CN109806242B - Risperidone microsphere preparation and preparation method thereof - Google Patents
Risperidone microsphere preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a risperidone microsphere preparation and a preparation method thereof, and the preparation method comprises the steps of (1) dissolving risperidone in a good-solubility organic solvent, dissolving PLGA in another volatile organic solvent, respectively dissolving the two solutions, and then mixing and stirring to form a homogeneous solution, wherein the final viscosity of the homogeneous solution is 150-350 cp; (2) feeding the homogeneous solution in the step (1) into a cup-shaped container in the center of a turntable device, enabling feed liquid in the cup-shaped container to cross a cup opening, impacting an outer disc-shaped turntable under the action of centrifugal force and gravity to disperse into micro-droplets, enabling the formed micro-droplets to continuously impact the outer disc-shaped turntable, and enabling the micro-droplets to fly out of the turntable to be solidified to form microspheres after two or more actions. The microsphere preparation obtained by the method has outstanding slow release capacity, no additional release regulator is required to be added, and the slow release period can reach 1-3 months.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a risperidone microsphere preparation and a preparation method thereof.
Background
Schizophrenia is a common major psychotic disorder. With the increasing social rhythm, people face more and more economic pressure and mental burden, more and more sick people form various obstacles such as perception, thinking, emotion, behavior and the like, and as a result, the mental problem is increasingly prominent. Schizophrenia is frequently caused in young and strong years, according to the statistics of the world health organization, the global schizophrenia prevalence rate is probably 3.8-8.4 per thousand, and the lifetime prevalence rate is as high as 13 per thousand. Once suffering from schizophrenia, the patient needs to take medication for life.
Anti-schizophrenia drugs can effectively control the psychotic symptoms of schizophrenia. Common antipsychotics found in the 50's of the 20 th century, such as chlorpromazine or haloperidol, are central dopamine D2 receptor blockers, are effective for the positive symptoms of schizophrenia, but are ineffective for the negative symptoms and cognitive impairment, and can also cause extrapyramidal dyskinesia, great toxicity to the heart vessels and liver, and many adverse reactions.
In order to overcome the above-mentioned drawbacks, a new generation of atypical antipsychotics was brought forward, risperidone was developed in 1984 by the pharmaceutical company of poplar at belgium, which remedied the obvious drawbacks of typical antipsychotics. Risperidone is a selective cholamine blocker with unique properties, and has high affinity with both 5-hydroxytryptamine 2 receptors and dopamine D2 receptors. Risperidone has good curative effect on improving positive and negative symptoms and cognitive function, causes little or no Extrapyramidal (EPS) adverse reaction, has almost no side effect, and does not need to be used together with anticholinergic drugs; the treatment has better tolerance and compliance. Risperidone is mainly metabolized through a cytochrome P4502D6 enzyme pathway, the active metabolite of the risperidone is 9-hydroxy risperidone, and the two components form the active ingredient for resisting schizophrenia.
The common dosage forms of risperidone include tablets, oral liquids, capsules, drops, etc. However, with conventional dosage forms, patients must generally take their medication on a daily basis, and the frequency of once-a-day or even multiple-a-day administration is very difficult for 75% of psychiatric patients. Poor compliance, missed taking of medicines, refusal of taking medicines, and even discontinuation of treatment can cause the condition of the patient to be worsened, which is the main reason for relapse and re-hospitalization of the patient.
Therefore, the development of the risperidone long-acting sustained-release preparation can reduce the administration frequency and improve the patient compliance, and has great clinical significance and economic significance. Risperidal serving as injection risperidone preparation clinically used at present
(Chinese name: Hengde), developed by Alkermes corporation, marketed in 8 months 2002. The product adopts Medisorb controlled drug release technology, the risperidone is encapsulated in PLGA with the molecular weight of 150,000, suspended in special solvent and is applied once every 2 weeks through intramuscular injection, and the administration frequency is reduced. However, the preparation has a lag phase of drug release in the first 3 weeks, only releases a small amount of drug, and releases the drug rapidly in the 4 th to 6 th weeks along with the degradation of the microsphere skeleton. Therefore, when the medicine is injected into a patient in the first 3 weeks, the patient needs to take the risperidone tablet orally to achieve the treatment effect, and the dosage is adjusted after 3 weeks, so that the clinical use is inconvenient, and the compliance of the patient is still poor. Moreover, the product adopts an emulsion extraction method to prepare microspheres, and adopts a binary organic solvent (benzyl alcohol/ethyl acetate) as an oil phase solventThe agent is mixed with oil and water phases through a static mixer, and is subjected to solvent extraction, twice washing and twice drying processes to effectively remove residual solvent. The preparation procedure is complicated, which causes high cost and price, and the popularization process is limited because patients with limited economic conditions are difficult to accept. The product selects PLGA with the molecular weight of up to 150,000 as a drug carrier, but has a longer lag phase in the first 3 weeks and a short quick release phase, which is attributed to the limitation of the microsphere preparation technology.
