A stable long-acting composition of paliperidone palmitate and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a stable long-acting composition of paliperidone palmitate and a preparation method thereof. The preparation method of the stable long-acting composition of paliperidone palmitate comprises: preparing a suspension of paliperidone palmitate; pouring the suspension into a double-chamber syringe and freeze-drying; after the double-chamber syringe is plugged for the first time, a reconstitution liquid is poured into a separate compartment; the double-chamber syringe is plugged for the second time to obtain the long-acting composition of paliperidone palmitate. The long-acting composition of paliperidone palmitate of the present invention uses paliperidone palmitate as an effective ingredient, which is filled in a syringe with a double-chamber structure, is easy to use, and has good redispersibility and physical stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a stable long-acting composition of paliperidone palmitate and its preparation method. Background Technology

[0002] Paliperidone palmitate is a prodrug of paliperidone, which is hydrolyzed in the body to paliperidone, the main metabolite of risperidone. Paliperidone palmitate injection is a second-generation atypical long-acting antipsychotic developed by Johnson & Johnson. The suspension contains particles of different sizes; initially, the release is primarily from small particles, allowing for rapid achievement of effective blood drug concentrations. Later in the course of administration, the release is primarily from larger particles, resulting in a long-lasting effect. This effectively overcomes the time lag barrier of other long-acting antipsychotics and can be used simultaneously for the treatment of both the acute and maintenance phases of schizophrenia. Currently, marketed paliperidone palmitate injection is packaged as a suspension in pre-filled syringes. Shaking before use ensures the solution is resuspended and homogenized, facilitating clinical administration.

[0003] Paliperidone palmitate injection is a thermodynamically unstable system. During long-term storage, it undergoes Ostwald ripening, characterized by the dissolution of smaller crystalline particles in the solute and their deposition on top of larger particles. This process leads to the disappearance of smaller particles and the growth of larger particles, resulting in an increase in the average particle size. Changes in particle size directly alter the drug release rate, thus posing risks to the clinical application of the drug and the treatment of diseases.

[0004] The European Medicines Agency (EMA) review report on paliperidone palmitate injection (injected once every 3 months) noted that a significant increase in particle size was observed under test conditions of 50°C. This increase in particle size due to Ostwald ripening was also observed under accelerated testing for 6 months (40°C / 25%RH) and long-term testing for 12 months (30°C).

[0005] To inhibit Ostwald ripening and improve formulation stability, pharmaceutical professionals have conducted extensive research. Chinese invention patent CN106137985A discloses a stable long-acting paliperidone palmitate formulation. This method utilizes airflow milling and ball milling techniques to control the particle size of paliperidone palmitate to 2–10 μm, then fills it into vials and freeze-dries it to obtain lyophilized paliperidone palmitate powder for injection. This technology avoids Ostwald ripening during drug storage and improves formulation stability. However, it requires immediate preparation for use, which is inconvenient. Furthermore, the vial packaging poses a problem of drug residue when the product is reconstituted and drawn into a syringe. Chinese invention patent CN116687849A discloses a method for preparing paliperidone palmitate injection. The method involves wet grinding and heating and pressurizing the final suspension. The resulting paliperidone palmitate injection exhibits good stability and improves the burst release phenomenon. However, the pressurization process in the preparation process places high demands on the production equipment, requiring pressure-resistant containers. This introduces additional costs to production and increases the risks of production operations.

[0006] Currently, the stability of paliperidone palmitate injection during long-term storage remains a critical issue that urgently needs to be addressed. Summary of the Invention

[0007] To address the shortcomings of the prior art, this invention provides a stable long-acting composition of paliperidone palmitate and its preparation method, which has good physical stability and resuspension properties. The drug can be continuously released in vivo for 1 to 3 months. It is packaged in a double-chamber pre-filled syringe for convenient use.

[0008] The specific technical solution is as follows:

[0009] The first objective of this invention is to provide a stable, long-acting composition of paliperidone palmitate, comprising a diluent and a lyophilized block containing paliperidone palmitate, wherein the diluent and the lyophilized block containing paliperidone palmitate are respectively filled into the two chambers of a dual-chamber syringe.

[0010] Furthermore, the lyophilized block containing paliperidone palmitate includes paliperidone palmitate, stabilizer, suspending agent, lyophilization protectant, and pH adjuster; the diluent includes water for injection.

