CN109806242A - A kind of Risperidone microsphere preparation and preparation method thereof - Google Patents
A kind of Risperidone microsphere preparation and preparation method thereof Download PDFInfo
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- CN109806242A CN109806242A CN201910100427.1A CN201910100427A CN109806242A CN 109806242 A CN109806242 A CN 109806242A CN 201910100427 A CN201910100427 A CN 201910100427A CN 109806242 A CN109806242 A CN 109806242A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 229960001534 risperidone Drugs 0.000 title claims abstract description 42
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 239000004005 microsphere Substances 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 238000010348 incorporation Methods 0.000 claims description 4
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- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
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- 238000001291 vacuum drying Methods 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical group FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
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- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of Risperidone microsphere preparations and preparation method thereof, the preparation method includes that Risperidone is dissolved in a kind of good dissolubility organic solvent by (1), PLGA is dissolved in another effumability organic solvent, after two kinds of solution dissolve respectively, it remixes stirring and forms homogeneous phase solution, the homogeneous phase solution end viscosity is 150~350cp；(2) homogeneous phase solution described in step (1) is fed to the cup-like containers at rotating-table apparatus center, feed liquid in cup-like containers crosses rim of a cup, the dish-shaped turntable in outside is hit under gravitational and centrifugal forces is dispersed into droplet, the droplet of formation continues to hit more lateral dish turntable, after acting on twice or repeatedly, the droplet turntable that flies out is formed by curing microballoon.The microball preparation slow-release capability that this method obtains is prominent, it is not necessary that additional release regulator is added, is sustained the phase up to 1~3 month.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of Risperidone microsphere preparation and preparation method thereof.
Background technique
Schizophrenia is a kind of common great phrenoblabia class disease.As social rhythm constantly accelerates, Ren Mensuo
It faces economic pressures and mental burden is increasing, it is multi-party that more and more patients form consciousness, thinking, emotion, behavior etc.
Face obstacle, the result is that psychic problems are increasingly prominent.Schizophrenia is mainly in person between twenty and fifty, according to the statistics of the World Health Organization, the whole world
Prevalence of schizophrenia is about 3.8 ‰~8.4 ‰, and lifetime prevalence is up to 13 ‰.Once suffering from schizophrenia, patient
It needs to take drugs all the life.
Antipsychotic drug can efficiently control schizoid mental symptom.Discovery the 1950s
Common antipsychotics, such as chlorpromazine or haloperidol are central dopamine D2 receptor blocking pharmacon, to schizophrenia sun
Property symptom it is effective but invalid to negative symptoms and Cognitive function damage, can also cause extrapyramidal motor obstacle, to cardiovascular and
Hepatotoxicity is larger, and with many adverse reactions.
To overcome drawbacks described above, atypical antipsychotic of new generation is born therewith, and Risperidone is in 1984 by Billy
When Janssen Pharmaceutica exploitation, compensate for the obvious shortcoming of classical antipsychotic object.Risperidone is with unique properties
Selective cholamine retarding agent all has very high affinity with 2 receptor of serotonin and d2 dopamine receptor.Risperidone is improving
There is good curative effect in terms of positive, negative symptoms and cognitive function, it is less or extrapyramidal system (EPS) will not be caused bad anti-
It answers, almost without side effect, without cooperating anticholinergic agent to use；The tolerance and compliance for the treatment of are preferable.Risperidone is main
It is metabolized through cytochrome P 4502 D 6 enzyme access, active metabolite is paliperidone, and the two collectively forms anti-spirit point
Split disease effective component.
Risperidone general formulation includes tablet, oral solution, capsule, drops etc..But for general formulation, patient is usual
It must take medicine on time daily, once a day even multiple administration frequency on the one is very difficult for 75% mental patient
's.Compliance is bad, misses and refuses medication object, even interrupts treatment, will lead to that sb.'s illness took a turn for the worse, is to cause Patients on Recurrence and be hospitalized again
The main reason for.