In order to overcome the defects of the microsphere preparation, researchers actively develop risperidone long-acting microspheres without release lag phase. The most common microsphere preparation method is an emulsion solvent volatilization method or an emulsion solvent extraction method, although the principle and the device structure of the method are simple, the workshop production steps are complicated, the intermittent operation is multiple, the process reproducibility is poor, the large-scale production is difficult, the drug loading and the encapsulation rate are low due to the existence of an external water phase and a surfactant, the drug has the risk of pouring to the external water phase, the size of liquid drops generated by depending on shearing force is not uniform, the diameter distribution of microspheres is wide, the target particle size can be selected only by depending on later-stage screening, and the production cost is increased.
The formation of droplets in the liquid phase has certain disadvantages that the drug is affected by interfacial tension or follows the principle of solvent-like compatibility, and the drug is easy to diffuse into the continuous phase with the removal of the organic solvent, so that the loss of the drug is increased, and the drug encapsulation efficiency cannot reach one hundred percent. In addition, in a liquid phase system, a large amount of organic solvent is often used for preparing the microspheres, and the organic solvent not only has certain toxicity, but also influences the stability of the microspheres, reduces the glass transition temperature of the microspheres and accelerates the degradation speed of the microspheres.
The above problems can be solved by forming droplets in a gas phase, and the rotating disk method is a droplet forming technique in a gas phase, in which a dispersion solution is atomized to form droplets by using a rotating disk rotating at a high speed, and an organic solvent is volatilized to generate solid particles. The higher oil phase concentration reduces the use amount of the organic solvent, the high-concentration oil drops have larger interfacial tension in the air, the spheres are easy to keep, and the drugs are difficult to diffuse to the gas phase.
However, the existing rotating disk device is not ideal enough, the droplet generating device used in CN 101816913 has a structure similar to a rotating disk, but the mixed liquid needs to be uniformly added to the center position of the rotating disk, otherwise, it cannot be ensured that the droplets are uniformly dispersed in all directions of the disk, and the disk is a horizontal disk, and the droplet is subjected to a small resistance, so the droplet motion freedom is large, and the stress is not uniform, so the appearance of the microsphere obtained by the method is not round enough. If the feed liquid is high in viscosity, the dispersion of the feed liquid by the high-speed centrifugal force of a plane disc is far from enough, and even if the feed liquid adopts ultrahigh rotating speed, the feed liquid is also unfavorable for equipment protection.
The invention content is as follows:
aiming at the defects, the invention provides a risperidone microsphere preparation and a preparation method thereof, wherein a turntable device is used in the preparation method, the turntable device can overcome the defects, a cup-shaped container rotating at a high speed is adopted to accelerate high-concentration feed liquid, the feed liquid impacts the surface of an outer disc-shaped turntable after certain acceleration, so that the feed liquid is dispersed into uniform liquid drops, the liquid drops are continuously accelerated to impact the surface of the outer disc-shaped turntable, and formed droplets fly out of the disc-shaped turntable to be solidified into microspheres after one or more actions. According to the invention, the oil phase viscosity is increased, so that the 'drying in liquid' is converted into the 'drying in air' mode, and the high-viscosity oil drops are quickly crushed to the target particle size by adopting a turntable device, so that even if the oil phase viscosity is higher (>200cp), the microspheres are all in a spherical shape and have no fibrous filaments. Then the temperature and the airflow mode are accurately controlled, and the organic solvent is effectively removed. Compared with a 'drying in liquid' mode, the method for preparing the microspheres has higher encapsulation efficiency and microsphere yield, extremely low residual solvent and obviously improved dispersibility.
The technical scheme adopted by the invention for realizing the purpose is as follows: a preparation method of a risperidone microsphere preparation comprises the following steps:
(1) dissolving risperidone in a well-soluble organic solvent, dissolving PLGA in another volatile organic solvent, respectively dissolving the two solutions, and mixing and stirring to form a homogeneous solution, wherein the final viscosity of the homogeneous solution is 150-350 cp;
(2) feeding the homogeneous solution in the step (1) into a cup-shaped container in the center of a turntable device, enabling feed liquid in the cup-shaped container to cross a cup opening, impacting an outer disc-shaped turntable under the action of centrifugal force and gravity to disperse into micro-droplets, enabling the formed micro-droplets to continuously impact the outer disc-shaped turntable, and enabling the micro-droplets to fly out of the turntable to be solidified to form microspheres after two or more actions.
