CN108703960A - A kind of palonosetron sustained-release micro-spheres and preparation method thereof and application method - Google Patents
A kind of palonosetron sustained-release micro-spheres and preparation method thereof and application method Download PDFInfo
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Abstract
The invention discloses a kind of palonosetron sustained-release micro-spheres and preparation method thereof and application methods.The preparation that the palonosetron sustained-release micro-spheres are made of the active constituent and auxiliary material of following weight percentage：Palonosetron or its salt 0.1%~15% and pharmaceutically acceptable Biodegradable high-molecular polymer 85%~99.9%.Palonosetron sustained-release micro-spheres grain size of the present invention is at 100 μm hereinafter, syringeability is good；Single-dose can be one week with sustained release, compared with the palonosetron Hcl listing preparation that the existing next day of needing is administered, it is only necessary to single-dose, you can the therapeutic effect for maintaining one week is remarkably improved patient medication compliance.
Description
Technical field
The present invention relates to pharmaceutical reagent preparing technical field, more particularly to a kind of palonosetron sustained-release micro-spheres and its preparation
Method and application method.
Background technology
Chemotherapy neasea vomit refers to vomiting reaction caused by chemotherapy.It is reported that showing 3/4ths or more chemotherapy disease
The side reaction that will appear different degrees of Nausea and vomiting per capita seriously affects the quality of life of patients undergoing chemotherapy, reduces Chemotherapy in Patients
Compliance.In addition, chemotherapy neasea vomit can also result in, electrolyte balance imbalance, immune reduction, malnutritive, stress is burnt
Consider, further influences chemotherapeutic efficacy.Therefore it is the important hand for ensureing chemotherapy and being smoothed out to prevent and mitigate chemotherapy neasea vomit
One of section.The generation of vomiting and various neurotransmitters such as dopamine, histamine, acetylcholine, opiate and serotonin (5-
HT), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 etc. is closely related.5-HT3 receptor antagonist classes drug can by with the 5-HT3 on nervus visceralis and vagus nerve
Receptor Competition combines, and blocks the 5-HT of gastrointestinal tract chromaffin cell release to be combined with 5-HT3 receptors and causes Vagus-pressor responses emerging
It puts forth energy and generates vomiting reflex.
Palonosetron is second generation 5-HT3 receptor selective antagonists, high compared with the first generation with the affinity of 5-HT3 receptors
Dan Siqiong, Granisetron etc. are 30-100 times strong, plasma drug long half time up to 40 hours, control rate to acute nausea and vomiting and
The first generation is similar, but is substantially better than first generation 5-HT3 receptor selective antagonists to the control rate of delayed emesis.Pa Luonuosi
Fine jade is developed by MGI Pharma companies of Switzerland and affiliate Helsinn Healthcare earliest, obtains within 2003 FDA batches
Standard has been recommended as US National synthesis cancer network with palonosetron Hcl injection (trade name A Le happinesses) listing
(NCCN) antiemetic guide Triple therapy medication spits acute nausea caused by chemotherapy, vomiting for preventing moderate and severe cause.Although
Palonosetron significantly improves Delayed emesis therapeutic effect, but single-dose compared with first generation 5-HT3 receptor antagonists
The Delayed emesis therapeutic effect later to 2 days after chemotherapy is still bad.Therefore, palonosetron Hcl dosage regimen is to change at present
It treats the 1st, 3,5 day and is administered.But be injected intravenously and be administered with common hydrochloric acid Pa Luonuosi injections, patient's medication compliance is poor,
And easily cause apparent blood concentration peak valley phenomenon.Therefore, palonosetron Hcl is prepared into the long-acting injection that can be sustained,
Intramuscular injection or subcutaneous administrations 1 time before chemotherapy can significantly improve disease while ensureing that lag phase alleviates nausea and vomiting
People's compliance.