Therefore exploitation Risperidone long-acting slow-release preparation reduces administration number of times, and improving patient compliance has great clinic
Meaning and economics meaning.The injection Risperidone preparation Risperidal clinically used at present(Chinese name:
Permanent moral), the listing of in August, 2002 is developed in by Alkermes company.The product uses Medisorb medicine controlled releasing technology, and benefit is trained
Ketone is encapsulated in the PLGA that molecular weight is 150,000, is suspended in dedicated solvent, and by intramuscular injection, applies one every 2 weeks
It is secondary, reduce administration number of times.But there are the lag phases of drug release at first 3 weeks for said preparation, a small amount of drug were only discharged, with microballoon
Skeleton degradation, the 4th~6 week quick release.Therefore, patient is while first 3 weeks injection medicines, it is also necessary to oral Risperidone tablet
Reach therapeutic effect, adjust dosage after 3 weeks again, clinical use is inconvenient, and patient compliance is still poor.Furthermore the product
Microballoon is prepared using emulsification and extraction method, oil phase solvent is used as using binary organic solvent (benzyl alcohol/ethyl acetate), passes through static state
Mixer miscella water phase, will also be subjected to solvent extraction, and washing, twice drying process, can just effectively remove residual solvent twice.
Preparation procedure is relatively complicated, and leads to the higher reason of its cost and price, and the limited patient of economic condition is difficult to receive,
Also limit its extension process.The product has selected the PLGA of up to 150,000 molecular weight as pharmaceutical carrier, but in addition to preceding 3
There is the lag phase in longer stage in week, the quick release phase is also more of short duration, is attributed to the limitation of its microsphere preparation technology.
For the defect for improving above-mentioned microball preparation, Risperidone of scientific research personnel's active development without the release lag phase is long-acting micro-
Ball.The most common method for preparing microsphere is emulsion-solvent evaporation method or emulsified solvent extraction, although this method principle and device
Simple structure, but Workshop Production complex steps, more intermittently operated, technique reproducibility official post are difficult to be mass produced, and due to outer
The presence of water phase and surfactant, microballoon drugloading rate, encapsulation rate are lower, the danger that the oriented outer aqueous phase of drug is come down in torrents, and rely on
The droplet size that shearing force generates is uneven, and microspherulite diameter distribution is wide, can only remove selection target partial size by later period screening, increase
Production cost.
Droplet is formed in the liquid phase there are certain drawbacks, i.e. drug will receive the influence of interfacial tension or follow solvent phase
, to increase drug loss, drug can not be made as the removal of organic solvent is easy to spread to continuous phase like compatibility principle
Encapsulation efficiency reaches absolutely.In addition, the preparation of microballoon generally requires largely to use organic solvent in liquid-phase system, have
Solvent not only has certain toxicity, while also will affect the stability of microballoon, reduces microballoon glass transition temperature, accelerates
Microballoon degradation speed.
Droplet is formed in the gas phase and is just able to solve the above problem, and spining disk method is droplet formation technology in a kind of gas phase, is
Make to disperse solution atomization formation droplet using high-speed rotating turntable, volatilizes organic solvent to generate solia particle.It is higher
Oily phase concentration reduces the usage amount of organic solvent, and interfacial tension is larger in air for high concentration oil droplet, very easy holding ball
Shape, and drug is not easy to be diffused into gas phase, if enabling high concentration feed liquid uniformly, to be continuously crushed using a kind of physical force, that
Production efficiency can not only be improved, while reducing production cost.
But current rotating-table apparatus is not ideal enough, and droplet generating device used in CN 101816913 has similar turn
The structure of disk, but need uniformly to add to mixed liquor the center of rotating compact disc, otherwise it is impossible to ensure that drop uniformly divides
Dissipate all directions in disk, and disk is horizontal disk, the resistance that droplet is subject to is smaller, therefore droplet freedom of motion compared with
Greatly, it is easy discontinuity, therefore this obtains the inadequate rounding of microballoon appearance using the patented method.If it is highly viscous feed liquid,
Depend alone planar disc the dispersion of high speed centrifugation power be it is far from being enough, even with the revolving speed of superelevation, also not to equipment protection
Benefit.
Summary of the invention:
In view of the above deficiencies, the present invention provides a kind of Risperidone microsphere preparation and preparation method thereof, uses in preparation method
Rotating-table apparatus, rotating-table apparatus of the invention just can overcome above-mentioned drawback, using high-speed rotating cup-like containers, give high concentration
Feed liquid accelerates, and after feed liquid has certain acceleration, goes to hit the dish-shaped disc surfaces in outside, feed liquid is made to be dispersed into uniform drop,
Continue that drop is accelerated to hit more lateral dish disc surfaces, after one or many effects, the droplet of formation flies out dish-shaped turn
Disk is formed by curing microballoon." fluid drying " is changed into " in gas dry " mode by increasing oil phase viscosity by the present invention, using turn
Highly viscous oil droplet is crushed to rapidly target grain size by disk device, even if oil phase viscosity is higher (> 200cp), microballoon is sphere
Form does not have filamental object.Then it is precisely controlled air temperature and current mode, effectively removes organic solvent.With " fluid drying "
Mode is compared, and this method prepares microballoon encapsulation efficiency with higher and microballoon yield, extremely low residual solvent and is obviously improved
Dispersibility.