Preferably, the rotary disc device is of a rotary disc structure, a cup-shaped container and a driving device thereof are arranged in the center of the rotary disc structure, at least two layers of butterfly rotary discs are sequentially nested outside the cup-shaped container, and each layer of butterfly rotary disc is provided with a corresponding driving device.
Preferably, the cup-shaped container is a narrow-mouth cup-shaped container with a narrow top and a wide bottom, and the cup-shaped container and the butterfly-shaped rotary disc outside the cup-shaped container are provided with smooth peripheral edges.
Preferably, the short diameter of the cup-shaped container is D1, the long diameter is D2, and the height is H1, wherein the ratio of D1 to D2 is 1/2-2/3.
Preferably, the inner diameter of the first layer of butterfly rotary disc is set to be D3 and the height is set to be H3, the inner diameter of the second layer of butterfly rotary disc is set to be D4 and the height is set to be H4, and the like; wherein the ratio of D3 to H3 is 1.5-2.0, and the ratio of H3 to H1 is 2.5-3.0.
Preferably, the ratio of D4/H4 is set smaller than D3/H3 to obtain a stronger secondary impact effect.
Preferably, the rotating speed of the cup-shaped container in the step (2) is 10-150 m/s, and the rotating speed of the outer disk-shaped rotating disk is 50-250 m/s.
Preferably, the risperidone in the step (1) is 10-40 wt%, preferably 25-35 wt%; the mass percentage of PLGA is 60-90 wt%, preferably 65-75 wt%.
Preferably, in the step (1), the well-soluble organic solvent is ethanol or dichloromethane, the volatile organic solvent is dichloromethane, the volume ratio of the well-soluble organic solvent to the volatile organic solvent is 20: 80-40: 60, the mixing time of the homogeneous solution is 0-3 h, and the final viscosity of the obtained homogeneous solution is 150-350 cp; preferably, the volume ratio of the well-soluble organic solvent to the volatile organic solvent is 25: 75-30: 70, and the mixing time of the homogeneous solution is 15-60 min.
Preferably, the final viscosity of the homogeneous solution in the step (1) is 200-300 cp.
Preferably, the PLGA has a LA: the GA mass percentage is 85: 25-50: 50; preferably, the PLGA has a LA: the GA mass percent is 75: 25.
It is to be noted that the person skilled in the art can obtain a primary emulsion of the desired viscosity by any known method.
The invention also aims to provide a risperidone microsphere preparation prepared by the method.
The quality of the microsphere product prepared by the invention is further improved, and Risperidal
In the patent, benzyl alcohol/ethyl acetate is used as an oil phase solvent, the boiling point of the benzyl alcohol is high, the benzyl alcohol is not easy to volatilize and can only be removed through solvent extraction and washing processes (25% ethanol), the process is complicated, and the residual amount of the benzyl alcohol is still high (0.7%). In addition, risperidone is an alkaline active substance and used as a nucleophilic reagent to catalyze PLGA degradation, so that the residual solvent can enable risperidone to be in a free state to accelerate PLGA degradation, and the risperidone has an explosive rapid release period (4-5 weeks). The microsphere prepared by the process has concentrated particle size distribution, the encapsulation rate is over 95 percent, and no solvent residue is basically left. Risperidal due to the closed cell effect of ethanol during washing
The lag phase is longer (3 weeks), whereas the microspheres of the invention have no release lag phase.
Drawings
FIG. 1 is a schematic structural diagram of a turntable device according to embodiment 1 of the present invention;
FIG. 2 is a schematic structural view of a cup-shaped container of a turntable device according to embodiment 1 of the present invention;
FIG. 3 is a schematic diagram showing the movement of the cup-shaped container and the outer disk set of the disk rotor in example 1 of the present invention;
FIG. 4 is a schematic structural view of a microsphere production apparatus according to example 2 of the present invention;
FIG. 5 is a graph showing the in vitro release profiles of risperidone microspheres of examples 3-4 and comparative example 1 in accordance with the present invention;
FIG. 6 is an optical microscope photograph of risperidone microspheres of example 3;
FIG. 7 is an optical microscope photograph of risperidone microspheres of example 4.
Detailed Description
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. In the following description and in the drawings, the same numbers in different drawings identify the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Rather, they are merely examples of apparatus consistent with certain aspects of the invention, as detailed in the claims below. Various embodiments of the present description are described in an incremental manner.
It should be noted that all the directional indicators (such as up, down, left, right, front, and rear … …) in the embodiment of the present invention are only used to explain the relative position relationship between the components, the movement situation, etc. in a specific posture (as shown in the drawing), and if the specific posture is changed, the directional indicator is changed accordingly.
