A Trazodone Hydrochloride Extended-Release Tablet and Its Preparation Method

Abstract

This invention provides a trazodone hydrochloride sustained-release tablet and its preparation method. The trazodone hydrochloride sustained-release tablet comprises, by weight percentage: 20-60 wt% trazodone hydrochloride, 10-50 wt% sustained-release matrix material, 0.01-0.5 wt% stabilizer, 10-50 wt% filler, and 0.5-3 wt% lubricant; wherein the sustained-release matrix material includes one or more of anhydrous lanolin, stearic acid, glyceryl tristearate, and stearyl alcohol. In this invention, the water-absorbing properties of lanolin are utilized in a breakthrough application to solid sustained-release tablets, enabling the slow release of trazodone hydrochloride over a certain period, achieving a good sustained-release effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a trazodone hydrochloride sustained-release tablet and its preparation method. Background Technology

[0002] Trazodone hydrochloride is widely used clinically to treat depression and improve sleep. Extensive clinical practice both domestically and internationally has confirmed that trazodone hydrochloride tablets and its extended-release formulations are comparable to, or even superior to, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin (5-HT) / norepinephrine reuptake inhibitors (SNRIs) in terms of efficacy and safety. Trazodone hydrochloride and its extended-release formulations have dose-dependent inhibitory effects on the 5-HT transporter (SERT), blocking 5-HT reuptake, antagonizing 5-HT receptors, and blocking alpha-adrenergic (α1, α2) effects; among these, it has the strongest affinity for the 5-HT2A receptor.

[0003] Patent CN101252932A discloses a sustained-release pharmaceutical composition for once-daily oral administration, comprising: about 15% to about 60 wt% of trazodone or a derivative thereof, and about 15% to about 85 wt% of a controlled-release excipient, wherein, when administered to mammals, the controlled-release excipient allows trazodone or a derivative thereof to maintain an effective plasma concentration for at least about 1 hour to at least about 24 hours after the first dose. Tablets prepared using the sustained-release excipient hydroxypropyl distarch phosphate may have accumulation problems due to insufficient drug release under intestinal conditions. Therefore, this product has been withdrawn from the US market due to safety concerns.

[0004] Patent CN102935074A discloses a method for preparing trazodone hydrochloride osmotic pump controlled-release tablets, which consist of three parts: a tablet core, a semi-permeable membrane coating, and a drug release pore. This preparation process is relatively complex, requires sophisticated equipment, and necessitates the use of organic solvents, which are costly and difficult to remove.

[0005] Patent CN105748421A discloses a sustained-release tablet containing trazodone hydrochloride. This tablet comprises 15-65% trazodone hydrochloride by weight, 30-85% a sustained-release matrix, and 0.1-10% other pharmaceutical excipients. The sustained-release matrix consists of high-viscosity hydroxypropyl methylcellulose and a water-soluble filler. It employs a direct powder compression process. However, due to the large proportion of ungranulated hydroxypropyl methylcellulose or raw material, it suffers from poor flowability and compressibility, resulting in uneven material mixing and poor tablet formability.

[0006] Patent CN116440093A discloses a trazodone sustained-release tablet and its preparation method. The sustained-release tablet contains trazodone hydrochloride, a waxy sustained-release matrix material, a pore-forming agent, a binder, and other pharmaceutical excipients. The process employs fluidized bed melt granulation, which is relatively complex and requires high-performance equipment, making industrialization difficult.

[0007] Patent CN116549406A relates to a trazodone hydrochloride sustained-release tablet. This formulation comprises trazodone hydrochloride, a filler, a sustained-release material, a binder, and a lubricant, wherein the sustained-release material includes carnauba wax and polyoxyethylene. The process still employs fluidized bed melt granulation, which is relatively complex and places high demands on equipment and performance, making industrialization difficult.

[0008] Lanolin is a secreted oil that adheres to wool. Its main components are esters and free alcohols formed from sterols, fatty alcohols, and triterpenoids with approximately equal amounts of fatty acids, along with small amounts of free fatty acids and hydrocarbons. Anhydrous lanolin is insoluble in water but can mix homogeneously with about twice its volume of water. Lanolin has the potential to be used as a sustained-release material in waxy matrix tablets. That is, when a drug is dispersed in lanolin, as the lanolin absorbs water, the drug dissolves in the water, and due to the concentration gradient, the drug is gradually released from the lanolin into the environment. Because lanolin has a relatively low water absorption capacity and rate, the drug dissolves and is released gradually, thus achieving a sustained-release effect.

