Paliperidone coated tablet and preparation method thereof

Abstract

The invention discloses a paliperidone coated tablet. The paliperidone coated tablet comprises a tablet core layer and a shell layer, the tablet core layer comprises the following components in parts by weight: 5-10 parts of paliperidone, 1-2 parts of a plasticizer, 0.1-0.5 part of a flow aid, 10-30 parts of a carrier, 22-28 parts of a retardant A, 40-70 parts of a sustained-release material A and 0.1-0.5 part of a lubricant A, wherein the sum of the parts of the raw materials is 100; the shell layer comprises the following components in parts by weight: 0.5-0.8 part of paliperidone, 250-260 parts of a sustained-release material B, 60-70 parts of a retardant B and 1-2 parts of a lubricant B, and the sum of the parts by weight of the raw materials is 320. The composition is simple in components, convenient to use, simple in preparation process and controllable in cost.

Description

Technical Field

[0001] This invention belongs to the field of drug preparation technology, specifically relating to a paliperidone chip and its preparation method. Background Technology

[0002] Schizophrenia is a serious and persistent chronic mental illness. Patients typically experience basic personality changes, dysfunction in emotions, thinking, and behavior, and exhibit significant aversion to their environment. It is most common in young adults and severely impacts their lives and mental and physical well-being.

[0004] Paliperidone is the main metabolite of risperidone. Its mechanism of action is not yet clear, but it mainly antagonizes central dopamine 2 (D2) receptors and serotonin 2 (5HT2A) receptors. It belongs to the new or second-generation antipsychotic class of drugs and is a novel atypical antipsychotic.

[0005] Paliperidone is mainly available in two dosage forms: injection and osmotic pump-type sustained-release tablets. Injection is a special dosage form that requires physician administration, which has certain limitations. Osmotic pump-type sustained-release tablets require laser drilling equipment, resulting in high production costs. Therefore, developing a new, convenient, and cost-effective dosage form of paliperidone is essential. Summary of the Invention

[0006] The purpose of this invention is to provide a paliperidone chip, and the preparation method thereof is also a second objective of this invention. This invention makes paliperidone into a chip, which is convenient to use and cost-effective.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0008] A paliperidone-coated chip, the chip comprising a core layer and a shell layer;

[0009] The core layer is composed of the following components by weight: 5-10 parts paliperidone, 1-2 parts plasticizer, 0.1-0.5 parts flow aid, 10-30 parts carrier, 22-28 parts inhibitor A, 40-70 parts slow-release material A, and 0.1-0.5 parts lubricant A, with the total of the above raw materials being 100 parts.

[0010] The shell layer consists of the following components by weight: 0.5-0.8 parts paliperidone, 250-260 parts sustained-release material B, 60-70 parts inhibitor B, and 1-2 parts lubricant B, totaling 320 parts.

[0011] As a further preferred embodiment of the present invention, the plasticizer in the core layer is one or both of PEG 6000 and TEC.

[0012] As a further preferred embodiment of the present invention, in the core layer, the flow aid is colloidal silica and the retardant A is RSPO.

[0013] As a further preferred embodiment of the present invention, in the core layer, the carrier is one or a mixture of two or more of kollidon VA64, PEO N10, and hydroxypropyl methylcellulose.

[0014] As a further preferred embodiment of the present invention, in the core layer, the carrier is Kollidon VA64, and the weight ratio of Kollidon VA64 to paliperidone is (2-3):1; the sustained-release material A is one or a mixture of two or more of hydroxypropyl methylcellulose K100LV, K250PH, K4M, and K15M.

[0015] As a further preferred embodiment of the present invention, the sustained-release material B is hydroxypropyl cellulose, specifically HPC-LFP and HPC-MFP, with a mass ratio of 5:1; the inhibitor B is Eutrich, specifically L100-55 and RSPO, with a mass ratio of 1:1.

[0016] As a further preferred embodiment of the present invention, both lubricant A and lubricant B are magnesium stearate.

[0017] As a further preferred embodiment of the present invention, the ratio of the shell layer active pharmaceutical ingredient paliperidone to the core layer active pharmaceutical ingredient paliperidone is (5-10):(90-95); the core layer is 7 mm thick and the shell layer is 11 mm thick.