[0011] Furthermore, in the lyophilized block containing paliperidone palmitate, the weight percentage of paliperidone palmitate is 65-90%, the weight percentage of stabilizer is 1-10%, the weight percentage of suspending agent is 1-10%, the weight percentage of lyophilization protectant is 1-15%, and the weight percentage of pH adjuster is 1-5%.

[0012] Furthermore, the stabilizer is selected from one or a mixture of several of polysorbate 20, polysorbate 80, sucrose palmitate, sucrose oleate, sucrose stearate, and sucrose laurate.

[0013] Preferably, the stabilizer is selected from polysorbate and sucrose ester, more preferably a mixture of polysorbate 20 and sucrose palmitate.

[0014] Furthermore, the suspending agent is selected from one or a mixture of several of polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, sodium carboxymethyl cellulose, gelatin, and methyl cellulose.

[0015] Preferably, the suspending agent is selected from polyethylene glycol 4000 and sodium carboxymethyl cellulose, more preferably sodium carboxymethyl cellulose.

[0016] Furthermore, the freeze-drying protectant is selected from one or a mixture of several of mannitol, sucrose, maltose, xylitol, sorbitol, and trehalose, with mannitol being preferred.

[0017] Furthermore, the pH adjuster is selected from one or a mixture of several of phosphates, sodium hydroxide, and citric acid, wherein the phosphates are preferably sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0018] A second objective of this invention is to provide a method for preparing the above-mentioned stable paliperidone palmitate long-acting composition, comprising the following steps:

[0019] (1) Dissolve the stabilizer in water for injection, filter it through a 0.2 μm filter for sterilization, add sterile paliperidone palmitate raw material, stir and mix well, grind to obtain paliperidone palmitate suspension I;

[0020] (2) Add the suspending agent, lyophilization protectant and pH adjuster to water for injection, stir to dissolve, filter with a 0.2μm filter for sterilization, and then add suspension I to obtain suspension II;

[0021] (3) Stir suspension II at 40-50°C for 2-6 hours, add water for injection to make up the volume, and obtain suspension III;

[0022] (4) The suspension III was injected into the first chamber of the dual-chamber syringe, freeze-dried, and stoppered. The diluent was injected into the second chamber of the dual-chamber syringe and the stopper was added again to obtain the long-acting composition of paliperidone palmitate.

[0023] Furthermore, in step (1), the particle size of the paliperidone palmitate sterile raw material is Dv(50)<100μm, preferably Dv(50)<80μm, and more preferably Dv(50)<50μm.

[0024] Furthermore, in step (1), the grinding media used in the grinding process is yttrium-stabilized zirconia beads, the grinding speed is 1000-2000 rpm, and the feed rate is 2-20 L / h, preferably 5-15 L / h.

[0025] Furthermore, in step (3), the concentration of paliperidone palmitate in suspension III is 156–312 mg / mL.

[0026] Furthermore, in step (4), the freeze-drying curve is as follows: pre-freeze at -40℃ for 4 to 6 hours, vacuum up to 200 μbar and maintain for 2 to 4 hours, raise the temperature to -20℃ in 60 minutes and maintain at 200 μbar for 20 to 30 hours, raise the temperature to -10℃ in 60 minutes and maintain at 200 μbar for 10 to 20 hours, raise the temperature to 0℃ in 60 minutes and continue drying at 200 μbar for 5 to 10 hours, and raise the temperature to 20℃ in 60 minutes and maintain at 200 μbar for 2 to 4 hours.

[0027] Furthermore, in step (4), the volume of the diluent is 1.0 to 2.5 mL.

