A trazodone hydrochloride liquid pharmaceutical composition with improved stability and preparation method thereof

Abstract

The present invention provides a trazodone hydrochloride liquid pharmaceutical composition with improved stability and a preparation method thereof, wherein the pharmaceutical composition comprises the following ingredients: 10-30 g / L trazodone hydrochloride, 90-220 g / L sorbitol, 150-320 g / L glycerol, 0.1-0.5 g / L benzoic acid or its salt, 1-5 g / L sodium glutamate, and constant volume of water; the pH of the trazodone hydrochloride liquid pharmaceutical composition is 4.2-5.0; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol, and sodium glutamate is 1:6.9-10.3:10-16.3:0.065-0.1. The trazodone hydrochloride liquid pharmaceutical composition prepared by the present invention has good stability, high bioavailability, and good patient compliance; the preparation process is simple, easy to control, convenient to operate, and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and in particular relates to a trazodone hydrochloride liquid pharmaceutical composition with improved stability and a preparation method thereof. Background Art

[0002] Trazodone, chemically known as 2-[3-[4-(3-chlorophenyl)-1-piperazinylpropyl]-1,2,4-triazolo[4,3-a]pyridine-3(2)-1, is an antidepressant that is neither a psychotropic agonist, nor a MAO inhibitor, nor a tricyclic antidepressant, although it has significant effects on serotonin receptors. In addition, trazodone has analgesic properties. Trazodone relieves characteristic symptoms of depression, particularly anxiety, somatization, psychomotor retardation, melancholia, mood swings, irritability, insomnia, apathy, fatigue and lack of energy, and depressed mood. Trazodone has also been shown to be effective in controlling prominent essential tremor, probably due to its serotonergic activity. In addition, the antidepressant and anxiolytic effects of trazodone have been shown to be useful in treating withdrawal symptoms from cocaine, benzodiazepines, and alcohol. In addition to the above effects, trazodone can also induce sleep activity.

[0003] In the treatment of depression, trazodone is taken orally as a hydrochloride salt, with an initial dose of 100 to 150 mg per day, which can be increased by 50 mg to 300 to 400 mg every 3 to 4 days. The daily dose can be distributed during the day, corresponding to meal times, or can be used as a single dose before bedtime. In severe depression, 800 mg can be taken per day. Trazodone is preferably used in the form of a pharmaceutically acceptable acid addition salt in medicine, and more preferably in the form of a hydrochloride salt. At present, most trazodone hydrochloride is used as a drug in the form of a tablet preparation, such as reported in patents CN118217254A, CN118662466A, CN109364031A, CN107028904A, CN102935074A, and CN10574821A. However, there are fewer liquid pharmaceutical preparations of trazodone hydrochloride, mainly because in the liquid phase, especially in water, trazodone hydrochloride has poor stability, produces impurities, and makes the aqueous solution yellow.

[0004] Currently commercially available oral drug products are either solid or liquid. Solid drug forms are also available as immediate-release or extended-release tablets. Although oral solid dosage forms are very popular, mainly for ease of administration, they are not necessarily a convenient option for some patients (e.g., children and the elderly), especially since these dosage forms are difficult to swallow. This lack of convenience leads to high rates of noncompliance and ineffective treatment. Even scored tablets are difficult to administer with a high degree of precision. Liquid drug forms, such as oral drops, have their advantages. They allow for greater modularity and personalization of therapeutic dosing. Various liquid preparations, either oral (drops, syrups) or injectable (ampoules), with trazodone hydrochloride concentrations of approximately 1% (w / v) are currently on the market.

[0005] However, liquid preparations of trazodone hydrochloride have certain disadvantages. First, trazodone is incompatible with ethanol. Therefore, it is best to avoid using ethanol as a cosolvent; second, the formation of degradation products of trazodone hydrochloride, whose physical appearance changes over time, and the solution turns yellow. Therefore, it is necessary to develop a liquid pharmaceutical composition of trazodone hydrochloride, wherein the content of trazodone hydrochloride is ≥1% (W / V), which can be stably dissolved, does not contain ethanol as a solvent or cosolvent, and does not turn yellow over time, that is, the impurities increase.