In addition, the descriptions related to "first", "second", etc. in the present invention are for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention.
Example 1:
as shown in fig. 1-3, a rotating disc device for generating droplets of liquid materials is a rotating disc structure, a cup-shaped container 24 and a first driving device 33 thereof are arranged in the center of the rotating disc structure, at least two layers of butterfly rotating discs are nested outside the cup-shaped container 24 in sequence, and each layer of butterfly rotating discs is provided with a corresponding driving device. The drawing shows two layers of butterfly turntables, namely a first layer butterfly turntable 26 and a second layer butterfly turntable 28, the first layer butterfly turntable 26 is driven to rotate by a second driving device 34, the second layer butterfly turntable 28 is driven to rotate by a third driving device 35, and the first driving device 33, the second driving device 34 and the third driving device 35 can be high-speed rotating motors or strong-magnetic high-speed motors.
The cup-shaped container 24 is a narrow-mouth cup-shaped container with a narrow top and a wide bottom, and the cup-shaped container 24 and a butterfly-shaped turntable on the outer side of the cup-shaped container are both provided with smooth peripheral edges; the rotation directions of the cup-shaped container 24 and the first layer of butterfly disks outside the cup-shaped container can be the same direction or opposite directions, and the rotation directions of every two adjacent layers of butterfly disks can also be the same direction or opposite directions.
The short diameter of the cup-shaped container 24 is set to be D1, the long diameter is set to be D2, the height is set to be H1, the ratio of the D1 to the D2 is 1/2-2/3, and the height H1 is close to the value of the long diameter D2.
Setting the inner diameter of the first layer of butterfly-shaped rotary disc 26 to be D3 and the height to be H3, the inner diameter of the second layer of butterfly-shaped rotary disc 28 to be D4 and the height to be H4, and so on; the capacity of the cup-shaped container 24 and the performance of the first driving device 33 determine the amount of the material solution that can be processed per unit time, and the volume is preferably 5-10 mL. Theoretically, the longer the D3 is/the higher the H3 is, the more the shaking is intensified during the rotation of the turntable; the shorter the D3/the shorter the H3, the closer the impact point of the droplet with the outer disk is to the edge of the disk or the edge of the flying disk as the cup 24 rotates at high speed, affecting the next impact spread of the droplet. Therefore, the preferred ratio of H3/H1 is 2.5-3.0, and the preferred ratio of D3/H3 is 1.5-2.0. When the ratio of D4/H4 of the second layer of disk-shaped turntable is set smaller than that of D3/H3, the secondary impact dispersion effect can be enhanced, and the height of H4 can be reduced by increasing the vertical distance L between the surfaces of adjacent disk-shaped turntables. Therefore, the key parameter range of the outer disc-shaped turntable can be wider to achieve the desired dispersion effect and the target particle size, and so on.
Example 2:
as shown in fig. 4, an apparatus for manufacturing microspheres, the apparatus comprising a main tank 23 and a carousel device for generating droplets of liquid material as described in example 1, the bottom of the carousel device being mounted in the main tank 23 by a supporting attachment structure 39;
the main tank body 23 is a double-layer tank body which is made of inverted cone stainless steel and can bear positive pressure, and a first temperature control element 40 capable of adjusting temperature is installed on the side wall of the tank body. The first temperature control element 40 can be an external temperature control water bath outside the jacket of the main tank 23.
The minimum inner diameter of the main tank 23 is preferably 80cm or more, and when the longest diameter disc rotor rotates at the highest rotation speed, the flying droplets do not contact the inner wall of the main tank 23. Any target particle size can be obtained by adjusting the rotational speed of the rotating discs or increasing the number of outer disc-shaped rotating discs.
Upstream of the main tank 23 there are sample preparation means, liquid supply means and gas flow means for renewing the gas composition of the main tank.
The sample preparation device comprises a liquid storage tank 16, a stirring device 13 is arranged in the liquid storage tank 16, and the stirring device 13 can be mechanical stirring, ultrasonic stirring or other stirring modes; the outer wall of the liquid storage tank 16 is provided with a second temperature control element 17, and the second temperature control element 17 can be an external temperature control water bath outside a jacket layer of the liquid storage tank 16; the liquid supply device comprises a fluid pipeline connecting the liquid storage device with the main tank 23, a switch valve 19 and a fluid pump 20, wherein the fluid pipeline is provided with a liquid supply port 22 at the tail end, the liquid supply port 22 is not particularly limited and is preferably arranged right above the cup-shaped container 24, and the material solution is added to the cup-shaped container 24 at a constant speed.
