table 1.
The type of 4.2 kinases inhibitors and its with the molar ratio of orlistat to the collaboration bacteriostasis for combining weight Influence
Use the PLGA that weight average molecular weight is 65:35 for 100000, lactic acid and glycolic acid molar ratio, and orlistat Be 1:5 with the mass ratio of PLGA, orlistat nanoparticle be prepared according to method described in Section 3 above, then according to Method described in 4.1 sections evaluates orlistat nanoparticle from different kinases inhibitors with (0.01~100): 1 mole Than, to the collaboration bacteriostasis of various bacteriums, the results are shown in Table 1 after combination.
Table 1
The influence for the collaboration bacteriostasis that 4.3PLGA molecular weight combines orlistat nanoparticle with kinases inhibitor
When nanoparticle combines generation optimum synergistic bacteriostasis (CI value is minimum) with each kinases inhibitor in selection table 1 Molar ratio and bacterium, as shown in table 2.
It is respectively 10000,50000,100000,150000 and 200000 using weight average molecular weight, lactose: hydroxyacetic acid rubs Your ratio is the PLGA of 65:35, and the mass ratio of orlistat and PLGA are 1:5, the method according to Section 3 above point Orlistat nanoparticle is not prepared, and method described in using Section 4.1 measures it with molar ratio as shown in Table 2 and egg To the collaboration bacteriostasis of bacterium shown in table 2 after white kinase inhibitor combination, CI value is as shown in table 2.
Table 2
Lactose in 4.4PLGA structure: glycolic acid molar ratio cooperates with orlistat nanoparticle with kinases inhibitor The influence of effect
Using lactose: glycolic acid molar ratio is respectively 50:50,65:35 and 85:15, and weight average molecular weight is 100000 PLGA, and the mass ratio of orlistat and PLGA are 1:5, and Austria is prepared in the method according to Section 3 above respectively Li Sita nanoparticle, and method described in using Section 4.1 measures it with molar ratio as shown in Table 2 and kinases inhibitor To the collaboration bacteriostasis of bacterium shown in table 2 after combination, CI value is as shown in table 3.
Table 3
Orlistat in 4.5 nanoparticles: PLGA mass ratio cooperates with work with kinases inhibitor to orlistat nanoparticle Influence
Use lactose: glycolic acid molar ratio is for 65:35, and weight average molecular weight is 100000 PLGA, Er Qieao The mass ratio of Li Sita and PLGA is 1:1,1:2.5,1:5,1:7.5 and 1:10, and the method according to Section 3 above is made respectively It is standby to obtain orlistat nanoparticle, and to measure it sharp with molar ratio as shown in Table 2 and albumen for method described in use Section 4.1 To the collaboration bacteriostasis of bacterium shown in table 2 after enzyme inhibitor combination, CI value is as shown in table 4.
5. the preparation method of oral solid formulation
Oral solid formulation of the present invention can be used method well known to those of ordinary skill in the art and be prepared, The method that specific method can refer to but be not limited in " pharmacy " (the 8th edition) that Fang Liang is edited, People's Health Publisher publishes.This The preparation method of the invention granule is to mix orlistat nanoparticle, kinases inhibitor, diluent, lubricant It closes to get the granule comprising kinases inhibitor Yu orlistat nanoparticle is arrived.
The preparation method of capsule of the present invention be by orlistat nanoparticle, kinases inhibitor, diluent, After mix lubricant, filling capsule to get arrive the capsule comprising kinases inhibitor Yu orlistat nanoparticle.
The preparation method of tablet of the present invention is by orlistat nanoparticle, kinases inhibitor, diluent, profit After lubrication prescription mixing, tabletting is carried out to get the tablet comprising kinases inhibitor Yu orlistat nanoparticle is arrived.
The content of kinases inhibitor in oral solid formulation of the present invention and orlistat nanoparticle and Thus the dosage being related to can be screened and be optimized, this hair by pharmacological testing well known to those of ordinary skill in the art It is bright to this without specifically limited.
