Doxepin hydrochloride tablet and preparation method thereof

Abstract

The invention discloses a doxepin hydrochloride tablet and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The doxepin hydrochloride tablet comprises 1-10 parts of doxepin hydrochloride, 60-90 parts of a filler, 3-12 parts of a disintegrating agent, 1-8 parts of an adhesive, 0.5-3 parts of a flow aid and 0.5-3 parts of a lubricant. Wherein the doxepin hydrochloride is a micronized bulk drug, the D90 particle size is less than or equal to 15 microns, and the disintegrating agent is a compound of polyvinylpolypyrrolidone and carboxymethyl starch sodium in a weight ratio of 1: (0.5-2). The preparation method comprises the following steps: micronizing doxepin hydrochloride, uniformly mixing the main medicine and the auxiliary materials by adopting an equivalent progressive increase mixing method, and directly tabletting to obtain the doxepin hydrochloride tablet. According to the invention, micronization treatment is combined with an equivalent progressive increase mixing process, so that the problem of poor content uniformity of tablets with low dosage specifications is solved; rapid disintegration is realized through a composite disintegrant system; the direct tabletting process avoids heat-moisture treatment and improves the stability of the preparation. The prepared tablet is good in content uniformity, rapid in disintegration, excellent in stability, simple and convenient in process and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a doxepin hydrochloride tablet and its preparation method. Background Technology

[0002] Doxepin hydrochloride is a tricyclic antidepressant. Its mechanism of action primarily involves inhibiting the reuptake of serotonin and norepinephrine in the central nervous system, thereby increasing the concentration of these two neurotransmitters in the synaptic cleft and exerting antidepressant, anti-anxiety, and sedative effects. Clinically, doxepin hydrochloride tablets (25mg, 50mg, etc.) are widely used to treat depression and anxiety neurosis. In recent years, low-dose doxepin hydrochloride (3mg, 6mg) has been shown to be effective in treating insomnia characterized by difficulty maintaining sleep. At low doses, it primarily exerts histamine H1 receptor antagonism, producing a sedative-hypnotic effect, while significantly reducing anticholinergic and other side effects, making it an important option for insomnia treatment.

[0003] Currently, the most common oral dosage form of doxepin hydrochloride is the conventional tablet. However, existing conventional tablets still face the following technical challenges in actual production and application: First, for low-dose formulations (3mg, 6mg), the active pharmaceutical ingredient (API) accounts for a very low percentage of the tablet weight (usually less than 5%). Conventional mixing processes can easily lead to uneven distribution of the API, resulting in significant differences in content between tablets, affecting clinical efficacy and medication safety. This is a key technical challenge commonly faced by low-dose formulations. Second, doxepin hydrochloride API itself has a certain degree of hygroscopicity, and under humid and hot conditions, it is prone to color changes and increased impurities, placing high demands on formulation stability. In addition, the disintegration properties of existing tablets need to be optimized. For insomnia patients who require rapid onset of action, slow disintegration can affect drug absorption rate and sleep onset time.

[0004] There are existing reports on doxepin hydrochloride tablets and their preparation methods.

[0005] Prior art 1 (CN121177231A) discloses a doxepin hydrochloride tablet and its preparation method. This technical solution addresses the problems of doxepin hydrochloride's high hygroscopicity, instability to humid heat, and tendency to stick and impact. It employs a method of preparing a solid dispersion of doxepin hydrochloride and polyethylene glycol 6000 (drug-to-carrier weight ratio of 1:4 to 1:8), highly dispersing the drug in molecular, colloidal, and amorphous states within the carrier material to achieve an "encapsulation" effect. This dispersion is then mixed with fillers, disintegrants, glidants, and lubricants before direct tableting. This technology effectively improves the drug's hygroscopicity and stability through solid dispersion technology and simplifies the production process through direct tableting. However, this technical solution has the following shortcomings: First, the preparation process of the solid dispersion involves heating and melting (the melting temperature of polyethylene glycol 6000 is about 60°C) and rapid cooling steps. Although it can achieve drug dispersion, the melting process has the potential risk of thermal degradation, and the process is relatively complex and energy-intensive. Second, this technology has not been specifically optimized for the content uniformity problem of low-dose specifications (3mg, 6mg). Its mixing process is conventional mixing, without the use of special mixing methods such as equal addition. For low-dose formulations with a very low proportion of active pharmaceutical ingredient, it is difficult to ensure sufficient content uniformity. Third, the disintegrants disclosed in this technology are only conventionally selected and do not involve specific combinations of disintegrants and their synergistic effects.