[0028] Furthermore, after reconstitution of the long-acting paliperidone palmitate composition obtained in step (4), the particle size distribution of paliperidone palmitate is Dv(10) 0.3-0.5 μm, Dv(50) 0.8-1.2 μm, and Dv(90) 2.0-3.0 μm; or the particle size distribution is Dv(10) 1.5-3.5 μm, Dv(50) 5.5-7.5 μm, and Dv(90) 12.0-20.0 μm.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] In this invention, polysorbate and sucrose ester are added as composite stabilizers to the formulation of the long-acting paliperidone palmitate composition. Suspension III is dispensed into a dual-chamber syringe, and freeze-drying ensures the long-term stability of paliperidone palmitate particle size. The long-acting paliperidone palmitate composition of this invention exhibits excellent redispersibility and suspension properties. The particle size remains essentially unchanged before and after freeze-drying. Under accelerated testing conditions (40±2℃, 75±5% RH) for 6 months, the particle size and release curve of the composition also show virtually no change, avoiding Ostwald ripening during storage and improving the stability of the formulation. The long-acting paliperidone palmitate composition of this invention disperses well upon reconstitution with gentle shaking and maintains excellent suspension properties. After 24 hours, no sedimentation was observed visually. Multiple light scattering analysis showed that the reconstituted suspension has a very low kinetic instability coefficient, avoiding needle blockage caused by sedimentation during clinical use. It can achieve continuous release in vivo for 1–3 months. The paliperidone palmitate long-acting composition of the present invention is packaged in a dual-chamber syringe, eliminating the need for drug aspiration and transfer during use, ensuring dosage accuracy, and making it very convenient for clinical use. Attached Figure Description

[0031] Figure 1 This is a comparison chart of the stability kinetic index detection of various embodiments and comparative samples of the present invention;

[0032] Figure 2 This is a comparison chart of particle size distribution of sample 0 days and accelerated test 6 months in Example 2 of the present invention;

[0033] Figure 3 This is a comparison diagram of the particle size distribution of Comparative Example 1 sample after 0 days and accelerated test after 6 months.

[0034] Figure 4 The graph shows the changes in Dv(50) and radial distance after 6 months of accelerated testing of various embodiments and comparative samples of the present invention;

[0035] Figure 5 This is a comparison chart of the release rate curves of sample 0 days and accelerated test 6 months in Example 2 of the present invention;

[0036] Figure 6 This is a comparison chart of the release rate curves of Comparative Example 1 sample at 0 days and accelerated test at 6 months.

[0037] Figure 7 This is a graph showing the drug-time (blood drug concentration-time) curve of the sample in SD rats in Example 2 of the present invention;

[0038] Figure 8 This is a pharmacokinetic curve of the sample in Example 4 of the present invention in SD rats. Detailed Implementation

[0039] The principles and features of the present invention are described below with reference to examples. The examples are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0040] Example 1

[0041] A stable long-acting composition of paliperidone palmitate, the components and dosages of which are shown in Table 1.

[0042] Table 1. Components and dosages of Example 1

[0043]

[0044]

[0045] A method for preparing a stable paliperidone palmitate long-acting composition includes the following steps:

[0046] (1) Add 12g of polysorbate 20 and 8g of sucrose palmitate to 300g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 156g of paliperidone palmitate (Dv(50) 36.9μm), stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1200rpm, feed rate 6L / h, to obtain paliperidone palmitate suspension I;

[0047] (2) Add 12g sodium carboxymethyl cellulose, 25g mannitol, 5g sodium dihydrogen phosphate monohydrate, 2.5g anhydrous disodium hydrogen phosphate and 0.8g sodium hydroxide to 400g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0048] (3) Stir suspension II at 45°C for 5 hours, add water for injection to 1000g to obtain suspension III;

[0049] (4) After filling the first chamber of the double-chamber syringe with the suspension III under stirring, insert the double-chamber syringe into the special support container and send it into the freeze dryer for freeze drying. Pre-freeze at -40℃ for 4h, evacuate to 200μbar and maintain for 2h, raise the temperature to -20℃ for 60min and maintain at 200μbar for 26h, raise the temperature to -10℃ for 60min and maintain at 200μbar for 16h, raise the temperature to 0℃ for 60min and continue drying at 200μbar for 8h, raise the temperature to 20℃ for 60min and maintain at 200μbar for 3h; after taking it out of the chamber, add a middle stopper to the double-chamber syringe, fill 1mL of water for injection into the second chamber, and stopper again to obtain the long-acting composition of paliperidone palmitate.

[0050] Example 2

[0051] A stable long-acting composition of paliperidone palmitate, the components and dosages of which are shown in Table 2.

