Agomelatine tablet composition as well as preparation method and application thereof

Abstract

The invention provides an agomelatine tablet composition as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method of the agomelatine tablet composition comprises the following steps: pre-mixing agomelatine with the filler, the adhesive and the disintegrating agent according to the weight percentage by using a high-shear wet type granulator; adding purified water into the high-shear wet type granulator for granulating, and stirring and shearing at the same time; the wet particles are transferred into a fluidized bed to be dried after being finished, and dry particles are obtained; finishing the dry particles, adding a lubricant, and blending to obtain total mixed particles; and adding the total mixed particles into a high-speed tablet press for tabletting. According to the invention, glyceryl behenate is adopted to replace stearic acid, so that the sticking problem caused by lower melting point of stearic acid in the tabletting process is avoided, the tablet pushing force can be reduced, and the compressibility in tablet and capsule production is improved; and the temperature control range of the sheet bed can be expanded to 35-50 DEG C.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an agomelatine tablet composition, a preparation method thereof and an application thereof. Background Art

[0002] Depression is a common mental illness around the world, which seriously threatens people's physical and mental health and causes a heavy burden on society and families. With the increasing incidence of depression year by year, the pathogenesis of depression has not been fully clarified. Current research believes that depression is related to the decrease in the content of neurotransmitters such as central norepinephrine, 5-hydroxytryptamine (5-HT), dopamine (DA), acetylcholine (Ach) and neuropeptides and the decline of their receptor functions induced by genetic, psychological, neuroendocrine and other factors.

[0003] Agomelatine is the world's first antidepressant drug that is a melatonin receptor agonist to obtain marketing approval in the European Union. It can improve the sleep quality of patients through its agonist effect on melatonin receptors (MT1 and MT2), and at the same time improve the patient's daytime wakefulness state, which helps to restore the disordered biological rhythm of the patient. At the same time, agomelatine is also a 5-HT2C receptor blocker, which can bind to the 5-HT2C receptor on the postsynaptic membrane of the nerve synapse, enhance the release of dopamine and norepinephrine in the prefrontal cortex, promote nerve regeneration, regulate the patient's mood, and thus exert its antidepressant effect without increasing the 5-HT concentration between synapses, so it has no common side effects of 5-HT reuptake inhibitor drugs.

[0004] The prescription of the agomelatine tablets disclosed in the European Pharmacopoeia is: agomelatine, lactose monohydrate, magnesium stearate, corn starch, polyvinylpyrrolidone, anhydrous colloidal silica, sodium carboxymethyl starch, stearic acid. The lubricant in the original research prescription includes stearic acid. On the one hand, due to its hydrophobic property, stearic acid has a certain sustained-release property in the product; on the other hand, the melting point of stearic acid is relatively low, about 55°C. Therefore, the drugs containing stearic acid in the prescription have higher requirements for temperature control during production and storage. For example, during the tabletting process, the prescription containing stearic acid will have sticking problems due to the heat generated during the tabletting process. When using aqueous film coating, sticking of the tablets will occur at lower temperatures, and pitting of the coating and slower dissolution will occur at higher temperatures. The temperature control range of the tablet bed during the production process is relatively narrow, and the requirements for temperature during the storage of the drug are also higher.

[0005] Patent CN104873470B discloses a preparation method of agomelatine tablets using magnesium stearate and silicon dioxide as lubricants. However, the dosage of silicon dioxide in the prescription is 4.2 - 5.0%, preferably 4.6%, far exceeding the recommended range of 0.1 - 0.5% in the Excipient Handbook (Fourth Edition). Due to the large specific surface area of silicon dioxide, it may increase the dissolution rate of the active pharmaceutical ingredient (API) by contacting and coating with the raw materials during the mixing process. At the same time, silicon dioxide has strong hydrophilicity, which can accelerate the disintegration of tablets and is not conducive to the stable release of drugs in the body. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides an agomelatine tablet composition, its preparation method and application.

[0007] In a first aspect, the present application provides an agomelatine tablet composition, comprising 7.0% - 25% by weight of agomelatine, 55% - 85% of a filler, 5% - 10% of a binder, 1% - 5% of a disintegrant, and 1.6% - 5.0% of a lubricant; the lubricant is a mixture of glyceryl behenate, silicon dioxide, and magnesium stearate.