The country there is no the report of palonosetron long-acting injection at present, rarely seen about palonosetron slow-release transdermal patch
Report.Japan Patent international publication number WO2009/139411 on November 19 2009 International Publication day, discloses one kind and contains
The percutaneous absorption patch of palonosetron, the patent patch add sodium hydroxide in preparation process, easily lead to storage process
In there is crystalline deposit and irritation can be generated.China Patent Publication No. CN104069505, publication date are on October 1st, 2014,
Entitled palonosetron percutaneous absorption patch of innovation and creation and preparation method thereof, this application discloses one kind being sustained one
The palonosetron percutaneous absorption patch in week includes palonosetron by beta cyclodextrin, delays drug release and reduce stimulation
Property, but the transdermal patch percutaneous penetration is shown, at 3 days drug accumulation high percentage up to 61%~79%, early period drug
Discharge too fast, it is excessively high to easily lead to administration initial stage blood concentration, leads to serious adverse reaction.
Therefore, this field reduces administration frequency, obtains stable blood there is an urgent need for developing a kind of palonosetron long-acting injection
Concentration improves patient's compliance.
Invention content
The technical problem to be solved in the present invention is to provide one kind capable of reducing administration frequency, obtains stable blood concentration,
Improve palonosetron sustained-release micro-spheres of patient's compliance and preparation method thereof and application method.
In order to solve the above-mentioned technical problem, the technical scheme is that：
A kind of palonosetron sustained-release micro-spheres, include the ingredient of following weight percent：Pa Luonuo as active constituent
Take charge of fine jade or palonosetron salt 0.1%~15% and as adjunct ingredient Biodegradable high-molecular polymer 85%~
99.9%；The Biodegradable high-molecular polymer molecular weight is 1000~60000 dalton.The palonosetron is slow
It releases in microballoon, as long as steadily 5 days the above object of sustained release can be realized, the weight percent of palonosetron or its salt is not special
Limitation.But from the point of view of maintaining effective blood drug concentration prolonged enough, preferably palonosetron or its salt accounts for sustained release
The weight percent of microballoon is 0.1%~15%, further preferably 2%~10%, more preferable 2%~5%.If palonosetron or
Its salt weight percent is too low, same dosage, then needs the sustained-release micro-spheres amount injected excessive, and it is uncomfortable easily to increase patient；And
When palonosetron or its salt weight percent are excessively high, then it is too fast to be easy to cause primary drugs rate of release, and initial stage blood medicine is administered
Excessive concentration leads to the generation of adverse reaction.
Preferably, include the ingredient of following weight percent：Palonosetron or palonosetron as active constituent
Salt 2%~10% and Biodegradable high-molecular polymer 90%~98% as adjunct ingredient.
Preferably, the Biodegradable high-molecular polymer is Poly(D,L-lactide-co-glycolide, polycaprolactone, gathers
Carbonic ester, polylactic acid, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polylactic acid-hydroxyacetic acid block copolymer and
At least one of polyethylene glycol hydroxyacetic acid block copolymer；The Biodegradable high-molecular polymer molecular weight is
5000~30000 dalton.In the palonosetron sustained-release micro-spheres, as long as steadily 5 days the above object of sustained release can be realized,
The molecular weight of Biodegradable high-molecular polymer is not particularly limited.The molecular weight bigger degradation week of usual high molecular polymer
Phase is longer, and drug release period is also longer, but can be by the way that the high molecular polymers of two kinds or more different degradation cycles is added
Adjust drug releasing rate.However, to ensure that twice in dosing interval, high molecular polymer can be degradable, preferably high score
The molecular weight of sub- polymer material is 1000~60000 dalton, more preferable 5000~3000 dalton.The Pa Luonuosi
In fine jade sustained-release micro-spheres, as long as steadily 5 days the above object of sustained release can be realized, to the END CAPPED GROUP of Biodegradable high-molecular polymer
Group is not particularly limited.The end-capping group of usual high molecular polymer is carboxy blocking, hydroxy-end capped and ester sealing end, usual END CAPPED GROUP
Group's polarity is smaller, and degradation cycle is longer, and drug release period is also longer, but can be by the way that two kinds or more different END CAPPED GROUPs are added
The high molecular polymer of group or different molecular weight adjusts drug releasing rate.
Preferably, the grain size of the palonosetron sustained-release micro-spheres is at 100 μm or less.It has been investigated that palonosetron
On the one hand sustained-release micro-spheres grain size can influence drug releasing rate, on the other hand can influence syringeability and local inflammation reaction.Microballoon
Grain size is excessive, and drug release period is short；Syringeability is poor, needs the needle for injection for selecting internal diameter larger administration, administration process
Middle feeling of pain is strong.Microspherulite diameter is too small, and it is fast to go out phase drug releasing rate, and later stage release is slow；And after injecting, injection site is scorching
Disease significant reaction.Therefore, palonosetron sustained-release micro-spheres grain size of the present invention at 100 μm hereinafter, it is preferred that 50 μm or less.