[0009] However, due to the complex composition of lanolin, it softens under relatively high temperatures over a long period, and some low molecular weight components tend to migrate or precipitate, affecting drug distribution and altering its sustained-release characteristics. On the other hand, at low temperatures, some low molecular weight components in lanolin are also prone to crystallization, which also affects drug distribution and alters its sustained-release characteristics, necessitating the addition of stabilizers. Summary of the Invention

[0010] The main objective of this invention is to provide a trazodone hydrochloride sustained-release tablet and its preparation method, aiming to provide a trazodone hydrochloride sustained-release tablet that can slowly release the drug within a certain time.

[0011] To achieve the above objectives, the trazodone hydrochloride sustained-release tablets proposed in this invention comprise the following components by weight percentage: 20-60 wt% trazodone hydrochloride, 10-50 wt% sustained-release matrix material, 0.01-0.5 wt% stabilizer, 10-50 wt% filler, and 0.5-3 wt% lubricant.

[0012] The sustained-release matrix material includes one or more of anhydrous lanolin, stearic acid, glyceryl tristearate, and octadecanol.

[0013] Optionally, the sustained-release skeleton material includes anhydrous lanolin and stearic acid.

[0014] Optionally, the particle size of the raw material for trazodone hydrochloride is 50–500 μm.

[0015] Optionally, the particle size of the raw material for trazodone hydrochloride is 150–350 μm.

[0016] Optionally, the stabilizer is trihydroxystearin.

[0017] Optionally, the filler is at least two of microcrystalline cellulose, lactose, and mannitol.

[0018] Optionally, the tap density of the filler should be 0.75~1.25 g / cm3.

[0019] Optionally, the lubricant is stearic acid and its acceptable salts.

[0020] This invention also proposes a method for preparing the above-mentioned trazodone hydrochloride sustained-release tablets, comprising the following steps:

[0021] S1. After melting the sustained-release skeleton material and stabilizer, add trazodone hydrochloride, disperse evenly, and then form fine particles;

[0022] S2. Mix the fine particles with filler and lubricant evenly to obtain the material;

[0023] S3. Compress the material into tablets to obtain trazodone hydrochloride sustained-release tablets.

[0024] Optionally, in step S1, the temperature at which the sustained-release skeleton material and stabilizer are melted and then added to trazodone hydrochloride is 45°C to 65°C.

[0025] In the technical solution of this invention, the water-absorbing properties of lanolin are utilized in a breakthrough application to solid sustained-release tablets, which can slowly release trazodone hydrochloride within a certain period of time, achieving a good sustained-release effect. Attached Figure Description

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

[0027] Figure 1 A schematic flowchart of an embodiment of the preparation method of trazodone hydrochloride sustained-release tablets provided by the present invention;

[0028] Figure 2Schematic diagrams of the release rates of trazodone hydrochloride sustained-release tablets provided by the present invention at different times for Examples 1-3 and Comparative Example 1;

[0029] Figure 3 Schematic diagrams of the release rates of trazodone hydrochloride sustained-release tablets provided by the present invention at different times in Examples 1, 4, 5 and Comparative Example 2;

[0030] Figure 4 The curves of release rate of Trazodone Hydrochloride Extended-Release Tablets provided by the present invention at different times are schematic diagrams.

[0031] The realization of the objective, functional features and advantages of the present invention will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them.

[0033] It should be noted that, unless specific conditions are specified in the embodiments, conventional conditions or conditions recommended by the manufacturer should be followed. Reagents or instruments whose manufacturers are not specified are all commercially available products. Furthermore, the meaning of "and / or" throughout the text includes three parallel solutions; for example, "A and / or B" includes solution A, solution B, or a solution that simultaneously satisfies A and B. In addition, the technical solutions of the various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. When the combination of technical solutions is contradictory or impossible to implement, such a combination should be considered non-existent and not within the scope of protection claimed by this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention.

[0034] Lanolin is a secreted oil that adheres to wool. Its main components are esters and free alcohols formed from sterols, fatty alcohols, and triterpenoids with approximately equal amounts of fatty acids, along with small amounts of free fatty acids and hydrocarbons. Anhydrous lanolin is insoluble in water but can be homogeneously mixed with about twice its volume of water. Lanolin has the potential to be used as a slow-release material in waxy matrix tablets.

