CN109045300A - Composition containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor - Google Patents
Composition containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor Download PDFInfo
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- CN109045300A CN109045300A CN201811310073.5A CN201811310073A CN109045300A CN 109045300 A CN109045300 A CN 109045300A CN 201811310073 A CN201811310073 A CN 201811310073A CN 109045300 A CN109045300 A CN 109045300A
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- buddhist nun
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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
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
- A61K31/495—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
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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
- A61K31/495—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
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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
- A61K31/495—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
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- 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
- A61P31/10—Antimycotics
Abstract
The present invention provides the compositions for having phosphodiesterase inhibitors grain and kinases inhibitor, it is characterized in that, the nanoparticle contains phosphodiesterase inhibitors and poly lactose hydroxyacetic acid, the phosphodiesterase 4 inhibitor and kinases inhibitor is all the product listed both at home and abroad, and the composition can generate the bacteriostasis (drug combination index < 1) of collaboration to various bacteria.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to press down containing phosphodiesterase inhibitors nanoparticle and protein kinase
The composition of preparation.
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.
There is studies have shown that phosphodiesterase (PDE) to have in the bacterium of part expressed, the intoxicating for also adjusting bacterium is made
With, but at present there is no be the phosphodiesterase inhibitors (PDEI) of representative for antibacterial technology religion using sildenafil citrate
It leads, also combines the introduction for generating collaboration bacteriostasis with kinases inhibitor without phosphodiesterase inhibitors, there are no di(2-ethylhexyl)phosphates
Esterase inhibitor nanoparticle combines 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 containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor
Composition, the composition can generate the bacteriostasis of collaboration.
To achieve the goals above, one aspect of the present invention provides a kind of sharp containing phosphodiesterase inhibitors grain and albumen
The composition of enzyme inhibitor, which is characterized in that the nanoparticle contains phosphodiesterase inhibitors and poly lactose hydroxyacetic acid
(PLGA), phosphodiesterase inhibitors be selected from silaenafil (sildenafil), Tadalafei (tadalafil), cut down ground that
Non- (vardenafil), avanaphil (avanafil), it is excellent ground that non-(udenafil) and roflumilast (roflumilast) in
One kind or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt solvate, the albumen swash
Enzyme inhibitor is to replace Buddhist nun (alectinib), pazopanib selected from Abemaciclib, Afatinib (afatinib), Ah coming
(axitinib), bosutinib (bosutinib), Brigatinib, plug are auspicious replaces Buddhist nun for Buddhist nun (ceritinib), gram azoles
(crizotinib), Dasatinib (dasatinib), Tarceva (erlotinib), Gefitinib (gefitinib), Yi Bu
For Buddhist nun (ibrutinib), Imatinib (imatinib), Lapatinib (lapatinib), logical sequence cut down for Buddhist nun (lenvatinib),
Nilotinib (nilotinib), Nintedanib (nintedanib), difficult to understand wish replace Buddhist nun (osimertinib), pa cypress Seeley
(Palbociclib), hydrochloric acid trains azoles pa Buddhist nun (pazopanib), Rui Gefeini (regorafenib), ribociclib, Suo Lafei
One of Buddhist nun (sorafenib) and Sutent (sunitinib) or its pharmaceutically acceptable salt or solvate or medicine
The solvate of acceptable salt on.
Preferably, kinases inhibitor of the present invention be selected from Abemaciclib, two maleic acid Afatinibs,
Hydrochloric acid Ah coming replace Buddhist nun, pazopanib, bosutinib, Brigatinib, plug it is auspicious for Buddhist nun, gram azoles for Buddhist nun, Dasatinib monohydrate,
Erlotinib Hydrochloride, Gefitinib, her cloth for Buddhist nun, imatinib mesylate, two tosilate monohydrate of Lapatinib,
Methanesulfonic acid logical sequence is cut down uncommon for Buddhist nun, pa cypress Seeley, salt for Buddhist nun, hydrochloric acid nilotinib monohydrate, ethanesulfonic acid Nintedanib, methanesulfonic acid Austria
Acid training azoles pa Buddhist nun, Rui Gefeini monohydrate, succinic acid ribociclib, Sorafenib Tosylate and the easypro Buddhist nun of malic acid replace
One of Buddhist nun.