A kind of preparation method of the palonosetron sustained-release micro-spheres, comprises the steps of：
(1) palonosetron or palonosetron salt have been dissolved in the Biodegradable high-molecular polymer
Solvent is configured to organic phase, and wherein the ratio between parts by weight of high molecular polymer and organic solvent are 4:100-50:100；
(2) high molecular weight water soluble polymer and acid-base modifier are dissolved in the water, are configured to water phase, wherein high water solubility
The ratio between parts by weight of Molecularly Imprinted Polymer and water are 0.1:100-14:100；The ratio between parts by weight of buffer salt and water are 0.1:
100-10:100；
(3) under high velocity agitation by the organic phase obtained by step (1), it is added into water phase, emulsification forms organic phase/water phase
The volume ratio of emulsion, wherein organic phase and water phase is 1:400-1:3；
(4) by the organic phase obtained by step (3)/water phase emulsion, organic solvent is removed, solidified microsphere suspension is obtained；
(5) it by step (4) thus obtained microsphere suspension, centrifuges, it is slow to be dried to obtain the palonosetron for deionized water washing
Release microballoon.
Preferably, the organic solvent of the step (1) is ether, petroleum ether, ethyl acetate, chloroform, dichloromethane, benzene first
At least one of alcohol, ethyl alcohol, isopropanol, propylene glycol, acetone, methanol, acetonitrile, dimethyl sulfoxide (DMSO) and dimethylformamide.
Preferably, the high molecular weight water soluble polymer of the step (2) is polyvinyl alcohol, polysorbate, poloxamer, carboxylic
At least one of sodium carboxymethylcellulose pyce, polyethylene pyrrole network alkanone and hydroxypropyl cellulose.
Preferably, the acid-base modifier of the step (2) is phosphoric acid, phosphate, acetic acid, acetate, citric acid, citric acid
At least one of salt, boric acid, borate, sodium hydroxide, hydrochloric acid and trishydroxymethylaminomethane.
A kind of application method of the palonosetron sustained-release micro-spheres, the palonosetron sustained-release micro-spheres are configured to mix
Outstanding injection, required object is administered to by injection system by the suspension injection.
Preferably, the injection system is injection in hypodermic injection, intramuscular injection, intracutaneous injection or abdomen.
The palonosetron sustained-release micro-spheres after drying, can be dispensed directly according to dosage, sterile powder for injection is made
End is prepared into suspension using preceding with injection physiological saline or the aqueous solution for injection containing suspending agent, isotonic agent is suspended uniform
Injection.
The palonosetron sustained-release micro-spheres after drying, can in microballoon the isotonic agent of mixture specified amount, stabilization
Agent etc. dispenses according still further to dosage, is prepared into injection sterile powder, is suspended uniformly with water for injection using preceding, is prepared into suspension
Injection.
Sustained-release micro-spheres suspension first can according to dosage be dispensed and is lyophilized again, uses by the palonosetron sustained-release micro-spheres
It is preceding with injection physiological saline or the aqueous solution for injection containing suspending agent, isotonic agent is suspended uniform, be prepared into suspension injection.
Using above-mentioned technical proposal, (1) present invention contains palonosetron or its salt in biodegradable macromolecule
In polymer, drug can slow release 7 days, drug releasing rate is steady, and Zero order release is presented.After single-dose, it can maintain flat
Steady blood concentration 7 days, inside and outside is without burst release or the characteristics of sustained release；(2) palonosetron provided by the present invention is slow
Release microballoon, compared with common palonosetron hydrochloride for injection, administration number of times by the next day be administered once, be administered three times within 7 days, reduce
It was administered once for 7 days, is remarkably improved patient compliance；(3) preparation of palonosetron sustained-release micro-spheres provided by the present invention
Method, be oil in water emulsion-solvent evaporation method, to the encapsulation rate of water soluble drug palonosetron or its salt be up to 70% with
On.Consolidate emulsion-compared with the common W/O/W emulsion-solvent evaporation method of other water-soluble drug sustained-release microspheres institute, oil-in-water packet
Solvent evaporation method or complex coacervation, preparation process is simpler, is easy to industrialized production；(4) palonosetron of the invention sustained release
Microballoon can be used to prevent height and cause to spit acute nausea caused by chemotherapy, vomiting, and prevents moderate cause and spit nausea caused by chemotherapy, vomit
It spits.
