CN112451483B - Preparation method of paliperidone palmitate suspension - Google Patents
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Abstract
The invention discloses a preparation method of paliperidone palmitate suspension, which comprises the following steps: (1) dispersing and dissolving paliperidone palmitate drug particles in a first good water-soluble solvent containing a surfactant to obtain a drug solution; (2) slowly adding the drug solution into a second water-soluble solvent, simultaneously adding energy to quickly precipitate drug particles, and re-suspending to obtain a suspension. The invention does not need complex equipment, has simple preparation process and does not have the problem of metal medium or organic solvent residue.
Description
Technical Field
The invention relates to the technical field of medicine production, and particularly relates to a preparation method of paliperidone palmitate suspension.
Background
Since the 90 s of the last century, a large number of new drug candidate molecules have been discovered in succession, but one of the great challenges facing the market for these new drug molecules is their low bioavailability in vivo, mainly due to their extremely low water solubility, which is understood to be that 40% of the new drug molecules belong to this class of poorly soluble drugs. To solve this problem, formulators have developed a variety of formulation approaches to increase their solubility and thus increase their bioavailability, including inclusion complex formation with cyclodextrins, micelle or lipid nanoparticle formation with amphiphilic materials, solubilization with surfactants, particle size reduction, and the like. Among them, the bioavailability of poorly soluble drugs is improved by decreasing the particle size of the drug and increasing the specific surface area, and such a formulation means for preparing nanocrystals or microcrystals has been considered to be very promising in recent years, and many new drug varieties based on this technology have been largely successful in the market (Jarvis M, Krishnen V, Mitragortri S. nanocrystals: A permanent on translational research and clinical trials [ J ]. Bioengineering & translational media, 2019,4(1): 5-16.).
Paliperidone (also translated as paliperidone), also called 9-hydroxyrisperidone, is the major active metabolite of risperidone. Paliperidone palmitate is a palmitate ester of paliperidone and is a monoaminergic antagonist that exhibits dopamine 2(D2) and serotonin (5-hydroxytryptamine type 2A, 5HT2A) antagonisms characteristic of second generation atypical antipsychotics. Paliperidone palmitate is named as (+/-) -3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidine ] ethyl ] -6, 7, 8, 9-tetrahydro-2-methyl-4-oxo-4H-pyridine [1, 2-a ] pyrimidin-9-yl palmitate and has the following chemical structural formula:
the above formula is paliperidone palmitate
Paliperidone palmitate has very low water solubility, only 0.007mg/mL in water, and low solubility in a variety of solvents, 330mg/mL in dichloromethane, 2.8mg/mL in ethyl acetate, and 0.35mg/mL in methanol at 20 deg.C, and it is also very slightly soluble in ethanol and methanol, practically insoluble in PEG400 and propylene glycol, and slightly soluble in ethyl acetate.
The poor solubility of paliperidone palmitate leads to very low bioavailability in vivo, and the particle size of the raw material medicament is reduced to prepare the paliperidone palmitate into a nanocrystal suspension clinically at present so as to improve the water solubility of the paliperidone palmitate and increase the absorption rate and the bioavailability of the paliperidone palmitate. The main products represented by this approach are the nanocrystalline products Invega Sustenna and Invega Triza marketed by Yanson company by the FDA in 2009 and 2015 successively
The patent technology greatly reduces the particle size of the paliperidone palmitate bulk drug by a ball milling method, thereby increasing the specific surface area and the bioavailability, and simultaneously achieving the slow release purpose of 1 month and 3 months by utilizing the storage effect of particles with different sizes at the injection part. At present, the preparation scientists at home and abroad prepare various paliperidone palmitate sustained-release preparations based on the method.