Supplementary product consumption in oral solid formulation of the present invention can be by well known to those of ordinary skill in the art Formulation method is screened and is optimized, and the present invention is to this without specifically limited.
Embodiment 1 includes the system of orlistat nanoparticle and the capsule of imatinib mesylate (molar ratio 0.01:1) It is standby
Prescription (g)
Preparation method
Orlistat nanoparticle, imatinib mesylate, sorbierite and the sodium stearyl fumarate of recipe quantity are taken, it is sufficiently mixed It closes, filling capsule, packing.
Embodiment 2 includes the preparation of orlistat nanoparticle and the tablet of Gefitinib (molar ratio 0.25:1)
Prescription (g)
Preparation method
Orlistat nanoparticle, Gefitinib, microcrystalline cellulose, the magnesium stearate for taking recipe quantity, are sufficiently mixed, tabletting.
Embodiment 3 includes the preparation of orlistat nanoparticle and the granule of erlotinib Hydrochloride (molar ratio 0.5:1)
Prescription (g)
Preparation method
Orlistat nanoparticle, erlotinib Hydrochloride, microcrystalline cellulose, the sodium stearyl fumarate of recipe quantity are taken, it is sufficiently mixed It closes, packing.
Embodiment 4 includes the system of orlistat nanoparticle and the capsule of Sunitinib malate (molar ratio 0.75:1) It is standby
Prescription (g)
Preparation method
Orlistat nanoparticle, Sunitinib malate, pregelatinized starch, the glycerin monostearate for taking recipe quantity, fill Divide mixing, filling capsule, packing.
Embodiment 5 includes the system of orlistat nanoparticle and the tablet of Sorafenib Tosylate (molar ratio 1:1) It is standby
PlaceSide (g)
Preparation method
Orlistat nanoparticle, Sorafenib Tosylate, mannitol, the sldium lauryl sulfate of recipe quantity are taken, it is sufficiently mixed It closes, tabletting.
Embodiment 6 include orlistat nanoparticle and two tosilate monohydrate of Lapatinib (molar ratio 25: 1) preparation of granule
Prescription (g)
Preparation method
Take the orlistat nanoparticle of recipe quantity, two tosilate monohydrate of Lapatinib, pregelatinized starch, hard Rouge fumaric acid sodium, is sufficiently mixed, packing.
Embodiment 7 includes the system of the capsule of orlistat nanoparticle and Dasatinib monohydrate (molar ratio 50:1) It is standby
Prescription (g)
Preparation method
The orlistat nanoparticle, Dasatinib monohydrate, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, fill Divide mixing, filling capsule, packing.
Embodiment 8 includes the capsule of orlistat nanoparticle and hydrochloric acid nilotinib monohydrate (molar ratio 75:1) Preparation
Prescription (g)
Preparation method
Orlistat nanoparticle, hydrochloric acid nilotinib monohydrate, sorbierite and the sodium stearyl fumarate for taking recipe quantity, fill Divide mixing, filling capsule, packing.
Embodiment 9 includes the preparation of the tablet of orlistat nanoparticle and hydrochloric acid training azoles pa Buddhist nun (molar ratio 100:1)
Prescription (g)
Preparation method
Orlistat nanoparticle, hydrochloric acid training the azoles pa Buddhist nun, microcrystalline cellulose, magnesium stearate for taking recipe quantity, are sufficiently mixed, press Piece.
Embodiment 10 includes the granule of orlistat nanoparticle and two maleic acid Afatinibs (molar ratio 0.01:1) Preparation
Prescription (g)
Preparation method
Orlistat nanoparticle, the two maleic acid Afatinibs, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, fill Divide mixing, packing.
Embodiment 11 includes the system of the capsule of orlistat nanoparticle and bosutinib monohydrate (molar ratio 1:1) It is standby
Prescription (g)
Preparation method
The orlistat nanoparticle, bosutinib monohydrate, pregelatinized starch, glycerin monostearate of recipe quantity are taken, It is sufficiently mixed, filling capsule, dispenses.
