A stable waxy matrix sustained release tablet and a method for preparing the same

Abstract

The application discloses a wax skeleton sustained-release tablet and a preparation method thereof, and raw materials of the wax skeleton sustained-release tablet comprise, in mass fractions, 50 parts of trazodone hydrochloride, 10 parts of a wax skeleton material, 2-7 parts of catechin hydrate, 13-18 parts of a high polymer carrier material, 16-23 parts of a pore forming agent and 1-2 parts of a lubricant. The wax material phase transition temperature is specifically improved, so that the stability of the wax skeleton material is solved. After fully understanding the essence of the stability of the wax material, special materials are combined with the wax material through intermolecular hydrogen bonds, so that the wax material phase transition temperature is improved. The application creatively utilizes intermolecular hydrogen bonds formed between the phase transition stabilizer catechin hydrate and the wax material, so that the wax material phase transition temperature is improved, and the heat-resistant stability is fundamentally improved.

Description

Technical Field

[0001] This invention relates to the field of sustained-release pharmaceuticals, specifically to a waxy matrix sustained-release tablet and its preparation method. Background Technology

[0002] Common types of sustained-release tablets include matrix systems, membrane-controlled systems, reservoir systems, and osmotic pump systems. Among these, matrix tablet systems are the simplest and most mature in terms of preparation technology, and are therefore widely used in oral sustained-release and controlled-release drug delivery systems. Matrix tablets typically use one or more inert solid matrix materials combined with the drug and compressed into tablets. The drug is uniformly dispersed within the inert solid matrix and slowly released through the pores in the material via various release mechanisms. Common sustained-release matrix materials include hydrophilic gel matrix materials, erodible matrix materials, insoluble matrix materials, and mixed matrix materials. Waxy matrix materials are a typical example of insoluble matrix materials. Unlike other sustained-release materials, such as cellulose and acrylic matrix materials, waxy matrix materials are inert, hydrophilic, and unaffected by pH. They effectively inhibit the burst release of water-soluble drugs, have a low melting point, are easy to produce, and have relatively simple formulation and process design, making them promising for widespread applications. Commonly used waxy skeleton materials include glyceryl behenate, carnauba wax, hydrogenated castor oil, and stearyl alcohol.

[0003] Waxy materials are amorphous substances that gradually soften and melt upon heating, and gradually solidify and harden upon cooling. In practical applications, these characteristics of the waxy framework greatly improve the ease of preparation, but also lead to poor stability of the formulation. The ability of waxy materials to melt upon heating and solidify upon cooling allows for the binding of raw materials and excipients into granules, which are then further processed into formulations. These formulations utilize the natural water insolubility of waxy materials to achieve a sustained-release effect in the human body. However, these characteristics also make the formulation highly susceptible to temperature fluctuations during subsequent storage, leading to instability issues. When the wax molecules are heated, they reach the phase transition temperature, initiating a slow and imperceptible phase transition. This phase transition becomes increasingly intense with rising temperature, and the initial hard solid gradually softens, eventually losing its solid state as the temperature approaches the melting point and melting away. At this point, the formulation exhibits changes in color and hardness, and its key quality attribute, dissolution, also changes significantly, which is highly detrimental to the sustained-release effect of the formulation.

[0004] Chinese patent document CN 101252932 A is a formulation process patent for trazodone hydrochloride sustained-release tablets (Oleptro) from AZ.CHIM.RIUN., which uses a cross-linked high amylose excipient (CLA). This patent uses a special excipient and a hydrophilic gel sustained-release material, hydroxypropyl methylcellulose (K100M), to control drug release. This mechanism differs from that of trazodone hydrochloride wax-based sustained-release tablets. The excipients in this product present accessibility issues, and the release mechanism is not significant for improving the stability of trazodone hydrochloride wax-based sustained-release tablets. Chinese patent document CN 116549406 A discloses a production process and formulation for trazodone hydrochloride, employing a fluidized bed granulation process. The formulation involves adding a specific proportion and type of polyoxyethylene to carnauba wax. It was found that this formulation can prevent the migration of raw materials within carnauba wax, thereby improving the compressibility, hardness, and stability of the sustained-release tablets. Adding polyoxyethylene physically encapsulates the drug in an incompatible phase, hindering drug migration. This process is a simple physical barrier and is highly dependent on process control. Furthermore, it requires strict and uniform spreading of polyoxyethylene and carnauba wax, and the amount and type of polyoxyethylene are also specific, posing certain limitations in the preparation and production process. Furthermore, while adding polyoxyethylene can hinder the migration of raw materials, it cannot change the problem of phase change of the slow-release matrix after heating. Therefore, the issue of improving the stability of wax materials themselves needs to be addressed. Summary of the Invention

[0005] Therefore, the technical problem to be solved by the present invention is the poor stability of existing wax matrix materials, thereby providing a wax matrix sustained-release tablet and its preparation method.