Chinese patent CN106137985 discloses a preparation method of paliperidone palmitate freeze-dried preparation, which actually reduces the particle size of the raw material drug by high-pressure homogenization or wet grinding, and freezes the suspension into powder injection after adding stabilizers such as surfactant, and the method has no substantial difference with the product of Yangsen, and only increases the storage stability of the suspension by freezing; indian patent WO2016157061 discloses a method for preparing sterile small particle paliperidone palmitate suspensions, which is also based on the yankee ball milling method, by grinding using two sizes of grinding beads one after the other to give a suspension with a mean particle size of less than 2 μm. The method still needs to rely on a grinder device, and during the process, grinding beads are replaced under aseptic conditions, so that the risk of aseptic challenge and the process complexity are increased;
international patent WO2019118722 is based on a ball milling method using polystyrene beads of 0.5mm to 1.5mm to obtain a paliperidone palmitate nanosuspension with a particle size distribution of 1 μm to 30 μm, the formulation composition of which is substantially the same as that of a vigorous product and includes a wetting agent, a suspending agent, a pH adjusting agent, and the like;
the products prepared by the ball milling method have great success in the world, but the 'Top-down' method for preparing the nanocrystalline based on complex equipment such as a homogenizer or a ball mill has certain limitations, such as long production time, possibly needing to reduce the particle size through airflow crushing equipment before homogenizing or ball milling, and possibly having the problems of medium residue and the like when the medium is used for milling.
In addition to the above-mentioned "Top-down" method, another method is also commonly used for the preparation of nanocrystals, namely the "Bottom-up" method, also known as "nano-precipitation" or "micro-precipitation", which mainly involves an anti-solvent precipitation technique, and does not require complicated production equipment and longer production time, nor concern about medium residues, compared to the "Top-down" method; however, organic solvents are generally used in such processes, and thus, solvent residues are a common drawback of such processes.
Chinese patent CN109400602 discloses a method for preparing a paliperidone palmitate nanocrystalline suspension, which utilizes the solubility difference of paliperidone palmitate in dichloromethane and n-heptane, and prepares a nanosuspension preparation with a small particle size by means of micro-precipitation, although the method is simple and does not need complex and expensive production equipment, the method cannot avoid the common defect of the micro-precipitation method, namely the residue of an organic solvent, and the good solvent and the non-good solvent used by the method are not aqueous solutions, so the risk of organic solvent residue is greater;
taiwan patent TW107120528A discloses a method for preparing paliperidone palmitate nanocrystalline suspension by micro-precipitation, 36 combinations are screened in the research, in order to precipitate as nanoparticles by using solubility difference of paliperidone palmitate in two mutual solvents, two combinations with better results are tetrahydrofuran/water and toluene/heptane (or hexane), a narrower particle size distribution is obtained, but from the screening result, it is still unavoidable to use a large amount of organic solvents;
international patent WO2016199170 discloses a nanosuspension prepared by a precipitation method, which is characterized in that API is instantaneously precipitated by using solubility differences of paliperidone palmitate in solvents of different temperatures, thereby possibly obtaining a nanocrystalline suspension with a narrow particle size distribution, wherein a large amount of ethanol is used, and the ethanol is rapidly cooled after being heated to 72-78 ℃, which has a great safety risk for industrial production and the ethanol residue cannot be avoided;
in the above-listed "Bottom-up" methods, the drug substance is precipitated by utilizing the solubility difference of drug particles in different organic solvents to prepare the nanocrystal preparation, and usually a good solvent or a poor solvent is preferably an aqueous solution to reduce the use of organic solvents. In addition, there is a preferable precipitation method which does not involve an organic solvent, such as preparation of nanoparticles using a difference in solubility of a drug in a buffer system of a specific pH. Neiwang et al (Neiwang, Shenbao, Shenying, etc. pH-dependent dissolution/precipitation method for preparing meloxicam nanosuspension [ J ]. China journal of medical industry, 2018,49(2):192-197.) utilize the characteristic of meloxicam weakly acidic compound to prepare nanosuspension with the average particle size of only 200nm by an alkali-soluble acid precipitation method; xiiaofeng Yang et al (Yang X, Liu Y, Zhao Y, et al. A. Stabilizer-free and organic solvent-free method to prepare 10-hydroxyamphytecen nanocrystals: in vitro and in vivo evaluation [ J ]. International journal of nanomedicine,2016,11:2979.) also utilized the principle of ring-opening dissolution of 10-hydroxycamptothecin ring in base and ring-closing precipitation in acid to prepare nanocrystalline formulations with an average particle size of 130 nm. Such a process has the advantage of not requiring complex and expensive high energy milling or homogenisation equipment, while avoiding the solvent residue problem of conventional anti-solvent precipitation processes. However, there are no relevant literature reports and researches on paliperidone palmitate particles with extremely poor water solubility.