The air flow device comprises a first air supply device 45 connected with the first sample collecting chamber 43, a second air supply device 51 positioned at the top of the main tank body 23 and used for providing unidirectional air flow, and an air exhaust device 57, wherein the tail end of the second air supply device 51 is provided with an air inlet 54 connected with the main tank body 23, and the opening of the air exhaust device 57 is provided with an air outlet 55 connected with the main tank body 23. The gas used by the first air blowing device 45 and the second air blowing device 51 may be nitrogen gas, air or other inert gas.
A first filter 46 is provided on a gas pipe connecting the first sample collecting chamber 43 and the first air blowing device 45, a second filter 52 is provided on a gas pipe connecting the second air blowing device 51 and the gas inlet 54, and a third filter 56 is provided on a gas pipe connecting the air discharge device 57 and the gas outlet 55. The three filters are sterile filters.
The first sample collection well 43 is a three-way cube container and the second sample collection well 60 is a two-way inverted cone container. The first sample collection chamber 43 and the second sample collection chamber 60 are made of microspheres and are not wall-hanging. The entire microsphere product can be enriched in the second sample collection chamber 60 and collected at its lower outlet.
The temperature and intensity of the air flow provided by the air flow device can be controlled, the air flow temperature is consistent with the temperature of the main tank body 23, the preferred vertical height of the air introducing port 54 and the cup-shaped container 24 is more than 20cm, and the air flow intensity does not interfere with the droplet running route.
Downstream of the main tank 23, there are a collecting device for collecting the microspheres, a drying device 71 and a transferring device 63 for transferring the microspheres collected by the collecting device to the drying device.
The collecting device at least comprises a first sample collecting chamber 43 at the narrow end of the main tank body 23 and a second sample collecting chamber 60 for enriching samples, the material transmission between the two collecting chambers is completed by a transfer device, the shape of the collecting chambers comprises but is not limited to a cube, a cone or a trapezoid, and the transfer device adopts the forms of air flow transmission, conveyor belt bed conveying, pipeline conveying, hopper transferring and the like, but is not limited to the forms.
In the process of forming the droplets, the liquid supply device continuously supplies the material solution into the cup-shaped container 24 through the liquid supply port 22, the centrifugal force generated by the high-speed rotation of the first driving device 33 enables the material solution in the cup-shaped container 24 to cross the cup mouth, fly to the outer side, the first layer of disc-shaped rotating disc 26 rotating reversely at high speed collides with the surface of the outer side, and is dispersed into droplets, the droplets continuously move to the edge of the rotating disc and fly out of the rotating disc under the action of the reverse centrifugal force, and the droplets collide with the second layer of disc-shaped rotating disc 28, are dispersed into finer droplets, and are subjected to multiple. Finally, the droplets move to the edge of the disk of longest diameter and fly out of the disk, where they solidify in the temperature controlled main tank 23 to form microspheres, and the dried microsphere product is collected in the first sample collection chamber 43 and the second sample collection chamber 60.
Preferably, the linear speed of the first driving device 33 is 10-150 m/s, the rotation speed of the second driving device 34 is 50-250 m/s, and the rotation speed of each outer disk-shaped turntable is not more than 250 m/s.
Because the surface property of the disk-shaped turntable influences the movement path of the microdroplets, theoretically, the microdroplets can be prepared from any material, the specification is met, the microdroplets need to be polished into mirror surfaces, and the preferred material is stainless steel. The cup 24 and the outer disk set each have a smooth peripheral edge.
The cup-shaped container 24 and the outer disk-shaped rotating disk can rotate in the same direction or in opposite directions, and if the two disk-shaped containers rotate in opposite directions, every two adjacent disk-shaped rotating disks rotate in opposite directions, the rotation mode can provide enough acceleration to rapidly crush the liquid drops to the target particle size (figure 4). In addition, the cup-shaped container 24 can be used for processing material solutions in different states, including uniformly dispersed solutions, suspensions or emulsions, and can also be used for processing highly viscous materials by heating the cup-shaped container to melt and form balls.
The preparation of microspheres using the apparatus of example 2 above is described below.
The end of the PLGA may be an ester group or a carboxyl group. PLGA used in the present invention is purchased from Evonik.
The oil phase viscosity detection is carried out by adopting an LVDV-II + PRO programmable control type rheometer (Brookfield) at the temperature of 20 ℃.
The invention is further illustrated by the following specific examples, which are not intended to be limiting.