[0006] Chinese patent CN101784257A discloses a stable liquid pharmaceutical composition based on trazodone, which contains propylene glycol and polyethylene glycol of different molecular weights as co-solvents, which can significantly increase the solubility of trazodone hydrochloride, and no precipitation will be produced when stored at 4°C for 30 days. However, PEG is a potential allergen. Danish scholars Wenande and Garvey reviewed 37 allergic cases reported from 1977 to 2017, pointing out the neglected sensitization potential of PEG, and the existence of cross-sensitization cases of PEG of different molecular weights, PEGylated drugs and PEG derivatives. The US FDA has registered 133 reports on PEG and allergic reactions since 1989. PEG-modified drugs such as the contrast agent SonoVue and PEG sulfur hexafluoride have had a few allergic reactions. In addition, in order to avoid the degradation of high-content trazodone solution to produce yellowing of the solution, the patent uses antioxidants, preferably gallic acid and its derivatives as antioxidants. However, long-term use of antioxidants is not friendly to organisms. In addition, the inventor found that the use of polyethylene glycol actually accelerates the degradation and oxidation of trazodone. The inventor speculates that it may be due to the self-oxidation of PEG, which produces oxidative degradation products such as formaldehyde. In particular, when there are certain metal residues in PEG, this oxidative degradation is usually accelerated, and the active fragments produced by degradation will continue to produce more related impurities. Therefore, the use of a large amount of PEG in this patent and the addition of antioxidants have certain safety risks, especially for children. Chinese patent CN105708796A discloses a sustained-release preparation containing trazodone hydrochloride oral solution, which is a suspension oral solution that achieves slow release within 24h. The suspension oral solution contains a solution and a drug resin coated microcapsule, and the drug resin coated microcapsule includes a drug resin polymer containing a psychotropic drug and an ion exchange resin, and a sustained-release material of the outer layer of the drug resin polymer. However, the preparation process of the coated microcapsule of this drug resin polymer is cumbersome and complicated, with ethanol residue, and the content of trazodone hydrochloride is between 18 and 65%, and the content uniformity is difficult to control, and the accuracy of feeding in the subsequent preparation production process and the content uniformity of the final product cannot be guaranteed. In addition, PEG in prescriptions also poses certain safety risks. Summary of the invention

[0007] The purpose of the present invention is to overcome the defect of instability of trazodone hydrochloride liquid preparations in the prior art. The present invention provides a trazodone hydrochloride stable liquid pharmaceutical composition with improved stability to solve the problems of poor medication compliance of existing oral solid preparations, incompatibility of trazodone with ethanol in oral liquid preparations, and poor stability. The trazodone hydrochloride liquid preparation of the present invention does not use an antioxidant, can also keep the preparation stable for a long time, will not cause the solution to turn yellow, and has both stability and safety.

[0008] To achieve the object, the present invention provides a trazodone hydrochloride liquid pharmaceutical composition with improved stability, comprising the following ingredients: 10-30 g / L of trazodone hydrochloride, 90-220 g / L of sorbitol, 150-320 g / L of glycerol, 0.1-0.5 g / L of benzoic acid or its salt, 1-5 g / L of sodium glutamate, and constant volume of water; the pH of the trazodone hydrochloride liquid pharmaceutical composition is 4.2-5.0; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol and sodium glutamate is 1:6.9-10.3:10-16.3:0.065-0.1.

[0009] Preferably, a trazodone hydrochloride liquid pharmaceutical composition with improved stability comprises the following ingredients: 10-20 g / L trazodone hydrochloride, 100-152 g / L sorbitol, 163-225 g / L glycerol, 0.1-0.3 g / L benzoic acid or its salt, 1-2 g / L sodium glutamate, and constant volume of water; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol, and sodium glutamate is 1:7.5-10.3:0.075-0.1.

