A coating composition, a coated pharmaceutical preparation prepared therefrom and a method of preparing the same

Abstract

The present application relates to the technical field of medicine, in particular to a coating composition, a coated pharmaceutical preparation prepared by the coating composition and a preparation method thereof.The coating composition comprises an inner coating composition and an outer coating composition; the inner coating composition is composed of low-viscosity hypromellose, sodium metabisulfite and the like, and the outer coating composition is composed of high-viscosity hypromellose, nano-zinc oxide, nano-titanium dioxide and the like.The coating composition of the present application realizes comprehensive protection of moisture, light and oxygen through the difference in viscosity and the redox potential gradient of spatial distribution, and the synergistic effect of the inner and outer layers significantly improves the stability of the pharmaceutical preparation.The coated pharmaceutical preparation prepared by the present application has excellent storage stability and is suitable for the development and application of light-sensitive drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a coating composition, a coated pharmaceutical preparation prepared by the same and a preparation method thereof. BACKGROUND

[0002] Photosensitive drug preparations play an important role in the field of medicine, and their main feature is that the active ingredients of the drugs are prone to chemical degradation under the action of light, oxygen or moisture. Such degradation not only leads to a decrease in drug content, but also may produce toxic or ineffective degradation products, thereby affecting the efficacy and safety of the drugs. For example, agomelatine, as a common photosensitive drug, is prone to oxidative degradation when exposed to light and oxygen, resulting in loss of drug activity and decreased stability of the preparation. Therefore, how to improve the stability of photosensitive drug preparations through reasonable formulation design and process optimization has become an important issue in the research of pharmaceutical preparations.

[0003] Traditional stability improvement methods usually include adding antioxidants, light-proof packaging and coating protection, etc. However, these methods have many limitations in practical application. For example, simply adding antioxidants may lead to unstable antioxidant effect due to the interaction between the drugs and excipients; light-proof packaging can reduce the impact of light on the preparation, but it cannot solve the degradation problem caused by oxygen penetration or moisture invasion during storage and transportation; and traditional coating technology is mainly single-layer coating, which has limited barrier capacity and is difficult to achieve comprehensive protection against moisture, light and oxygen.

[0004] In recent years, multi-layer coating technology has significantly improved the stability of photosensitive drugs by constructing gradient functional layers (such as inner moisture barrier and outer light shielding), but it still has problems such as poor interlayer compatibility, insufficient functional synergy, and prominent contradiction between release and barrier performance,

[0005] In summary, in view of the problems of easy oxidative degradation and poor light stability of photosensitive drug preparations, it is urgent to develop a new type of coating layer system to comprehensively improve the stability of the preparation under harsh storage conditions. This not only can significantly prolong the shelf life of the drug, but also can improve the clinical efficacy and safety of the drug, which has important research value and application prospect. SUMMARY

[0006] Therefore, the purpose of the present application is to provide a coating composition, a coated pharmaceutical preparation prepared by the same and a preparation method thereof, to solve the problems of easy oxidative degradation and poor light stability of existing photosensitive drug preparations (such as agomelatine).

[0007] In order to achieve the above purpose, the present application provides a coating composition, which comprises an inner layer coating composition and an outer layer coating composition.

[0008] Further, the weight ratio of the inner layer coating composition and the outer layer coating composition is 4.5-5.5:8.5-9.5.

[0009] Further, the inner layer coating composition comprises the following components by weight percentage: sodium pyrosulfite 2.4%-3.2%, triethyl citrate 8%-12%, talc 3%-8%, caramel color 0.1%-0.3%, and the balance is hydroxypropyl methyl cellulose; the viscosity of a 2wt% aqueous solution of the hydroxypropyl methyl cellulose at 20°C is 2.5-3.5mPa·s.

[0010] Further, the outer layer coating composition comprises the following components by weight percentage: sodium sulfite 3.8%-4.6%, nano-zinc oxide 8%-15%, nano-titanium dioxide 10%-20%, polyethylene glycol 6%-10%, colloidal silicon dioxide 1%-5%, and the balance is hydroxypropyl methyl cellulose; the viscosity of a 2wt% aqueous solution of the hydroxypropyl methyl cellulose at 20°C is 14-16mPa·s.

[0011] Preferably, the particle size D50 of the nano-zinc oxide is 10-30nm.

[0012] Preferably, the nano-titanium dioxide is rutile titanium dioxide, and the particle size D50 is 20-50nm.