[0052] Table 2 Components and dosages of Example 2

[0053]

[0054]

[0055] A method for preparing a stable paliperidone palmitate long-acting composition includes the following steps:

[0056] (1) Add 10g of polysorbate 20 and 6g of sucrose palmitate to 300g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 156g of paliperidone palmitate (Dv(50)42.3μm), stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1600rpm, feed rate 8L / h, to obtain paliperidone palmitate suspension I;

[0057] (2) Add 12g sodium carboxymethyl cellulose, 30g mannitol, 5g sodium dihydrogen phosphate monohydrate, 2.5g anhydrous disodium hydrogen phosphate and 0.8g sodium hydroxide to 400g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0058] (3) Stir suspension II at 45°C for 5 hours, add water for injection to 1000g to obtain suspension III;

[0059] (4) After filling the first chamber of the double-chamber syringe with the suspension III under stirring, insert the double-chamber syringe into the special support container and send it into the freeze dryer for freeze drying. Pre-freeze at -40℃ for 4h, evacuate to 200μbar and maintain for 2h, raise the temperature to -20℃ for 60min and maintain at 200μbar for 26h, raise the temperature to -10℃ for 60min and maintain at 200μbar for 18h, raise the temperature to 0℃ for 60min and continue drying at 200μbar for 8h, raise the temperature to 20℃ for 60min and maintain at 200μbar for 3h; after taking it out of the chamber, add a middle stopper to the double-chamber syringe, fill 1mL of water for injection into the second chamber, and stopper again to obtain the long-acting composition of paliperidone palmitate.

[0060] Example 3

[0061] A stable long-acting composition of paliperidone palmitate, the components and dosages of which are shown in Table 3.

[0062] Table 3 Components and dosages of Example 3

[0063] Components Dosage Remark Paliperidone palmitate 312g Polysorbate 20 8g Sucrose palmitate 2g Sodium carboxymethyl cellulose 12g Mannitol 20g Sodium dihydrogen phosphate monohydrate 3.75g Sodium hydroxide 0.9g Water for Injection / Add to 1000g, remove during freeze-drying process

[0064] A method for preparing a stable paliperidone palmitate long-acting composition includes the following steps:

[0065] (1) Add 8g of polysorbate 20 and 2g of sucrose palmitate to 350g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 312g of paliperidone palmitate (Dv(50)29.8μm), stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1400rpm, feed rate 7L / h, to obtain paliperidone palmitate suspension I;

[0066] (2) Add 12g sodium carboxymethyl cellulose, 20g mannitol, 3.75g sodium dihydrogen phosphate monohydrate and 0.9g sodium hydroxide to 250g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0067] (3) Stir suspension II at 45°C for 4 hours, add water for injection to 1000g to obtain suspension III;

[0068] (4) After filling the first chamber of the double-chamber syringe with the suspension III under stirring, insert the double-chamber syringe into a special support container and send it into a freeze dryer for freeze drying. Pre-freeze at -40℃ for 5h, evacuate to 200μbar and maintain for 4h, raise the temperature to -20℃ for 60min and maintain at 200μbar for 28h, raise the temperature to -10℃ for 60min and maintain at 200μbar for 18h, raise the temperature to 0℃ for 60min and continue drying at 200μbar for 8h, raise the temperature to 20℃ for 60min and maintain at 200μbar for 3h; after taking it out of the chamber, add a middle stopper to the double-chamber syringe, fill the second chamber with 1.5mL of water for injection, and stopper again to obtain the long-acting composition of paliperidone palmitate.

[0069] Example 4

[0070] A stable long-acting composition of paliperidone palmitate, the components and dosages of which are shown in Table 4.

[0071] Table 4. Components and dosages of Example 4

[0072] Components Dosage Remark Paliperidone palmitate 312g Polysorbate 20 8g Sucrose palmitate 4g Sodium carboxymethyl cellulose 12g Mannitol 20g Sodium dihydrogen phosphate monohydrate 3.75g Sodium hydroxide 0.9g Water for Injection / Add to 1000g, remove during freeze-drying process

[0073] A method for preparing a stable paliperidone palmitate long-acting composition includes the following steps:

[0074] (1) Add 8g of polysorbate 20 and 4g of sucrose palmitate to 350g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 312g of paliperidone palmitate (Dv(50) 36.9μm), stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1600rpm, feed rate 8L / h, to obtain paliperidone palmitate suspension I;