[0018] The present invention further discloses a method for preparing the paliperidone drug package chip, comprising the following steps:

[0019] (1) Preparation of core layer: Paliperidone, plasticizer, glidant and carrier are mixed evenly in a wet granulator; hot melt extrusion is performed using a twin-screw hot melt extruder at an extrusion temperature of 140°C; the extrudate is crushed and passed through a 60-mesh sieve; external auxiliary materials such as retardant A, slow-release material A and lubricant A are added and mixed in a mixer to obtain core layer material;

[0020] (2) Preparation of shell layer: All materials except magnesium stearate are mixed in a wet granulator, the mixture is granulated in a fluidized bed, the binder is an aqueous solution, the granules are sieved through a 24-mesh sieve, and then magnesium stearate is added to the mixer to obtain the shell layer material.

[0021] (3) Tableting: using shell material and core material to press the tablet to obtain paliperidone tablet.

[0022] As a further preferred embodiment of the present invention, the core is made of a 7mm circular flat oblique punch; the shell is made of an 11mm circular shallow concave punch; in step (2), it is passed through a 24-mesh sieve.

[0023] Compared with the prior art, the present invention has the following technical effects: Unlike existing injections and osmotic pump type sustained-release tablets, the present invention makes paliperidone into a new chip-encapsulated dosage form, which is convenient to use and cost controllable. Attached Figure Description

[0024] Figure 1 This is the dissolution result of Example 3;

[0025] Figure 2 This is the dissolution result of Example 4;

[0026] Figure 3 This refers to the dissolution effect of Example 5;

[0027] Figure 4 and Figure 5 This is the result of the average blood drug concentration in the cynomolgus monkey PK experiment. Specific Implementation

[0028] To better illustrate the technical solution of the present invention, the following embodiments are provided, but the present invention is not limited thereto.

[0029] Example 1: Effect of Plasticizer on Core Composite

[0030] To investigate the effect of plasticizers on the present invention, core compositions containing different plasticizers, formulations 1 and 2, were prepared. Their raw material composition and extrusion effect are shown in Table 1.

[0031] Table 1. Raw material composition and extrusion effect in Example 1

[0032]

[0033] Its preparation process is as follows:

[0034] (1) Mix the materials in a wet granulation machine at a speed of 300 rpm and a cutting speed of 300 rpm for 10 min.

[0035] (2) Set the extrusion temperature of the twin-screw hot melt extruder for extrusion. The extrusion temperature of Formula 1 is set to 140℃. The extrusion temperature of Formula 2 is first set to 140℃ and then increased to 160℃.

[0036] (3) The extrudate is mechanically crushed and then passed through a 60-mesh sieve.

[0037] Comparative Example 1: Plasticizer-free core composition

[0038] Table 2 Comparative Example 1: Raw Material Composition and Extrusion Effect

[0039]

[0040] The preparation process is the same as in Example 1.

[0041] The results from Example 1 and Comparative Example 1 show that when the plasticizer is PEG 6000, the extrusion temperature is 140°C, the extrudate is basically transparent, and the extrudate content reaches 99.2%, indicating that the raw material is basically not degraded during extrusion. When the plasticizer is TEC, the extrudate does not completely melt at the extrusion temperature of 140°C, resulting in uneven extrusion. The extrusion temperature needs to be increased to 160°C for smooth extrusion, but the extrudate content is only 88.6%, indicating that the raw material degrades at 160°C. When no plasticizer is present (as in Comparative Example 1), even at an extrusion temperature of 160°C, the extrudate still contains a large amount of particulate matter, proving that the raw material does not completely melt. Therefore, for the present invention, the choice of plasticizer affects the extrusion temperature and extrusion effect of the core composition to a certain extent.

[0042] Example 2: Effect of different carriers on the core composition

[0043] To investigate the effects of different carriers on the core composition, formulations 3, 4, 5, 6 and 7 were prepared in this embodiment, and their weight composition and extrusion effect are shown in Table 3.

[0044] Table 3. Raw material composition and extrusion effect in Example 2

[0045]

[0046]

[0047] Preparation process:

[0048] (1) Mix the materials in a wet granulation machine at a speed of 300 rpm and a cutting speed of 300 rpm for 10 min.

[0049] (2) Set the extrusion temperature of the twin-screw hot melt extruder for extrusion;

[0050] (3) The extrudate is mechanically crushed and then passed through a 60-mesh sieve.

[0051] Through comparison of the carriers, it was found that hydroxypropyl methylcellulose K100LV and PEO N10 are not suitable as carriers for the sheet composition of the present invention. When Kollidon VA64 is selected as the carrier, especially when the weight ratio of Kollidon VA64 to paliperidone is (2-3):1, the extrusion effect is the best, the extrusion process is smooth, and the extrudate is basically completely transparent.