[0006] Prior art 2 (CN108096363A) discloses a doxepin hydrochloride tablet and its preparation method. This technical solution aims to reduce the side effects of doxepin hydrochloride tablets by compounding doxepin hydrochloride with Schisandra chinensis extract to form tablets. The synergistic effect of Schisandra chinensis extract reduces the side effects of doxepin hydrochloride such as excessive sweating, dry mouth, and dizziness, while improving the therapeutic effect. This technology employs a wet granulation process, using starch, dextrin, or ethyl cellulose as a binder and 75% ethanol as a wetting agent, through steps including granulation, drying, sizing, and tableting. However, this technical solution has the following shortcomings: First, the addition of Schisandra chinensis extract complicates the formulation, increases the difficulty of quality control, and the components of traditional Chinese medicine extracts are complex, making it difficult to guarantee batch-to-batch consistency; Second, this technology uses a wet granulation process, which requires the addition of a wetting agent and heating and drying. For doxepin hydrochloride raw material, which has strong hygroscopicity, the wet granulation process may introduce moisture and heat, increasing the risk of impurity formation; Third, this technology does not perform micronization of the raw material, nor does it use an equal-volume incremental mixing process, making it difficult to guarantee content uniformity for low-dose specifications; Fourth, this technology does not use a disintegrant (starch as a binder), and the disintegration performance of the tablets depends on the water absorption and swelling of starch, resulting in a limited disintegration rate.

[0007] In summary, existing technologies lack a method for producing doxepin hydrochloride tablets that effectively ensures content uniformity in low-dose formulations, overcomes the hygroscopicity of the active pharmaceutical ingredient (API), and is simple and suitable for large-scale production. In particular, how to comprehensively improve the content uniformity, disintegration performance, and stability of low-dose doxepin hydrochloride tablets (3mg, 6mg) through synergistic optimization of API pretreatment and mixing processes, without introducing complex formulations and processes, remains a pressing technical problem to be solved in this field. Summary of the Invention

[0008] To address the technical problems of doxepin hydrochloride tablets in the prior art, such as poor content uniformity in low-dose specifications, the impact of the active pharmaceutical ingredient's hygroscopicity on stability, the need for optimization of disintegration performance, and complex preparation processes, this invention provides a doxepin hydrochloride tablet with good content uniformity, rapid disintegration, excellent stability, and a simple preparation process, along with its preparation method. This method effectively solves the problem of uneven distribution of the active pharmaceutical ingredient in low-dose tablets by pre-treating the doxepin hydrochloride active pharmaceutical ingredient with micronization and combining it with an equal-volume incremental mixing process. Simultaneously, a composite disintegrant system composed of crospovidone and sodium carboxymethyl starch is used to achieve rapid disintegration. The direct compression process avoids the influence of damp heat on drug stability and simplifies the production process.

[0009] This invention includes the following technical solutions: A doxepin hydrochloride tablet is manufactured from the following raw materials by direct compression process in parts by weight: Doxepin hydrochloride 1-10 parts 60-90 parts of filler 3-12 parts of disintegrant 1-8 parts of adhesive 0.5-3 parts of limpness aid Lubricant 0.5-3 parts; The doxepin hydrochloride is a micronized active pharmaceutical ingredient (API) with a D90 particle size ≤15μm. The disintegrant is a complex of crospovidone and sodium carboxymethyl starch, with a weight ratio of 1:0.5-2. This combination of APIs, through the synergistic effect of micronization pretreatment and the composite disintegrant system, ensures uniformity of content and rapid disintegration in low-dose tablets. Micronization of the API improves the dispersibility and specific surface area of ​​the active pharmaceutical ingredient, while the composite disintegrant achieves rapid disintegration through a dual mechanism of swelling and capillary action, jointly ensuring tablet quality stability and clinical efficacy.

[0010] The doxepin hydrochloride tablets are prepared by a direct compression process including the following steps: (1) Micronize the doxepin hydrochloride active pharmaceutical ingredient (API) to control its D90 particle size to ≤15μm. Micronization can be performed using an air jet mill with a grinding pressure of 0.6-1.0MPa and a feeding speed of 5-15kg / h. By controlling the particle size of the API to below 15μm through micronization, the specific surface area and dispersibility of the active pharmaceutical ingredient are significantly improved, laying the foundation for subsequent uniform mixing. Especially for low-dose formulations (3-6mg), micronization is a key prerequisite for ensuring content uniformity.

[0011] (2) Using the equal-volume incremental mixing method, the micronized doxepin hydrochloride is mixed evenly with the filler, disintegrant, and binder. Specifically, the micronized doxepin hydrochloride is first mixed with an equal amount of filler for 5-10 minutes, then the remaining filler, disintegrant, and binder are added and mixed for 10-20 minutes, and finally the gliding agent and lubricant are added and mixed for 3-8 minutes to obtain the total mixture. The equal-volume incremental mixing method avoids the problem of uneven distribution that may occur when low-dose active pharmaceutical ingredient is directly mixed with a large amount of excipients by gradually increasing the mixing ratio, and ensures that the active pharmaceutical ingredient is evenly dispersed in the mixture. It is the core technical means to ensure the uniformity of the content of low-dose tablets. The gliding agent and lubricant are added in the later stage of mixing to avoid excessive coating of particles and affecting the compressibility of the powder.

[0012] (3) The total mixture is directly compressed into tablets, and the compression pressure is controlled at 5-15kN to obtain tablet cores. The direct compression process does not require the addition of wetting agents or binder solutions, thus avoiding the adverse effects of wet heat treatment on the stability of doxepin hydrochloride raw material. The compression pressure of 5-15kN can ensure that the tablets obtain appropriate hardness (40-80N), which not only meets the packaging and transportation requirements, but also ensures that the disintegration time is controlled within 5 minutes, thus achieving rapid disintegration effect.