[0075] (2) Add 12g sodium carboxymethyl cellulose, 20g mannitol, 3.75g sodium dihydrogen phosphate monohydrate and 0.9g sodium hydroxide to 250g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0076] (3) Stir suspension II at 45°C for 5 hours, add water for injection to 1000g to obtain suspension III;

[0077] (4) After filling the first chamber of the double-chamber syringe with the suspension III under stirring, insert the double-chamber syringe into a special support container and send it into a freeze dryer for freeze drying. Pre-freeze at -40℃ for 5h, evacuate to 200μbar and maintain for 4h, raise the temperature to -20℃ for 60min and maintain at 200μbar for 28h, raise the temperature to -10℃ for 60min and maintain at 200μbar for 18h, raise the temperature to 0℃ for 60min and continue drying at 200μbar for 8h, raise the temperature to 20℃ for 60min and maintain at 200μbar for 3h; after taking it out of the chamber, add a middle stopper to the double-chamber syringe, fill the second chamber with 1.5mL of water for injection, and stopper again to obtain the long-acting composition of paliperidone palmitate.

[0078] Comparative Example 1

[0079] A paliperidone palmitate composition, the components and dosages of which are shown in Table 5.

[0080] Table 5. Components and dosages of Comparative Example 1

[0081] Components Dosage Paliperidone palmitate 156g Polysorbate 20 12g polyethylene glycol 4000 30g Citric acid monohydrate 5g Sodium dihydrogen phosphate monohydrate 2.5g Anhydrous disodium hydrogen phosphate 5g Sodium hydroxide 2.84g Water for Injection Add to 1000mL

[0082] A method for preparing a paliperidone palmitate composition includes the following steps:

[0083] (1) Add 12g of polysorbate 20 to 300g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 156g of paliperidone palmitate, stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1400rpm, feed rate 7L / h, to obtain paliperidone palmitate suspension I;

[0084] (2) Add 30g polyethylene glycol 4000, 5g citric acid monohydrate, 2.5g sodium dihydrogen phosphate monohydrate, 5g anhydrous disodium hydrogen phosphate, and 2.84g sodium hydroxide to 400g water for injection. After stirring and dissolving, filter through a 0.2μm filter membrane, add suspension I, and add water for injection to 1000mL to obtain suspension II.

[0085] (3) Fill suspension II into a pre-filled syringe to obtain paliperidone palmitate composition.

[0086] Comparative Example 2

[0087] A paliperidone palmitate composition, the components and dosages of which are shown in Table 6.

[0088] Table 6. Components and dosages of Comparative Example 2

[0089] Components Dosage Remark Paliperidone palmitate 156g Polysorbate 20 10g Sodium carboxymethyl cellulose 10g lactose 20g Sodium dihydrogen phosphate monohydrate 5g Anhydrous disodium hydrogen phosphate 2.5g Sodium hydroxide 0.8g Water for Injection / Add to 1000g, remove during freeze-drying process

[0090] A method for preparing a paliperidone palmitate composition includes the following steps:

[0091] (1) Add 10g of polysorbate 20 to 300g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 156g of paliperidone palmitate, stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1200rpm, feed rate 6L / h, to obtain paliperidone palmitate suspension I;

[0092] (2) Add 10g sodium carboxymethyl cellulose, 20g lactose, 5g sodium dihydrogen phosphate monohydrate, 2.5g anhydrous disodium hydrogen phosphate and 0.8g sodium hydroxide to 400g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0093] (3) Stir suspension II at 45°C for 5 hours, add water for injection to 1000g to obtain suspension III;

[0094] (4) The suspension III was filled into vials with stirring, and after being partially stoppered, it was sent to a freeze dryer for freeze drying. It was pre-frozen at -40℃ for 4 hours, vacuumed to 200μbar and maintained for 2 hours, heated to -20℃ for 60 minutes and maintained at 200μbar for 26 hours, heated to -10℃ for 60 minutes and maintained at 200μbar for 16 hours, heated to 0℃ for 60 minutes and continued drying at 200μbar for 8 hours, heated to 20℃ for 60 minutes and maintained at 200μbar for 3 hours; the rubber stopper was pressed, the vial was removed from the box, and the cap was crimped to obtain the paliperidone palmitate composition.

[0095] Comparative Example 3

[0096] A paliperidone palmitate composition, the components and dosages of which are shown in Table 7.