To realize the above purposes, the technical scheme adopted is as follows: a kind of preparation method of Risperidone microsphere preparation,
The following steps are included:
(1) Risperidone is dissolved in a kind of good dissolubility organic solvent, PLGA, which is dissolved in another effumability, to be had
In solvent, after two kinds of solution dissolve respectively, remixing stirring and form homogeneous phase solution, the homogeneous phase solution end viscosity is 150~
350cp；
(2) homogeneous phase solution described in step (1) is fed to the cup-like containers at rotating-table apparatus center, the feed liquid in cup-like containers
Rim of a cup is crossed, the dish-shaped turntable in outside is hit under gravitational and centrifugal forces and is dispersed into droplet, the droplet of formation continues to hit
More lateral dish turntable, after acting on twice or repeatedly, the droplet turntable that flies out is formed by curing microballoon.
Preferably, the rotating-table apparatus be turntable structure, the turntable structure be provided centrally with cup-like containers and its
Driving device, successively nested at least two layers of butterfly turntable, each layer of butterfly turntable are each equipped with corresponding drive in cup-like containers outside
Dynamic device.
Preferably, the cup-like containers are up-narrow and down-wide slot cup-like containers, and the cup-like containers and its outside
Butterfly turntable all have smooth neighboring.
Preferably, the minor axis of cup-like containers is set as D1, and major diameter D2 is highly H1, and wherein the ratio of D1 and D2 is 1/2
~2/3.
Preferably, the internal diameter of first layer butterfly turntable is set as D3, is highly H3, and the internal diameter of second layer butterfly turntable is
D4 is highly H4, and so on；The ratio that wherein D3 and H3 ratio are 1.5~2.0, H3 and H1 is 2.5~3.0.
Preferably, the ratio that D4/H4 is arranged is less than D3/H3, to obtain stronger secondary impact effect.
Preferably, in the step (2) cup-like containers revolving speed be 10~150m/s, outside dish rotary speed be 50~
250m/s。
Preferably, the Risperidone mass percent in the step (1) be 10~40wt%, preferably 25~35%；PLGA
Mass percent be 60~90wt%, preferably 65~75%.
Preferably, in the step (1), the good dissolubility organic solvent is ethyl alcohol or methylene chloride, and effumability has
Solvent is methylene chloride, and the volume ratio of good dissolubility organic solvent and effumability organic solvent is 20:80~40:60,
Phase solution incorporation time is 0~3h, and obtained homogeneous phase solution end viscosity is 150~350cp；Preferably, good dissolubility is organic molten
The volume ratio of agent and effumability organic solvent is 25:75~30:70, and homogeneous phase solution incorporation time is 15~60min.
Preferably, the homogeneous phase solution end viscosity in the step (1) is 200~300cp.
Preferably, LA:GA mass percent is 85:25~50:50 in the PLGA；Preferably, LA:GA in the PLGA
Mass percent is 75:25.
It should be noted that those skilled in the art can obtain the colostrum of required viscosity by any of method
Liquid.
It is a further object of the present invention to provide a kind of Risperidone microsphere preparations that the above method is prepared.