[0013] (4) Optionally, the tablet core is coated with a film to obtain doxepin hydrochloride tablets. The weight of the film coating layer is 2%-4% of the weight of the tablet core. Film coating can further isolate air and moisture, improve the long-term stability of the formulation, and reduce the formation rate of related substances.

[0014] The preferred dosage of doxepin hydrochloride is 3-6 parts by weight. This low-dose formulation is suitable for treating insomnia characterized by difficulty maintaining sleep. At low doses, it primarily exerts histamine H1 receptor antagonism, producing a sedative-hypnotic effect, while significantly reducing anticholinergic and other side effects. The filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the binder is selected from one or more of hydroxypropyl methylcellulose, povidone, and hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose; the flow aid is selected from one or more of silica and talc, preferably silica; and the lubricant is selected from one or more of magnesium stearate and sodium stearate fumarate, preferably magnesium stearate. The selection and proportioning of the above excipients have been optimized and verified to ensure an optimal balance between powder flowability, compressibility, and tablet disintegration properties.

[0015] Furthermore, in the aforementioned doxepin hydrochloride tablets, the disintegrant is a complex of crospovidone and sodium carboxymethyl starch, with a weight ratio of 1:0.5-2. This ratio range ensures that the two disintegrants work synergistically: crospovidone promotes rapid water penetration into the tablet through capillary action and swelling effect, while sodium carboxymethyl starch generates a disintegration driving force through strong swelling. Together, they achieve rapid disintegration (disintegration time ≤ 5 minutes). A ratio that is too high or too low will result in a decreased disintegration rate or insufficient tablet hardness.

[0016] Furthermore, in the aforementioned doxepin hydrochloride tablets, the filler, binder, glidant, and lubricant are all sieved through an 80-100 mesh sieve before use. Sieving eliminates raw material agglomeration, ensures uniform powder particle size, and guarantees the uniformity of mixing and the smoothness of the tableting process.

[0017] Furthermore, in the above-mentioned preparation process of doxepin hydrochloride tablets, the mixing speed of the mixer in step (2) is 15-25 rpm. The medium speed of 15-25 rpm can avoid electrostatic adsorption and material stratification caused by high-speed mixing, and at the same time ensure that each component reaches uniform distribution within a reasonable time. In particular, for the micronized doxepin hydrochloride raw material, the medium speed can prevent it from agglomerating due to electrostatic adsorption.

[0018] Furthermore, in the preparation process of the above-mentioned doxepin hydrochloride tablets, the tableting environment temperature in step (3) is controlled at 20-25℃ and the relative humidity is controlled at 40%-50%. This temperature and humidity range can prevent the raw materials and excipients from absorbing moisture, avoid sticking, and at the same time ensure the stability of powder flowability and prevent drug degradation.

[0019] The use of doxepin hydrochloride tablets as described in any of the above-mentioned technical solutions in the preparation of a medicament for treating depression, anxiety neurosis, or insomnia. Further, the insomnia is characterized by difficulty maintaining sleep; the tablets are administered orally, once or twice daily.

[0020] Compared with the prior art, the present invention has the following outstanding advantages: This invention addresses the technical challenge of uneven drug distribution in low-dose (3-6 mg) tablets by micronizing doxepin hydrochloride raw material (D90 particle size ≤ 15 μm) and combining it with an equal-volume incremental mixing process. This results in an A+2.2S value below 5.0 and an RSD value below 2.5%. Furthermore, by employing a composite disintegrant system composed of crospovidone and sodium carboxymethyl starch in a 1:0.5-2 ratio, the disintegration time of the tablets is controlled within 90 seconds through a synergistic mechanism of capillary action and swelling effect, achieving rapid disintegration. The direct compression process avoids the wet heat treatment and melting of solid dispersions required in wet granulation, resulting in a total impurity increase value below 0.12% after 6 months of accelerated testing, significantly improving stability. Finally, the invention features a simple preparation process, requiring no wetting agents or binder solutions, making it suitable for large-scale production and possessing promising industrial application prospects. Attached Figure Description

[0021] Figure 1 Comparative experiment on the content uniformity of the tablets prepared according to the present invention (A+2.2S); Figure 2 This is a comparative experiment on the disintegration time of the tablets prepared according to the present invention; Figure 3 This is a comparative experiment on the stability of the tablets prepared according to the present invention; Figure 4 This is a comparative experiment on the hardness and compressibility of the tablets prepared according to the present invention; Figure 5 This is a comparative experiment on the dissolution rate of the tablets prepared according to the present invention. Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] The raw materials used in this invention are as follows.

[0024] Example 1 A doxepin hydrochloride tablet is made from the following raw materials in parts by weight: Doxepin hydrochloride 3 parts 75 parts of microcrystalline cellulose 4 parts of crospovidone 4 parts of sodium carboxymethyl starch 3 parts hydroxypropyl methylcellulose 1 part silicon dioxide 1 part magnesium stearate; Among them, doxepin hydrochloride is a micronized raw material with a D90 particle size ≤10μm.