[0013] Further, the present application also provides a coated pharmaceutical preparation, comprising a tablet core and a coating; the coating is obtained by coating the tablet core surface with an inner layer coating composition, and then coating with an outer layer coating composition.

[0014] Preferably, the weight ratio of the tablet core and the coating is 250:13-15.

[0015] Preferably, the tablet core is prepared from the following raw materials by weight percentage: agomelatine raw material 10%-14%, lactose 14%-30%, corn starch 4%-14%, sodium carboxymethyl starch 4%-8%, povidone 2.4%-8%, colloidal silicon dioxide 0.04%-0.4%, L-ascorbyl palmitate 0.4%-0.56%, stearic acid 0.8%-1.2%, magnesium stearate 0.8%-2%, and the balance is microcrystalline cellulose.

[0016] Preferably, the preparation steps of the tablet core are as follows:

[0017] S1: mixing agomelatine raw material, microcrystalline cellulose, lactose, corn starch, sodium carboxymethyl starch, and povidone to obtain a mixed powder;

[0018] S2: adding L-ascorbyl palmitate into an aqueous ethanol solution to obtain a spraying solution;

[0019] S3: Spraying the spraying liquid to the surface of the mixed powder, fluidizing and drying to obtain dry granules;

[0020] S4: Mixing the dry granules, colloidal silicon dioxide, stearic acid and magnesium stearate, and compressing to obtain the tablet core.

[0021] Further, the application also provides a preparation method of the coated pharmaceutical preparation, comprising the following steps:

[0022] (1) adding the inner layer coating composition into pure water, and high-pressure homogenizing to obtain an inner layer coating liquid;

[0023] (2) adding the outer layer coating composition into pure water, and high-pressure homogenizing to obtain an outer layer coating liquid;

[0024] (3) preheating the tablet core to 38-42℃, setting the fluidized bed inlet air temperature to 50-55℃, the atomization pressure to 0.15-0.22 MPa, the spraying liquid rate to 6-8 mL / min, bottom spraying the inner layer coating liquid, when the coating weight gain reaches 1.8%-2.2%, switching to drying, drying at 50℃ / 20%RH for 1h, and drying at 45℃ / 15%RH for 2h, then adjusting the fluidized bed inlet air temperature to 46-50℃, the atomization pressure to 0.14-0.16 MPa, and the spraying liquid rate to 8-10 mL / min, bottom spraying the outer layer coating liquid, and stopping when the coating weight gain reaches 3.3%-3.7% to obtain the coated tablet;

[0025] (4) drying the coated tablet by using a gradient drying program, the first stage: 55℃ / 5%RH for 4h, the second stage: 40℃ / 10%RH for 8h, eliminating internal stress, and the third stage: 25℃ / 40%RH for 24h to obtain the coated pharmaceutical preparation.

[0026] Preferably, the amount of pure water added in step (1) is 5-6 times the weight of the inner layer coating composition.

[0027] Preferably, the amount of pure water added in step (2) is 3.5-4.5 times the weight of the outer layer coating composition.

[0028] The application has the following beneficial effects:

[0029] The application realizes the synergistic effect of moisture barrier, light shielding and oxidation protection by constructing a gradient coating layer system. The inner dense coating effectively blocks the penetration of moisture, the outer nanocomposite layer provides light scattering protection, and the dynamic antioxidant network is formed by cooperating with the oxidation-reduction gradient system, which significantly improves the stability of the preparation under harsh storage conditions.

[0030] The application innovatively adopts a differential viscosity coating material combination, the inner coating liquid adopts a lower viscosity hydroxypropyl methyl cellulose, which helps to form a dense and well-adhesive base layer, and improves the adhesion and mechanical strength of the coating layer; and the outer coating liquid adopts a higher viscosity hydroxypropyl methyl cellulose, which can further enhance the barrier effect of the film layer, so as to maintain the appearance stability of the preparation in the light stability test.

[0031] The application realizes the time sequence activation and regional cooperation of the antioxidant components by establishing a spatial distribution of oxidation-reduction potential gradient. The outer antioxidant preferentially removes the permeable oxygen, and the inner sustained-release antioxidant component continuously maintains a low oxygen environment, forming a multi-level and relay protection mechanism. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical scheme and advantages of the application more clear, the application is further described in detail below with specific examples.