[0097] Table 7. Components and dosages of Comparative Example 3

[0098] Components Dosage Remark Paliperidone palmitate 312g Polysorbate 20 8g Sodium carboxymethyl cellulose 12g lactose 20g Sodium dihydrogen phosphate monohydrate 3.75g Sodium hydroxide 0.9g Water for Injection / Add to 1000g, remove during freeze-drying process

[0099] A method for preparing a paliperidone palmitate composition includes the following steps:

[0100] (1) Add 8g of polysorbate 20 to 350g of water for injection, stir to dissolve, filter with a 0.2μm filter membrane, add 312g of paliperidone palmitate, stir evenly, use yttrium-stabilized zirconia beads as grinding media for grinding, grinding speed 1400rpm, feed rate 7L / h, to obtain paliperidone palmitate suspension I;

[0101] (2) Add 12g sodium carboxymethyl cellulose, 20g mannitol, 3.75g sodium dihydrogen phosphate monohydrate and 0.9g sodium hydroxide to 250g water for injection, stir to dissolve, filter through a 0.2μm filter membrane, add suspension I to obtain suspension II;

[0102] (3) Stir suspension II at 45°C for 4 hours, add water for injection to 1000g to obtain suspension III;

[0103] (4) The suspension III was filled into vials with stirring, and after being partially stoppered, it was sent to a freeze dryer for freeze drying. It was pre-frozen at -40℃ for 5h, vacuumed to 200μbar and maintained for 4h, heated to -20℃ for 60min and maintained at 200μbar for 28h, heated to -10℃ for 60min and maintained at 200μbar for 18h, heated to 0℃ for 60min and continued drying at 200μbar for 8h, heated to 20℃ for 60min and maintained at 200μbar for 3h; the rubber stopper was pressed, the vial was removed from the box, and the cap was crimped to obtain the paliperidone palmitate composition.

[0104] Experiment 1: Comparison of suspension stability between each embodiment and the comparative sample

[0105] The stability of the samples in each embodiment and comparative example was measured using a Turbiscan Tower stability analyzer. The samples were scanned from top to bottom using a pulsed near-infrared light source, and the intensity data of transmitted light and backscattered light were monitored and acquired using two simultaneous optical detectors. The resulting curves depicted the change in backscattering intensity over time. Kinetic instability was assessed based on the curve slope. A larger turbiscan stability index (TSI) and a steeper slope indicated a higher degree of particle aggregation and a less stable dispersion system. Conversely, a smaller TSI and a shallower slope indicated a higher degree of particle dispersion and a more stable dispersion system.

[0106] The reconstituted suspensions of Examples 1-4, the product suspension of Comparative Example 1, and the reconstituted suspensions of Comparative Examples 2-3 were placed in a multiple light scattering instrument. The instrument was set to scan the samples once every 3 minutes, with a measurement temperature of 20°C and a measurement time of 2 hours. The test results are as follows: Figure 1 As shown.

[0107] Figure 1 The test results show that the TSI of the reconstituted suspensions in each embodiment is lower, reflecting that the stability of their dispersion system is better than that of the comparative examples.

[0108] Comparison of particle size stability under accelerated test conditions between each embodiment and the comparative sample in Experiment 2

[0109] The samples prepared in each example and comparative example were placed at 40±2℃ / 75±5%RH for 6 months to examine the changes in particle size distribution of each sample.

[0110] Particle size distribution determination method: Malvern Mastersizer 3000 laser particle size analyzer was used for red light detection. The pump speed was 1250 rpm, the particle refractive index was 1.56, the particle absorptivity was 0.01, the test time was 30 seconds, and the test was performed in triplicate.

[0111] Before testing, the diluent for the products prepared in each embodiment was gently pushed into chamber one, gently shaken, and after the lyophilized block was reconstituted, water was added to dilute to 250 mL for testing. For the product prepared in Comparative Example 1, 1 mL was taken and diluted to 250 mL with water, mixed well, and then tested.