From the above patents and literature techniques, the main means for preparing paliperidone palmitate nanocrystalline preparation is high-energy medium grinding, high-pressure homogenization or solvent precipitation, and the preparation methods have certain limitations in terms of production equipment, production process, medium residue and solvent residue.
Disclosure of Invention
The invention aims to provide a preparation method of paliperidone palmitate suspension, which does not need complex equipment, has simple preparation process and does not have the problem of metal medium or organic solvent residue.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of paliperidone palmitate suspension comprises the following steps:
(1) dispersing and dissolving paliperidone palmitate drug particles in a first good water-soluble solvent containing a surfactant to obtain a drug solution;
(2) slowly adding the drug solution into a second water-soluble solvent, simultaneously adding energy to quickly precipitate drug particles, and re-suspending to obtain a suspension.
The suspension has narrow particle size distribution and good stability, and can be quickly dispersed by shaking after standing and storage. No organic solvent is needed, the yield is high, and the method is suitable for the industrial production requirement.
Because paliperidone palmitate has extremely poor water solubility and relatively low solubility in various solvents, organic solvents with relatively high solubility such as dichloromethane, tetrahydrofuran, toluene, hot ethanol (methanol, isopropanol and the like) and the like can not be avoided when the suspension is prepared by an anti-solvent precipitation method, but the organic solvents are usually extremely low in exposure limit in a human body, have relatively high solvent residue overrun risk, and are relatively unfriendly to the environment and experimenters.
The inventor finds in research that, although the solubility of paliperidone palmitate drug particles in aqueous solutions under various pH conditions is very low (<0.001g/100ml), when the paliperidone palmitate particles are dispersed in a certain proportion of acetic acid solution, the drug particles are rapidly dissolved by slight shaking, and the solution is clear and transparent; and once the acetic acid solution ratio is decreased or the drug-dissolved solution is added to the poor solvent, the drug particles are rapidly precipitated.
Paliperidone and paliperidone palmitate have pKa of 8.76, and are alkaline, which is mainly determined by the tertiary amine nitrogen on the piperidine ring in the paliperidone molecular structure, but because of the strong hydrophobicity of the two drug molecules, the solubility is low even in an acidic solution. However, in a certain concentration of acetic acid solution, it is suspected that the solubility of the drug molecule is increased probably due to the effect of hydrogen bond formation between acetic acid and tertiary amine nitrogen on piperidine ring of the drug molecule, so the acetic acid solution in a specific concentration range becomes a good solvent for the paliperidone palmitate drug molecule. On the other hand, when the acetic acid concentration is lowered or a solution of a drug dissolved in an acetic acid solution is added to a poor solvent, intermolecular hydrogen bonding is broken, so that the drug is rapidly precipitated.
In addition, another reason for selecting acetic acid in the present invention is that acetic acid is easily volatilized and very easily removed by a conventional manner.
Preferably, in the step (1), the first good water-soluble solvent is an acid solution.
Preferably, the acid solution is an acetic acid solution, and the concentration of the acetic acid solution is 30-80%.
Preferably, in step (2), the drug solution is slowly added to the second water-soluble solvent such that the final mass concentration of the acid in the mixture is less than 20%.
Preferably, in the step (1), the surfactant content in the first good water-soluble solvent containing the surfactant is 1.2-3.6 wt%; the surfactant is an ionic surfactant, and the ionic surfactant is selected from one or more of polysorbate and sodium dodecyl sulfate. The ionic surfactant is preferably polysorbate 20.
Preferably, in step (2), the second water-soluble solvent is water.
Preferably, the second water-soluble solvent contains 0.1-3 wt% of a stabilizer; the stabilizer is one or more selected from polysorbate 20, polysorbate 80, sodium dodecyl sulfate, carbomer, poloxamer, methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone. The stabilizers are preferably polysorbate 20 and polyethylene glycol 4000.