[0025] The preparation method of the above-mentioned doxepin hydrochloride tablets includes the following steps: (1) The doxepin hydrochloride raw material was micronized using an air jet mill with a grinding pressure of 0.8 MPa and a feeding speed of 10 kg / h, and its D90 particle size was controlled to be ≤10 μm. (2) Using the equal-volume incremental mixing method: First, mix 3 parts of micronized doxepin hydrochloride with 3 parts of microcrystalline cellulose for 8 minutes, then add the remaining 72 parts of microcrystalline cellulose, 4 parts of cross-linked polyvinylpyrrolidone, 4 parts of sodium carboxymethyl starch and 3 parts of hydroxypropyl methylcellulose and mix for 15 minutes, and finally add 1 part of silicon dioxide and 1 part of magnesium stearate and mix for 5 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the compression pressure is controlled at 10kN to obtain tablet cores with a hardness of 55N. (4) Coat the tablet core with a film, the weight of the coating layer being 3% of the weight of the tablet core, to obtain doxepin hydrochloride tablets.

[0026] Example 2 A doxepin hydrochloride tablet is made from the following raw materials in parts by weight: Doxepin hydrochloride 6 parts 70 parts of microcrystalline cellulose 5 parts of crospovidone 4 parts of sodium carboxymethyl starch 5 parts hydroxypropyl methylcellulose 1.5 parts silicon dioxide 1.5 parts magnesium stearate; Among them, doxepin hydrochloride is a micronized raw material with a D90 particle size ≤12μm.

[0027] The preparation method of the above-mentioned doxepin hydrochloride tablets includes the following steps: (1) The doxepin hydrochloride raw material was micronized using an air jet mill with a grinding pressure of 0.7 MPa and a feeding speed of 12 kg / h, and its D90 particle size was controlled to be ≤12 μm. (2) Using the equal-volume incremental mixing method: First, mix 6 parts of micronized doxepin hydrochloride with an equal amount of 6 parts of microcrystalline cellulose for 10 minutes, then add the remaining 64 parts of microcrystalline cellulose, 5 parts of cross-linked polyvinylpyrrolidone, 4 parts of sodium carboxymethyl starch, and 5 parts of hydroxypropyl methylcellulose and mix for 20 minutes. Finally, add 1.5 parts of silica and 1.5 parts of magnesium stearate and mix for 6 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the compression pressure is controlled at 12kN to obtain tablet cores with a hardness of 62N. (4) Coat the tablet core with a film, the weight of the coating layer being 3.5% of the weight of the tablet core, to obtain doxepin hydrochloride tablets.

[0028] Example 3 A doxepin hydrochloride tablet is made from the following raw materials in parts by weight: 10 parts of doxepin hydrochloride 65 parts lactose 3 parts of crospovidone 6 parts of sodium carboxymethyl starch 8 parts of hydroxypropyl methylcellulose 2 parts silicon dioxide 2 parts magnesium stearate; Among them, doxepin hydrochloride is a micronized active pharmaceutical ingredient with a D90 particle size ≤15μm.

[0029] The preparation method of the above-mentioned doxepin hydrochloride tablets includes the following steps: (1) The doxepin hydrochloride raw material was micronized using an air jet mill with a grinding pressure of 0.6 MPa and a feeding speed of 15 kg / h, and its D90 particle size was controlled to be ≤15 μm. (2) Using the equal-volume incremental mixing method: First, mix 10 parts of micronized doxepin hydrochloride with an equal amount of 10 parts of lactose for 5 minutes, then add the remaining 55 parts of lactose, 3 parts of cross-linked polyvinylpyrrolidone, 6 parts of sodium carboxymethyl starch, and 8 parts of hydroxypropyl methylcellulose and mix for 10 minutes. Finally, add 2 parts of silicon dioxide and 2 parts of magnesium stearate and mix for 8 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the compression pressure is controlled at 8kN to obtain tablet cores with a hardness of 48N. (4) Coat the tablet core with a film, the weight of which is 2.5% of the weight of the tablet core, to obtain doxepin hydrochloride tablets.

[0030] Example 4 A doxepin hydrochloride tablet is made from the following raw materials in parts by weight: Doxepin hydrochloride 3 parts 80 parts mannitol 6 parts of crospovidone 3 parts sodium carboxymethyl starch 4 parts of hydroxypropyl methylcellulose 1 part silicon dioxide 1 part magnesium stearate; Among them, doxepin hydrochloride is a micronized active pharmaceutical ingredient with a D90 particle size ≤ 8 μm.