[0035] In view of this, the present invention provides a trazodone hydrochloride sustained-release tablet, which, by weight percentage, comprises the following components: 20-60 wt% trazodone hydrochloride, 10-50 wt% sustained-release matrix material, 0.01-0.5 wt% stabilizer, 10-50 wt% filler, and 0.5-3 wt% lubricant; wherein, the sustained-release matrix material comprises one or more of anhydrous lanolin, stearic acid, glyceryl tristearate, and stearyl alcohol; the sustained-release matrix material comprises anhydrous lanolin and stearic acid; the particle size of the trazodone hydrochloride raw material is 50-500 μm, preferably 150-350 μm; the stabilizer is trihydroxystearin; the filler is at least two of microcrystalline cellulose, lactose, and mannitol; the tap density of the filler should be 0.75-1.25 g / cm3; and the lubricant is stearic acid and its acceptable salts.

[0036] In the technical solution of this invention, the water-absorbing properties of lanolin are utilized in a breakthrough application to solid sustained-release tablets, which can slowly release trazodone hydrochloride within a certain period of time, thus achieving a better sustained-release effect.

[0037] This invention also provides a method for preparing the above-mentioned trazodone hydrochloride sustained-release tablets; please refer to [link to relevant documentation]. Figure 1 , Figure 1 This is an embodiment of the preparation method of trazodone hydrochloride sustained-release tablets proposed in this invention, and the specific steps are as follows.

[0038] Step S1: Melt the sustained-release skeleton material and stabilizer, add trazodone hydrochloride, disperse evenly, and then form fine particles.

[0039] In practice, the melting temperature of the slow-release skeleton material and stabilizer is maintained at 55±10℃, then trazodone hydrochloride is added, dispersed evenly, cooled into a solid and crushed into fine particles, or fine particles are obtained by hot melt extrusion technology.

[0040] Step S2: Mix the fine particles with filler and lubricant evenly to obtain the material.

[0041] Step S3: Compress the obtained material into tablets to obtain trazodone hydrochloride sustained-release tablets.

[0042] In the technical solution of the present invention, the above preparation method is a conventional tablet production process. The overall process is simple and easy to implement, and is suitable for industrial production.

[0043] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only used to explain the present invention and are not intended to limit the present invention.

[0044] (I) Experiment on the effect of trazodone hydrochloride particle size on release rate

[0045] Example 1 / 2 / 3

[0046] According to the dosage in the table below, 75 mg of trazodone hydrochloride was pulverized and sieved; 50 mg of anhydrous lanolin, 25 mg of stearic acid, and 0.1 mg of trihydroxystearin were melted and then added to the pulverized and sieved trazodone hydrochloride. After being dispersed evenly, the mixture was stirred and gradually cooled to a solid state; the mixture was pulverized into fine particles and sieved for granulation; the fine particles were mixed evenly with 20 mg of microcrystalline cellulose, 25.9 mg of lactose, and 4 mg of magnesium stearate; the resulting material was compressed into tablets with a hardness controlled at 4-8 kg to obtain sustained-release tablets.

[0047] In Examples 1-3, the particle sizes of trazodone hydrochloride were 250±100μm, 50±20μm, and 650±150μm, respectively; in addition, the original reagent Trittico was used as Comparative Example 1.

[0048]

[0049] The release rates of Examples 1-3 and Comparative Example 1 at different time points were investigated using the paddle method with 1000 ml of pH 6.0 phosphate buffer as the dissolution medium, a paddle speed of 100 rpm, and a temperature of 37.0 °C.

[0050] Please see Figure 2 In the figure, Example 1 corresponds to curve 1, Example 2 corresponds to curve 2, Example 3 corresponds to curve 3, and Comparative Example 1 corresponds to curve RLD. From the curves, it can be seen that the dissolution characteristics of curve 1 are consistent with the original formulation; however, excessively small particle size of trazodone hydrochloride can cause a burst release phenomenon (as shown in curve 2); excessively large particle size of trazodone hydrochloride can cause a slower initial release, but the overall dissolution characteristics are basically consistent with the original formulation (as shown in curve 3).