[0008] In an embodiment of the present application, the filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, pregelatinized starch, corn starch, and potato starch.

[0009] In an embodiment of the present application, the filler is a mixture of lactose and corn starch.

[0010] In an embodiment of the present application, lactose accounts for 40% - 60% by weight of the agomelatine tablet composition, and corn starch accounts for 15% - 25% by weight of the agomelatine tablet composition.

[0011] In an embodiment of the present application, the binder is selected from one or more of polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose.

[0012] In an embodiment of the present application, the binder is polyvinylpyrrolidone.

[0013] In an embodiment of the present application, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch.

[0014] In an embodiment of the present application, the disintegrant is sodium carboxymethyl starch.

[0015] In one embodiment of the present application, the weight percentage of glyceryl behenate in the agomelatine tablet composition is 1% - 3%; the weight percentage of silicon dioxide in the agomelatine tablet composition is 0.1% - 0.5%; the weight percentage of magnesium stearate in the agomelatine tablet composition is 0.5% - 1.5%.

[0016] In one embodiment of the present application, the silicon dioxide is colloidal silicon dioxide.

[0017] Second, the present application provides a method for preparing an agomelatine tablet composition, comprising the following steps:

[0018] Premix agomelatine with a filler, a binder, and a disintegrant by weight percentage using a high-shear wet granulator;

[0019] Add purified water to the high-shear wet granulator for granulation while stirring and shearing;

[0020] Screen the wet granules and transfer them to a fluidized bed for drying to obtain dry granules;

[0021] Screen the dry granules and add a lubricant by weight percentage for blending to obtain total blended granules;

[0022] Add the total blended granules to a tableting machine for tableting.

[0023] Third, the present application provides an agomelatine film-coated tablet, which is composed of an agomelatine tablet composition and a coating material coated on the surface of the tablet.

[0024] In one embodiment of the present application, the coating material is a gastric-soluble film coating material.

[0025] In one embodiment of the present application, the gastric-soluble film coating material is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol 6000, glycerol, magnesium stearate, yellow iron oxide, and titanium dioxide.

[0026] In one embodiment of the present application, the coating weight gain is 2.5% - 4.5% of the agomelatine tablet composition.

[0027] In one embodiment of the present application, the tablet bed temperature during coating is 35 - 50 °C.

[0028] Fourth, the present application provides the use of an agomelatine tablet composition or an agomelatine film-coated tablet in the preparation of a drug for treating diseases related to depression, sleep disorders, and circadian rhythm abnormalities.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The present invention uses glyceryl behenate to replace stearic acid, avoiding the sticking problem caused by the relatively low melting point of stearic acid during tabletting. At the same time, it can reduce the pushing force of the tablet and improve the compressibility in the production of tablets and capsules.

[0031] (2) The present invention uses glyceryl behenate to replace stearic acid, avoiding the problem of pitted coating caused by the relatively low melting point of stearic acid during coating and the problem of temperature needing to be controlled in a relatively low range. It can expand the temperature control range of the tablet bed to 35 - 50 °C.

[0032] (3) The dosages of the lubricants used in the present invention are all within the recommended ranges of the Excipient Manual (Fourth Edition). The dosage ranges of silica, glyceryl behenate, and magnesium stearate in the agomelatine tablet composition are 0.1% - 0.5%, 1% - 3%, and 0.5% - 1.5% respectively; all are within the recommended ranges of 0.1% - 0.5%, 1% - 3%, and 0.25% - 5% in the Excipient Manual (Fourth Edition).

[0033] (4) The preparation method of the present invention uses inexpensive and easily available excipients, has a simple process, and is easy to scale up production. Detailed implementation manners

[0034] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all of them. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative efforts belong to the scope of protection of the present application.

[0035] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundary of the specific range. The range defined in this way can include the end values or not include the end values, and can be combined arbitrarily, that is, any lower limit can be combined with any upper limit to form a range.

[0036] Example 1

[0037] Table 1 Formulation of Preparation 1

[0038]

[0039] Prepare agomelatine tablets according to the formulation in Table 1. The preparation method includes the following steps:

[0040] (1) Premix the active ingredient agomelatine with lactose, corn starch, polyvinylpyrrolidone, and sodium carboxymethyl starch using a high-shear wet granulator.