[0052] Example 3: A tablet core composition containing different sustained-release materials

[0053] To investigate the effects of different sustained-release materials on the tablet core composition, formulations 8, 9, 10, and 11 were prepared in this embodiment. Their weight composition and dissolution effects are shown in Tables 4 and 5. Figure 1 As shown.

[0054] Table 4. Composition of each raw material in Example 3

[0055]

[0056]

[0057] Its preparation process is as follows:

[0058] (1) Mix the materials in a wet granulation machine at a speed of 300 rpm and a cutting speed of 300 rpm for 10 min.

[0059] (2) Set the extrusion temperature of the twin-screw hot melt extruder to 140℃ for extrusion;

[0060] (3) The extrudate is mechanically pulverized and then passed through a 60-mesh sieve;

[0061] (4) Add the external auxiliary materials to the extrudate after crushing and sieving and mix them in a mixer. First add the retardant and slow-release material and mix for 15 minutes at a mixer speed of 10 rpm. Then add magnesium stearate and mix for 5 minutes at a mixer speed of 10 rpm.

[0062] (5) Tableting.

[0063] The dissolution results are shown in Table 5 and Figure 1 As shown:

[0064] Table 5 Dissolution results of Example 3

[0065]

[0066] According to Table 5 and Figure 1 The dissolution results of the tablet cores show that the dissolution results of prescription 10 are in line with expectations, prescriptions 8 and 9 dissolve too quickly, and prescription 11 dissolves too slowly.

[0067] Example 4: Shell Composition Containing Different Sustained-Release Materials

[0068] To investigate the effect of not using sustained-release materials on the shell composition, this embodiment provides formulations 12, 13 and 14, the weight composition of which is shown in Table 6.

[0069] Table 6. Composition of each raw material in Example 4

[0070]

[0071]

[0072] Its preparation process:

[0073] Chip:

[0074] S1. Mix the materials in a wet granulator at a speed of 300 rpm and a cutting speed of 300 rpm for 10 minutes.

[0075] S2. Set the extrusion temperature of the twin-screw hot melt extruder to 140℃ for extrusion;

[0076] S3. Mechanically pulverize the extrudate and pass it through a 60-mesh sieve.

[0077] S4. Add the external auxiliary materials to the extrudate after crushing and sieving and mix them in a mixer. First, add the retardant and slow-release material and mix for 15 minutes at a mixer speed of 10 rpm. Then add magnesium stearate and mix for 5 minutes at a mixer speed of 10 rpm.

[0078] S5, Pressed core.

[0079] Shell:

[0080] A1. Mix all materials except magnesium stearate in a wet granulator at a speed of 300 rpm and a cutting speed of 300 rpm for 10 minutes.

[0081] A2. The material mixed evenly in step 1 is subjected to fluidized bed granulation, and the binder is an aqueous solution;

[0082] A3. Dry granulation of the granulated material is carried out by passing it through a 24-mesh sieve.

[0083] A4. Add magnesium stearate to the material in step 3 and mix it in a mixer for 5 minutes at a speed of 10 rpm.

[0084] A5. Pressing: Prepare the chip by pressing the die. The die is an 11mm circular shallow concave punch.

[0085] The dissolution results are shown in Table 7 and Figure 2 As shown:

[0086] Table 7 Dissolution effect of Example 4

[0087]

[0088] From Table 7 and Figure 2 The results showed that when LFP:MFP = 5:1, the dissolution was highly similar to that of the reference formulation.

[0089] Example 5: Core and shell compositions containing different amounts of raw materials

[0090] This embodiment modifies the ratio of paliperidone, the shell-layer active pharmaceutical ingredient, to paliperidone, the core-layer active pharmaceutical ingredient, based on formulation 14, as shown in Table 8.

[0091] Table 8

[0092] The preparation process is the same as in Example 4. The dissolution results are shown in Table 9 and... Figure 3 As shown: Table 9 Dissolution effect of Example 5

[0093] From Table 9 and Figure 3 The results showed that when 5-10% paliperidone raw material was placed in the shell, the dissolution of the self-developed reagent and the reference reagent were highly similar.