[0051] (II) Experiment on the effect of sustained-release matrix material on release rate Example 4

[0052] According to the dosage in the table below, 75 mg of trazodone hydrochloride was pulverized and sieved; 60 mg of anhydrous lanolin, 15 mg of stearic acid, and 0.1 mg of trihydroxystearin were melted and then added to the pulverized and sieved trazodone hydrochloride. After being dispersed evenly, the mixture was stirred and gradually cooled to a solid state; the mixture was pulverized into fine particles and sieved for granulation; the fine particles were mixed evenly with 20 mg of microcrystalline cellulose, 25.9 mg of lactose, and 4 mg of magnesium stearate; the resulting material was compressed into tablets, with the hardness controlled at 4-8 kg, to obtain sustained-release tablets. Example 5

[0053] According to the dosage in the table below, 75 mg of trazodone hydrochloride was pulverized and sieved; 15 mg of anhydrous lanolin, 60 mg of stearic acid, and 0.1 mg of trihydroxystearin were melted and then added to the pulverized and sieved trazodone hydrochloride. After being dispersed evenly, the mixture was stirred and gradually cooled to a solid state; the mixture was pulverized into fine particles and sieved for granulation; the fine particles were mixed evenly with 20 mg of microcrystalline cellulose, 25.9 mg of lactose, and 4 mg of magnesium stearate; the resulting material was compressed into tablets with a hardness controlled at 4-8 kg to obtain sustained-release tablets.

[0054] In Examples 1, 4, and 5, only the amount of the sustained-release skeleton material changed, while the rest remained the same; in addition, the original reagent Trittico was used as Comparative Example 2.

[0055]

[0056] The release rate of Examples 1, 4, and 5, as well as Comparative Example 2, was investigated at different time points using the paddle method with 1000 ml of pH 6.0 phosphate buffer as the dissolution medium, a paddle rotation speed of 100 rpm, and a temperature of 37.0 °C. Samples were taken at 1, 2, 4, 6, 9, and 12 hours.

[0057] Please see Figure 3 In the figure, Example 1 corresponds to curve 1, Example 4 corresponds to curve 4, Example 5 corresponds to curve 5, and Comparative Example 2 corresponds to curve RLD. The curves show that when the amount of lanolin is too high (refer to curve 4), trazodone hydrochloride is released too quickly. This is related to the increased water absorption and easier dissolution and release of trazodone hydrochloride after the increase in lanolin dosage. Furthermore, since the melting point of lanolin is around 40℃, a higher dosage will also result in a lower melting point for trazodone hydrochloride particles, making them more prone to softening, deformation, and dispersion during dissolution, thus accelerating drug release. In reality, high-proportion lanolin formulations are prone to material sticking during pulverization and require low-temperature pulverization; sticking and other phenomena may also occur during tableting.

[0058] When the amount of stearic acid is high (refer to curve 5), trazodone hydrochloride is encapsulated by a large amount of stearic acid. Due to the low amount of lanolin, water has difficulty entering the trazodone hydrochloride particles, resulting in slow and incomplete release of trazodone hydrochloride.

[0059] (III) Experiment on the effect of trihydroxystearin on release rate Example 6

[0060] According to the dosage in the table below, 75 mg of trazodone hydrochloride is pulverized and sieved; 50 mg of anhydrous lanolin and 25 mg of stearic acid are melted and then added to the pulverized and sieved trazodone hydrochloride. After being dispersed evenly, the mixture is stirred and gradually cooled to a solid state; the mixture is pulverized into fine particles and sieved for granulation; the fine particles are mixed evenly with 20 mg of microcrystalline cellulose, 26 mg of lactose, and 4 mg of magnesium stearate; the resulting material is compressed into tablets, with the hardness controlled at 4-8 kg, to obtain sustained-release tablets. Example 7

[0061] According to the dosage in the table below, 75 mg of trazodone hydrochloride is pulverized and sieved; 50 mg of anhydrous lanolin, 25 mg of stearic acid, and 2 mg of trihydroxystearin are melted and then added to the pulverized and sieved trazodone hydrochloride. After being dispersed evenly, the mixture is stirred and gradually cooled to a solid state; the mixture is pulverized into fine particles and sieved for granulation; the fine particles are mixed evenly with 20 mg of microcrystalline cellulose, 24 mg of lactose, and 4 mg of magnesium stearate; the resulting material is compressed into tablets, with the hardness controlled at 4-8 kg, to obtain sustained-release tablets.

[0062] In Examples 1, 6 and 7, only the amount of trihydroxystearin was changed, while the rest remained the same; in addition, the original reagent Trittico was used as Comparative Example 3.