Description of the drawings
Fig. 1 is with reference to the palonosetron sustained-release micro-spheres of 1 the method for embodiment preparation and with reference to 2 the method for comparative example
The grain size distribution of the palonosetron sustained-release micro-spheres of preparation；
Fig. 2 is the electronic scanner microscope figure of the palonosetron sustained-release micro-spheres prepared with reference to 1 the method for embodiment.
The palonosetron sustained-release micro-spheres of Fig. 3 reference 1 the method for embodiment preparations, reference 1 the method system of comparative example
Standby palonosetron hydrochloride for injection and the palonosetron sustained-release micro-spheres that prepare with reference to 2 the method for comparative example are in 10mM phosphorus
Drug accumulation releasing curve diagram (mean ± SD, n=3) in phthalate buffer (pH7.4).
The palonosetron sustained-release micro-spheres of Fig. 4 reference 1 the method for embodiment preparations, reference 1 the method system of comparative example
Standby palonosetron hydrochloride for injection and the palonosetron sustained-release micro-spheres that prepare with reference to 2 the method for comparative example are in 10mM phosphorus
Drug accumulation releasing curve diagram (mean ± SD, n=3) in phthalate buffer (pH7.4).
Fig. 5 is slow in 10mM phosphate with reference to palonosetron sustained-release micro-spheres prepared by 10 the method for embodiment 6- embodiments
Drug accumulation releasing curve diagram (mean ± SD, n=3) in fliud flushing (pH7.4).
Palonosetron sustained-release micro-spheres prepared by 15 the method for Fig. 6 reference embodiment 11- embodiments are in 10mM phosphate
Drug accumulation releasing curve diagram (mean ± SD, n=3) in buffer solution (pH7.4).
Palonosetron sustained-release micro-spheres prepared by 20 the method for Fig. 7 reference embodiment 16- embodiments are in 10mM phosphate
Drug accumulation releasing curve diagram (mean ± SD, n=3) in buffer solution (pH7.4).
Fig. 8 with reference to 1 the method for embodiment prepare palonosetron sustained-release micro-spheres (dosage 0.135mg/kg), with reference to right
1 the method for ratio prepare palonosetron hydrochloride for injection (dosage 0.045mg/kg) and with reference to 2 the method for comparative example
Palonosetron blood plasma of the palonosetron sustained-release micro-spheres (dosage 0.135mg/kg) of preparation after rat is given in intramuscular injection
Concentration time curve figure (mean ± SD, n=6).
Specific implementation mode
The specific implementation mode of the present invention is described further below in conjunction with the accompanying drawings.It should be noted that for
The explanation of these embodiments is used to help understand the present invention, but does not constitute limitation of the invention.In addition, disclosed below
The each embodiment of the present invention in involved technical characteristic can be combined with each other as long as they do not conflict with each other.
Embodiment 1
Under the conditions of 4 DEG C, by 0.05g palonosetron Hcls, the polylactic acid-glycolic that 1.5g molecular weight is 15000 dalton
Acetic acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension
Centrifugation, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.
Properties evaluations
The palonosetron sustained-release micro-spheres that 0.01g is prepared are weighed, 2ml is scattered in and contains 0.2% (w/v) polyoxyethylene sorbitan monoleate
Aqueous solution in, be uniformly dispersed.It takes appropriate suspension in particle size determination instrument, particle diameter distribution is measured using laser diffractometry.It adopts
With its drugloading rate of high effective liquid chromatography for measuring, computational envelope rate；And observe its form using scanning electron microscope.
As shown in Figure 1, which is 8~60 μm, is evenly distributed.Encapsulation rate
Up to 81.2%.As shown in Figure 2, the palonosetron sustained-release micro-spheres surface is smooth, and roundness is high, no microsphere breakage phenomenon.