Microspheres product quality prepared by the present invention is further promoted, RisperidalBenzene is used in patent
For methanol/ethyl acetate as oil phase solvent, benzyl alcohol boiling point is higher, not volatile, can only pass through solvent extraction and washing process
(25% ethyl alcohol) removes, and technique is cumbersome, and benzyl alcohol residual quantity remains unchanged higher (0.7%).In addition, Risperidone is basic activated object
Matter, as nucleopilic reagent catalysis PLGA degradation, therefore residual solvent can make Risperidone be in free state to accelerate PLGA to drop
Solution, thus lead to Risperidone there are the quick release phase of explosion type (4~5 weeks).Present invention process prepares microspherulite diameter distribution collection
In, encapsulation rate be up to 95% or more, basic no solvent residue.In washing process, since ethyl alcohol has closed pore effect, so
RisperidalLag phase is longer (3 weeks), and microballoon of the present invention is without the release lag phase.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of 1 rotating-table apparatus of the embodiment of the present invention；
Fig. 2 is the structural schematic diagram of the cup-like containers of 1 rotating-table apparatus of the embodiment of the present invention；
Fig. 3 is the cup-like containers of the embodiment of the present invention 1 and the movement schematic diagram of outside dish turntable group；
Fig. 4 is the structural schematic diagram of the Microsphere manufacture equipment of the embodiment of the present invention 2；
Fig. 5 is 1 Risperidone microballoon In-vitro release curves of 3-4 of the embodiment of the present invention and comparative example；
Fig. 6 is 3 Risperidone microsphere optical microscope figure of the embodiment of the present invention；
Fig. 7 is 4 Risperidone microsphere optical microscope figure of the embodiment of the present invention.
Specific embodiment
Example embodiments are described in detail here, and the example is illustrated in the accompanying drawings.Following description and attached
When figure, unless otherwise indicated, the same numbers in different drawings indicate the same or similar elements.In following exemplary embodiment
Described embodiment does not represent all embodiments consistented with the present invention.On the contrary, they be only with it is such as appended
It is described in detail in middle claims, the example of the consistent device of some aspects of the invention.Each implementation of this specification
Example is described in a progressive manner.
It is to be appreciated that the directional instruction (such as up, down, left, right, before and after ...) of institute is only used in the embodiment of the present invention
In explaining in relative positional relationship, the motion conditions etc. under a certain particular pose (as shown in the picture) between each component, if should
When particular pose changes, then directionality instruction also correspondingly changes correspondingly.
In addition, the description for being related to " first ", " second " etc. in the present invention is used for description purposes only, and should not be understood as referring to
Show or imply its relative importance or implicitly indicates the quantity of indicated technical characteristic." first ", " are defined as a result,
Two " feature can explicitly or implicitly include at least one of the features.In addition, the technical solution between each embodiment can
It to be combined with each other, but must be based on can be realized by those of ordinary skill in the art, when the combination of technical solution occurs
Conflicting or cannot achieve when, will be understood that the combination of this technical solution is not present, also not the present invention claims protection model
Within enclosing.
Embodiment 1:
As shown in Figure 1-3, a kind of, for liquid material to be generated to the rotating-table apparatus of droplet, described device is turntable structure,
It is provided centrally with cup-like containers 24 and its first driving device 33 in the turntable structure, 24 outside of cup-like containers is successively nested
At least two layers of butterfly turntable, each layer of butterfly turntable are each equipped with corresponding driving device.Two layers of butterfly turntable is provided in attached drawing,
That is first layer butterfly turntable 26 and second layer butterfly turntable 28, first layer butterfly turntable 26 are turned by the driving of the second driving device 34
Dynamic, second layer butterfly turntable 28 is driven by third driving device 35 and is rotated, first driving device 33, the second driving device 34 and the
Three driving devices 35 can be high-speed rotary motor, be also possible to strong magnetic high-speed motor.
The cup-like containers 24 are up-narrow and down-wide slot cup-like containers, and the butterfly in the cup-like containers 24 and its outside
Shape turntable all has smooth neighboring；The direction of rotation of the cup-like containers 24 and its outside first layer butterfly turntable can be with
Direction of rotation for equidirectional or opposite direction, every adjacent two layers butterfly turntable is also possible to equidirectional or opposite direction.
The minor axis of cup-like containers 24 is set as D1, major diameter D2 is highly H1, and wherein the ratio of D1 and D2 is 1/2~2/
3, and height H1 is close with major diameter D2 numerical value.
The internal diameter of first layer butterfly turntable 26 is set as D3, is highly H3, the internal diameter of second layer butterfly turntable 28 is D4, high
Degree is H4, and so on；The capacity of cup-like containers 24 and its performance of first driving device 33 determine can in the unit time
The amount of material solution is handled, preferred volume is 5~10mL.Theoretically, D3 it is longer/H3 it is higher when, in turntable rotary course, shake
More aggravate；D3 is shorter/H3 it is shorter when, cup-like containers 24 rotate at high speed when, the rum point of droplet and outside turntable is closer to turning
Plate edge or the disk edge that flies out influence the dispersion of shock next time of droplet.Therefore it is preferred that H3/H1 ratio range 2.5~3.0, D3/
H3 ratio range 1.5~2.0.When second layer dish turntable D4/H4 setting odds ratio D3/H3 is smaller, secondary hit can be reinforced
Dispersion effect is hit, while increasing the vertical range L of adjacent dish-shaped disc surfaces, H4 height can be reduced.Therefore outside dish turntable
Key parameter range can be wider to reach desired dispersion effect and target grain size, and so on.