[0041] (2) Add purified water for granulation while stirring and shearing. The stirring speed is 240 rpm, the cutting speed is 2000 rpm, and the granulation time is 2.0 min;

[0042] (3) Screen the granules prepared in step (2) and transfer them to a fluidized bed for drying;

[0043] (4) Screen the dry granules obtained in step (3) and blend them with colloidal silicon dioxide, glyceryl behenate, and magnesium stearate;

[0044] (5) Add the total blended granules obtained in step (4) to a high-speed tableting machine for tableting;

[0045] (6) Coat the plain tablets obtained in step (5) with a gastric-soluble film coating material. Control the tablet bed temperature at 35 - 50 °C and the coating weight gain at 3.5% to obtain Preparation 1.

[0046] Example 2

[0047] Table 2 Formulation of Preparation 2

[0048]

[0049]

[0050] Prepare agomelatine tablets according to the formulation in Table 2. The preparation method includes the following steps:

[0051] (1) Premix the active ingredient agomelatine with lactose, corn starch, polyvinylpyrrolidone, and sodium carboxymethyl starch using a high-shear wet granulator;

[0052] (2) Add purified water for granulation while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 1.0 min;

[0053] (3) Screen the granules prepared in step (2) and transfer them to a fluidized bed for drying;

[0054] (4) Screen the dry granules obtained in step (3) and blend them with colloidal silicon dioxide, glyceryl behenate, and magnesium stearate;

[0055] (5) Add the total blended granules obtained in step (4) to a high-speed tableting machine for tableting;

[0056] (6) Coat the plain tablets obtained in step (5) with a gastric-soluble film coating material. Control the tablet bed temperature at 35 - 50 °C and the coating weight gain at 4.0% to obtain Preparation 2.

[0057] Example 3

[0058] Table 3 Formulation of Preparation 3

[0059]

[0060] Prepare agomelatine tablets according to the formulation in Table 3. The preparation method includes the following steps:

[0061] (1) Premix the raw material drug agomelatine with lactose, corn starch, povidone, and sodium carboxymethyl starch using a high-shear wet granulator;

[0062] (2) Add purified water for granulation, while performing stirring and shearing. The stirring speed is 300 rpm, the cutting speed is 1000 rpm, and the granulation time is 3.5 min;

[0063] (3) Screen the granules prepared in step (2) and transfer them to a fluidized bed for drying;

[0064] (4) Screen the dry granules obtained in step (3) and blend them with colloidal silicon dioxide, glyceryl behenate, and magnesium stearate;

[0065] (5) Add the total blended granules obtained in step (4) to a high-speed tableting machine for tableting;

[0066] (6) Coating the plain tablets obtained in step (5) with a gastric-soluble film coating material, controlling the tablet bed temperature at 35 - 50 °C, and the coating weight gain is 2.5%, to obtain Preparation 3.

[0067] Example 4

[0068] Table 4 Formulation of Preparation 4

[0069]

[0070]

[0071] Prepare agomelatine tablets according to the formulation in Table 4. The preparation method includes the following steps:

[0072] (1) Premix the raw material drug agomelatine with lactose, corn starch, povidone, and sodium carboxymethyl starch using a high-shear wet granulator;

[0073] (2) Add purified water for granulation, while performing stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 1.0 min;

[0074] (3) Screen the granules prepared in step (2) and transfer them to a fluidized bed for drying;

[0075] (4) Screen the dry granules obtained in step (3) and blend them with colloidal silicon dioxide, glyceryl behenate, and magnesium stearate;

[0076] (5) Add the total mixed granules obtained in step (4) to a high-speed tableting machine for tableting;

[0077] (6) Coating the plain tablets obtained in step (5) with a gastric-soluble film coating material, controlling the tablet bed temperature at 35 - 50 °C, with a coating weight gain of 4.5%, to obtain Preparation 4.