Embodiment 2
Under the conditions of 4 DEG C, 0.15g palonosetron Hcls, the polylactic acid that 1.5g molecular weight is 10000 dalton are dissolved in
In 20ml dichloromethane, it is prepared into organic phase.8g polyvinyl alcohol is dissolved in 800ml water, water phase is prepared into.3000 turns/
Under minute high-speed stirred, organic phase is quickly adding into water phase, 3000 revs/min of high-speed stirreds 3 minutes.3 are stirred at 25 DEG C
Hour, dichloromethane is removed, microsphere suspension is obtained.Microsphere suspension is centrifuged, washing three times, is freeze-dried to get Pa Luonuo
Take charge of fine jade sustained-release micro-spheres.The palonosetron sustained release that the present embodiment is prepared is observed according to performance test methods in embodiment 1
Microspherulite diameter range is at 5~70 μm, encapsulation rate 72.1%.
Embodiment 3
It is under the conditions of 4 DEG C, 0.15g palonosetron Hcls, 1.5g molecular weight is molten for the polycaprolactone of 15000 dalton
In the in the mixed solvent of 18ml dichloromethane and 2ml benzyl alcohols, it is prepared into organic phase.6g polyvinyl alcohol is dissolved in 600ml water
In, it is prepared into water phase.Under 3000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 3000 revs/min of height
Speed stirring 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.Microsphere suspension is centrifuged, washing three
It is secondary, it is freeze-dried to get palonosetron sustained-release micro-spheres.The present embodiment system is observed according to performance test methods in embodiment 1
Standby obtained palonosetron sustained-release micro-spheres particle size range is at 5~80 μm, encapsulation rate 70.2%.,
Embodiment 4
It is under the conditions of 4 DEG C, 0.15g palonosetron Hcls, 1.5g molecular weight is molten for the makrolon of 20000 dalton
In the in the mixed solvent of 18ml dichloromethane and 2ml benzyl alcohols, it is prepared into organic phase.4g polyvinyl alcohol and 2g sodium acetates are dissolved
In 400ml water, it is prepared into water phase.Under 3000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 3000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
The palonosetron sustained-release micro-spheres particle size range that embodiment is prepared is at 10~90 μm, encapsulation rate 80.1%.
Embodiment 5
Under the conditions of 4 DEG C, by 0.1g palonosetron Hcls, the polylactic acid-glycolic base that 1.2g molecular weight is 30000 dalton
Acetate multipolymer and the Poly(D,L-lactide-co-glycolide that 0.3g molecular weight is 5000 dalton are dissolved in 20ml dichloromethane,
It is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in 1000ml water, water phase is prepared into.5000 turns/
Under minute high-speed stirred, organic phase is quickly adding into water phase, 5000 revs/min of high-speed stirreds 3 minutes.3 are stirred at 25 DEG C
Hour, dichloromethane is removed, microsphere suspension is obtained.Microsphere suspension is centrifuged, washing three times, is freeze-dried to get Pa Luonuo
Take charge of fine jade sustained-release micro-spheres.The palonosetron sustained release that the present embodiment is prepared is observed according to performance test methods in embodiment 1
10~80 μm of microspherulite diameter range, encapsulation rate 85.1%.
Embodiment 6
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.01g palonosetrons and 1.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
8-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 82.5%.
Embodiment 7
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.10g palonosetrons and 1.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 81.9%.
Embodiment 8
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.15g palonosetrons and 1.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
2-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 78.2%.
Embodiment 9
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.20g palonosetrons and 1.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-70 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 75.6%.
Embodiment 10
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.22g palonosetrons and 1.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
4-65 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 73.1%.
Embodiment 11
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.017g palonosetrons and 0.5g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-30 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 85.3%.
Embodiment 12
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.034g palonosetrons and 1.0g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-40 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 84.9%.
Embodiment 13
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.068g palonosetrons and 2.0g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 85.9%.
Embodiment 14
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.17g palonosetrons and 5.0g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-70 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 83.8%.
Embodiment 15
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.34g palonosetrons and 10.0g molecular weight are 1000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g disodium hydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
10-90 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 86.9%.
Embodiment 16
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.05g palonosetrons and 1.5g molecular weight are 10000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g sodium dihydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 80.1%.