[0010] The inventors unexpectedly found that the trazodone hydrochloride liquid pharmaceutical composition obtained according to the above formula is very stable within a specific pH range, and in particular, the addition of sodium glutamate significantly enhances the stability of the trazodone hydrochloride liquid pharmaceutical composition, although the reason is unknown. However, the addition of sodium glutamate needs to be in a specific pH range to fully enhance the stability.

[0011] Furthermore, the benzoate is selected from at least one of the sodium salt and potassium salt of benzoic acid.

[0012] Furthermore, the trazodone hydrochloride liquid pharmaceutical composition also includes the following excipients: a sweetener, a pH regulator, and a flavoring agent.

[0013] Furthermore, the sweetener is selected from at least one of aspartame, saccharin sodium, acesulfame potassium, sucralose, maltitol, sucrose, acesulfame potassium, and steviol glycosides; the pH adjuster is selected from at least one of sodium hydroxide, potassium hydroxide, ammonia solution, potassium citrate, triethanolamine, sodium citrate, hydrochloric acid, malic acid, acetic acid, citric acid, tartaric acid, lactic acid, fumaric acid, maleic acid, succinic acid, aspartic acid, and glutamic acid; the flavoring agent is selected from at least one of strawberry flavor, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor, milk flavor, clove oil, and cardamom oil.

[0014] The dosage of sweeteners and pH adjusters is well known in the art. In one embodiment of the present invention, the trazodone hydrochloride liquid pharmaceutical composition contains 0.1-5 g / L sweetener, and the pH adjuster is used to adjust the pH of the system to meet the requirements, that is, the pH is adjusted to 4.2-5.0.

[0015] The present invention also provides a method for preparing the above-mentioned trazodone hydrochloride liquid pharmaceutical composition, comprising the following steps: uniformly mixing trazodone hydrochloride, sorbitol, glycerol, benzoic acid or its salt, sodium glutamate and water, and adjusting the pH to be within a specified range to obtain the trazodone hydrochloride liquid pharmaceutical composition.

[0016] Furthermore, the preparation method of the trazodone hydrochloride liquid pharmaceutical composition comprises the following steps:

[0017] (S1) dissolving sorbitol, glycerol and sodium glutamate in water to prepare a mixture;

[0018] (S2) adding trazodone hydrochloride to the mixture obtained in (S1) to dissolve, adding benzoic acid or its salt, and optionally, adding a sweetener and a flavoring agent;

[0019] (S3) adjusting the pH of the system to 4.2-5.0;

[0020] (S4) diluting the volume with water and filtering to obtain a trazodone hydrochloride liquid pharmaceutical composition.

[0021] The present invention also provides use of the trazodone hydrochloride liquid pharmaceutical composition in preparing a drug for treating or relieving depression, anxiety, neurasthenia and sleep disorders.

[0022] Furthermore, the trazodone hydrochloride liquid pharmaceutical composition has a single dose of 150 mg / day to 600 mg / day, calculated as trazodone hydrochloride.

[0023] The beneficial effect of the present invention is that the present invention significantly improves the stability of trazodone hydrochloride in water and glycerol co-solvents under specific pH conditions through the reasonable compatibility of various components, especially the combination of sorbitol and sodium glutamate, and does not turn yellow over time. In addition, the pharmaceutical composition of the present invention does not need to add antioxidants, is more friendly to organisms, does not contain ethanol, and is suitable for children. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described clearly and completely below in conjunction with specific implementation methods. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Example 1

[0026] The present embodiment provides a trazodone hydrochloride liquid pharmaceutical composition, the raw materials of the composition are calculated by weight: 1.2 g of trazodone hydrochloride, 12.4 g of sorbitol, 19.6 g of glycerol, 0.12 g of sodium glutamate, 12 mg of benzoic acid, 30 mg of sodium saccharin, 40 mg of orange flavor, and an appropriate amount of sodium hydroxide.