Preferably, phosphodiesterase inhibitors of the present invention are selected from sildenafil citrate, Tadalafei, hydrochloric acid
One of Vardenafil trihydrate, avanaphil, excellent that non-and roflumilast of ground.
Preferably, phosphodiesterase inhibitors and the molar ratio of kinases inhibitor exist in composition of the present invention
(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, phosphodiesterase inhibitors and poly lactose hydroxyl in phosphodiesterase inhibitors nanoparticle of the present invention
The mass ratio of guanidine-acetic acid is in 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 be selected from Cedecea neteri Cedecea neteri,
The autochthonal cryptococcus of Cryptococcus humicola, Yersinia frederiksenii Yersinia fredericksenii,
Streptococcus uberis streptococcus uberis, Peptostreptococcus micros peptostreptococcus micros,
Staphylococcus cohnii urealyticum Staphylococcus cohnis solution urea subspecies, Pasteurella gr.EF4 Bath
Moral flora EF4, Brevibacterium epidermidis brevibacterium epidermidis, 2 smell sand thunder bacterium of Serratia odorifera
2 types, Chryseobacterium indologenes produce indoles Chryseobacterium sp, Pichia etchellsii angstrom cuts Pichia pastoris,
Klebsiella pneumonia rhinoscleromatis Klebsiella Pneumoniae nose scleroma subspecies, Serratia ficaria
Serratia ficaria, Cryptococcus albidus light white latent ball yeast, Corynebacterium diphtheriae
Mitis mitigates corynebacterium diphtheriae, Yersinia enterocolitica yersinia enterocolitica, Arcanobacterium
Haemolyticum arcanobacterium haemolyticum, Candida rugosa fold candida, Haemophilus influenzae
III type of III haemophilus influenzae, Clostridium paraputrificum class clostridium septicum, Burkholderia
Diminuta Burkholderia cepacia, Aeromonas hydrophila gr. Aeromonas hydrophila group, Ceotruchum
Penicillatum Pan Shi mould, Citrobacter amalonaticua without one of malonic acid citric acid bacillus.
The invention of bacteriostatic test result, phosphodiesterase inhibitors nanoparticle and kinases inhibitor provided by the present invention
Combination to Cedecea neteri Cedecea neteri, the autochthonal cryptococcus of Cryptococcus humicola, Yersinia
Frederiksenii Yersinia fredericksenii, Streptococcus uberis streptococcus uberis, Peptostreptococcus
Micros peptostreptococcus micros, Staphylococcus cohnii urealyticum Staphylococcus cohnis solution urea subspecies,
Pasteurella gr.EF4 Pasteur flora EF4, Brevibacterium epidermidis brevibacterium epidermidis, Serratia
2 smell sand thunder bacterium of odorifera, 2 type, Chryseobacterium indologenes produce indoles Chryseobacterium sp, Pichia
Etchellsii angstroms to cut Pichia pastoris, Klebsiella pneumonia rhinoscleromatis Klebsiella Pneumoniae nose hard
Tie subspecies, Serratia ficaria Serratia ficaria, Cryptococcus albidus light white latent ball yeast,
Corynebacterium diphtheriae mitis mitigates corynebacterium diphtheriae, Yersinia enterocolitica small intestine knot
Enteritis Yersinia, Arcanobacterium haemolyticum arcanobacterium haemolyticum, Candida rugosa gauffer vacation silk
Yeast, III type of Haemophilus influenzae III haemophilus influenzae, Clostridium paraputrificum class
Clostridium septicum, Burkholderia diminuta Burkholderia cepacia, the thermophilic aqueous vapor of Aeromonas hydrophila gr.
Unit cell flora, Ceotruchum penicillatum Pan Shi mould, Citrobacter amalonaticua without malonic acid lemon
Various bacteria in acidfast bacilli generates the bacteriostasis (drug combination index CI < 1) of collaboration
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 phosphodiesterase inhibitors nanoparticle and kinases inhibitor,
In, the kinases inhibitor is the drug under ATC classification L01XE, and has obtained U.S. FDA and China CFDA batches
The mutatis mutandis treatment in tumour.
