Doxepin hydrochloride tablet and preparation method thereof

Abstract

The invention relates to a doxepin hydrochloride tablet. The doxepin hydrochloride tablet is prepared from doxepin hydrochloride, polyethylene glycol 6000, a filling agent, a disintegrating agent, a flow aid and a lubricating agent. The preparation method comprises the following steps: heating and melting polyethylene glycol 6000, adding a doxepin hydrochloride raw material according to a prescription proportion, and uniformly stirring and mixing; and after complete melting, rapidly cooling and solidifying to form a solid dispersion. And after curing, drying in a drying oven, crushing and sieving. And uniformly mixing the crushed particles with the filler and the lubricant, and directly tabletting. The doxepin hydrochloride has high hygroscopicity, is unstable to damp and heat and easily generates a large amount of impurities under strong oxidation conditions, the doxepin hydrochloride is firstly prepared into a solid dispersion and then is directly compressed, so that the medicine is highly dispersed in a carrier material in the states of molecules, colloids, amorphous forms, microcrystals and the like, and the effect of wrapping the medicine is achieved by controlling the ratio of the medicine to the carrier. Direct contact between the medicine and air is avoided, so that the problems of hygroscopicity and instability of the medicine are solved, and the product stability is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a doxepin hydrochloride tablet and a preparation method thereof. BACKGROUND

[0002] Depression refers to a mood disorder or emotional disorder caused by various reasons, and the main symptom is depression. Depression is a relatively common mental illness in clinical practice, and has high morbidity, disability rate, recurrence rate and mortality, which seriously affects the life safety and quality of life of patients. At present, the clinical treatment method of depression mainly relies on antidepressant drug treatment.

[0003] Doxepin hydrochloride belongs to tricyclic drugs, and its mechanism of action is not clear. Current studies have shown that it may inhibit the reuptake of 5-hydroxytryptamine and norepinephrine in the central nervous system, thereby increasing the concentration of these two neurotransmitters in the synaptic cleft and exerting an antidepressant effect. Doxepin hydrochloride was first marketed in the United States by Pfizer in 1969 and is used to treat depression, anxiety and psychotic depression. There are capsules and oral concentrates. In 2010, a small dose of doxepin hydrochloride tablets was marketed in the United States for the treatment of insomnia characterized by difficulty maintaining sleep.

[0004] Figure 1 The chemical structure of doxepin hydrochloride is shown in the figure, and the chemical name is N,N-dimethyl-3-dibenz(b,e)-oxepin-11(6H)yl-1-propylamine hydrochloride. The molecular formula is C 19 H 21 NO·HCl, and the molecular weight is 315.84.

[0005] Doxepin hydrochloride is classified as BCS I in the biopharmaceutics classification system, which is a high-solubility and high-permeability drug. The raw material is white powder, which is easily hygroscopic, and the color gradually changes to yellowish after hygroscopicity. Because of its strong hygroscopicity, it is not suitable for traditional wet granulation process, and it is easy to appear sticky and colliding phenomenon in the industrial production process. At the same time, studies have shown that under strong oxidation and high temperature conditions, a large amount of impurities are produced, and the chemical properties are unstable.

[0006] Therefore, the present application prepares the doxepin hydrochloride into a solid dispersion first, and then directly compresses the solid dispersion into tablets, so that the drug is highly dispersed in the carrier material in the state of molecules, colloidal, amorphous and microcrystalline, etc., the drug is "wrapped" by controlling the ratio of the drug and the carrier, the direct contact of the drug with air is avoided, the sticking and bumping phenomenon is avoided, and the stability of the product is significantly improved. Meanwhile, it is shown by research that the water-soluble carrier matrix polyethylene glycol has small toxicity, is easily absorbed in the gastrointestinal tract, does not interfere with the content analysis of the drug, can significantly increase the dissolution rate of the drug, and improves the bioavailability of the drug. The present application uses polyethylene glycol 6000 as the carrier to effectively promote the rapid dissolution of the doxepin hydrochloride and improve the bioavailability thereof. Nowadays, the solid dispersion technology is mature, the preparation process is simple, is suitable for large-scale industrial production, and can provide a train of thought for the development of the doxepin hydrochloride tablets. SUMMARY

[0007] The main purpose of the present application is to overcome the deficiencies of the prior art of the doxepin hydrochloride tablets, and to provide a simple and efficient preparation method which can effectively improve the stability and bioavailability.