[0033] Example 1:

[0034] (1) 25 g of agomelatine raw material (particle size D50 is 15 μm), 158.9 g of microcrystalline cellulose (model MCCPH200), 35 g of lactose (monohydrate), 10 g of corn starch (pre-gelatinized type), 10 g of sodium carboxymethyl starch (type A) and 6 g of povidone K30 were put into a mixer, mixed at a speed of 15 rpm for 15 min in an environment with a relative humidity of 20%, to obtain a mixed powder;

[0035] (2) 1 g of L-ascorbic acid palmitate was added to 60 g of an ethanol aqueous solution with a concentration of 30 vol%, and the temperature was raised to 40℃, and stirred at a speed of 350 rpm for 10 min to obtain a spraying liquid;

[0036] (3) The mixed powder was preheated to 36℃, the fluidized bed inlet air temperature was set to 53℃, the atomization pressure was 0.4 MPa, and the coating liquid prepared in step (2) was sprayed at a rate of 5 mL / min, and the granulation endpoint was controlled to have a particle moisture of 1%, to obtain dry granules;

[0037] (4) The dry granules, 0.1 g of colloidal silicon dioxide (Aerosil®200 Pharma), 2 g of stearic acid and 2 g of magnesium stearate were mixed, and a 8 mm shallow concave punch was used to press the tablet core, and the hardness was controlled to be 80 N, to obtain a tablet core with a tablet weight of 250 mg;

[0038] Example 2:

[0039] ​(1) 30 g of agomelatine drug substance (particle size D50 of 15 μm), 108.3 g of microcrystalline cellulose (type MCC PH200), 55 g of lactose (monohydrate), 22 g of corn starch (pre-gelatinized type), 15 g of sodium carboxymethyl starch (type A), and 12 g of povidone K30 were put into a mixer and mixed at a rotation speed of 15 rpm for 15 min in an environment with a relative humidity of 20% to obtain a mixed powder;

[0040] (2) 1.2 g of L-ascorbic acid palmitate was added to 60 g of an ethanol aqueous solution with a concentration of 30 vol%, and the temperature was raised to 40°C, and the solution was stirred at a rotation speed of 350 rpm for 10 min to obtain a spraying solution;

[0041] (3) The mixed powder was preheated to 36°C, the inlet air temperature of the fluidized bed was set to 53°C, the atomization pressure was set to 0.4 MPa, and the coating liquid prepared in step (2) was sprayed at a rate of 5 mL / min, and the granulation endpoint was controlled to have a particle moisture of 1% to obtain dry granules;

[0042] (4) The dry granules, 0.5 g of colloidal silicon dioxide (Aerosil® 200 Pharma), 2.5 g of stearic acid, and 3.5 g of magnesium stearate were mixed, and a tablet core was pressed using a 8 mm shallow concave die, and the hardness was controlled to be 80 N to obtain a tablet core with a tablet weight of 250 mg;

[0043] Example 3:

[0044] (1) 35 g of agomelatine drug substance (particle size D50 of 15 μm), 54.6 g of microcrystalline cellulose (type MCC PH200), 75 g of lactose (monohydrate), 35 g of corn starch (pre-gelatinized type), 20 g of sodium carboxymethyl starch (type A), and 20 g of povidone K30 were put into a mixer and mixed at a rotation speed of 15 rpm for 15 min in an environment with a relative humidity of 20% to obtain a mixed powder;

[0045] (2) 1.4 g of L-ascorbic acid palmitate was added to 60 g of an ethanol aqueous solution with a concentration of 30 vol%, and the temperature was raised to 40°C, and the solution was stirred at a rotation speed of 350 rpm for 10 min to obtain a spraying solution;

[0046] (3) The mixed powder was preheated to 36°C, the inlet air temperature of the fluidized bed was set to 53°C, the atomization pressure was set to 0.4 MPa, and the coating liquid prepared in step (2) was sprayed at a rate of 5 mL / min, and the granulation endpoint was controlled to have a particle moisture of 1% to obtain dry granules;

[0047] (4) The dry granules, 1 g of colloidal silicon dioxide (Aerosil® 200 Pharma), 2.5 g of stearic acid, and 3.5 g of magnesium stearate were mixed, and a tablet core was pressed using a 8 mm shallow concave die, and the hardness was controlled to be 80 N to obtain a tablet core with a tablet weight of 250 mg; ​200 Pharma), 3 g of stearic acid and 5 g of magnesium stearate are mixed, and a tablet core is pressed using an 8 mm shallow concave die, with the hardness controlled to 80 N, to obtain a tablet core with a weight of 250 mg;

[0048] Example 4:

[0049] (1) 865 g of hypromellose (type METHOCEL K100M, viscosity of 3 mPa-s (2% aqueous solution, 20°C) is added to 5 kg of purified water, and high-pressure homogenization is performed 3 times at 55 MPa to obtain an inner coating liquid; TM E3 PERMIUM LV), 24 g of sodium metabisulfite, 80 g of triethyl citrate, 30 g of talc and 1 g of caramel pigment are added to 5 kg of purified water, and high-pressure homogenization is performed 3 times at 55 MPa to obtain an inner coating liquid;

[0050] (2) 712 g of hypromellose (type METHOCEL K100M, viscosity of 15 mPa-s (2% aqueous solution, 20°C) is added to 3.5 kg of purified water, and high-pressure homogenization is performed 3 times at 70 MPa to obtain an outer coating liquid; TM E15 PERMIUM LV), 38 g of sodium sulfite, 80 g of nano-zinc oxide (particle size D50 of 20 nm), 100 g of nano-titanium dioxide (rutile type, particle size D50 of 30 nm), 60 g of polyethylene glycol 6000 and 10 g of colloidal silicon dioxide are added to 3.5 kg of purified water, and high-pressure homogenization is performed 3 times at 70 MPa to obtain an outer coating liquid;

[0051] (3) The tablet core provided in Example 2 is preheated to 38°C, the inlet air temperature of the fluidized bed is set to 50°C, the atomization pressure is 0.15 MPa, the liquid spraying rate is 6 mL / min, the inner coating liquid is sprayed from the bottom, and when the coating weight reaches 1.8%, the drying is switched in, and a gradient drying program is used, the first stage is drying at 50°C / 20% RH for 1 h, the second stage is drying at 45°C / 15% RH for 2 h, then the inlet air temperature of the fluidized bed is adjusted to 46°C, the atomization pressure is 0.14 MPa, the liquid spraying rate is 8 mL / min, the outer coating liquid is sprayed from the bottom, and when the coating weight reaches 3.3%, the process is stopped to obtain coated tablets;

[0052] (4) The coated tablets are dried using a gradient drying program, the first stage is drying at 55°C / 5% RH for 4 h, the second stage is drying at 40°C / 10% RH for 8 h to eliminate internal stress, and the third stage is equilibrium at 25°C / 40% RH for 24 h to obtain a coated pharmaceutical preparation.

[0053] Example 5:

[0054] (1) 670 g of hypromellose (type METHOCEL K100M, viscosity of 3 mPa-s (2% aqueous solution, 20°C) is added to 5 kg of purified water, and high-pressure homogenization is performed 3 times at 55 MPa to obtain an inner coating liquid; TME3 PERMIUM LV), 28 g sodium metabisulfite, 100 g triethyl citrate, 50 g talc and 2 g caramel color were added into 5.5 kg purified water, and treated by high pressure homogenization 3 times at 60 MPa to obtain the inner coating liquid;

[0055] (2) 450 g of hypromellose (type METHOCEL K100M available from Dow Chemicals, viscosity 15 mPa-s (2% aqueous solution, 20°C)) was added into 4 kg purified water, and treated by high pressure homogenization 3 times at 60 MPa to obtain the inner coating liquid; TM E15 PERMIUM LV), 42 g sodium sulfite, 120 g nano-zinc oxide (particle size D50 20 nm), 150 g nano-titanium dioxide (rutile type, particle size D50 30 nm), 80 g polyethylene glycol 6000 and 30 g colloidal silicon dioxide were added into 4 kg purified water, and treated by high pressure homogenization 3 times at 80 MPa to obtain the outer coating liquid;

[0056] (3) The tablet cores provided in Example 2 were preheated to 40°C, and the inner coating liquid was sprayed from the bottom of the fluidized bed at an inlet air temperature of 52°C, an atomization pressure of 0.18 MPa and a spraying rate of 7 mL / min. When the coating weight reached 2.0%, the drying was started, and a gradient drying procedure was used, i.e. 50°C / 20% RH for 1 h in the first stage and 45°C / 15% RH for 2 h in the second stage. Then the inlet air temperature was adjusted to 48°C, the atomization pressure to 0.15 MPa and the spraying rate to 9 mL / min, and the outer coating liquid was sprayed from the bottom of the fluidized bed. When the coating weight reached 3.5%, the spraying was stopped, and coated tablets were obtained.