[0006] Therefore, the present invention adopts the following technical solution:

[0007] This invention provides a waxy matrix sustained-release tablet comprising the following raw materials:

[0008]

[0009] Furthermore, the waxy skeleton material includes carnauba wax.

[0010] The polymeric carrier material includes at least one of copovidone, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, and ethylcellulose.

[0011] The pore-forming agent includes at least one of lactose, sucrose, and mannitol.

[0012] The lubricant includes at least one of magnesium stearate, stearic acid, and glyceryl monostearate.

[0013] The present invention also provides a method for preparing the above-mentioned waxy matrix sustained-release tablets, comprising the following steps:

[0014] S1: Premix the raw materials after removing the lubricant;

[0015] S2: The premixed raw materials are hot-melted and extruded into granules;

[0016] S3: The obtained particles and lubricant are then fully mixed;

[0017] S4: Compress the final mixed material into tablets to obtain the waxy matrix sustained-release tablets.

[0018] Further, the premixing in step S1 involves putting the raw materials, polymer carrier materials, and pore-forming agents into a mixer and premixing them at a speed of 12±1 rpm for 6-12 minutes; then putting the waxy skeleton materials and phase change stabilizers into the mixer and mixing them together at a speed of 12±1 rpm for 3-8 minutes.

[0019] The hot melt extrusion granulation in step S2 involves feeding the premixed raw materials into a hot melt extruder, setting the feed rate to 0.4-0.6 kg / h, the screw speed to 130-170 rpm, the conveying zone to be unheated, the melting zone to be heated to 95-105℃, and the mixing zone, exhaust zone, and homogenization zone to be heated to 140-150℃. After the granules are discharged, they are granulated through a 20-mesh screen.

[0020] In step S3, the final mixing speed is 12±1 and the mixing time is 2-4 min.

[0021] The tablet compression in step S4 is performed using a 16×5mm long capsule-shaped die, with a tablet weight of 300mg and a hardness of 60~120N.

[0022] The technical solution of this invention has the following advantages:

[0023] (1) This invention specifically improves the phase transition temperature of waxy materials, thereby solving the stability problem of waxy framework materials. After fully understanding the essence of the stability problem of waxy materials, a special material is used to form hydrogen bonds between the waxy material molecules, thereby increasing the phase transition temperature of the waxy material. This invention creatively utilizes the phase transition stabilizer catechin hydrate to form intermolecular hydrogen bonds with the waxy material, thereby increasing the phase transition temperature of the waxy material and fundamentally improving its heat resistance stability.

[0024] (2) Catechins are a class of natural phenolic substances with abundant hydroxyl groups in their molecules. These hydroxyl groups, influenced by the conjugated structure of the benzene ring, readily act as proton donors. Wax materials contain a relatively abundant number of proton acceptor groups. Furthermore, the melting point of catechin hydrates is relatively moderate, ranging from 93 to 96°C, slightly higher than that of carnauba wax. In this invention, when catechin hydrates and wax materials are mixed in a molten state, the intermolecular distance between the two is kept very close and the interaction is prolonged, ensuring the formation of strong intermolecular hydrogen bonds, thereby increasing the overall phase transition temperature of the wax material.

[0025] (3) This invention employs a hot-melt extrusion process. Utilizing the characteristics of this process, under the specific extrusion settings of this invention, the phase change stabilizer and wax material are repeatedly stirred and combined in a hot-melt state by the mechanical extrusion force of the screw. This ensures sufficient contact and bonding between the phase change stabilizer catechin hydrate and the proton acceptor groups of the wax material, thereby forming hydrogen bonds and resolving the stability issue of the wax matrix formulation. The added polymeric carrier material ensures the smooth progress of the process and further improves the stability of the wax material system. Furthermore, the hot-melt extrusion process has continuous production capabilities, low scale-up risk, and a simple and controllable production process. 。 Attached Figure Description

[0026] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0027] Figure 1 The endothermic peak conditions are shown in the embodiments and comparative examples of the present invention. Detailed Implementation

[0028] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0029] In the specific implementation, the copovidone used is VA64 from Boai New Open Source Medical Technology Group Co., Ltd.; hydroxypropyl methylcellulose is K100M from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; and hydroxypropyl methylcellulose succinate is HP50 from Shin-Etsu Chemical Co., Ltd. of Japan.