Embodiment 2:
As shown in figure 4, a kind of equipment for manufacturing microballoon, the equipment includes main tank body 23 and described in embodiment 1
For liquid material to be generated to the rotating-table apparatus of droplet, the bottom of the rotating-table apparatus is by supporting accessory structure 39 to be mounted on master
In tank body 23；
The main tank body 23 is back taper stainless steel and the double layers of tank body that can bear positive pressure, is equipped on the side wall of tank body
First temperature control element 40 of temperature-adjustable.First temperature control element 40 can be the external temperature controlled water bath of 23 chuck layer of main tank body.
23 minimum diameter of main tank body is preferably in 80cm or more, when longest diameter dish turntable is rotated with fastest rotary speed,
The droplet to fly out does not contact 23 inner wall of main tank body.It can be obtained by the quantity for adjusting the revolving speed of turntable or increase the dish-shaped turntable in outside
Obtain arbitrary target partial size.
The upstream of main tank body 23 includes sample preparation apparatus, liquid feed device and the air-flow for updating main tank body gas composition
Device.
The sample preparation apparatus includes fluid reservoir 16, and fluid reservoir 16 is built-in with agitating device 13, the agitating device
13 can be the stirring of mechanical stirring or ultrasonic agitation or other forms；16 outer wall of fluid reservoir is equipped with the second temperature control element 17, the
Two temperature control elements 17 can be the external temperature controlled water bath of 16 chuck layer of fluid reservoir；Liquid feed device includes connection device for storing liquid and main tank body
23 fluid circuit, the switch valve 19 on fluid circuit and fluid pump 20, the end of fluid circuit are supply opening 22, feed flow
Mouth 22 is not specifically limited, and is preferably placed in right above cup-like containers 24, material solution is at the uniform velocity added to cup-like containers 24.
The airflow apparatus includes the first air supply device 45 being connected with the first sample collection room 43, is located at main tank body 23
Top provides the second air supply device 51 and air exhausting device 57 of one-way gas flow, the end of second air supply device 51 be equipped with
The connected gas introduction port 54 of main tank body 23, the opening of the air exhausting device 57 are equipped with the gas export being connected with main tank body 23
Mouth 55.The gas that first air supply device 45 and the second air supply device 51 use can be nitrogen, air or other inert gases.
First filter 46 is provided on the gas piping that first sample collection room 43 is connected with the first air supply device 45, the
The second filter 52, air exhausting device 57 and gas are provided on the gas piping that two air supply devices 51 are connected with gas introduction port 54
Third filter 56 is provided on the connected gas piping of export mouth 55.Three filters are sterilizing filter.
First sample collection room 43 is threeway cube container, and the second sample collection room 60 is two logical negative angle containers.Institute
The material for stating the first sample collection room 43 and the second sample collection room 60 is microballoon not wall built-up material.Whole microspheres products can be with
It is enriched in the second sample collection room 60, outlet is collected thereunder.
Airflow apparatus provides the temperature of air-flow and intensity and can control, and gas flow temperature is consistent with 23 temperature of main tank body,
For the preferred vertical height of gas introduction port 54 and cup-like containers 24 in 20cm or more, current rate should not interfere droplet to run road
Line.
The downstream of main tank body 23 includes for collecting the collection device of microballoon, drying device 71 and for receiving collection device
The microballoon collected is transferred to the transmitting device 63 of drying device.
The collection device includes at least positioned at first sample collection room 43 at 23 slot end of main tank body and for being enriched with
Second sample collection room 60 of sample, the material transferring between two collecting chambers are completed by transloading equipment, the collecting chamber
Shape includes but is not limited to cube, centrum or trapezoidal, transloading equipment using air stream transportation, conveyor bed is sent, pipeline transmits, expects
The forms such as bucket transfer, but not limited to this.