[0008] The present application provides the following technical solutions:

[0009] A doxepin hydrochloride tablet is characterized in that a prescription is prepared into a solid dispersion by doxepin hydrochloride and polyethylene glycol 6000, and then mixed with a filler, a disintegrant, a glidant and a lubricant to directly compress the solid dispersion into tablets.

[0010] The weight ratio of the doxepin hydrochloride and the polyethylene glycol 6000 is 1:4-1:8.

[0011] The filler includes one or more of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, sorbitol, mannitol and calcium silicate.

[0012] The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate and calcium stearate.

[0013] The glidant includes one or more of talc and colloidal silicon dioxide.

[0014] The disintegrant includes one or more of starch, croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0015] The preparation method of the doxepin hydrochloride tablet of the present application includes the following steps:

[0016] After the polyethylene glycol 6000 is heated and melted, the doxepin hydrochloride raw material in the prescription ratio is added, and the mixture is fully stirred for 5-10 min to make the mixture uniform.

[0017] After the raw material and the polyethylene glycol 6000 are completely melted, the mixture is rapidly cooled and solidified in an ice bath.

[0018] After solidification, put into 30-40℃ oven to dry until moisture is less than 2%;

[0019] After drying, crush through 40-80 mesh sieve;

[0020] Mix the crushed particles with the fillers, disintegrants, glidants, disintegrants evenly, and directly compress into tablets.

[0021] The idea of the present application is briefly described as follows:

[0022] It is found that the ratio of doxepin hydrochloride raw material to polyethylene glycol 6000 carrier has a significant effect on compressibility, so the effects of different ratios of raw material and carrier on flowability and compressibility are investigated. The process is as follows: weigh the polyethylene glycol 6000 according to the proportion, melt it, then add the doxepin hydrochloride raw material according to the prescription ratio, stir for 8 min to mix evenly. After complete melting, quickly cool and solidify to form a solid dispersion. After solidification, put into 35℃ oven to dry, crush through 60 mesh sieve. Mix the crushed particles with the fillers, disintegrants, glidants, disintegrants evenly, and directly compress into tablets.

[0023]

[0024]

[0025] The experimental results show that when the weight ratio of doxepin hydrochloride to polyethylene glycol 4000 is 1:4-1:8, the tabletting process is not easy to stick and the tablet surface is smooth, and the preferred ratio is 1:6. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is the chemical structure of doxepin hydrochloride. DETAILED DESCRIPTION

[0027] The content of the present application is further illustrated by the examples of the present application given below, but the present application is not limited by the examples.

[0028] Example 1

[0029] Name Single dose amount (mg / tablet) Doxepin hydrochloride 10 Polyethylene glycol 50 Silicified microcrystalline cellulose 113 Sodium starch glycolate 4.5 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 180

[0030] Weigh the polyethylene glycol 6000 according to the proportion, melt it, then add the doxepin hydrochloride raw material according to the prescription ratio, stir for 5 min to mix evenly. After complete melting, quickly cool and solidify to form a solid dispersion. After solidification, put into 35℃ oven to dry until moisture is less than 2.0%. Crush through 60 mesh sieve. Mix the crushed particles with the siliconized microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, magnesium stearate evenly, and directly compress into tablets.

[0031] Example 2

[0032]

[0033]

[0034] The weighed polyethylene glycol 6000 was heated and melted, then the doxepin hydrochloride raw material in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35°C oven for drying until the moisture content was less than 2.0%. The powder was crushed through a 60-mesh sieve. The crushed particles were then mixed with silicified microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate, and directly compressed into tablets.

[0035] Example 3

[0036] Name Single dose amount (mg / tablet) Doxepin hydrochloride 10 Polyethylene glycol 70 Silicified microcrystalline cellulose 93 Sodium starch glycolate 4.5 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 150

[0037] The weighed polyethylene glycol 6000 was heated and melted, then the doxepin hydrochloride raw material in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35°C oven for drying until the moisture content was less than 2.0%. The powder was crushed through a 60-mesh sieve. The crushed particles were then mixed with silicified microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate, and directly compressed into tablets.

[0038] Example 4

[0039] Name Single dose amount (mg / tablet) Doxepin hydrochloride 10 Polyethylene glycol 60 Microcrystalline cellulose 103 Sodium starch glycolate 4.5 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 150

[0040] The weighed polyethylene glycol 6000 was heated and melted, then the doxepin hydrochloride raw material in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35°C oven for drying until the moisture content was less than 2.0%. The powder was crushed through a 60-mesh sieve. The crushed particles were then mixed with silicified microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate, and directly compressed into tablets.