Preferably, in the step (2), the mode of the external energy is selected from one or a combination of more of high-speed shearing, ultrasound and rapid cooling.
Preferably, the average particle size of the paliperidone palmitate drug particles is 5-200 μm; the final concentration of paliperidone palmitate drug particles in the suspension is 1-10 wt%. The average particle size of the paliperidone palmitate drug particles is preferably 5-100 mu m.
Preferably, the method further comprises a step (3), wherein the step (3) is to remove acetic acid from the suspension by one or a combination of heating evaporation, vacuum removal and rotary evaporation, so that the final concentration of the acetic acid in the suspension is below 3.5 g/L.
The invention has the beneficial effects that: the invention utilizes the solubility difference of insoluble drug paliperidone palmitate in acetic acid solutions with different concentrations, adopts a micro-precipitation method, and adds energy in a physical mode to further prepare the paliperidone palmitate suspension preparation with uniform particle size distribution and better stability.
Drawings
FIG. 1 is a graph showing the particle size distribution of the finished suspension prepared in examples 1-3; wherein 1 represents the finished suspension of example 1, 2 represents the finished suspension of example 2, and 3 represents the finished suspension of example 3.
FIG. 2 shows the appearance and resuspension of the suspensions of the final products prepared in examples 1-3.
FIG. 3 is the stability at room temperature of the suspension prepared in example 1.
Figure 4 is the stability at room temperature of the suspension prepared in example 2.
Figure 5 is the stability at room temperature of the suspension prepared in example 3.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
General description of the embodiments
A preparation method of paliperidone palmitate suspension comprises the following steps:
(1) dispersing and dissolving paliperidone palmitate drug particles in a first good water-soluble solvent containing a surfactant to obtain a drug solution; the first good water-soluble solvent is an acid solution. The acid solution is an acetic acid solution, and the concentration of the acetic acid solution is 30-80%. The surfactant content of the first water-soluble good solvent containing the surfactant is 1.2-3.6% by weight.
(2) Slowly adding the drug solution into a second water-soluble solvent containing a stabilizer, adding energy into the drug solution into the second water-soluble solvent containing the stabilizer, rapidly precipitating drug particles, and performing heavy suspension to obtain a suspension; and removing acetic acid from the suspension by one or more of heating evaporation, vacuum removal and rotary evaporation, so that the final concentration of the acetic acid in the suspension is below 0.35%. The weight percentage content of the stabilizer in the second water-soluble solvent containing the stabilizer is 0.1-3%, and the second water-soluble solvent is water. The stabilizer is one or more selected from polysorbate 20, polysorbate 80, sodium dodecyl sulfate, carbomer, poloxamer, methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone. The average particle size of the paliperidone palmitate drug particles is 5-200 mu m; the final concentration of paliperidone palmitate drug particles in the suspension is 1-10 wt%. The mode of the external energy is selected from one or a combination of more of high-speed shearing, ultrasonic and rapid cooling.
Example 1
Preparation of a suspension with a final concentration of active substance (pharmaceutical ingredient) of about 1%:
sequentially stirring and dissolving 5g of glacial acetic acid and 0.6g of polysorbate 20 in 6g of ultrapure water until the solution is clear, dispersing and dissolving 5g of paliperidone palmitate particles (the average particle size is about 5 mu m) in the aqueous solution at room temperature, and fully stirring and uniformly mixing until the solution is clear;
dropwise adding the dissolved clear solution into 450g of ice water containing 2% of polysorbate 20 (the water temperature is controlled to be 0-3 ℃) through a peristaltic pump (Cole-Parmer, 07523-80) and an injection needle (the speed is controlled so that the solubility of the dissolved hydrophobic drug particles is rapidly reduced and separated out), and simultaneously adding high shear (IKA, T25 shear head) into the ice water bath at the rotation speed of 13000 rpm; in the dropping process, the drug particles are continuously separated out and dispersed; after the dropwise addition is finished, continuously carrying out ice bath and heat preservation (at 0-3 ℃) and stirring for 0.5-1 h; standing the solution to return to room temperature, adding a prepared phosphate buffer solution, keeping physiological osmotic pressure, and adjusting the pH value of the suspension to about 7.0; vacuumizing and stirring the suspension for 4-5 h at room temperature until the concentration of acetic acid is lower than 3.5 g/L;
the final suspension was measured to have a particle size distribution of: d10 ═ 0.603 μm; d50 ═ 1.096 μm; d90 ═ 2.758 μm.