In droplet generation process, material solution is constantly fed cup-like containers 24 by supply opening 22 by liquid feed device, the
The centrifugal force that one driving device, 33 high speed rotation generates makes the material solution in cup-like containers 24 cross rim of a cup, and it is reversed to fly to outside
High-speed rotating first layer dish turntable 26 hits its Dispersion on surface into droplet, and droplet continues to move under the effect of reversed centrifugal force
To disk edge and the turntable that flies out, hits second layer dish turntable 28 and be dispersed into more tiny droplet, disperse by multiple impact
Obtain the droplet with target grain size.The turntable finally, the dish-shaped disk edge that droplet shifts to longest diameter flies out, in temperature-controllable
It is formed by curing microballoon in main tank body 23, dry microballoon is collected in the first sample collection room 43 and the second sample collection room 60 and produces
Product.
Preferably, 33 linear velocity range of first driving device is 10~150m/s, 34 revolving speed 50 of the second driving device~
250m/s, hereafter the driving revolving speed of each more lateral dish turntable is no more than 250m/s.
Since the surface nature of dish-shaped turntable influences the moving line of droplet, can theoretically be prepared using any material,
Specification meets, but needs to be polished to mirror surface, and preferably material is stainless steel.Cup-like containers 24 and outside dish turntable group have
There is smooth neighboring.
Cup-like containers 24 and outside dish turntable can be in the same direction or reverse rotations, if the two is rotated with opposite direction, every phase
Adjacent two dish-shaped turntables are rotated with opposite direction, this rotation mode be capable of providing enough acceleration drop is crashed rapidly to
Target grain size (Fig. 4).In addition, cup-like containers 24 can handle the material solution of different conditions, including evenly dispersed solution, suspend
Liquid or lotion can also handle highly viscous material by heating cup-like containers, be allowed to melting and balling-up.
It is described below using the equipment of above-described embodiment 2 and prepares microballoon.
The end PLGA of the present invention can be ester group, or carboxyl.PLGA used in the present invention is purchased from
Evonik。
Oil phase viscosity detection of the present invention is existed using LVDV-II+PRO programmable control standard rheometer (Brookfield)
It is measured under the conditions of 20 DEG C.
Below by way of specific embodiment, the present invention is further elaborated, listed embodiment is not intended to limit the present invention.
Embodiment 3:
(1) 40g Risperidone is weighed, is dissolved in methylene chloride 1, (Mw12 × 10 60gPLGA are weighed4) it is dissolved in dichloromethane
In alkane 2, methylene chloride 1 and 2 volume ratio of methylene chloride are 25:75, are stirred 15min after dissolving respectively, what is obtained mixes
Liquid end viscosity is 335cp；
(2) by step, (1) the homogeneous phase solution feeds cup-like containers through supply opening (liquid supply speed 10mL/min), adjusts and turns
Dynamic driving device, setting cup-like containers revolving speed are 40m/s, and first layer dish rotary speed is 80m/s, and second layer dish turntable turns
Speed is 120m/s, and under the action of the centrifugal force, the feed liquid in cup-like containers crosses rim of a cup, hits the first layer dish of reverse direction operation
Disc surfaces are dispersed into droplet, and the droplet of formation continues to hit the second layer dish turntable of reverse direction operation, by dispersing twice
Afterwards, droplet flies out turntable, and at temperature (solidification temperature is set as 25 DEG C) and airflow function, organic solvent constantly volatilizees, Li Pei
Crystallization is precipitated in ketone inside microballoon, and the microballoon after solidification is collected by the collecting chamber of bottom of device.
Embodiment 4:
(1) 40g Risperidone is weighed, is dissolved in alcohol solvent, (Mw8 × 10 60gPLGA are weighed4) it is dissolved in methylene chloride
In solvent, ethyl alcohol and methylene chloride volume ratio are 25:75, are stirred 60min after dissolving respectively, obtained homogeneous phase solution is viscous eventually
Degree is 166cp；
(2) by step, (1) the homogeneous phase solution feeds cup-like containers through supply opening (liquid supply speed 5mL/min), adjusts and turns
Dynamic driving device, setting cup-like containers revolving speed are 30m/s, and first layer dish rotary speed is 60m/s, and second layer dish turntable turns
Speed is 80m/s, and under the action of the centrifugal force, the feed liquid in cup-like containers crosses rim of a cup, hits the first layer dish of reverse direction operation
Disc surfaces are dispersed into droplet, and the droplet of formation continues to hit the second layer dish turntable of reverse direction operation, by dispersing twice
Afterwards, droplet flies out turntable, and at temperature (solidification temperature is set as 25 DEG C) and airflow function, organic solvent constantly volatilizees, Li Pei
Crystallization is precipitated in ketone inside microballoon, and the microballoon after solidification is collected by the collecting chamber of bottom of device.