[0031] The preparation method of the above-mentioned doxepin hydrochloride tablets includes the following steps: (1) The doxepin hydrochloride raw material was micronized using an air jet mill with a grinding pressure of 0.9 MPa and a feeding speed of 8 kg / h, and its D90 particle size was controlled to be ≤8 μm. (2) Using the equal-volume incremental mixing method: First, mix 3 parts of micronized doxepin hydrochloride with 3 parts of mannitol for 8 minutes, then add the remaining 77 parts of mannitol, 6 parts of cross-linked polyvinylpyrrolidone, 3 parts of sodium carboxymethyl starch and 4 parts of hydroxypropyl methylcellulose and mix for 15 minutes, and finally add 1 part of silicon dioxide and 1 part of magnesium stearate and mix for 5 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the tableting pressure is controlled at 9kN to obtain tablet cores with a hardness of 52N. (4) Coat the tablet core with a film, the weight of the coating layer being 3% of the weight of the tablet core, to obtain doxepin hydrochloride tablets.

[0032] Example 5 A doxepin hydrochloride tablet is made from the following raw materials in parts by weight: Doxepin hydrochloride 6 parts 72 parts of microcrystalline cellulose 5 parts of crospovidone 5 parts sodium carboxymethyl starch 5 parts hydroxypropyl methylcellulose 1 part silicon dioxide 1 part magnesium stearate; Among them, doxepin hydrochloride is a micronized raw material with a D90 particle size ≤10μm.

[0033] The preparation method of the above-mentioned doxepin hydrochloride tablets includes the following steps: (1) The doxepin hydrochloride raw material was micronized using an air jet mill with a grinding pressure of 0.8 MPa and a feeding speed of 10 kg / h, and its D90 particle size was controlled to be ≤10 μm. (2) Using the equal-volume incremental mixing method: First, mix 6 parts of micronized doxepin hydrochloride with an equal amount of 6 parts of microcrystalline cellulose for 8 minutes, then add the remaining 66 parts of microcrystalline cellulose, 5 parts of cross-linked polyvinylpyrrolidone, 5 parts of sodium carboxymethyl starch and 5 parts of hydroxypropyl methylcellulose and mix for 18 minutes, and finally add 1 part of silicon dioxide and 1 part of magnesium stearate and mix for 5 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the tableting pressure is controlled at 11kN to obtain tablet cores with a hardness of 58N. (4) Coat the tablet core with a film, the weight of the coating layer being 3% of the weight of the tablet core, to obtain doxepin hydrochloride tablets.

[0034] Comparative Example 1 Prepared according to the method of Example 1 of Existing Invention 1 (CN121177231A): Prescription: Doxepin hydrochloride 10mg / tablet (10g total based on 1000 tablets), polyethylene glycol 6000 50g, silicified microcrystalline cellulose 113g, sodium carboxymethyl starch 4.5g, colloidal silica 1.5g, magnesium stearate 1.0g.

[0035] Preparation method: After heating and melting polyethylene glycol 6000, add doxepin hydrochloride raw material and stir for 5 minutes to mix it evenly; after complete melting, cool and solidify quickly; after solidification, dry in a 35℃ oven until the moisture content is less than 2.0%; pulverize and pass through a 60-mesh sieve; then mix the pulverized particles evenly with siliconized microcrystalline cellulose, sodium carboxymethyl starch, colloidal silica and magnesium stearate, and directly compress into tablets.

[0036] Comparative Example 2 Prepared according to the method of Example 1 of Existing Invention 2 (CN108096363A) (excluding Schisandra chinensis extract): Prescription: Doxepin hydrochloride 10g, starch 184g, talcum powder 6g (based on 1000 tablets).

[0037] Preparation method: Pass doxepin hydrochloride, starch and talc through an 80-mesh sieve; mix doxepin hydrochloride and starch in a mixer for 10 minutes, spray with 75% ethanol to make a soft mass, granulate through an 18-mesh sieve; dry in an oven at 50℃ for 5 minutes; after granulation through a 22-mesh sieve, add talc and mix evenly; compress into tablets under a pressure of 10kN.

[0038] Comparative Example 3 Micronization was not used.

[0039] The prescription is the same as in Example 1, but the doxepin hydrochloride raw material was not micronized (D90 particle size is about 50μm) and was used directly.

[0040] The preparation method is the same as in Example 1, using an equal-volume incremental mixing process and direct tableting.

[0041] Comparative Example 4 The equal-volume incremental mixing process was not adopted.

[0042] The formulation is the same as in Example 1. The doxepin hydrochloride raw material is micronized (D90 particle size ≤ 10 μm), but the mixing steps are as follows: the micronized doxepin hydrochloride is added to a mixer along with all fillers, disintegrants and binders and mixed for 15 minutes, and then the gliding agent and lubricant are added and mixed for 5 minutes.

[0043] Comparative Example 5 It uses a single disintegrant, not a complex disintegrant.

[0044] The prescription is the same as in Example 1, but the disintegrant is only 8 parts of crospovidone and does not contain sodium carboxymethyl starch.

[0045] The preparation method is the same as in Example 1.

[0046] Comparative Example 6 No adhesive was added.

[0047] Prescription: 3 parts doxepin hydrochloride, 78 parts microcrystalline cellulose, 4 parts crospovidone, 4 parts sodium carboxymethyl starch, 1 part silicon dioxide, 1 part magnesium stearate (excluding binder hydroxypropyl methylcellulose).

[0048] The preparation method is the same as in Example 1.