Embodiment 17
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.05g palonosetrons and 1.5g molecular weight are 10000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 2.5g sodium dihydrogen phosphates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 82.1%.
Embodiment 18
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.05g palonosetrons and 1.5g molecular weight are 10000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g sodium citrates are dissolved in
In 1000ml water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000
Rev/min high-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.By microsphere suspension from
The heart, washing three times, are freeze-dried to get palonosetron sustained-release micro-spheres.This is observed according to performance test methods in embodiment 1
5-60 μm of the palonosetron sustained-release micro-spheres particle size range that embodiment is prepared, encapsulation rate 79.8%.
Embodiment 19
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.05g palonosetrons and 1.5g molecular weight are 10000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g sodium acetates are dissolved in 1000ml
In water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000 revs/min
High-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.Microsphere suspension is centrifuged, is washed
Three times, freeze-drying is to get palonosetron sustained-release micro-spheres.The present embodiment is observed according to performance test methods in embodiment 1
5-60 μm of palonosetron sustained-release micro-spheres particle size range being prepared, encapsulation rate 83.0%.
Embodiment 20
Under the conditions of 4 DEG C, by the polylactic acid-glycolic base second that 0.05g palonosetrons and 1.5g molecular weight are 10000 dalton
Acid copolymer is dissolved in 20ml dichloromethane, is prepared into organic phase.10g polyvinyl alcohol and 5g Boratexes are dissolved in 1000ml
In water, it is prepared into water phase.Under 5000 revs/min of high-speed stirreds, organic phase is quickly adding into water phase, 5000 revs/min
High-speed stirred 3 minutes.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.Microsphere suspension is centrifuged, is washed
Three times, freeze-drying is to get palonosetron sustained-release micro-spheres.The present embodiment is observed according to performance test methods in embodiment 1
5-60 μm of palonosetron sustained-release micro-spheres particle size range being prepared, encapsulation rate 82.1%.
Comparative example 1：0.25g palonosetron Hcls are dissolved in 100ml waters for injection, filtration sterilization is to get hydrochloric acid
Injection of palonosetron.
Comparative example 2：Under the conditions of 4 DEG C, 0.05g palonosetron Hcls are dissolved in 2ml water, as inner aqueous phase W1.It will
1.5g molecular weight is that the Poly(D,L-lactide-co-glycolide of 10000 dalton is dissolved in 20ml dichloromethane, is prepared into organic phase
O.10g polyvinyl alcohol is dissolved in 1000ml water, outer aqueous phase W is prepared into2.It, will be interior under 12000 revs/min of high-speed stirreds
Water phase adds in organic phase rapidly, high-speed stirred 3 minutes, forms inner aqueous phase W1/ organic phase O breasts.By gained inner aqueous phase W1/ organic
Phase O breasts are quickly adding into outer aqueous phase W2In, 5000 revs/min of high-speed stirreds 3 minutes form inner aqueous phase W1/ organic phase O/ outer aqueous phases
W2Emulsion.It is stirred 3 hours at 25 DEG C, removes dichloromethane, obtain microsphere suspension.Microsphere suspension is centrifuged, washing is three times, cold
It is lyophilized dry to get palonosetron sustained-release micro-spheres.1~20 μm of particle size range, gained grain size distribution is as shown in Figure 1.With implementation
Example 1- embodiments 20 are compared, and particle diameter distribution is uneven.It is only 21.2% to measure encapsulation rate, far below embodiment 1- embodiments 20
Encapsulation rate (>70%).
Embodiment 21
Palonosetron sustained-release micro-spheres properties evaluations
It is accurate respectively to weigh the palonosetron sustained-release micro-spheres being prepared in 10mg embodiment 1- embodiments 20, comparative example
The palonosetron sustained-release micro-spheres being prepared in the palonosetron hydrochloride for injection and comparative example 2 that are prepared in 1, respectively
It is added in the test tube containing 2ml dissolution mediums (10mM pH7.4 phosphate buffer solutions), in 37 DEG C, 100rpm shaking baths
Oscillation was sampled respectively at 2h, 12h, 1,2,3,4,5,6,7 days, and 8000rpm centrifuges 5min, takes out all supernatants, mends simultaneously
Equivalent fresh dissolution medium is filled, after persistent oscillation.Using palonosetron concentration in high effective liquid chromatography for measuring dissolution medium, and
Accumulation dissolution is calculated, drug release patterns are drawn.Drug release patterns figure is as shown in Fig. 3-Fig. 7.