Specifically, kinases inhibitor of the present invention is selected from Abemaciclib, Afatinib
(afatinib), Ah coming replace Buddhist nun (alectinib), pazopanib (axitinib), bosutinib (bosutinib),
Brigatinib, plug are auspicious to replace Buddhist nun (crizotinib), Dasatinib (dasatinib), E Luo for Buddhist nun (ceritinib), gram azoles
Buddhist nun (ibrutinib) is replaced for Buddhist nun (erlotinib), Gefitinib (gefitinib), her cloth, Imatinib (imatinib), is drawn
Pa cuts down for Buddhist nun (lapatinib), logical sequence for Buddhist nun (lenvatinib), nilotinib (nilotinib), Nintedanib
(nintedanib), difficult to understand uncommon for Buddhist nun (osimertinib), pa cypress Seeley (Palbociclib), hydrochloric acid training azoles pa Buddhist nun
(pazopanib), Rui Gefeini (regorafenib), ribociclib, Sorafenib (sorafenib) and Sutent
One of (sunitinib) or the solvent of its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt closes
Object.Preferably, kinases inhibitor of the present invention be selected from Abemaciclib, two maleic acid Afatinibs, hydrochloric acid Ah
To replace Buddhist nun, pazopanib, bosutinib, Brigatinib, plug auspicious in distress for Buddhist nun, Dasatinib monohydrate, hydrochloric acid for Buddhist nun, gram azoles
Buddhist nun, imatinib mesylate, two tosilate monohydrate of Lapatinib, methanesulfonic acid are replaced for Buddhist nun, Gefitinib, her cloth in Lip river
Logical sequence is cut down uncommon for Buddhist nun, pa cypress Seeley, hydrochloric acid training azoles for Buddhist nun, hydrochloric acid nilotinib monohydrate, ethanesulfonic acid Nintedanib, methanesulfonic acid Austria
In Pa Ni, Rui Gefeini monohydrate, succinic acid ribociclib, Sorafenib Tosylate and Sunitinib malate
It is a kind of.
2. phosphodiesterase inhibitors
Phosphodiesterase inhibitors of the present invention include the silaenafil (sildenafil) of FDA approval, Ta Dala
Non- (tadalafil), Vardenafil (vardenafil), avanaphil (avanafil), roflumilast (roflumilast) with
Excellent that non-(udenafil) of ground of Korean market or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt
Solvate.
3. nanoparticulate carriers
Phosphodiesterase inhibitors nanoparticle has been prepared as carrier using poly lactose hydroxyacetic acid in the present invention.It is described
Poly lactose hydroxyacetic acid (abbreviation PLGA) be 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.
4. preparation and the structural characterization of nanoparticle
The di(2-ethylhexyl)phosphate has been prepared using solvent evaporation method well known to those of ordinary skill in the art in the present invention
Esterase inhibitor nanoparticle, preparation method are as described below:
It precisely weighs the phosphodiesterase inhibitors of certain mass ratio and the mixture (gross mass 60g) of PLGA is dissolved in
In 200mL ethyl alcohol, oily phase is made in ultrasonic echography sufficiently dissolution in 2 minutes；Above-mentioned oil is mutually injected into concentration dropwise at 25 DEG C
In the 400mL polyvinyl alcohol water solution of 5mg/mL, to stir 2min under 2000rpm, first time lotion is formed；It again will be newborn for the first time
Liquid is injected into the 1000mL polyvinyl alcohol water solution that concentration is 5mg/mL, and 5 hours are stirred under 500rpm to organic solvent volatilization
Completely, second of lotion is formed；It is centrifuged 20 minutes, is washed with deionized 2 times under last 4000rpm.Grain is collected, at room temperature very
Sky dries 12 hours nanoparticles to get white, seals and is kept in dark place at 5 DEG C, spare.
All data relevant to the amount of nanoparticle of the present invention, represent the amount of phosphodiesterase inhibitors in nanometer.
The present invention is determined the partial size of preparation-obtained nanoparticle using scanning electron microscope, specifically originally
The average grain diameter for inventing the nanoparticle of preparation is 129nm ± 85nm.