[0030] The following specific embodiments further illustrate the present invention. The examples given do not represent all embodiments of the present invention; only some embodiments are described as examples. Specific embodiments are as follows:

[0031] Example 1

[0032] This embodiment provides a wax-based sustained-release tablet, the raw materials of which are shown in the table below:

[0033] Table 1. Raw material usage for Example 1 (batch size 5000 tablets)

[0034] Trazodone Hydrochloride 150mg 750g Brazilian carnauba wax 30mg 150g Catechin hydrate 20mg 100g Copolyvinylpyrrolidone 40mg 200g sucrose 55mg 275g magnesium stearate 5mg 25g

[0035] The specific preparation method is as follows:

[0036] (1) Add trazodone hydrochloride, copovidone and sucrose into a mixer for premixing. The mixer speed is 12 rpm and the mixture is mixed for 10 min. Then add carnauba wax and catechin hydrate into the mixer and mix them together. The mixer speed is 12 rpm and the mixture is mixed for 5 min.

[0037] (2) The premixed raw materials are fed into the hot melt extruder. The feed rate is set to 0.5 kg / h, the screw speed is set to 150 rpm, the conveying zone is not heated, the melting zone is heated to 100℃, and the mixing zone, exhaust zone and homogenization zone are all heated to 145℃. After the granules are discharged, they are granulated through a 20-mesh sieve.

[0038] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0039] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0040] Example 2

[0041] This embodiment provides a wax-based sustained-release tablet, the raw materials of which are shown in the table below:

[0042] Table 2. Raw material usage for Example 2 (batch size 5000 tablets)

[0043] Trazodone Hydrochloride 150mg 750g Brazilian carnauba wax 30mg 150g Catechin hydrate 8mg 40g Copolyvinylpyrrolidone 40mg 200g sucrose 67mg 335g magnesium stearate 5mg 25g

[0044] The specific preparation method is as follows:

[0045] (1) Add trazodone hydrochloride, copovidone and sucrose into a mixer for premixing. The mixer speed is 12 rpm and the mixture is mixed for 10 min. Then add carnauba wax and catechin hydrate into the mixer and mix them together. The mixer speed is 12 rpm and the mixture is mixed for 5 min.

[0046] (2) The premixed raw materials are fed into the hot melt extruder. The feed rate is set to 0.5 kg / h, the screw speed is set to 150 rpm, the conveying zone is not heated, the melting zone is heated to 100℃, and the mixing zone, exhaust zone and homogenization zone are all heated to 145℃. After the granules are discharged, they are granulated through a 20-mesh sieve.

[0047] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0048] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0049] Example 3

[0050] This embodiment provides a wax-based sustained-release tablet, the raw materials of which are shown in the table below:

[0051] Table 3. Raw material usage for Example 3 (batch size 5000 tablets)

[0052] Trazodone Hydrochloride 150mg 750g Brazilian carnauba wax 30mg 150g Catechin hydrate 14mg 70g Hydroxypropyl methylcellulose 52mg 260g lactose 49mg 245g magnesium stearate 5mg 25g

[0053] The specific preparation method is as follows:

[0054] (1) Add trazodone hydrochloride, hydroxypropyl methylcellulose and lactose into a mixer and premix. Mix at 12 rpm for 10 min. Then add carnauba wax and catechin hydrate into the mixer and mix together. Mix at 12 rpm for 5 min.

[0055] (2) The premixed raw materials are fed into the hot melt extruder. The feed rate is set to 0.5 kg / h, the screw speed is set to 150 rpm, the conveying zone is not heated, the melting zone is heated to 100℃, and the mixing zone, exhaust zone and homogenization zone are all heated to 145℃. After the granules are discharged, they are granulated through a 20-mesh sieve.

[0056] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0057] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0058] Example 4

[0059] This embodiment provides a wax-based sustained-release tablet, the raw materials of which are shown in the table below:

[0060] Table 4. Raw material usage for Example 4 (batch size 5000 tablets)

[0061]

[0062]

[0063] The specific preparation method is as follows:

[0064] (1) Add trazodone hydrochloride, hydroxypropyl methylcellulose succinate and mannitol to a mixer for premixing. Mix at 12 rpm for 10 min. Then add carnauba wax and catechin hydrate to the mixer and mix together at 12 rpm for 5 min.

[0065] (2) The premixed raw materials are fed into the hot melt extruder. The feed rate is set to 0.5 kg / h, the screw speed is set to 150 rpm, the conveying zone is not heated, the melting zone is heated to 100℃, and the mixing zone, exhaust zone and homogenization zone are all heated to 145℃. After the granules are discharged, they are granulated through a 20-mesh sieve.