[0057] (4) The coated tablets were dried using a gradient drying procedure, i.e. 55°C / 5% RH for 4 h in the first stage, 40°C / 10% RH for 8 h in the second stage to eliminate internal stress, and 25°C / 40% RH for 24 h in the third stage to balance, and a pharmaceutical preparation was obtained.

[0058] Example 6:

[0059] (1) 775 g of hypromellose (type METHOCEL K4M available from Dow Chemicals, viscosity 3 mPa-s (2% aqueous solution, 20°C)) was added into 6 kg purified water, and treated by high pressure homogenization 3 times at 65 MPa to obtain the inner coating liquid; TM E3 PERMIUM LV), 28 g sodium metabisulfite, 100 g triethyl citrate, 50 g talc and 2 g caramel color were added into 5.5 kg purified water, and treated by high pressure homogenization 3 times at 60 MPa to obtain the inner coating liquid;

[0060] (2) 454 g of hypromellose (type METHOCEL K100M available from Dow Chemicals, viscosity 15 mPa-s (2% aqueous solution, 20°C)) was added into 4 kg purified water, and treated by high pressure homogenization 3 times at 60 MPa to obtain the inner coating liquid; TME15 PERMIUM LV), 46 g of sodium sulfite, 150 g of nano-zinc oxide (particle size D50 of 20 nm), 200 g of nano-titanium dioxide (rutile type, particle size D50 of 30 nm), 100 g of polyethylene glycol 6000 and 50 g of colloidal silicon dioxide, 4.5 kg of pure water were added, and high-pressure homogenization was performed 3 times at 90 MPa to obtain an outer coating liquid;

[0061] (3) The tablet core provided in Example 2 was preheated to 42℃, the fluidized bed inlet air temperature was set to 55℃, the atomization pressure was 0.22 MPa, the liquid spraying rate was 8 mL / min, the inner layer coating liquid was sprayed from the bottom, when the coating weight gain reached 2.2%, the drying was switched on, the gradient drying program was used, the first stage was drying at 50℃ / 20%RH for 1 h, the second stage was drying at 45℃ / 15%RH for 2 h, then the fluidized bed inlet air temperature was adjusted to 50℃, the atomization pressure was 0.16 MPa, the liquid spraying rate was 10 mL / min, the outer layer coating liquid was sprayed from the bottom, when the coating weight gain reached 3.7%, the process was stopped, and coated tablets were obtained.

[0062] (4) The coated tablets were dried using a gradient drying program, the first stage was drying at 55℃ / 5%RH for 4 h, the second stage was drying at 40℃ / 10%RH for 8 h to eliminate internal stress, and the third stage was equilibrium at 25℃ / 40%RH for 24 h, and a coated pharmaceutical preparation was obtained.

[0063] Comparative Example 1:

[0064] The difference between Comparative Example 1 and Example 2 is that the hydroxypropyl methyl cellulose (type number is METHOCEL TM E15 PERMIUM LV) with a viscosity of 15 mPa·s (2% aqueous solution, 20℃) in step (6) is replaced by hydroxypropyl methyl cellulose (type number is METHOCEL TM E3 PERMIUM LV) with a viscosity of 3 mPa·s (2% aqueous solution, 20℃).

[0065] Comparative Example 2:

[0066] The difference between Comparative Example 2 and Example 2 is that the sodium sulfite in step (1) is replaced by sodium sulfite.

[0067] Comparative Example 3:

[0068] The difference between Comparative Example 3 and Example 2 is that the sodium sulfite in step (2) is replaced by sodium pyrosulfite.

[0069] Comparative Example 4:

[0070] The difference between Comparative Example 4 and Example 2 is that the amount of sodium pyrosulfite in step (1) is replaced by 42 g, and the amount of sodium sulfite in step (2) is replaced by 28 g.

[0071] Comparative Example 5:

[0072] The difference between Comparative Example 5 and Example 2 is that sodium sulfite is used as the tablet core raw material instead of L-ascorbyl palmitate.

[0073] Comparative Example 6:

[0074] The difference between Comparative Example 6 and Example 2 is that the inner coating liquid and the outer coating liquid are mixed, homogenized under high pressure, and then coated by low-pressure spraying in a fluidized bed. The coating process is stopped when the coating weight gain reaches 5.5%.