Embodiment 12 includes the preparation of orlistat nanoparticle and gram azoles for the tablet of Buddhist nun (molar ratio 100:1)
Prescription (g)
Preparation method
It takes orlistat nanoparticle, gram azoles of recipe quantity for Buddhist nun, mannitol, sldium lauryl sulfate, is sufficiently mixed, tabletting.

Claims (10)

1. a kind of composition containing orlistat nanoparticle and kinases inhibitor, which is characterized in that the Ao Lisi His nanoparticle contains orlistat and poly lactose hydroxyacetic acid, and the kinases inhibitor non-is replaced selected from Imatinib is lucky Buddhist nun, Sutent, Sorafenib, Lapatinib, Dasatinib, nilotinib, training azoles pa Buddhist nun, Afatinib, wins Tarceva It relaxes and replaces the molten of one of Buddhist nun or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt for Buddhist nun and gram azoles Object is closed in agent.
2. composition according to claim 1, which is characterized in that the kinases inhibitor is replaced selected from her horse of methanesulfonic acid Buddhist nun, Gefitinib, erlotinib Hydrochloride, Sunitinib malate, Sorafenib Tosylate, Lapatinib two are to toluene sulphur Hydrochloride-hydrate, Dasatinib monohydrate, hydrochloric acid nilotinib monohydrate, hydrochloric acid train azoles pa Buddhist nun, two maleic acid Ah methods For Buddhist nun, bosutinib monohydrate and gram azoles for one of Buddhist nun.
3. composition according to claim 1, which is characterized in that orlistat and kinases inhibitor in the composition Molar ratio in (0.01~100): between 1.
4. composition according to claim 1, which is characterized in that the weight average molecular weight of the poly lactose hydroxyacetic acid exists Between 10000~200000.
5. composition according to claim 1, which is characterized in that lactose and hydroxyacetic acid in the poly lactose hydroxyacetic acid Molar ratio is between 50:50~85:15.
6. composition according to claim 1, which is characterized in that orlistat and poly lactose in the orlistat nanoparticle The mass ratio of hydroxyacetic acid is in 1:(1~10) between.
7. the oral drug preparation containing the composition of any one according to claim 1~7, which is characterized in that the system The dosage form of agent is selected from one of tablet, capsule and granule.
8. oral solid formulation according to claim 7, which is characterized in that the oral solid formulation further contains diluent With lubricant.
9. the composition of any one is preparing the purposes in the drug for treating bacterium infection according to claim 1~7.
10. purposes according to claim 9, which is characterized in that the bacterium is selected from methicillin-resistant S Portugal Grape coccus, methicillin resistance coagulase-negative staphylococci, enterococcus faecalis, enterococcus faecium, streptococcus pneumonia, large intestine angstrom are uncommon One of bacterium, Klebsiella Pneumoniae, pseudomonas aeruginosa.
CN201811293207.7A 2018-11-01 2018-11-01 Composition containing orlistat nanoparticle and kinases inhibitor Pending CN109276719A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110314232A (en) * 2019-08-03 2019-10-11 黄泳华 The composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor
CN110357812A (en) * 2019-08-03 2019-10-22 黄泳华 The eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1486193A (en) * 2000-11-06 2004-03-31 Effective antitumor treatment method
EP3368079A1 (en) * 2015-10-30 2018-09-05 Bergen Teknologioverforing AS Wnt/beta-catenin signal transduction inhibitors and their use in treatment or prevention of diseases and conditions linked with said transduction

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1486193A (en) * 2000-11-06 2004-03-31 Effective antitumor treatment method
EP3368079A1 (en) * 2015-10-30 2018-09-05 Bergen Teknologioverforing AS Wnt/beta-catenin signal transduction inhibitors and their use in treatment or prevention of diseases and conditions linked with said transduction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MICHIO KUROSU等: "Bacterial Protein Kinase Inhibitors", 《DRUG DEVELOPMENT RESEARCH》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110314232A (en) * 2019-08-03 2019-10-11 黄泳华 The composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor
CN110357812A (en) * 2019-08-03 2019-10-22 黄泳华 The eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor

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