[0066] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0067] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0068] Comparative Example 1

[0069] The only difference between this comparative example and Example 1 is that catechin hydrate is not added.

[0070] Comparative Example 2

[0071] The only difference between this comparative example and Example 1 is that the amount of catechin hydrate was changed from 20 mg to 4 mg.

[0072] Comparative Example 3

[0073] The only difference between this comparative example and Example 1 is that a fluidized bed process is used, and the specific preparation method is as follows:

[0074] (1) Add trazodone hydrochloride, copovidone and sucrose into a mixer for premixing. The mixer speed is 12 rpm and the mixture is mixed for 10 min. Then add carnauba wax and catechin hydrate into the mixer and mix them together. The mixer speed is 12 rpm and the mixture is mixed for 5 min.

[0075] (2) Add the premixed raw and auxiliary materials into the fluidized bed, turn on the blower with a blower frequency of 30Hz, an inlet air temperature of 90℃, and a material temperature of 85℃ to ensure that the material is in a fluidized state. After granulation, discharge the granules and pass them through a 20-mesh granulator.

[0076] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0077] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0078] Comparative Example 4

[0079] The only difference between this comparative example and Example 1 is the change in the parameters during hot melting. The specific preparation method is as follows:

[0080] (1) Add trazodone hydrochloride, copovidone and sucrose into a mixer for premixing. The mixer speed is 12 rpm and the mixture is mixed for 10 min. Then add carnauba wax and catechin hydrate into the mixer and mix them together. The mixer speed is 12 rpm and the mixture is mixed for 5 min.

[0081] (2) The premixed raw materials are fed into the hot melt extruder. The feed rate is set to 0.3 kg / h, the screw speed is set to 100 rpm, the conveying zone is not heated, the melting zone is heated to 100℃, and the mixing zone, exhaust zone and homogenization zone are all heated to 145℃. After the granules are discharged, they are granulated through a 20-mesh sieve.

[0082] (3) Put the granulated dry granules into the mixer, then add magnesium stearate and mix. The mixing speed is 12 rpm and the mixing time is 3 min.

[0083] (4) Use a 16*5mm long capsule-shaped die to press tablets, control the tablet weight to 300mg, and the hardness to 60~120N.

[0084] Comparative Example 5

[0085] The only difference between this comparative example and Example 1 is that catechin hydrate is replaced with epicatechin.

[0086] Experimental Example 1

[0087] The obtained product was subjected to DSC testing to determine its phase change endothermic temperature. The specific method was to use a TA SDT 2960 instrument with a heating rate of 5K / min.

[0088] The results are as follows Figure 1 And as shown in the table below:

[0089] Table 5. Endothermic Temperatures of Examples and Comparative Examples

[0090] Example 1 74℃ 124℃ Example 2 76℃ 128℃ Example 3 75℃ 127℃ Example 4 74℃ 125℃ Comparative Example 1 32℃ 82℃ Comparative Example 2 52℃ 92℃ Comparative Example 3 35℃ 83℃ Comparative Example 4 46℃ 89℃

[0091] like Figure 1As shown in the table above, the endothermic temperature curves of Examples 1-4 and Comparative Examples 1-4 were detected by DSC to compare the differences in melting endothermic temperature. Examples 1-4 significantly improved the phase transition temperature and melting point of the waxy framework material by adding the phase change stabilizer catechin hydrate. Comparative Example 1, without the addition of the phase change stabilizer catechin hydrate, showed no significant increase in initial endothermic temperature and melting point temperature. Comparative Example 2, with insufficient catechin hydrate, showed a slight increase in initial endothermic temperature and melting point temperature, but this was significantly lower than that of Examples 1-4. Comparative Example 3 used a fluidized bed granulation process, but because this process could not promote a tight bond between the phase change stabilizer and the waxy framework material molecules, intermolecular hydrogen bonds could not be fully formed, resulting in no significant change in initial endothermic temperature and melting point temperature. Although Comparative Example 4 adopted a hot melt granulation process, it could not promote the tight bonding between the phase change stabilizer and the waxy skeleton material molecules due to the failure to achieve the optimal process parameters. Therefore, it could not fully form intermolecular hydrogen bonds. The initial endothermic temperature and melting point temperature were increased to some extent, but they were significantly different from the initial endothermic temperature and melting point temperature of Examples 1 to 4.