[0063]

[0064] The paddle method was used, with 1000 ml of pH 6.0 phosphate buffer as the dissolution medium, a rotation speed of 100 rpm, and a temperature of 37.0 °C. Samples were taken at 1, 2, 4, 6, 9, and 12 hours to investigate the release rates of Examples 1, 6, and 7 and Comparative Example 3 at different time points, as well as the release rates of Examples 1 and 7 at accelerated release for 6 months (40 °C).

[0065] The results showed that when the formulation did not contain trihydroxystearin (Example 6), more white spots appeared on the edge of the mixing tank during the cooling process due to the greater cooling, indicating that some low molecular weight components in lanolin solidified first. This could easily cause uneven content and change the release behavior of the sustained-release tablets, thus the curve of Example 6 was missing.

[0066] Please see Figure 4 In the figure, Example 1 corresponds to curve 1 (0 month) and curve 1 (6 month), Example 7 corresponds to curve 7 (0 month) and curve 7 (6 month), and Comparative Example 3 corresponds to curve RLD. The results showed that the release rate of Example 7 was significantly reduced. This may be because trihydroxystearin enhances the anti-crystallization properties of lanolin, causing its strength to gradually increase, reducing its water absorption capacity, and thus slowing down the release.

[0067] (iv) Effect of temperature on the dispersion of trazodone hydrochloride

[0068] Examples 8-11

[0069]

[0070] Examples 8-11 investigated the dispersion of the sustained-release framework material and stabilizer after melting and adding trazodone hydrochloride at 40℃, 55℃, 65℃, and 75℃, respectively. The experimental data showed that at lower temperatures, the material nearly solidified, and trazodone hydrochloride could not be well dispersed, resulting in an excessively high content in the upper layer. At higher temperatures, trazodone hydrochloride precipitated to the bottom, and even increasing the stirring speed or time did not result in uniform dispersion.

[0071] (v) Effect of different particle sizes of trazodone hydrochloride on dispersion

[0072] Examples 12-14

[0073]

[0074] Examples 12-14 investigated the dispersion of trazodone hydrochloride with particle sizes of 250±100 μm, 50±20 μm, and 650±150 μm at 55 °C. The experimental data show that trazodone hydrochloride cannot be well dispersed when the particle size is large.

[0075] (vi) Effect of fillers with different tap densities on the content of trazodone hydrochloride particles

[0076] Examples 15-19

[0077]

[0078] The tap density of particles containing trazodone hydrochloride is approximately 1.02 g / cm³. 3 Examples 15-19 investigated the changes in the content of fillers with different tap densities and trazodone hydrochloride particles during tableting. The experimental data clearly show that when the tap density of the filler and the trazodone hydrochloride particles differ significantly, stratification occurs during tableting, resulting in large differences in content during the tableting process.

[0079] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0080] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A sustained release tablet of Trazodone hydrochloride, characterized in that, It includes the following components by mass percentage: 20-60 wt% trazodone hydrochloride, 10-50 wt% sustained-release matrix material, 0.01-0.5 wt% stabilizer, 10-50 wt% filler and 0.5-3 wt% lubricant; The sustained-release matrix material is a combination of anhydrous lanolin and stearic acid; The stabilizer is trihydroxystearin.

2. The trazodone hydrochloride sustained release tablet according to claim 1, wherein The raw material particle size of the trazodone hydrochloride is 50-500 μm.

3. The trazodone HC1 sustained release tablet according to claim 2, wherein The raw material particle size of the trazodone hydrochloride is 150-350 μm.

4. The trazodone HC1 sustained release tablet according to claim 1, wherein The filler is at least two of microcrystalline cellulose, lactose, and mannitol.

5. The trazodone HC1 sustained release tablet according to claim 1, wherein The tap density of the filler should be 0.75 to 1.25 g / cm 3 .

6. The trazodone hydrochloride sustained release tablet according to claim 1, wherein The lubricant is stearic acid and its acceptable salts.

7. A process for the preparation of the sustained release tablet of Trazodone hydrochloride according to any one of claims 1 to 6, characterized in that, Includes the following steps: S1. After melting the sustained-release skeleton material and stabilizer, add trazodone hydrochloride, disperse evenly, and then form fine particles; S2. Mix the fine particles with filler and lubricant evenly to obtain the material; S3. Compress the material into tablets to obtain trazodone hydrochloride sustained-release tablets.

8. The method for preparing trazodone hydrochloride sustained-release tablets as described in claim 7, characterized in that, In step S1, the temperature at which the sustained-release skeleton material and stabilizer are melted and then added to trazodone hydrochloride is 45℃~65℃.

Images