Embodiment 5:
Particle size distribution analysis is carried out to embodiment 3-4 microsphere sample using Particle Size Analyzer (Mastersizer 2000),
Wet process measurement is selected, medium selects 80 solution of 0.1%Tween.
Microspherulite diameter testing result shows that implementation method provided by the invention can get different grain size range, and granularity point
Cloth is concentrated, and homogeneity is good.
1 microsphere particle size distribution results of table
Embodiment 6:
Drugloading rate and entrapment efficiency determination are carried out to embodiment 3-4 microsphere sample using HPLC (Agilent).Sample preparation side
Method are as follows: precision weighs the microballoon 10mg after drying, and 2mL acetonitrile is added and sufficiently dissolves, crosses 0.22 μm of PVDF filter membrane, HPLC exists
Risperidone peak area is detected at 274nm, and medicament contg is calculated according to standard curve.Wherein:
Drugloading rate (%)=practical microsphere drug content/microspheres quality × 100%
Encapsulation rate (%)=practical microsphere drug content/theory microsphere drug content × 100%
Microsphere encapsulation rate the results show that implementation method microsphere encapsulation rate provided by the invention 96% or more.
2 microballoon drugloading rate of table and encapsulation rate result
Embodiment 7:
It is measured using residual solvent of the gas-chromatography (Shimadzu, GC-2014C) to embodiment 3-4 microsphere sample.
3 residual solvent result of table
Embodiment 8:
The measurement of Risperidone microballoon release in vitro is carried out using the vitro Release Medium that FDA guide is recommended.Release in vitro liquid
(20L) preparation method are as follows:
40g Sodium azide is weighed to be added in 760g deionized water；
18.76kg deionized water is weighed to be added in the container of 20L；
200g 1M HEPES buffer solution is added into said vesse；
116g sodium chloride is weighed to be added in 1kg deionized water；
Sodium chloride solution is added into said vesse；
80mL sodium azide solution is added into said vesse；
4mLTween 20 is added into said vesse；
PH to 7.4 ± 0.1 is adjusted with HCl；
Osmotic pressure is maintained at 200 ± 20mOsm.
20mg Risperidone microballoon is weighed, is dispersed in the above-mentioned release in vitro liquid of 50mL, 37 DEG C of standings, spot sampling carries out
HPLC detection.Comparative example 1 is using the injection Risperidone preparation Risperidal clinically used at present(Chinese name:
Permanent moral), it is developed by Alkermes company, is listed in August, 2002.The microballoon In-vitro release curves of embodiment 3-4 and comparative example 1
As shown in Figure 5.With Risperidal in comparative example 1It compares, the embodiment of the present invention obtains Risperidone microsphere sustained-release effect
More preferably, no lag phase early period, later period release is steady, and clinical application takes orally Risperidone tablet without early period.
Embodiment 9:
Morphological observation is carried out to microsphere sample using optical microscopy, as a result as shown in fig. 6-7, embodiment 3-4 preparation
Risperidone microsphere surface rounding, dispersion degree is higher, without being adhered between microballoon.
Comparative example 1RisperidalPreparation process
(1) 40g Risperidone is weighed, is dissolved in benzyl alcohol solvent, weighs (Mw12 × 10 60gPLGA4) it is dissolved in dichloromethane
In alkane solvents, benzyl alcohol and methylene chloride volume ratio are 1:3, are stirred 15min after dissolving respectively, obtain homogeneous phase solution.
(2) 1%PVA aqueous solution is prepared, ethyl acetate is added and makes up to saturation state.
(3) 2.0% ethyl acetate aqueous solution of 25kg is prepared, is cooled to 6 DEG C.
Using static mixer mixing it is above-mentioned oil mutually (1) with water phase (3), the thick cream of formation be pumped into cooling bath (3) in,
4h is extracted under the conditions of 250rpm.
(5) microballoon is collected, and aqueous solution rinses, vacuum drying.