[0078] Comparative Example 1

[0079] Table 5 Formulation of Comparative Preparation 1

[0080]

[0081] Prepare agomelatine tablets according to the formulation in the above table. The preparation method includes the following steps:

[0082] (1) Premix the active ingredient agomelatine with lactose, corn starch, polyvinylpyrrolidone, and sodium carboxymethyl starch using a high-shear wet granulator;

[0083] (2) Add purified water for granulation, while stirring and shearing. The stirring speed is 240 rpm, the cutting speed is 2000 rpm, and the granulation time is 2.0 min;

[0084] (3) Screen the granules prepared in step (2) and transfer them to a fluidized bed for drying;

[0085] (4) Screen the dry granules obtained in step (3) and blend them with colloidal silicon dioxide, stearic acid, and magnesium stearate;

[0086] (5) Add the total mixed granules obtained in step (4) to a high-speed tableting machine for tableting;

[0087] (6) Coating the plain tablets obtained in step (5) with a gastric-soluble film coating material, controlling the tablet bed temperature at 35 - 50 °C, with a coating weight gain of 3.5%, to obtain Comparative Preparation 1.

[0088] Testing Section

[0089] I. Coating Temperature Test

[0090] Conduct a coating temperature test on Preparation 1 and Comparative Preparation 1 obtained in Example 1 and Comparative Example 1 (using Valdoxan as the reference preparation). Control the tablet bed temperature at 35 - 40 °C, 40 - 45 °C, and 45 - 50 °C respectively, and investigate the changes in the coating appearance and dissolution curve. The results are shown in Tables 6 - 7.

[0091] Table 6 Influence of Tablet Bed Temperature on Coating Appearance

[0092]

[0093] Table 7 Influence of Tablet Bed Temperature on Dissolution Curve

[0094]

[0095] According to the results in the above table, when stearic acid is contained in the prescription, sticking problems will occur when the tablet bed temperature is less than 35°C, and pitted surfaces will appear on the coating appearance when the tablet bed temperature is greater than 40°C, and the dissolution will also slow down significantly. Replacing stearic acid with glyceryl behenate can improve the above problems, and the control range of the tablet bed temperature can be expanded to 35 - 50°C, the appearance of the finished product is qualified, and the dissolution rate is consistent with that of the reference preparation Vidal.

[0096] II. Stability Test

[0097] Under the environment of 40 ± 2°C and relative humidity of 75 ± 5%, the stability of the preparations 1 - 4 prepared in Examples 1 - 4 and Comparative Example 1 and Comparative Preparation 1 was tested by placing them for 30 days. The HPLC detection results are shown in Table 8.

[0098] Table 8 Stability of Preparations 1 - 4 and Comparative Preparation 1

[0099]

[0100] Among them, impurity 1 is the degradation impurity of agomelatine and is the internal control impurity included in the quality standard. From the above stability data, it can be seen that the related substance indexes of the agomelatine pharmaceutical composition of the present invention have no significant changes. Replacing stearic acid with glyceryl behenate will not affect the quality of the product, and the sample quality is stable.

[0101] III. Dissolution Test

[0102] Determination of the dissolution of agomelatine: According to the dissolution and release determination method (Method 2 of General Principles 0931, Volume IV, Chinese Pharmacopoeia 2015 Edition), 900 mL of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 revolutions per minute. The results are shown in Table 9.

[0103] Table 9 Dissolution of Preparations 1 - 4 and Comparative Preparation 1

[0104] 5min 10min 15min 30min 45min Reference Preparation 1 10％ 31％ 52％ 79％ 88％ Preparation 1 9％ 30％ 50％ 78％ 89％ Preparation 2 13％ 33％ 54％ 79％ 89％ Preparation 3 9％ 27％ 49％ 78％ 89％ Preparation 4 12％ 33％ 53％ 78％ 89％ Amiansulpride 10％ 29％ 50％ 78％ 88％

[0105] According to the data in the above table, it can be seen that in 0.1 mol / L hydrochloric acid solution, within 45 minutes, the dissolution of Comparative Preparation 1, Preparations 1 - 4 and the commercial preparation Vidal is basically the same. Replacing stearic acid with glyceryl behenate will not affect the quality of the product, and the dissolution rate of the sample is consistent with that of the reference preparation.

[0106] IV. Bioavailability Evaluation

[0107] Beagle dogs were used as experimental animals, and the dosing conditions were as follows:

[0108] Fasting period: The animals are not fed in the evening before drug administration. Water and regular feed (SSNIFF hdH) are given 1 hour and 4 hours respectively after drug administration.

[0109] Feeding period: 10 minutes before drug administration, the animals receive 50 g of high-fat diet (SSNIFF EF Dog FDA high-fat model) (the diet has an energy value of 100 kcal and is composed of 15% protein, 25% carbohydrates and 50 - 60% fat). Then water and regular feed (SSNIFF hdH) are given 1 hour and 4 hours respectively after drug administration.