[0049] Test Example 1 Comparison experiment on content uniformity.

[0050] Objective: To verify the effect of the micronization process combined with the equal-volume incremental mixing process of the present invention on improving the content uniformity of low-dose doxepin hydrochloride tablets.

[0051] method: Sample preparation: Tablet samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 were prepared respectively, and 20 tablets were randomly selected from each sample.

[0052] Detection method: The content uniformity test method was performed according to the General Chapter 0941 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0053] Instrument: High Performance Liquid Chromatograph (Model: Agilent 1260 Infinity II) Chromatographic conditions: C18 column (4.6 mm × 250 mm, 5 μm), mobile phase methanol-acetonitrile-0.2% triethylamine solution (40:15:45), detection wavelength 254 nm, flow rate 1.0 mL / min, column temperature 30 ℃, injection volume 20 μL.

[0054] Determination procedure: Take each tablet and place it in a 100mL volumetric flask. Add an appropriate amount of mobile phase, sonicate to dissolve, cool, dilute to the mark with mobile phase, shake well, filter, and inject the filtrate for determination.

[0055] Content uniformity calculation: Calculate the content (X) of each tablet, labeled as A, calculate the absolute value and standard deviation S of the difference between A and X, and calculate according to the formula A+2.2S.

[0056] Data statistics: 20 samples were measured in parallel for each sample, and the mean ± SD was calculated.

[0057] The results are shown in Table 1 and... Figure 1 .

[0058] Analysis: The A+2.2S values ​​of Examples 1 and 2 are 4.2 and 4.9, respectively, far below the 15.0 limit specified in the pharmacopoeia, and the RSD values ​​are 1.9% and 2.2%, respectively, indicating that the tablets prepared by the technical solution of the present invention have excellent content uniformity. Comparative Example 3 (without micronization) has an A+2.2S value of 12.8 and an RSD value of 7.3%, indicating that the unmicronized active pharmaceutical ingredient has a larger particle size and poor dispersibility, leading to a significant decrease in content uniformity. Comparative Example 4 (without equal-volume incremental mixing) has an A+2.2S value of 9.6 and an RSD value of 5.1%, indicating that conventional mixing methods are difficult to ensure the uniform distribution of low-dose active pharmaceutical ingredient in excipients. The A+2.2S values ​​of Comparative Example 1 (solid dispersion) and Comparative Example 2 (wet granulation) are 8.7 and 11.6, respectively, both higher than the examples, proving that micronization combined with equal-volume incremental mixing is superior to existing technologies in ensuring content uniformity of low-dose specifications. Micronization reduces the particle size and increases the specific surface area of ​​the active pharmaceutical ingredient, thus improving its dispersibility. Equal-volume incremental mixing avoids uneven distribution that occurs when low-dose active pharmaceutical ingredients are directly mixed with large amounts of excipients by gradually increasing the mixing ratio. The synergistic effect of the two significantly improves the uniformity of content.

[0059] Conclusion: The present invention, through micronization combined with an equal-volume incremental mixing process, produces doxepin hydrochloride tablets with significantly better content uniformity than existing technologies, meeting pharmacopoeia requirements.

[0060] Test Example 2 Disintegration time limit comparison experiment.

[0061] Objective: To verify the effect of the composite disintegrant system of the present invention on improving the disintegration performance of tablets.

[0062] method: Sample preparation: Tablet samples of Example 1, Example 5, Comparative Example 1, Comparative Example 2, Comparative Example 5 and Comparative Example 6 were prepared respectively.

[0063] Test method: The test was performed according to the "Disintegration time limit test" method in General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0064] Instrument: Intelligent Disintegration Analyzer (Model: ZB-1E) Medium: purified water, temperature 37℃±1℃ Test procedure: Take 6 tablets and place them in the glass tubes of the basket respectively. Start the disintegration apparatus and record the time it takes for the tablets to completely disintegrate and pass through the sieve.

[0065] Data statistics: Six samples were measured in parallel for each sample, and the average value was taken.

[0066] The results are shown in Table 2 and Figure 2 .

[0067] Analysis: The disintegration times of Examples 1 and 5 were 78 seconds and 73 seconds, respectively, both less than 90 seconds, achieving rapid disintegration. Comparative Example 5 (single disintegrant) had a disintegration time of 172 seconds, significantly longer than the examples, demonstrating a synergistic effect between the crospovidone and sodium carboxymethyl starch composite disintegrant. Crospovidone rapidly absorbs water into the tablet via capillary action, producing a swelling effect; sodium carboxymethyl starch expands dramatically after absorbing water, generating a strong disintegration driving force; the synergistic effect of both allows water to penetrate rapidly and the tablet to disintegrate quickly. The disintegration time of Comparative Example 1 (solid dispersion) was 207 seconds, and that of Comparative Example 2 (wet granulation) was 486 seconds, both significantly longer than the examples, indicating that the composite disintegrant system of this invention is superior to existing single-disintegrant or non-disintegrant solutions in terms of rapid disintegration. Comparative Example 6 (without binder) had a disintegration time of 87 seconds, which is close to that of the Example, but its hardness was only 37 N (see Test Example 4), and the tablet brittleness was unqualified. This shows that the addition of binder is a necessary condition to achieve rapid disintegration while ensuring hardness.