[0027] The preparation method of the trazodone hydrochloride liquid pharmaceutical composition provided in this embodiment 1 comprises the following steps:

[0028] S1. Dissolve sorbitol, glycerol and sodium glutamate in purified water at 30° C. to prepare a mixture;

[0029] S2, adding trazodone hydrochloride to the mixture obtained in S1 to dissolve;

[0030] S3, cool the mixture obtained in S2 to room temperature, add benzoic acid, sodium saccharin and flavor to dissolve;

[0031] S4, adjusting the pH value of the mixture obtained in S3 to 4.2 with sodium hydroxide;

[0032] S5. Add purified water to make the mixture obtained in S4 to 120 mL;

[0033] S6, filtering the mixture obtained in S5 using a 10 μm polypropylene filter;

[0034] S7, filling and sealing in soda-lime glass molded pharmaceutical bottles;

[0035] S8, labeling, boxing and cartoning.

[0036] Example 2

[0037] Other conditions and operations were the same as those in Example 1, except that in the raw materials, the amount of trazodone hydrochloride was 2.4 g, the amount of sorbitol was 18.2 g, the amount of glycerol was 26.7 g, and the amount of sodium glutamate was 0.18 g.

[0038] Example 3

[0039] Other conditions and operations were the same as those in Example 1, except that in the raw materials, the amount of trazodone hydrochloride was 3.6 g, the amount of sorbitol was 24.8 g, the amount of glycerol was 36.0 g, and the amount of sodium glutamate was 0.25 g.

[0040] Example 4

[0041] Other conditions and operations are the same as those in Example 1, except that in step S4, the pH is adjusted to 4.5.

[0042] Example 5

[0043] Other conditions and operations are the same as those in Example 1, except that in step S4, the pH is adjusted to 5.0.

[0044] Comparative Example 1

[0045] Other conditions and operations are the same as those in Example 1, except that in step S4, the pH is adjusted to 4.0.

[0046] Comparative Example 2

[0047] Other conditions and operations are the same as those in Example 1, except that in step S4, the pH is adjusted to 5.5.

[0048] Comparative Example 3

[0049] Other conditions and operations are the same as those in Example 1, except that in step S1, sodium glutamate is not added.

[0050] Comparative Example 4

[0051] Other conditions and operations are the same as those in Example 1, except that in step S1, sorbitol is replaced by an equal mass of hydroxypropyl methylcellulose.

[0052] Comparative Example 5

[0053] Other conditions and operations were the same as those in Example 1, except that in step S1, sorbitol was replaced with an equal mass of PEG400.

[0054] Application Examples

[0055] The trazodone hydrochloride liquid pharmaceutical composition obtained in the example was stable when stored at 40° C. for 30 days, in a refrigerator at 4° C. for 30 days, and at room temperature, and remained clear without precipitation.

[0056] The trazodone hydrochloride liquid pharmaceutical compositions of the examples and comparative examples were placed at 40° C. and 75% relative humidity for 6 months. The examples did not turn yellow, while the comparative examples had different degrees of solution yellowing. The results are shown in Table 1 below. The absorbance was tested at 400 nm.

[0057] Table 1 Solution color change

[0058] .

[0059] The trazodone hydrochloride liquid pharmaceutical compositions of the above examples and comparative examples were placed at 40° C. and 75% relative humidity for 6 months, and the mass percentages of the relevant substances were tested. The results are shown in Table 2 below.

[0060] Table 2 Related substances detection

[0061]

[0062] The growth rate of impurities in the comparative examples is significantly greater than that in Examples 1 to 5, and the growth rate of impurities in Comparative Example 3 (without sodium glutamate) is the largest, indicating that the addition of sodium glutamate plays a key role in the stability of this product. In addition, when sorbitol is replaced with hydroxypropyl methylcellulose (Comparative Example 4) or PEG400 (Comparative Example 5), the product stability is not ideal, indicating that sorbitol is selected as the thickener for this product. In addition, in addition to the components that require reasonable compatibility, the pharmaceutical composition of the present invention also needs to strictly control the pH value. When the pH value is in the range of 4.2 to 5.0, the impurity growth is significantly less than the pH value of 4.0 (Comparative Example 1) and 5.5 (Comparative Example 2). It can be seen that the stability of the trazodone hydrochloride liquid pharmaceutical composition of the present invention is sensitive to pH, and the pH value needs to be strictly controlled within the range of 4.2 to 5.0.