[0110] The treatment groups are set as follows:

[0111] Treatment 1: Reference preparation 1 tablets, fasting condition, oral route;

[0112] Treatment 2: Preparation 1 tablets, fasting condition, oral route;

[0113] Reference treatment 1: Valdoxan (25 mg specification), fasting condition, oral route;

[0114] Treatment 3: Reference preparation 1 tablets, feeding condition, oral route;

[0115] Treatment 4: Preparation 1 tablets, feeding condition, oral route;

[0116] Reference treatment 2: Valdoxan (25 mg specification), feeding condition, oral route.

[0117] Sampling and analysis:

[0118] Blood samples are collected in plastic tubes containing lithium heparin as anticoagulant before treatment and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48, 72, 96 and 120 hours after treatment in each treatment group.

[0119] The plasma concentration of agomelatine is determined by liquid chromatography - mass spectrometry coupling (LC - MS / MS) using an exploratory analysis method.

[0120] The following pharmacokinetic parameters are measured for each treatment:

[0121] C max (ng / mL): Corresponding to the observed maximum plasma concentration;

[0122] T max (h): Corresponding to the observed time to obtain the maximum concentration;

[0123] AUC last: Area under the curve or integral corresponding to the plasma concentration as a function of time t, calculated from t0 to the time corresponding to the last measurable concentration by the trapezoidal method;

[0124] AUC: Area under the curve or integral corresponding to the plasma concentration as a function of time extrapolated to infinity;

[0125] T 1 / 2z : Final elimination half-life.

[0126] Table 10 Pharmacokinetic parameters of agomelatine (mean ± SD, n = 6 for each formulation)

[0127]

[0128] The results are shown in Table 10. In the fasting and fed states, the C max and AUC observed for the agomelatine tablets provided by the present invention are similar to the C max and AUC calculated for commercially available Valdoxan. Replacing stearic acid with glyceryl behenate does not affect the quality of the product, and the sample bioavailability is consistent with that of the reference preparation.

Claims

1. An agomelatine tablet composition, characterized in that, It contains agomelatine at a weight percentage of 7.0% - 25%, a filler at 55% - 85%, a binder at 5% - 10%, a disintegrant at 1% - 5% and a lubricant at 1.6% - 5.0%; the lubricant is a mixture of glyceryl behenate, silicon dioxide and magnesium stearate; the weight percentage of glyceryl behenate is 1% - 3%; the weight percentage of silicon dioxide is 0.1% - 0.5%; the weight percentage of magnesium stearate is 0.5% - 1.5%.

2. The agomelatine tablet composition according to claim 1, characterized in that, The filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, pregelatinized starch, corn starch and potato starch.

3. The agomelatine tablet composition according to claim 1, characterized in that, The filler is a mixture of lactose and corn starch, the weight percentage of lactose is 40% - 60%, and the weight percentage of corn starch is 15% - 25%.

4. The agomelatine tablet composition according to claim 1, characterized in that, The binder is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose, ethyl cellulose and sodium carboxymethyl cellulose.

5. The agomelatine tablet composition according to claim 1, characterized in that, The disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch.

6. A method for preparing the agomelatine tablet composition according to any one of claims 1 to 5, characterized in that, It includes the following steps: Premix agomelatine with the filler, binder and disintegrant by weight percentage using a high-shear wet granulator. Add purified water to the high-shear wet granulator for granulation while stirring and shearing. Screen the wet granules and transfer them to a fluidized bed for drying to obtain dry granules. Screen the dry granules and add the lubricant for blending to obtain blended granules. Add the blended granules to a tableting machine for tableting.

7. An agomelatine film-coated tablet, characterized in that, It consists of the agomelatine tablet composition according to any one of claims 1 to 5 and a coating material coated on the tablet surface.

8. The agomelatine film-coated tablet according to claim 7, characterized in that, The coating weight gain is 2.5% - 4.5% of the agomelatine tablet composition.

9. The agomelatine film-coated tablet according to claim 7, characterized in that, The tablet bed temperature during coating is 35 - 50°C.

10. Use of the agomelatine tablet composition according to claim 1 or the agomelatine film-coated tablet according to claim 7 in the preparation of a drug for treating diseases related to depression, sleep disorders and circadian rhythm abnormalities.

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