[0094] Experimental Example: Crab-eating Monkey vs. Crab-eating Monkey Experiment Four male cynomolgus monkeys were selected for a comparative experiment against the reference formulation. They were weighed one day prior to the experiment and randomly divided into two groups of two monkeys each. The monkeys underwent two cycles of administration, with each group receiving paliperidone tablets via gavage. Blood samples were collected before each cycle and at 1, 2, 4, 8, 12, 16, 20, 24, 30, 36, 48, 72, and 96 hours after administration.

[0095] The results of the PK experiment are shown in Table 10 and Figure 4 , Figure 5 As shown: Table 10 The experimental results show that the Cmax of the self-developed reagent is 94% of that of the reference reagent, and the AUC0-t and AUC0-∞ are both 102% of those of the reference reagent, all meeting the requirements of the 80-125% range. Figure 4 and Figure 5 It can be seen that the blood concentration trends of the self-developed reagent and the reference reagent in cynomolgus monkeys are basically the same. Therefore, it can be concluded that the self-developed reagent and the reference reagent are equivalent in cynomolgus monkeys.

[0096] The present invention has been described in detail above through specific embodiments and examples, but these are not intended to limit the invention. Many modifications and improvements can be made by those skilled in the art without departing from the principles of the invention, and these should also be considered within the scope of protection of the present invention.

Claims

1. A paliperidone-coated chip, characterized in that, The chip package includes a chip core layer and a shell layer; The core layer comprises the following components by weight: 5-10 parts paliperidone, 1-2 parts plasticizer, 0.1-0.5 parts flow aid, 10-30 parts carrier, 22-28 parts inhibitor A, 40-70 parts sustained-release material A, and 0.1-0.5 parts lubricant A, with the total of the above raw materials being 100 parts. The shell layer consists of the following components by weight: 0.5-0.8 parts paliperidone, 250-260 parts sustained-release material B, 60-70 parts inhibitor B, and 1-2 parts lubricant B, totaling 320 parts.

2. The paliperidone chip according to claim 1, characterized in that, In the core layer, the plasticizer is one or both of PEG6000 and TEC.

3. The paliperidone chip according to claim 1, characterized in that, In the core layer, the flow aid is colloidal silica, and the retardant A is RSPO.

4. The paliperidone chip according to claim 1, characterized in that, In the core layer, the carrier is one or a mixture of two or more of kollidon VA64, PEO N10, and hydroxypropyl methylcellulose.

5. The paliperidone chip according to claim 1, characterized in that, In the core layer, the carrier is Kollidon VA64, and the weight ratio of Kollidon VA64 to paliperidone is (2-3):1; the sustained-release material A is one or a mixture of two or more of hydroxypropyl methylcellulose K100LV, K250PH, K4M, and K15M.

6. The paliperidone chip according to claim 1, characterized in that, In the shell layer, the sustained-release material B is hydroxypropyl cellulose, model HPC-LFP and HPC-MFP, and the ratio of their amounts (by mass) is 5:1; the inhibitor B is Eutrich, model L100-55 and RSPO, and the ratio of their amounts (by mass) is 1:

1.

7. The paliperidone chip according to claim 1, characterized in that, Both lubricant A and lubricant B are magnesium stearate.

8. The paliperidone chip according to claim 1, characterized in that, The ratio of paliperidone, the raw material for the shell layer, to paliperidone, the raw material for the tablet core layer is (5-10):(90-95); the core layer is 7mm thick and the shell layer is 11mm thick.

9. The method for preparing paliperidone drug chip according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Preparation of tablet core layer: Paliperidone, plasticizer, glidant and carrier are mixed evenly in a wet granulator; hot melt extrusion is performed using a twin-screw hot melt extruder at an extrusion temperature of 140°C, the extrudate is crushed and passed through a 60-mesh sieve; external excipients such as retardant A, slow-release material A and lubricant A are added and mixed in a mixer, and tableting is performed to obtain the core layer material; (2) Preparation of shell layer: All materials except magnesium stearate are mixed in a wet granulator, the mixture is granulated in a fluidized bed, the binder is an aqueous solution, the granules are sieved through a 24-mesh sieve, and then magnesium stearate is added and mixed in a mixer to obtain shell layer material. (3) Tableting: using shell material and core material to press the tablet into a chip to obtain paliperidone-coated tablets.

10. The method for preparing paliperidone-coated chips according to claim 9, characterized in that, In step (3), the core is made using a 7mm round flat angled punch; the shell is made using an 11mm round shallow concave punch; in step (2), it is passed through a 24-mesh sieve.

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