The present invention determines the encapsulation rate of preparation-obtained nanoparticle using dialysis, specifically, prepared by the present invention
The encapsulation rate of nanoparticle is between 87.44%~91.47%.
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 by phosphodiesterase inhibitors nanoparticle, kinases inhibitor, diluent, profit
Lubrication prescription mixes to arrive the granule comprising kinases inhibitor Yu phosphodiesterase inhibitors nanoparticle.
The preparation method of capsule of the present invention is to inhibit phosphodiesterase inhibitors nanoparticle, protein kinase
After agent, diluent, mix lubricant, filling capsule is received to get to comprising kinases inhibitor and phosphodiesterase inhibitors
The capsule of the grain of rice.
The preparation method of tablet of the present invention be by phosphodiesterase inhibitors nanoparticle, kinases inhibitor,
After diluent, mix lubricant, tabletting is carried out to get to including kinases inhibitor and phosphodiesterase inhibitors nanoparticle
Tablet.
Kinases inhibitor and phosphodiesterase inhibitors nanoparticle in oral solid formulation of the present invention
Content and the dosage being thus related to can be carried out by pharmacological testing well known to those of ordinary skill in the art screening with
Optimization, the present invention is 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.
The antibacterial work of collaboration that 1 phosphodiesterase inhibitors nanoparticle (NaPDEI) of test example is combined with kinases inhibitor
With evaluation
Measure phosphodiesterase inhibitors nanoparticle, kinases inhibitor and di-phosphate ester respectively using filter paper enzyme
Bacteriostatic activity of the combined system of enzyme inhibitor nanoparticle and kinases inhibitor to various bacteria.Specifically, using liquid-transfering gun
Draw prepared bacterial suspension (1 × 105/ mL, preparation method: will be enterprising in slant tube culture medium for examination strain
Row activation [37 ± 1 DEG C, 3 days] recycles oese to beat easily a small amount of lawn from inclined-plane, is respectively added to be contained with 50mL sterile
In the conical flask of physiological saline), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.Sterilizing filter paper piece is taken,
It is let off in the tested material methanol solution of 6 kinds of concentration gradients respectively and impregnates 1h, the 6mm circular filter paper piece impregnated is attached to above-mentioned system
On good plate containing bacterium, each culture dish (diameter 90mm) sticks 3 dipped same mass concentration tested material methanol solutions
Filter paper (filter paper is spaced identical as far as possible), using 50% methanol solution as blank control.Processed plate containing bacterium is placed in
It is cultivated in 37 DEG C of insulating boxs for 24 hours, colony diameter is measured using crossing method, and calculate 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 phosphodiesterase inhibitors nanoparticle and kinases inhibitor when generating 30% inhibition, respectively
IC30(A)With IC30(B)Value.For drug combination, then with inhibiting rate (IR) to phosphodiesterase inhibitors nanoparticle in drug combination
Concentration (according to phosphodiesterase inhibitors meter) logarithm (log (c)) mapping, and carries out linear regression with Excel, according to time
Phosphodiesterase inhibitors nanoparticle concentration when equation being returned to extrapolate 30% inhibition in combined system, i.e. IC30(mixA), further according to
The molar ratio of phosphodiesterase inhibitors nanoparticle and kinases inhibitor in combined system, combination when extrapolating 30% inhibition
The concentration of kinases inhibitor, i.e. IC in system30(mixB)。
Phosphodiesterase inhibitors nanoparticle is calculated according to the following formula and is combined with protein kinase enzyme inhibitor inhibits various bacteriums
Drug combination index CI.
As CI < 1, synergistic effect is indicated, and the smaller representative synergistic effect of CI is stronger.