Fig. 3 is shown, compared with comparative example 1 and comparative example 2, the palonosetron sustained-release micro-spheres drug prepared by embodiment 1
Rate of release is slower, and nearly Zero order release is presented.Fig. 4-Fig. 7 display, the palonosetron prepared by embodiment 1- embodiments 20
Sustained-release micro-spheres can uniform speed slow release drug 6 days or more.
Embodiment 22
The rat Internal pharmacokinetics of palonosetron sustained-release micro-spheres are evaluated
18 SD rats are taken, male, weight (200 ± 20) g, Southern Yangtze University's Experimental Animal Center provides, and sets experimental situation
After raising 4 days, 3 groups are randomly divided into, every group 6, fasting 12h before testing, is joined respectively at rat right rear leg injection 0.135mg/kg
Palonosetron sustained-release micro-spheres (A groups), the 0.045mg/kg prepared according to 1 the method for the present embodiment is square with reference to described in comparative example 1
The Pa Luonuo that palonosetron hydrochloride for injection (B groups) and 0.135mg/kg prepared by method is prepared with reference to 2 the method for comparative example
Take charge of fine jade sustained-release micro-spheres (C groups).0.25,0.5,1,2,4,6,8 and 12h, 1,2,3,4,5,6 and 7 are day by eye socket after administration
Rear vein beard takes blood about 0.3mL, sets in the 1.5mL points bottom centrifuge tube of advance test tube of hepari, 4000rpm centrifugation 10min, in absorption
Layer blood plasma is to be measured in -80 DEG C of preservations.
Plasma sample processing：Precision takes 100 μ L of plasma sample in 7ml centrifuge tubes, and saturated sodium bicarbonate solution 100 is added
Ethyl acetate 3mL is added in μ L, vortex mixing, and vortex 10min, 4000rpm centrifuge 10min.It takes in supernatant to 5mL centrifuge tubes,
Air stream dries up, to be measured in -20 DEG C of preservations.200 μ L methanol are added before measuring, vortex 5min, 12000rpm centrifugation 10min takes
Supernatant measures blood concentration using ultra high efficiency liquid chromatography mass spectrometric combined instrument.Each administration group blood concentration-time curve such as Fig. 8 institutes
Show.
Fig. 8 is shown, is given greatly through intramuscular injection with reference to palonosetron hydrochloride for injection prepared by 1 the method for comparative example
After mouse at 15 minutes, blood concentration is up to 156.1ng/mL, and subsequent blood concentration declines rapidly, and blood concentration is only at 2 days
1.2ng/mL is less than lower limit of quantitation, no slow releasing function after 4 days.The palonosetron sustained release prepared with reference to 2 the method for comparative example
Microballoon is after rat is given in intramuscular injection at 15 minutes, and blood concentration is reduced to 76.2ng/mL, and blood concentration drops to after 5 days
5ng/mL hereinafter, have certain slow releasing function, but can only be sustained 5 days in vivo.It is prepared with reference to 1 the method for the present embodiment
Palonosetron sustained-release micro-spheres are after rat is given in intramuscular injection at 15 minutes, and blood concentration is only 12.1ng/mL, substantially less than
Comparative example 1 and comparative example 2, being expected to, which reduces common palonosetron hydrochloride for injection, draws at administration initial stage since blood concentration is excessively high
The toxic side effect risen；Blood concentration is still maintained at 5ng/mL or more when being administered 7 days, has apparent slow releasing function.The above results
Show that the palonosetron sustained-release micro-spheres prepared by the present invention can be sustained 7 days in vivo, and there is stable blood concentration, has
It hopes and reduces administration number of times, realize single-dose, you can the therapeutic effect for maintaining 7 days is expected to obviously improve patient medication compliance.
Embodiments of the present invention are explained in detail above in association with attached drawing, but the present invention is not limited to described implementations
Mode.For a person skilled in the art, in the case where not departing from the principle of the invention and spirit, to these embodiments
A variety of change, modification, replacement and modification are carried out, are still fallen in protection scope of the present invention.