Claims

1. A trazodone hydrochloride liquid pharmaceutical composition with improved stability, characterized in that: The invention is composed of the following ingredients: 10-30 g / L of trazodone hydrochloride, 90-220 g / L of sorbitol, 150-320 g / L of glycerol, 0.1-0.5 g / L of benzoic acid or its salt, 1-5 g / L of sodium glutamate, and constant volume of water; the pH value of the trazodone hydrochloride liquid pharmaceutical composition is 4.2-4.5; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol and sodium glutamate is 1:6.9-10.3:10-16.3:0.065-0.1; The preparation method of the trazodone hydrochloride liquid pharmaceutical composition with improved stability comprises the following steps: uniformly mixing trazodone hydrochloride, sorbitol, glycerol, benzoic acid or its salt, sodium glutamate and water, and adjusting the pH to 4.2-4.5 to obtain the trazodone hydrochloride liquid pharmaceutical composition.

2. The trazodone hydrochloride liquid pharmaceutical composition with improved stability according to claim 1, characterized in that: The invention is composed of the following ingredients: 10-20 g / L of trazodone hydrochloride, 100-152 g / L of sorbitol, 163-225 g / L of glycerol, 0.1-0.3 g / L of benzoic acid or its salt, 1-2 g / L of sodium glutamate, and constant volume of water; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol, and sodium glutamate is 1:7.6-10.3:11.15-16.3:0.075-0.

1.

3. The trazodone hydrochloride liquid pharmaceutical composition with improved stability according to claim 1, characterized in that: The salt of benzoic acid is selected from at least one of sodium salt and potassium salt of benzoic acid.

4. A trazodone hydrochloride liquid pharmaceutical composition with improved stability, characterized in that: The composition comprises the following ingredients: 10-30 g / L of trazodone hydrochloride, 90-220 g / L of sorbitol, 150-320 g / L of glycerol, 0.1-0.5 g / L of benzoic acid or its salt, 1-5 g / L of sodium glutamate, a sweetener, a flavoring agent, and constant volume of water; the pH value of the trazodone hydrochloride liquid pharmaceutical composition is 4.2-4.5; and the mass ratio of trazodone hydrochloride, sorbitol, glycerol, and sodium glutamate is 1:6.9-10.3:10-16.3:0.065-0.1; The method for preparing the trazodone hydrochloride liquid pharmaceutical composition with improved stability comprises the following steps: (S1) dissolving sorbitol, glycerol and sodium glutamate in water to prepare a mixture; (S2) adding trazodone hydrochloride to the mixture obtained in (S1) to dissolve, and adding benzoic acid or its salt, sweetener, and flavoring agent; (S3) adjusting the pH of the system to 4.2-4.5; (S4) diluting the volume with water and filtering to obtain a trazodone hydrochloride liquid pharmaceutical composition.

5. The trazodone hydrochloride liquid pharmaceutical composition with improved stability according to claim 4, characterized in that: The sweetener is selected from at least one of aspartame, saccharin sodium, sucralose, maltitol, sucrose, acesulfame potassium, and steviol glycosides; the flavoring agent is selected from at least one of strawberry flavor, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor, milk flavor, clove oil, and cardamom oil.

6. Use of the trazodone hydrochloride liquid pharmaceutical composition according to any one of claims 1 to 5 in the preparation of drugs for treating or relieving depression, anxiety, neurasthenia, and sleep disorders.

7. The use according to claim 6, characterized in that The trazodone hydrochloride liquid pharmaceutical composition has a single dose of 150 mg / day to 600 mg / day, calculated as trazodone hydrochloride.

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