Example 3:
weighing 40g risperidone, and dissolvingDissolve in dichloromethane 1, weigh 60g PLGA (Mw 12X 10)4) Dissolving in dichloromethane 2, wherein the volume ratio of dichloromethane 1 to dichloromethane 2 is 25:75, respectively dissolving, stirring and mixing for 15min to obtain a homogeneous solution with the final viscosity of 335 cp;
the homogeneous solution is supplied to a cup-shaped container through a liquid supply port (the liquid supply speed is 10mL/min), a rotation driving device is adjusted, the rotating speed of the cup-shaped container is set to be 40m/s, the rotating speed of a first layer of disc-shaped rotating disc is 80m/s, the rotating speed of a second layer of disc-shaped rotating disc is 120m/s, under the action of centrifugal force, liquid in the cup-shaped container crosses the cup port, the liquid impacts the surface of the first layer of disc-shaped rotating disc running in the opposite direction and is dispersed into micro-droplets, the formed micro-droplets continue to impact the second layer of disc-shaped rotating disc running in the opposite direction, after twice dispersion, the micro-droplets fly out of the rotating discs, under the temperature (the solidification temperature is set to be 25 ℃) and the airflow action, organic solvent continuously volatilizes, risperidone is separated out of.
Example 4:
first, 40g of risperidone was dissolved in an ethanol solvent, and 60g of plga (Mw8 × 10) was weighed out4) Dissolving in a dichloromethane solvent, wherein the volume ratio of ethanol to dichloromethane is 25:75, respectively dissolving, stirring and mixing for 60min to obtain a homogeneous solution with the final viscosity of 166 cp;
the homogeneous solution is supplied to a cup-shaped container through a liquid supply port (the liquid supply speed is 5mL/min), a rotation driving device is adjusted, the rotating speed of the cup-shaped container is set to be 30m/s, the rotating speed of a first layer of disc-shaped rotating disc is 60m/s, the rotating speed of a second layer of disc-shaped rotating disc is 80m/s, under the action of centrifugal force, liquid in the cup-shaped container crosses the cup port, the liquid impacts the surface of the first layer of disc-shaped rotating disc running in the opposite direction and is dispersed into micro-droplets, the formed micro-droplets continue to impact the second layer of disc-shaped rotating disc running in the opposite direction, after twice dispersion, the micro-droplets fly out of the rotating discs, under the temperature (the solidification temperature is set to be 25 ℃) and the airflow action, organic solvent continuously volatilizes, risperidone is separated out of.
Example 5:
the particle size distribution of the microsphere samples of examples 3-4 was analyzed by a particle size analyzer (Mastersizer 2000) by wet method, and the medium was 0.1% Tween 80 solution.
The detection result of the particle size of the microspheres shows that the implementation method provided by the invention can obtain different particle size ranges, and the particle size distribution is concentrated and the uniformity is good.
TABLE 1 microsphere particle size distribution results
Example 6:
drug loading and encapsulation efficiency measurements were performed on the microsphere samples of examples 3-4 using HPLC (Agilent). The sample preparation method comprises the following steps: accurately weighing 10mg of dried microspheres, adding 2mL of acetonitrile to fully dissolve the microspheres, filtering the microspheres through a 0.22 mu m VDF filter membrane, detecting the risperidone peak area at 274nm by HPLC, and calculating the drug content according to a standard curve. Wherein:
the drug loading capacity (%) < actual microsphere drug content/microsphere mass x 100%
The encapsulation ratio (%) - < actual microsphere drug content/theoretical microsphere drug content × 100%
The microsphere encapsulation efficiency result shows that the microsphere encapsulation efficiency of the implementation method provided by the invention is more than 96%.
TABLE 2 microsphere drug loading and encapsulation efficiency results
Example 7:
residual solvent was determined by gas chromatography (Shimadzu, GC-2014C) on microsphere samples from examples 3-4.
TABLE 3 residual solvent results
Example 8:
risperidone microsphere in vitro release assays were performed using in vitro release media recommended by FDA guidelines. The preparation method of the in vitro release liquid (20L) comprises the following steps:
weighing 40g of sodium azide and adding the sodium azide into 760g of deionized water;
weighing 18.76kg of deionized water into a 20L container;
adding 200g of 1M HEPES buffer solution to the container;
weighing 116g of sodium chloride and adding into 1kg of deionized water;
adding a sodium chloride solution to the vessel;
adding 80mL of sodium azide solution into the container;
adding 4ml of tween 20 to the vessel;
adjusting the pH value to 7.4 +/-0.1 by using HCl;
the osmotic pressure was maintained at 200. + -. 20 mOsm.
20mg of risperidone microspheres were weighed, dispersed in 50mL of the in vitro release solution, and then allowed to stand at 37 ℃ to sample at a fixed point for HPLC detection. Comparative example 1Risperidal, a Risperidal preparation for injection currently used clinically, was used
(Chinese name: Hengde), developed by the company Alkermes, marketed in 8 months in 2002. The in vitro release profiles of the microspheres of examples 3-4 and comparative example 1 are shown in FIG. 5. And Risperidal in comparative example 1
Compared with the prior art, the risperidone microsphere obtained by the embodiment of the invention has better slow release effect, no early lag phase, stable later release and no need of oral risperidone tablets in the early stage for clinical administration.