(6) 25% ethanol solution washs the microballoon after drying, washs 4h under the conditions of 250rpm.
(7) microballoon is collected, and aqueous solution rinses, vacuum drying.
The drugloading rate of microballoon is 35.8%, encapsulation rate 79.6%.
Compared with comparative example 1 (solvent extraction), the present invention can accurately control microsphere particle size distribution, without removal of being sieved
Organic solvent residual total amount (benzyl alcohol 0.7%, ethyl acetate 0.05%, ethyl alcohol 0.1%) is reduced to by > 150 μm of microballoons
0.05% hereinafter, yield is promoted to 93% from 62%, and encapsulation rate is promoted to 97% from 89%.
Batch processing amount of the present invention can at least be improved from (500g, 3000) thousands of of traditional handicraft to (2000g, 2.4
Ten thousand) up to ten thousand, the implementation method of offer of the invention is more suitable for large-scale industrial production.
Above embodiments are not intended to limit the present invention in any form, and are also deposited under the premise of without departing from claim
In other modifications.
Claims (12)
1. a kind of preparation method of Risperidone microsphere preparation, which comprises the following steps:
(1) Risperidone is dissolved in a kind of good dissolubility organic solvent, it is organic molten that PLGA is dissolved in another effumability
In agent, after two kinds of solution dissolve respectively, remixing stirring and form homogeneous phase solution, the homogeneous phase solution end viscosity is 150~
350cp；
(2) homogeneous phase solution described in step (1) is fed to the cup-like containers at rotating-table apparatus center, the feed liquid in cup-like containers is crossed
Rim of a cup hits the dish-shaped turntable in outside under gravitational and centrifugal forces and is dispersed into droplet, and the droplet of formation continues to hit outer
Side dish turntable, after acting on twice or repeatedly, the droplet turntable that flies out is formed by curing microballoon.
2. preparation method according to claim 1, it is characterised in that: the rotating-table apparatus is turntable structure, at described turn
Dish structure is provided centrally with cup-like containers and its driving device, successively nested at least two layers of butterfly turntable on the outside of cup-like containers,
Each layer of butterfly turntable is each equipped with corresponding driving device.
3. preparation method according to claim 2, which is characterized in that the cup-like containers are up-narrow and down-wide slot cup
Shape container, and the cup-like containers and its butterfly turntable in outside all have smooth neighboring.
4. preparation method according to claim 3, which is characterized in that set the minor axis of cup-like containers as D1, major diameter D2,
Height is H1, and wherein the ratio of D1 and D2 is 1/2~2/3.
5. the preparation method according to claim 4, which is characterized in that set the internal diameter of first layer butterfly turntable as D3, it is high
Degree is H3, and it is highly H4 that the internal diameter of second layer butterfly turntable, which is D4, and so on；Wherein D3 and H3 ratio are 1.5~2.0, H3
Ratio with H1 is 2.5~3.0.
6. the preparation method according to any one of claim 2-5, which is characterized in that the ratio that D4/H4 is arranged is less than D3/
H3, to obtain stronger secondary impact effect.
7. preparation method according to claim 1, which is characterized in that in the step (2) cup-like containers revolving speed be 10~
150m/s, outside dish rotary speed are 50~250m/s.
8. preparation method according to claim 1, which is characterized in that the Risperidone mass percent in the step (1)
For 10~40wt%, preferably 25~35%；PLGA mass percent be 60~90wt%, preferably 65~75%.
9. preparation method according to claim 1, which is characterized in that in the step (1), the good dissolubility is organic molten
Agent is ethyl alcohol or methylene chloride, and effumability organic solvent is methylene chloride, and good dissolubility organic solvent and effumability are organic
The volume ratio of solvent is 20:80~40:60, and homogeneous phase solution incorporation time is 0~3h；Preferably, good dissolubility organic solvent and
The volume ratio of effumability organic solvent is 25:75~30:70, and homogeneous phase solution incorporation time is 15~60min.
10. preparation method according to claim 1, which is characterized in that the homogeneous phase solution end viscosity in the step (1) is
200~300cp.
11. described in any item preparation methods according to claim 1~13, which is characterized in that LA:GA mass hundred in the PLGA
Divide than being 85:25~50:50；Preferably, LA:GA mass percent is 75:25 in the PLGA.
12. a kind of Risperidone microsphere preparation being prepared by any one of claim 1~11 the method.
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