[0092] Experimental Example 2

[0093] The obtained product was subjected to stability testing to determine the effect of different external storage temperatures on the dissolution of the key quality attribute of the formulation. The dissolution test method was the rotating basket method, with a rotation speed of 100 rpm and a temperature of 37°C. The dissolution medium was a phosphate buffer solution with a pH of 6.0 (potassium dihydrogen phosphate 7.99 g / L and disodium hydrogen phosphate 1.42 g / L).

[0094] The results are shown in the table below:

[0095] Table 6 Results of direct testing on freshly made products

[0096]

[0097] As can be seen from the table above, there are no significant differences in the dissolution behavior and dissolution curves of the formulation samples prepared in Examples 1-4 and Comparative Examples 1-5 on day 0, and all of them exhibit stable sustained-release behavior.

[0098] Table 7 shows the product results after testing at 40°C for one week.

[0099]

[0100] As can be seen from the table above, the dissolution behavior and dissolution curves of the formulations prepared in Examples 1-4 remained unchanged after being placed at 40°C for one week, exhibiting stable sustained-release behavior. The dissolution rates of the formulations prepared in Comparative Examples 1, 3, and 5 showed a significant increasing trend after being placed at 40°C for one week, especially after 4 hours. The dissolution rate of the formulation prepared in Comparative Example 2 showed a slight increasing trend after being placed at 40°C for one week. The dissolution rate of the formulation prepared in Comparative Example 4 showed almost no significant change after being placed at 40°C for one week.

[0101] Table 8 shows the product results after testing at 60°C for one week.

[0102]

[0103] As can be seen from the table above, the formulation samples prepared in Examples 1-4 showed no change in dissolution behavior and dissolution curves after being placed at 60°C for one week, exhibiting stable sustained-release behavior. However, the formulation samples prepared in Comparative Examples 1-5 showed significant changes in dissolution rate after being placed at 60°C for one week, with a markedly faster dissolution rate, indicating a loss of sustained-release capability. Therefore, it can be concluded that the absence of a phase change stabilizer or insufficient addition of a phase change stabilizer resulted in insufficient contact between the phase change stabilizer and the waxy matrix material molecules during preparation, preventing the formation of sufficient intermolecular hydrogen bonds. Consequently, the initial melting temperature and melting point of the waxy matrix material could not be increased, and the sustained-release effect of the waxy matrix material was completely destroyed at a high temperature of around 60°C.

[0104] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A waxy matrix sustained-release tablet, characterized in that, Raw materials including the following components: 50 parts of trazodone hydrochloride; 10 parts of carnauba wax; 2-7 parts of catechin hydrate; 13-18 parts of polymer carrier material; 16-23 parts of pore-forming agent; 1-2 parts lubricant; The method for preparing the waxy matrix sustained-release tablet includes the following steps: S1: Premix the raw materials after removing the lubricant; S2: The premixed raw materials are hot-melted and extruded into granules; S3: The obtained particles and lubricant are then fully mixed; S4: Compress the final mixed material into tablets to obtain the waxy matrix sustained-release tablets; The hot melt extrusion granulation in step S2 involves feeding the premixed raw materials into a hot melt extruder, setting the feed rate to 0.4-0.6 kg / h, the screw speed to 130-170 rpm, the conveying zone to be unheated, the melting zone to be heated to 95-105℃, and the mixing zone, exhaust zone, and homogenization zone to be heated to 140-150℃. After the granules are discharged, they are granulated through a 20-mesh screen.

2. The waxy matrix sustained-release tablet according to claim 1, characterized in that, The polymeric carrier material includes at least one of copovidone, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, and ethylcellulose.

3. The waxy matrix sustained-release tablet according to claim 1 or 2, characterized in that, The pore-forming agent includes at least one of lactose, sucrose, and mannitol.

4. The waxy matrix sustained-release tablet according to claim 1 or 2, characterized in that, The lubricant includes at least one of magnesium stearate, stearic acid, and glyceryl monostearate.

5. The waxy matrix sustained-release tablet according to claim 1 or 2, characterized in that, The premixing in step S1 involves putting the raw materials, polymer carrier material, and pore-forming agent into a mixer and mixing them at a speed of 12±1 rpm for 6-12 minutes; then adding carnauba wax and catechin hydrate into the mixer and mixing them together at a speed of 12±1 rpm for 3-8 minutes.

6. The waxy matrix sustained-release tablet according to claim 1 or 2, characterized in that, In step S3, the final mixing speed is 12±1 and the mixing time is 2-4 min.

7. The waxy matrix sustained-release tablet according to claim 1 or 2, characterized in that, The tablet compression in step S4 is performed using a 16×5mm long capsule-shaped die, with a tablet weight controlled at 300mg and a hardness of 60~120N.

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