Example 9:
morphological observation is carried out on the microsphere sample by adopting an optical microscope, and the results are shown in fig. 6-7, and the risperidone microspheres prepared in examples 3-4 have round surfaces, higher dispersity and no adhesion among the microspheres.
Comparative example 1Risperidal
Preparation ofProcess for the preparation of a coating
First, 40g of risperidone was weighed and dissolved in a benzyl alcohol solvent, and 60g of plga (Mw12 × 10) was weighed (Mw12 ×)4) Dissolving in a dichloromethane solvent, wherein the volume ratio of benzyl alcohol to dichloromethane is 1: and 3, respectively dissolving, stirring and mixing for 15min to obtain a homogeneous solution.
Preparing 1% PVA aqueous solution, and adding ethyl acetate to enable the PVA aqueous solution to reach a saturated state.
Preparing 25kg of 2.0% ethyl acetate aqueous solution, and cooling to 6 ℃.
And fourthly, mixing the oil phase and the water phase by using a static mixer, pumping the formed coarse milk into a cold immersion liquid three, and extracting for 4 hours at 250 rpm.
And fifthly, collecting the microspheres, washing with an aqueous solution, and drying in vacuum.
Sixthly, washing the dried microspheres with 25% ethanol solution at 250rpm for 4 hours.
And collecting microspheres, washing with an aqueous solution, and drying in vacuum.
The drug loading of the microspheres was 35.8% and the encapsulation efficiency was 79.6%.
Compared with the comparative example 1 (solvent extraction method), the method can accurately control the particle size distribution of the microspheres, remove microspheres with particle sizes larger than 150 μm without sieving, reduce the total residual organic solvent (0.7 percent of benzyl alcohol, 0.05 percent of ethyl acetate and 0.1 percent of ethanol) to be less than 0.05 percent, increase the yield from 62 percent to 93 percent and increase the encapsulation efficiency from 89 percent to 97 percent.
The batch processing amount of the invention can be increased from (500g, 3000) thousands of traditional processes to (2000g, 2.4 ten thousand) thousands of traditional processes, and the implementation method provided by the invention is more suitable for large-scale industrial production.
The above embodiments are not intended to limit the invention in any way, and other variations may exist without departing from the claims.
Claims (15)
1. A preparation method of a risperidone microsphere preparation is characterized by comprising the following steps:
dissolving risperidone in a well-soluble organic solvent, dissolving PLGA in another volatile organic solvent, respectively dissolving the two solutions, and mixing and stirring to form a homogeneous solution, wherein the final viscosity of the homogeneous solution is 150-350 cp;
and (2) feeding the homogeneous solution obtained in the step (1) into a cup-shaped container in the center of the turntable device, enabling the feed liquid in the cup-shaped container to cross over a cup mouth, impacting an outer disc-shaped turntable under the action of centrifugal force and gravity to disperse into micro-droplets, continuously impacting the outer disc-shaped turntable with the formed micro-droplets, and after two or more actions, enabling the micro-droplets to fly out of the turntable to be solidified to form microspheres.
2. The method of claim 1, wherein: the turntable device is of a turntable structure, a cup-shaped container and a driving device thereof are arranged in the center of the turntable structure, at least two layers of disc-shaped turntables are sequentially nested outside the cup-shaped container, and each layer of disc-shaped turntable is provided with a corresponding driving device.
3. The method according to claim 2, wherein the cup-shaped container is a narrow-mouth cup-shaped container having a narrow top and a wide bottom, and the cup-shaped container and the outer disk-shaped rotating disk thereof have smooth outer peripheral edges.
4. The method for preparing the glass-shaped container according to claim 3, wherein the short diameter of the cup-shaped container is D1, the long diameter is D2, and the height is H1, wherein the ratio of D1 to D2 is 1/2-2/3.
5. The manufacturing method according to claim 4, wherein the inner diameter of the disc-shaped rotating disc of the first layer is set to D3 and the height is set to H3, the inner diameter of the disc-shaped rotating disc of the second layer is set to D4 and the height is set to H4, and so on; wherein the ratio of D3 to H3 is 1.5-2.0, and the ratio of H3 to H1 is 2.5-3.0.
6. The production method according to claim 5, wherein the ratio of D4/H4 is set smaller than D3/H3 to obtain a stronger secondary collision effect.
7. The method according to claim 1, wherein the rotation speed of the cup-shaped container in the step (2) is 10 to 150m/s, and the rotation speed of the outer disk-shaped rotating disk is 50 to 250 m/s.