Claims (10)
1. a kind of palonosetron sustained-release micro-spheres, it is characterised in that：Include the ingredient of following weight percent：As active constituent
Palonosetron or palonosetron salt 0.1%~15% and the Biodegradable high-molecular polymer as adjunct ingredient
85%~99.9%；The Biodegradable high-molecular polymer molecular weight is 1000~60000 dalton.
2. palonosetron sustained-release micro-spheres according to claim 1, it is characterised in that：Including following weight percent at
Point：As the palonosetron or palonosetron salt 2%~10% of active constituent and as the biodegradable of adjunct ingredient
High molecular polymer 90%~98%.
3. the palonosetron sustained-release micro-spheres according to claim 1 or claim 2, it is characterised in that：The biology can
Degraded macromolecular polymer is Poly(D,L-lactide-co-glycolide, polycaprolactone, makrolon, polylactic acid, polyethylene glycol
Lactic acid block copolymer, polyethylene glycol-polylactic acid-hydroxyacetic acid block copolymer and polyethylene glycol hydroxyacetic acid block are total
At least one of polymers；The Biodegradable high-molecular polymer molecular weight is 5000~30000 dalton.
4. the palonosetron sustained-release micro-spheres according to claim 1 or claim 2, it is characterised in that：The Pa Luonuo
The grain size of fine jade sustained-release micro-spheres is taken charge of at 100 μm or less.
5. a kind of preparation method according to any palonosetron sustained-release micro-spheres of claim 1-4, it is characterised in that：Packet
Containing following steps：
(1) palonosetron or palonosetron salt are dissolved in the Biodegradable high-molecular polymer organic molten
Agent is configured to organic phase, and wherein the ratio between parts by weight of high molecular polymer and organic solvent are 4:100-50:100；
(2) high molecular weight water soluble polymer and acid-base modifier are dissolved in the water, are configured to water phase, wherein water soluble polymer
The ratio between parts by weight of polymer and water are 0.1:100-14:100；The ratio between parts by weight of buffer salt and water are 0.1:100-
10:100；
(3) under high velocity agitation by the organic phase obtained by step (1), it is added into water phase, emulsification forms organic phase/water phase breast
The volume ratio of agent, wherein organic phase and water phase is 1:400-1:3；
(4) by the organic phase obtained by step (3)/water phase emulsion, organic solvent is removed, solidified microsphere suspension is obtained；
(5) it by step (4) thus obtained microsphere suspension, centrifuges, deionized water washing, it is micro- to be dried to obtain the palonosetron sustained release
Ball.
6. the preparation method of palonosetron sustained-release micro-spheres according to claim 5, it is characterised in that：The step (1)
Organic solvent be ether, petroleum ether, ethyl acetate, chloroform, dichloromethane, benzyl alcohol, ethyl alcohol, isopropanol, propylene glycol, third
At least one of ketone, methanol, acetonitrile, dimethyl sulfoxide (DMSO) and dimethylformamide.
7. the preparation method of palonosetron sustained-release micro-spheres according to claim 5, it is characterised in that：The step (2)
High molecular weight water soluble polymer be polyvinyl alcohol, polysorbate, poloxamer, sodium carboxymethylcellulose, polyethylene pyrrole network alkane
At least one of ketone and hydroxypropyl cellulose.
8. the preparation method of palonosetron sustained-release micro-spheres according to claim 5, it is characterised in that：The step (2)
Acid-base modifier be phosphoric acid, phosphate, acetic acid, acetate, citric acid, citrate, boric acid, borate, sodium hydroxide, salt
At least one of acid and trishydroxymethylaminomethane.
9. a kind of application method according to any palonosetron sustained-release micro-spheres of claim 1-4, it is characterised in that：It will
The palonosetron sustained-release micro-spheres are configured to suspension injection, the suspension injection is administered to by injection system needed for
Object.
10. the application method of palonosetron sustained-release micro-spheres according to claim 9, it is characterised in that：The injection side
Formula is injection in hypodermic injection, intramuscular injection, intracutaneous injection or abdomen.
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| CN114867470A (en) * | 2019-11-08 | 2022-08-05 | 丸仁制药株式会社 | Microspheres for sustained release and method of making same |
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