Example 2
Preparation of a suspension with a final concentration of active substance of about 5%:
sequentially stirring and dissolving 5g of glacial acetic acid and 0.45g of polysorbate 20 in 2g of ultrapure water until the solution is clear, dispersing and dissolving 5g of paliperidone palmitate particles (the average particle size is about 76 mu m) in the aqueous solution at room temperature, and fully stirring and uniformly mixing until the solution is clear;
dropwise adding the dissolved clear solution into 85g of ice water containing 3% polyethylene glycol 4000 (the water temperature is controlled to be 0-3 ℃) through a peristaltic pump (Cole-Parmer, 07523-80) and an injection needle (the speed is controlled so that the solubility of the dissolved hydrophobic drug particles is rapidly reduced and separated out), and simultaneously adding high shear (IKA, T25 shear head) into the ice water bath at the rotation speed of 13000 rpm; in the dropping process, the drug particles are continuously separated out and dispersed; after the dropwise addition is finished, continuously carrying out ice bath and heat preservation (at 0-3 ℃) and stirring for 0.5-1 h; standing the solution to return to room temperature, adding a prepared phosphate buffer solution, keeping physiological osmotic pressure, and adjusting the pH value of the suspension to about 7.0; rotationally evaporating the suspension for 1-2 h at about 30 ℃ in a water bath until the concentration of the acetic acid is lower than 3.5 g/L; the final suspension particle size distribution was measured as: d10 ═ 2.143 μm; d50 ═ 3.751 μm; d90 ═ 6.513 μm.
Example 3
Preparation of a suspension with a final concentration of active substance of about 10%:
sequentially stirring 8g of glacial acetic acid and 0.54g of polysorbate 20 and dissolving in 1.4g of ultrapure water until the solution is clear, dispersing and dissolving 5g of paliperidone palmitate particles (the average particle size is 192 microns) in the aqueous solution at room temperature, and fully stirring and uniformly mixing until the solution is clear;
dropwise adding the dissolved clear solution into 35g of ice water containing 2.85% of sodium carboxymethylcellulose (the water temperature is controlled to be 0-3 ℃) through a peristaltic pump (Cole-Parmer, 07523-80) and an injection needle (the speed is controlled so that the solubility of the dissolved hydrophobic drug particles is rapidly reduced and precipitated), and simultaneously adding high shear (IKA, T25 shear head) into the ice water bath at the rotation speed of 15000 rpm; in the dropping process, the drug particles are continuously separated out and dispersed; after the dropwise addition is finished, continuously carrying out ice bath and heat preservation (at 0-3 ℃) and stirring for 0.5-1 h; standing the solution to return to room temperature, adding a prepared phosphate buffer solution, keeping physiological osmotic pressure, and adjusting the pH value of the suspension to about 7.0; vacuumizing and stirring the suspension for 1-2 h at room temperature until the concentration of acetic acid is lower than 3.5 g/L;
the final suspension was measured to have a particle size distribution of: d10 ═ 2.03 μm; d50 ═ 5.096 μm; d90 ═ 12.158 μm.
Example 4
Particle size distribution
The particle size distributions of the finished suspensions prepared in examples 1 to 3 were measured by a malvern 2000 particle sizer, and the results are shown in fig. 1, wherein the particle size distributions of the suspensions of 3 active ingredients with different concentrations are narrow, and the corresponding span (span) values are 1.97, 1.17 and 1.99 (the span value of the santa suspension of the yanson company is in the range of 1.7 to 2.0).
Resuspension
After the suspension prepared in examples 1 to 3 was allowed to stand at room temperature for 1 week, it was re-shaken and dispersed, and its resuspension was observed. The results are shown in figure 2, the suspensions of 3 active ingredients with different concentrations are layered after standing, the upper layer is clearer, and the lower layer is drug particle sediment; after shaking up, it was observed that the suspension immediately redispersed uniformly and no more demixed in a short time. Thus, the finished suspension prepared in 3 examples has better redispersibility.