[0041] Example 5

[0042] Name Single dose amount (mg / tablet) Doxepin hydrochloride 10 Polyethylene glycol 60 Silicified microcrystalline cellulose 103 Croscarmellose sodium 4.5 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 150

[0043] The weighed polyethylene glycol 6000 was heated and melted, then the doxepin hydrochloride raw material in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35°C oven for drying until the moisture content was less than 2.0%. The powder was crushed through a 60-mesh sieve. The crushed particles were then mixed with silicified microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate, and directly compressed into tablets.

[0044] Example 6

[0045] Name Single dose amount (mg / tablet) Doxepin hydrochloride 10 Polyethylene glycol 60 Microcrystalline cellulose 103 Crospovidone 4.5 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 150

[0046] The polyethylene glycol 6000 weighed in proportion was heated and melted, then the raw material of doxepin hydrochloride in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35℃ oven for drying until the moisture content was less than 2.0%. The crushed particles were passed through a 60-mesh sieve. The crushed particles were then mixed with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate, and directly compressed into tablets.

[0047] Example 7

[0048]

[0049]

[0050] The polyethylene glycol 6000 weighed in proportion was heated and melted, then the raw material of doxepin hydrochloride in the prescription proportion was added, and stirred for 5 min to mix. After complete melting, it was quickly cooled and solidified to form a solid dispersion. After solidification, it was placed in a 35℃ oven for drying until the moisture content was less than 2.0%. The crushed particles were passed through a 60-mesh sieve. The crushed particles were then mixed with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate, and directly compressed into tablets.

[0051] Example 8

[0052] The products prepared by the prescription processes of the technical solutions of examples 1-7 of the present application all meet the specified quality indicators.

[0053]

[0054] Example 9

[0055] According to the "Guidelines on Stability Testing of Raw Materials and Preparations" in Appendix 9001 of the Chinese Pharmacopoeia 2020 Edition, the sample prepared in example 1 of the optimal combination was subjected to stability test investigation:

[0056] Accelerated test: the sample was placed in a constant temperature and humidity box at a temperature of 40±2℃ and a relative humidity of 75±5% RH, and was placed for 6 months. Samples were taken at 1, 2, 3 and 6 months, respectively, and were detected according to the stability test items and compared with the data at 0 months.

[0057] Long-term test: the sample was placed in an intermediate condition at a temperature of 25±2℃ and a relative humidity of 60±5% RH, and was placed for 6 and 12 months, respectively. The samples were detected according to the test items and compared with the data at 0 months.

[0058] The stability test results show that after the accelerated test of the doxepin hydrochloride tablets for 6 months and the long-term test for 12 months, the quality meets the requirements, and the quality of the doxepin hydrochloride tablets prepared by the technical scheme is stable and controllable.

[0059] Time Appearance Dissolution (%) Content (%) Total impurities (%) 0 month White to slightly yellow tablets 99.0 99.8 0.18 Accelerated 1 month White to slightly yellow tablets 99.1 99.6 0.18 Accelerated 2 months White to slightly yellow tablets 98.7 99.5 0.19 Accelerated 3 months White to slightly yellow tablets 98.8 99.6 0.21 Accelerated 6 months White to slightly yellow tablets 98.5 99.1 0.25 Long-term 6 months White to slightly yellow tablets 98.7 99.0 0.20 Long-term 12 months White to slightly yellow tablets 98.4 98.9 0.24

Claims

1. A doxepin hydrochloride tablet, characterized in that... The formulation is prepared into a solid dispersion by doxepin hydrochloride and polyethylene glycol 6000, which is then mixed with fillers, disintegrants, glidants and lubricants, and directly compressed into tablets.

2. The doxepin hydrochloride tablet according to claim 1, characterized in that... The preparation process of the solid dispersion includes the following steps: Polyethylene glycol 6000 is heated and melted, then doxepin hydrochloride raw material in the prescribed proportion is added, and the mixture is stirred thoroughly for 5-10 minutes to ensure homogeneity. After complete melting, it is rapidly cooled and solidified in an ice bath. After solidification, it is dried in an oven at 30-40℃ until the moisture content is less than 2%. The solidified material is then pulverized and passed through a 60-mesh sieve.

3. The doxepin hydrochloride tablets according to claim 1, characterized in that... The weight ratio of doxepin hydrochloride to polyethylene glycol 6000 is 1:4 to 1:

8.

4. The doxepin hydrochloride tablet according to claim 1, characterized in that... The filler includes one or more of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, sorbitol, mannitol, and calcium silicate. The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, and calcium stearate. The flow aid includes one or more of talc and silica. The disintegrant includes one or more of starch, croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

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