[0068] Conclusion: The present invention utilizes the synergistic effect of crosslinked polyvinylpyrrolidone and sodium carboxymethyl starch composite disintegrant to prepare doxepin hydrochloride tablets with rapid disintegration and a disintegration time significantly superior to existing technologies.

[0069] Test Example 3 Stability comparison experiment.

[0070] Objective: To verify the effect of the direct tableting process of the present invention on improving the stability of the formulation.

[0071] method: Sample preparation: Tablet samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were prepared respectively.

[0072] Accelerated testing conditions: Refer to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" in General Chapter 9001 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, and place the samples in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% relative humidity for 6 months.

[0073] Detection method: Samples were taken in 0 months, 3 months and 6 months respectively, and the relevant substances (total impurities) were determined according to the method under the Doxepin Hydrochloride Tablets section of the 2020 edition of the Chinese Pharmacopoeia, Part II.

[0074] Instrument: High Performance Liquid Chromatograph (Model: Agilent 1260 Infinity II) Chromatographic conditions: Same as test example 1 Sample preparation: Grind the tablets into a fine powder, accurately weigh an appropriate amount, add the mobile phase to dissolve and dilute to the mark, filter, and inject the filtrate for analysis.

[0075] Data statistics: Each time point was measured in parallel three times, and the average value was taken.

[0076] The results are shown in Table 3 and Figure 3 .

[0077] Analysis: The initial total impurities in Examples 1 and 2 were 0.11% and 0.12%, respectively. After 6 months of acceleration, the total impurities increased to 0.22% and 0.23%, respectively, with an increase of 0.11% in both cases, indicating that the tablets prepared by the direct compression process of this invention have good stability. Comparative Example 1 (solid dispersion) had an initial total impurity of 0.29%, which increased to 0.38% after acceleration, with an increase of 0.09%. Although the increase was small, the initial impurity level was high, possibly related to the heat treatment during the melting process. Comparative Example 2 (wet granulation) had an initial total impurity of 0.36%, which increased to 0.54% after acceleration, with an increase of 0.18%, significantly higher than the examples, indicating that moisture and heat treatment during wet granulation have an adverse effect on the stability of doxepin hydrochloride. Comparative Example 3 (unmicronized) had an initial total impurity of 0.17%, which increased to 0.30% after acceleration, a growth of 0.13%, slightly higher than the example. This may be related to the larger particle size of the active pharmaceutical ingredient and uneven heating during mixing. Doxepin hydrochloride active pharmaceutical ingredient is hygroscopic and easily undergoes oxidative degradation under humid and hot conditions, generating impurities. The direct tableting process of this invention avoids the humid and hot treatment of wet granulation and the melting treatment of solid dispersions, effectively reducing the risk of impurity formation.

[0078] Conclusion: This invention, through direct tableting, avoids the influence of damp heat on drug stability. The prepared doxepin hydrochloride tablets show a small increase in impurities under accelerated testing conditions and exhibit better stability than existing technologies.

[0079] Test Example 4 Comparison experiment of hardness and compressibility.

[0080] Objective: To verify the effects of the formulation and process of this invention on tablet hardness and compressibility.

[0081] method: Sample preparation: Tablet samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 6 were prepared respectively.

[0082] Hardness determination: referring to the "Tablet Hardness Determination Method" in General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the hardness of tablets was determined using an intelligent tablet hardness tester (model: YD-1). Ten tablets were tested for each sample, and the average value was taken.

[0083] Friability determination: Refer to the "Tablet Friability Test Method" in General Chapter 0923 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. Take about 6.5g of tablets, place them in the friability tester, rotate them 100 times, take them out and weigh them, and calculate the percentage of weight loss.

[0084] The results are shown in Table 4 and Figure 4 .

[0085] Analysis: The hardness of Examples 1 and 2 were 56N and 61N, respectively, and the friability was 0.24% and 0.19%, respectively, both conforming to the pharmacopoeia requirements (friability ≤1%). The tablets had a smooth appearance, indicating that the formulation of this invention has good compressibility. Comparative Example 1 (solid dispersion) had a hardness of 44N and a friability of 0.45%, with acceptable compressibility but lower than that of this invention. Comparative Example 2 (wet granulation) had a hardness of 37N and a friability of 0.71%, with a rough appearance and cracking, possibly related to uneven particle hardness distribution during wet granulation. Comparative Example 6 (without binder) had a hardness of only 37N and a friability of 0.73%, significantly higher than the examples, proving that the addition of binder is key to ensuring tablet hardness and anti-friability performance. Hydroxypropyl methylcellulose, as a dry powder binder, forms a strong bond between particles through plastic deformation during tableting, while its hydrophilic properties do not affect the disintegration performance of the tablets, making it an ideal binder choice in direct compression processes.

[0086] Conclusion: By optimizing the formulation, especially by adding hydroxypropyl methylcellulose as a dry powder binder, the present invention prepares doxepin hydrochloride tablets with suitable hardness and good anti-brittleness properties, meeting the requirements for production and use.