[0112] The particle size variation results for each embodiment and comparative example are shown in Table 8. A comparison of particle size distribution changes between Example 2 and Comparative Example 1 is provided. Figure 2 , Figure 3 As shown, the variations in Dv(50) and radial distance between each embodiment and the comparative example are shown in the figure. Figure 4It should be noted that Dv(10) refers to the particle size corresponding to the cumulative particle size distribution number of particles in the system reaching 10%, Dv(50) refers to the particle size corresponding to the cumulative particle size distribution number of particles in the system reaching 50%, and Dv(90) refers to the particle size corresponding to the cumulative particle size distribution number of particles in the system reaching 90%. The diameter distance indicates the distribution width of the particles: diameter distance = (Dv(90) - Dv(10)) / Dv(50). The larger the diameter distance, the wider the distribution width.

[0113] Table 8 Summary of sample particle size changes under accelerated testing conditions

[0114]

[0115] The particle size distribution measurement results showed that under accelerated test conditions (40±2℃ / 75±5%RH) for 6 months, the particle size of each comparative sample changed to varying degrees, while the particle size and distribution of the sample in the embodiment of the present invention did not change significantly compared with day 0.

[0116] Experiment 3

[0117] The release curves of the samples prepared in Example 2 and Comparative Example 1 were compared and determined after 0 months and 6 months of storage at 40±2℃ / 75±5%RH. The samples from Example 2 were reconstituted with diluent and shaken well before testing, while the samples from Comparative Example 1 were shaken well before testing.

[0118] Release rate testing method:

[0119] The dissolution and release determination method was performed according to Method II of the Chinese Pharmacopoeia 2020 edition. 900 mL of 0.001 mol / L hydrochloric acid solution of 0.489% polysorbate 20 was used as the release medium. The medium temperature was 25 ± 0.5℃, and the rotation speed was 50 rpm. A suspension equivalent to 78 mg of paliperidone palmitate was added. At 1.5 min, 5 min, 8 min, 10 min, 20 min, 30 min, 45 min, and 60 min after the start of the test, 4.5 mL of the release medium was collected and filtered through a 0.22 μm pore size filter membrane. 3 mL was discarded, and 1.5 mL of the subsequent filtrate was used as the test solution for detection by high performance liquid chromatography (HPLC).

[0120] Chromatographic conditions:

[0121] The chromatographic column was a C18 column, with mobile phase A (0.01 mol / L ammonium acetate solution: formic acid = 1000:1) - mobile phase B (acetonitrile: isopropanol: formic acid = 700:300:1) (25:75), flow rate 1.2 mL / min, detection wavelength 275 nm, column temperature 35 ℃, and injection volume 20 μL.

[0122] Test results are shown Figure 5 and Figure 6 .

[0123] The results of the in vitro release rate determination showed that the release rate curve of the sample in Example 2 did not change significantly before and after the accelerated test, while the release rate curve of the sample in Comparative Example 1 was significantly slower after 6 months of accelerated testing than that on day 0, which was related to the increase in its particle size.

[0124] Experiment 4: Pharmacokinetic Study in Rats

[0125] Six SD rats were weighed and administered the reconstituted suspension from Example 2 via intramuscular injection at a dose of 20 mg / kg (calculated as paliperidone). Blood samples were collected from the orbital cavity at 15 min, 1 h, 6 h, 24 h, 2 d, 3 d, 5 d, 7 d, 9 d, 11 d, 14 d, 18 d, 21 d, 25 d, 28 d, 32 d, and 35 d after administration.

[0126] Six SD rats were weighed and administered the reconstituted suspension from Example 4 via intramuscular injection at a dose of 50 mg / kg (calculated as paliperidone). Blood samples were collected from the orbital cavity at 15 min, 1 h, 6 h, 24 h, 2 d, 3 d, 5 d, 7 d, 9 d, 11 d, 14 d, 21 d, 28 d, 35 d, 42 d, 49 d, 56 d, 63 d, 70 d, 77 d, 84 d, and 91 d after administration.

[0127] Blood was collected from each rat (0.25 mL) and placed in a heparin-treated centrifuge tube. The tubes were centrifuged at 12000 rpm for 5 min, and the supernatant was collected and frozen at -80°C for analysis. The plasma concentration of paliperidone was determined by LC-MS / MS, and the results are as follows: Figure 7 and Figure 8 As shown.

[0128] The results showed that the sample in Example 2 could be continuously released in rats for more than 1 month, and the sample in Example 4 could be continuously released in rats for up to 3 months.