Stability of
The suspension prepared in the embodiment 1-3 is placed at room temperature for 1, 3 and 6 months respectively, the particle size of the suspension is measured by sampling, as shown in the attached drawings 3-5, the particle size fluctuation of each suspension sample is small in stability test at room temperature for 6 months, and the paliperidone palmitate suspension prepared by the invention has good stability.
Example 5
Solubility study of drug solution in acetic acid solution
Respectively dripping the paliperidone palmitate solution containing the surfactant into the solutionThe dissolution was observed in acetic acid solutions of different concentrations and is detailed in the following table:
| acetic acid mass concentration (%) | Solution state after drug addition | Measurement of solubility (mg/mL) |
| 5 | Turbidity | Much less than 0.03 |
| 10 | Turbidity | Much less than 0.03 |
| 20 | Clarification | About 0.03 |
| 30 | Clarification | Is about 500 |
The experimental result shows that the solubility of the paliperidone palmitate is lower when the acetic acid concentration is less than 20%, and the solubility is obviously increased when the acetic acid concentration is increased to 30%. Therefore, 30-80 wt% of acetic acid solution is selected as the dissolving and dispersing solution in the first step (considering that the hydrophobicity of the drug is strong, pure glacial acetic acid is not beneficial to the dispersing and dissolving of the drug).
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (7)
1. A preparation method of paliperidone palmitate suspension is characterized by comprising the following steps:
(1) dispersing and dissolving paliperidone palmitate drug particles in a first good water-soluble solvent containing a surfactant to obtain a drug solution;
(2) slowly adding the drug solution into a second water-soluble solvent, simultaneously adding energy to quickly precipitate drug particles, and performing heavy suspension to obtain a suspension;
in the step (1), the first water-soluble good solvent is an acid solution; the acid solution is an acetic acid solution, and the mass concentration of the acetic acid solution is 30-80%;
in the step (2), after the drug solution is slowly added into the second water-soluble solvent, the final mass concentration of the acid in the mixed solution is less than 20%.
2. The preparation method according to claim 1, wherein in the step (1), the surfactant content in the first good water-soluble solvent containing the surfactant is 1.2-3.6 wt%; the surfactant is an ionic surfactant, and the ionic surfactant is selected from one or more of polysorbate and sodium dodecyl sulfate.
3. The method according to claim 1, wherein in the step (2), the second water-soluble solvent is water.
4. The method according to claim 3, wherein the second water-soluble solvent contains 0.1 to 3wt% of a stabilizer; the stabilizer is one or more selected from polysorbate 20, polysorbate 80, sodium dodecyl sulfate, carbomer, poloxamer, methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone.
5. The preparation method according to claim 1, wherein in the step (2), the external energy is selected from one or more of high-speed shearing, ultrasound and rapid cooling.
6. The preparation method according to claim 1, wherein the average particle size of the paliperidone palmitate drug particles is 5-200 μm; the final concentration of paliperidone palmitate drug particles in the suspension is 1-10 wt%.
7. The preparation method according to claim 1, further comprising a step (3), wherein the step (3) is to remove acetic acid from the suspension by one or more of heating evaporation, vacuum removal and rotary evaporation, so that the final concentration of acetic acid in the suspension is below 3.5 g/L.
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| FR2608988B1 (en) * | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOPARTICLES |
| US7037528B2 (en) * | 2000-12-22 | 2006-05-02 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
| CN101322682A (en) * | 2008-07-29 | 2008-12-17 | 沈阳药大制剂新技术有限公司 | Preparation of indissoluble medicament nano granule |
| US9963449B2 (en) * | 2015-01-19 | 2018-05-08 | Aurobindo Pharma Ltd | Process for the preparation of Paliperidone palmitate |
| CN104887626A (en) * | 2015-05-29 | 2015-09-09 | 沈阳药科大学 | Preparation method of nano suspension |
| CN109400602B (en) * | 2017-08-15 | 2021-09-28 | 正大天晴药业集团股份有限公司 | Preparation method of paliperidone palmitate |
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