For the design of bacteriostatic test, the present invention is respectively provided with three kinds of phosphodiesterases for every kind of tested bacterium and inhibits
The combination of agent nanometer and three kinds of kinases inhibitor different mol ratios, each parameter of every kind of nanoparticle is fixed, such as 1 institute of table
Show.Cooperateing with bacteriostasis, the results are shown in Table 2
Table 1
Table 2
The preparation of particle of the embodiment 1 containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor
Prescription
Preparation method
It precisely weighs the phosphodiesterase inhibitors of certain mass ratio and the mixture (gross mass 60g) of PLGA is dissolved in
In 200mL ethyl alcohol, oily phase is made in ultrasonic echography sufficiently dissolution in 2 minutes；Above-mentioned oil is mutually injected into concentration dropwise at 25 DEG C
In the 400mL polyvinyl alcohol water solution of 5mg/mL, to stir 2min under 2000rpm, first time lotion is formed；It again will be newborn for the first time
Liquid is injected into the 1000mL polyvinyl alcohol water solution that concentration is 5mg/mL, and 5 hours are stirred under 500rpm to organic solvent volatilization
Completely, second of lotion is formed；It is centrifuged 20 minutes, is washed with deionized 2 times under last 4000rpm.Grain is collected, at room temperature very
Sky dries 12 hours nanoparticles to get white, seals and is kept in dark place at 5 DEG C, spare.
Take above-mentioned nanoparticle, the kinases inhibitor of recipe quantity, diluent, mix lubricant to get to comprising albumen
The granule of kinase inhibitor and phosphodiesterase inhibitors nanoparticle.
The preparation of capsule of the embodiment 2 containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor
Prescription
It precisely weighs the phosphodiesterase inhibitors of certain mass ratio and the mixture (gross mass 60g) of PLGA is dissolved in
In 200mL ethyl alcohol, oily phase is made in ultrasonic echography sufficiently dissolution in 2 minutes；Above-mentioned oil is mutually injected into concentration dropwise at 25 DEG C
In the 400mL polyvinyl alcohol water solution of 5mg/mL, to stir 2min under 2000rpm, first time lotion is formed；It again will be newborn for the first time
Liquid is injected into the 1000mL polyvinyl alcohol water solution that concentration is 5mg/mL, and 5 hours are stirred under 500rpm to organic solvent volatilization
Completely, second of lotion is formed；It is centrifuged 20 minutes, is washed with deionized 2 times under last 4000rpm.Grain is collected, at room temperature very
Sky dries 12 hours nanoparticles to get white, seals and is kept in dark place at 5 DEG C, spare.
Take above-mentioned nanoparticle, with recipe quantity kinases inhibitor, diluent, mix lubricant after, filling capsule to get
To the capsule comprising kinases inhibitor Yu phosphodiesterase inhibitors nanoparticle.
The preparation of tablet of the embodiment 3 containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor
It precisely weighs the phosphodiesterase inhibitors of certain mass ratio and the mixture (gross mass 60g) of PLGA is dissolved in
In 200mL ethyl alcohol, oily phase is made in ultrasonic echography sufficiently dissolution in 2 minutes；Above-mentioned oil is mutually injected into concentration dropwise at 25 DEG C
In the 400mL polyvinyl alcohol water solution of 5mg/mL, to stir 2min under 2000rpm, first time lotion is formed；It again will be newborn for the first time
Liquid is injected into the 1000mL polyvinyl alcohol water solution that concentration is 5mg/mL, and 5 hours are stirred under 500rpm to organic solvent volatilization
Completely, second of lotion is formed；It is centrifuged 20 minutes, is washed with deionized 2 times under last 4000rpm.Grain is collected, at room temperature very
Sky dries 12 hours nanoparticles to get white, seals and is kept in dark place at 5 DEG C, spare.
After taking above-mentioned nanoparticle and recipe quantity kinases inhibitor, diluent, mix lubricant, carry out tabletting to get
To the tablet comprising kinases inhibitor Yu phosphodiesterase inhibitors nanoparticle.