8. The preparation method according to claim 1, wherein the risperidone in the step (1) is 10-40 wt%; the PLGA accounts for 60-90 wt%.
9. The preparation method according to claim 8, wherein the risperidone in the step (1) is 25-35% by mass; the mass percentage of the PLGA is 65-75%.
10. The preparation method according to claim 1, wherein in the step (1), the well-soluble organic solvent is ethanol or dichloromethane, the volatile organic solvent is dichloromethane, the volume ratio of the well-soluble organic solvent to the volatile organic solvent is 20: 80-40: 60, and the mixing time of the homogeneous solution is 0-3 h.
11. The preparation method according to claim 10, wherein in the step (1), the volume ratio of the well-soluble organic solvent to the volatile organic solvent is 25: 75-30: 70, and the mixing time of the homogeneous solution is 15-60 min.
12. The method according to claim 1, wherein the final viscosity of the homogeneous solution in the step (1) is 200 to 300 cp.
13. The method according to any one of claims 1 to 12, wherein the ratio of LA: the GA mass percentage is 85: 25-50: 50.
14. The method of claim 13, wherein the ratio of LA: the GA mass percent is 75: 25.
15. A risperidone microsphere formulation prepared by the method of any one of claims 1-12.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4256677A (en) * | 1976-04-12 | 1981-03-17 | Magnavox Government And Industrial Electronics Co. | Apparatus and method for making small spheres |
| CN85104032A (en) * | 1984-05-18 | 1986-11-19 | 华盛顿大学技术协会公司 | Method and apparatus for coating fine particles and liquid droplets |
| JPH0747261A (en) * | 1993-06-04 | 1995-02-21 | Hosokawa Micron Corp | Particle treatment apparatus |
| CN101304763A (en) * | 2005-09-07 | 2008-11-12 | 西南研究所 | Biodegradable microparticle pharmaceutical formulations exhibiting improved release rates |
| KR20080101559A (en) * | 2007-05-18 | 2008-11-21 | 삼성코닝정밀유리 주식회사 | Rotary type drying atomizer and drying chmber comprising the same |
| CN101816913A (en) * | 2010-05-20 | 2010-09-01 | 吴传斌 | Method and equipment for manufacturing microspheres |
| CN102099101A (en) * | 2008-07-07 | 2011-06-15 | 荷兰应用自然科学研究组织Tno | Multi component particle generating system |
| US20180207602A1 (en) * | 2015-06-26 | 2018-07-26 | Southwest Research Institute | Multi-Disk Spinning Disk Assembly for Atomization and Encapsulation with Spacing Disks for Adjusting Exit Gap |
| CN109049266A (en) * | 2018-08-27 | 2018-12-21 | 天津水泥工业设计研究院有限公司 | A kind of Granulation Equipments, system and the technique of the dry method flouring technology for low water absorption glazed tile |
-
2019
- 2019-01-31 CN CN201910100427.1A patent/CN109806242B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4256677A (en) * | 1976-04-12 | 1981-03-17 | Magnavox Government And Industrial Electronics Co. | Apparatus and method for making small spheres |
| CN85104032A (en) * | 1984-05-18 | 1986-11-19 | 华盛顿大学技术协会公司 | Method and apparatus for coating fine particles and liquid droplets |
| JPH0747261A (en) * | 1993-06-04 | 1995-02-21 | Hosokawa Micron Corp | Particle treatment apparatus |
| CN101304763A (en) * | 2005-09-07 | 2008-11-12 | 西南研究所 | Biodegradable microparticle pharmaceutical formulations exhibiting improved release rates |
| KR20080101559A (en) * | 2007-05-18 | 2008-11-21 | 삼성코닝정밀유리 주식회사 | Rotary type drying atomizer and drying chmber comprising the same |
| CN102099101A (en) * | 2008-07-07 | 2011-06-15 | 荷兰应用自然科学研究组织Tno | Multi component particle generating system |
| CN101816913A (en) * | 2010-05-20 | 2010-09-01 | 吴传斌 | Method and equipment for manufacturing microspheres |
| US20180207602A1 (en) * | 2015-06-26 | 2018-07-26 | Southwest Research Institute | Multi-Disk Spinning Disk Assembly for Atomization and Encapsulation with Spacing Disks for Adjusting Exit Gap |
| CN109049266A (en) * | 2018-08-27 | 2018-12-21 | 天津水泥工业设计研究院有限公司 | A kind of Granulation Equipments, system and the technique of the dry method flouring technology for low water absorption glazed tile |
Non-Patent Citations (1)
| Title |
|---|
| 微丸制备与设备进展;邹龙贵;《机电信息》;20071231(第170期);第37-41页 * |
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