[0129] The above experiments demonstrate that the stable paliperidone palmitate long-acting formulation of the present invention exhibits excellent dispersion stability in its suspension. Furthermore, after 6 months of accelerated stability testing, there were no significant changes in particle size, particle size distribution, or release rate. In contrast, the comparative sample showed inferior suspension stability compared to the examples, and after 6 months under accelerated testing conditions, the particle size increased, and the release rate decreased. In vivo pharmacokinetic studies indicate that the examples can achieve sustained drug release in rats for 1–3 months.

[0130] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A stable long-acting composition of paliperidone palmitate, characterized in that: The invention comprises a diluent and a lyophilized mass containing paliperidone palmitate, wherein the diluent and the lyophilized mass containing paliperidone palmitate are respectively filled in two chambers of a double-chamber syringe; The freeze-dried mass containing paliperidone palmitate comprises paliperidone palmitate, a stabilizer, a suspending agent, a freeze-drying protective agent, and a pH regulator; the diluent comprises water for injection; The stabilizer is selected from a mixture of polysorbate 20 and sucrose palmitate; In the freeze-dried mass containing paliperidone palmitate, the weight percentage of paliperidone palmitate is 65-90%, the weight percentage of the stabilizer is 1-10%, the weight percentage of the suspending agent is 1-10%, the weight percentage of the lyoprotectant is 1-15%, and the weight percentage of the pH adjuster is 1-5%; The preparation method of the stable long-acting paliperidone palmitate composition comprises the following steps: (1) Dissolve the stabilizer in water for injection, add paliperidone palmitate, stir and mix, grind to obtain paliperidone palmitate suspension I; (2) Add the suspending agent, lyophilization protective agent and pH adjuster to water for injection, stir to dissolve, and then add suspension I to obtain suspension II; (3) Stir suspension II at 40-50°C for 2-6 hours, add water for injection to make up to volume, and obtain suspension III; (4) The suspension III is poured into the first chamber of the double-chamber syringe, freeze-dried, and stoppered. The diluent is poured into the second chamber of the double-chamber syringe, and stoppered again to obtain the paliperidone palmitate long-acting composition.

2. The stable long-acting composition of paliperidone palmitate according to claim 1, characterized in that: The suspending agent is selected from one of polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, sodium carboxymethyl cellulose, gelatin, and methyl cellulose, or a mixture of several of them.

3. The stable long-acting composition of paliperidone palmitate according to claim 1, characterized in that: The freeze-drying protective agent is selected from one or a mixture of mannitol, sucrose, maltose, xylitol, sorbitol and trehalose.

4. The stable long-acting composition of paliperidone palmitate according to claim 1, characterized in that: The pH regulator is selected from one or a mixture of phosphate, sodium hydroxide and citric acid.

5. A method for preparing the stable long-acting paliperidone palmitate composition according to any one of claims 1 to 4, characterized in that: The steps include: (1) Dissolve the stabilizer in water for injection, add paliperidone palmitate, stir and mix, grind to obtain paliperidone palmitate suspension I; (2) Add the suspending agent, lyophilization protective agent and pH adjuster to water for injection, stir to dissolve, and then add suspension I to obtain suspension II; (3) Stir suspension II at 40-50°C for 2-6 hours, add water for injection to make up to volume, and obtain suspension III; (4) The suspension III is poured into the first chamber of the double-chamber syringe, freeze-dried, and stoppered. The diluent is poured into the second chamber of the double-chamber syringe, and stoppered again to obtain the paliperidone palmitate long-acting composition.

6. The method for preparing the stable long-acting paliperidone palmitate composition according to claim 5, characterized in that: In the step (4), the freeze-drying curve is: pre-freezing at -40°C for 4 to 6 hours, evacuating to 200 μbar and maintaining for 2 to 4 hours, heating to -20°C for 60 minutes and maintaining at 200 μbar for 20 to 30 hours, heating to -10°C for 60 minutes and maintaining at 200 μbar for 10 to 20 hours, heating to 0°C for 60 minutes and continuing drying at 200 μbar for 5 to 10 hours, heating to 20°C for 60 minutes and maintaining at 200 μbar for 2 to 4 hours.

7. The method for preparing the stable long-acting paliperidone palmitate composition according to claim 5, characterized in that: In the step (3), the concentration of paliperidone palmitate in the suspension III is 156-312 mg / mL.

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