Claims (10)
1. a kind of composition containing phosphodiesterase inhibitors grain and kinases inhibitor, which is characterized in that described receives
The grain of rice contains phosphodiesterase inhibitors and poly lactose hydroxyacetic acid, phosphodiesterase inhibitors be selected from silaenafil, he reaches
Draw non-, Vardenafil, avanaphil), that is non-one of with roflumilast or its pharmaceutically acceptable salt or solvent on excellent ground
The solvate of object or pharmaceutically acceptable salt is closed, the kinases inhibitor is replaced selected from Abemaciclib, Ah method
Buddhist nun, Ah coming replace Buddhist nun, pazopanib, bosutinib, Brigatinib, plug it is auspicious for Buddhist nun, gram azoles for Buddhist nun, Dasatinib, Tarceva,
Gefitinib, her cloth cut down for Buddhist nun, Imatinib, Lapatinib, logical sequence and replace Buddhist nun, Pa Bai for Buddhist nun, nilotinib, Nintedanib, difficult to understand wish
Seeley, hydrochloric acid train one of azoles pa Buddhist nun, Rui Gefeini, ribociclib, Sorafenib and Sutent or it pharmaceutically may be used
The salt or solvate of receiving or the solvate of pharmaceutically acceptable salt.
2. composition according to claim 1, which is characterized in that the kinases inhibitor be selected from Abemaciclib,
Two maleic acid Afatinibs, hydrochloric acid Ah coming replace Buddhist nun, pazopanib, bosutinib, Brigatinib, plug it is auspicious for Buddhist nun, gram azoles for Buddhist nun,
Dasatinib monohydrate, erlotinib Hydrochloride, Gefitinib, her cloth replace Buddhist nun, imatinib mesylate, Lapatinib two to first
Benzene sulfonate monohydrate, methanesulfonic acid logical sequence are cut down difficult to understand for Buddhist nun, hydrochloric acid nilotinib monohydrate, ethanesulfonic acid Nintedanib, methanesulfonic acid
It is uncommon to be drawn for Buddhist nun, pa cypress Seeley, hydrochloric acid training azoles pa Buddhist nun, Rui Gefeini monohydrate, succinic acid ribociclib, p-methyl benzenesulfonic acid rope
One of non-Buddhist nun and Sunitinib malate.
3. composition according to claim 1, which is characterized in that the phosphodiesterase inhibitors are selected from citric acid west ground
One of that non-, Tadalafei, Vardenafil hydrochloric acid trihydrate, avanaphil, excellent that non-and roflumilast of ground.
4. composition according to claim 1, which is characterized in that the phosphodiesterase inhibitors and kinases inhibitor
Molar ratio is in (0.01~100): between 1.
5. composition according to claim 1, which is characterized in that the weight average molecular weight of the poly lactose hydroxyacetic acid is 10000
Between~200000.
6. composition according to claim 1, which is characterized in that lactose and hydroxyacetic acid rubs in the poly lactose hydroxyacetic acid
That ratio is between 50:50~85:15.
7. composition according to claim 1, which is characterized in that phosphodiesterase inhibitors and poly lactose hydroxyl in the nanoparticle
The mass ratio of guanidine-acetic acid is in 1:(1~10) between.
8. 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.
9. arbitrary composition according to claim 1~7 is preparing the purposes in the drug for treating bacterium infection.
10. purposes according to claim 9, which is characterized in that the bacterium be selected from Cedecea neteri, autochthonal cryptococcus,
Yersinia fredericksenii, streptococcus uberis, peptostreptococcus micros, Staphylococcus cohnis solution urea subspecies, Pasteur flora EF4, table
Skin brevibacterium, 2 type of smell sand thunder bacterium produce indoles Chryseobacterium sp, angstrom cut Pichia pastoris, Klebsiella Pneumoniae nose scleroma subspecies, nothing
Flowers and fruits sand thunder bacterium, light white latent ball yeast mitigate corynebacterium diphtheriae, yersinia enterocolitica, arcanobacterium haemolyticum, gauffer vacation
Silk yeast, III type of haemophilus influenzae, class clostridium septicum, Burkholderia cepacia, Aeromonas hydrophila group, Pan Shi it is mould,
Without one of malonic acid citric acid bacillus.
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| CN201811310073.5A CN109045300A (en) | 2018-11-04 | 2018-11-04 | Composition containing phosphodiesterase inhibitors nanoparticle and kinases inhibitor |
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Cited By (1)
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| CN112107582A (en) * | 2019-06-21 | 2020-12-22 | 长庚大学 | Pharmaceutical composition and use of libacillin for treating patients suffering from phosphodiesterase 4 mediated diseases |
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