[0087] Test Example 5 Dissolution comparison experiment.

[0088] Objective: To verify the dissolution performance of the tablets of the present invention.

[0089] method: Sample preparation: Tablet samples of Example 1, Example 2, Comparative Example 1, and Comparative Example 2 were prepared respectively.

[0090] Test method: The test was performed according to the "Dissolution test" (paddle method) of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0091] Instrument: Intelligent Dissolution Tester (Model: RC-8MD) Dissolution medium: 0.1 mol / L hydrochloric acid solution, volume 900 mL, temperature 37℃±0.5℃, rotation speed 50 rpm. Sampling times: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min Detection method: The concentration of doxepin hydrochloride in the sample at each time point was determined by high performance liquid chromatography (same as test example 1), and the cumulative dissolution rate was calculated.

[0092] The results are shown in Table 5 and Figure 5 .

[0093] Analysis: Examples 1 and 2 achieved dissolution rates of 94.9% and 93.6% within 15 minutes, and 97.7% and 96.8% within 30 minutes, respectively, demonstrating rapid and complete dissolution characteristics. Comparative Example 1 (solid dispersion) achieved a dissolution rate of 91.9% within 30 minutes, slightly lower than the examples; Comparative Example 2 (wet granulation) achieved a dissolution rate of only 77.6% within 30 minutes and only 84.8% within 60 minutes, showing a significantly slower dissolution rate. The rapid dissolution of the tablets in this invention is due to: micronization increasing the specific surface area of ​​the active pharmaceutical ingredient, facilitating rapid penetration of the dissolution medium; the compound disintegrant rapidly disintegrating the tablets into fine particles, increasing the contact area between the drug and the dissolution medium; and the direct compression process avoiding drug particle agglomeration that may occur during wet granulation, ensuring the drug's dispersion. For low-dose doxepin hydrochloride tablets indicated for insomnia, rapid dissolution helps the drug to be quickly absorbed and take effect after being taken before bedtime, shortening the time to fall asleep.

[0094] Conclusion: The doxepin hydrochloride tablets prepared by this invention dissolve rapidly and completely, with a dissolution rate of over 90% within 15 minutes and near-complete dissolution within 30 minutes. The dissolution performance is superior to that of existing technologies.

Claims

1. A doxepin hydrochloride tablet, characterized in that, The tablets contain the following components in parts by weight: Doxepin hydrochloride 1-10 parts, 60-90 parts of filler 3-12 parts disintegrant 1-8 parts adhesive 0.5-3 parts of glidin. Lubricant 0.5-3 parts; The doxepin hydrochloride is a micronized active pharmaceutical ingredient with a D90 particle size ≤ 15 μm.

2. The doxepin hydrochloride tablets according to claim 1, characterized in that, The dosage of doxepin hydrochloride is 3-6 parts by weight.

3. The doxepin hydrochloride tablets according to claim 1, characterized in that, The disintegrant is a complex of crospovidone and sodium carboxymethyl starch, with a weight ratio of 1:0.5-2.

4. The doxepin hydrochloride tablets according to claim 1, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the binder is selected from one or more of hydroxypropyl methylcellulose, povidone, and hydroxypropyl cellulose; the flow aid is selected from one or more of silica and talc; and the lubricant is selected from one or more of magnesium stearate and sodium stearate fumarate.

5. The doxepin hydrochloride tablets according to claim 1, characterized in that, The adhesive is hydroxypropyl methylcellulose, the flow aid is silicon dioxide, and the lubricant is magnesium stearate.

6. The doxepin hydrochloride tablets according to claim 1, characterized in that, The tablets also include a film coating layer, the weight of which is 2%-4% of the tablet core weight.

7. A method for preparing doxepin hydrochloride tablets as described in any one of claims 1-6, characterized in that, Includes the following steps: (1) Micronize the doxepin hydrochloride raw material to control its D90 particle size to ≤15μm; (2) Using the equal-volume incremental mixing method, micronized doxepin hydrochloride is mixed evenly with filler, disintegrant and binder. Specifically, micronized doxepin hydrochloride is first mixed with an equal amount of filler for 5-10 minutes, then the remaining filler, disintegrant and binder are added and mixed for 10-20 minutes, and finally the flow aid and lubricant are added and mixed for 3-8 minutes to obtain the total mixture. (3) The total mixture is directly compressed into tablets, and the compression pressure is controlled at 5-15kN to obtain tablet cores; (4) Optionally, the tablet core is coated with a film to obtain doxepin hydrochloride tablets.

8. The preparation method according to claim 7, characterized in that, In step (1), the micronization process is carried out using an air jet mill with a grinding pressure of 0.6-1.0 MPa and a feeding speed of 5-15 kg / h.

9. The preparation method according to claim 7, characterized in that, The core obtained in step (3) has a hardness of 40-80N and a disintegration time of ≤5 minutes.

10. The preparation method according to claim 7, characterized in that, In step (3), no wetting agent or adhesive solution is added when directly compressing tablets.

Images