[0075] Performance testing:

[0076] Dissolution: Follow the ChP2020 Part IV General Rules 0931, Method II. Dissolution conditions: Use 1000 mL of 0.01 mol / L hydrochloric acid solution as the dissolution medium, set the rotation speed at 75 rpm, and operate according to the regulations. Sample after 45 minutes. Test solution: Take the dissolution solution and filter it through a 0.45 μm polyethersulfone filter membrane. Discard 3 mL of the initial filtrate and collect the subsequent filtrate. Reference solution: Accurately weigh agomelatine reference substance, add acetonitrile-water (40:60) and ultrasonically dissolve and quantitatively dilute to prepare a solution containing 0.30 mg per 1 mL. Accurately measure an appropriate amount of the above solution and quantitatively dilute with dissolution medium to prepare a solution containing approximately 30 μg of agomelatine per 1 mL. Determination method: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 276 nm according to the UV-visible spectrophotometric method (ChP2020 Part IV General Rules 0401). Calculate the dissolution rate of each tablet. The results are shown in Table 2.

[0077] Accelerated stability: Seal the sample in double aluminum packaging and place it at a temperature of 40±2℃ and a relative humidity of 75±5% for 6 months according to the test method of ChP 2020 Part IV General Rules 9001, and then test the total impurity content.

[0078] Light stability: According to the test method of ChP 2020 Part IV General Rules 9001, the sample was spread flat in a transparent glass dish and placed in a light box. It was continuously irradiated at an illumination of 4500±500Lx for 14 days. The total impurity content and ΔE color difference value were tested. The ΔE color difference value was calculated by measuring the chromaticity value of the sample before and after illumination with a spectrophotometer. Refer to ChP 2020 version Part IV General Rules 0401. The results are shown in Table 2.

[0079] Total impurity content test: HPLC method (ChP 2020 four-part general 0512) was used, the solvent was acetonitrile-water in a volume ratio of 40:60, 5 tablets of sample were taken, placed in a 100 mL flask, added about 60 mL of solvent, ultrasonic for 5 min, shaken for 30 s, ultrasonic for 25 min, cooled to room temperature, diluted to the mark with solvent, filtered through a 0.22 μm PTFE filter membrane (or equivalent filter membrane), discarded at least 3 mL of the initial filtrate, took the subsequent filtrate, accurately measured 2 mL of the subsequent filtrate, placed in a 25 mL flask, diluted to the mark with solvent, shaken well, to obtain the test solution; an appropriate amount of agomelatine reference substance was accurately weighed, ultrasonically dissolved and quantitatively diluted to prepare a solution containing 0.2 μg per 1 mL, which was the reference solution; an appropriate amount of reference solution was accurately measured, diluted with solvent to prepare a solution of about 0.05 μg per 1 mL, which was the sensitivity solution; phenylsilane bonded silica gel was used as the filler (ZORBAX SB-Phenyl, 4.6 mm x 250 mm, 5 μm); 0.1% phosphoric acid aqueous solution was used as mobile phase A, and acetonitrile was used as mobile phase B; gradient elution was performed according to the following Table 1; the flow rate was 1.0 mL per minute; the column temperature was 40°C; the detection wavelength was 230 nm; the injection volume was 10 μL; the test sample solution and the reference solution were accurately measured and injected into the liquid chromatograph, respectively, and the chromatogram was recorded, and the total impurity content was calculated by the external standard method of the main component.

[0080] Table 1 Gradient elution

[0081]

[0082]

[0083] Table 2 Performance test results

[0084]

[0085] Data analysis:

[0086] From the data of examples 4-6 in Table 2, it can be seen that the preparation shows excellent performance in dissolution rate, accelerated stability test and light stability test, and exhibits good release characteristics and stability. This may be related to the design of multi-factor synergistic optimization in the preparation process. By precisely controlling the preparation parameters of the tablet core and the composition of the coating liquid and the spraying process, a multi-layer structure with uniformity and stability is formed.

[0087] As can be seen from the data of Example 5 and Comparative Example 1 in Table 2, the selection of the viscosity of hypromellose in the inner and outer coating liquids has a significant influence on the performance of the preparation. In Example 2, hypromellose with different viscosities was used as the matrix material of the inner and outer coating liquids, respectively, which may optimize the functional division of the inner and outer coatings through the viscosity difference. The use of hypromellose with a lower viscosity in the inner coating liquid helps to form a dense and well-adhesive base layer, thereby improving the adhesion and mechanical strength of the coating layer; while the use of hypromellose with a higher viscosity in the outer coating liquid may further enhance the barrier effect of the film layer, thereby effectively reducing the ΔE color difference value in the light stability test and maintaining the appearance stability of the preparation.

[0088] As can be seen from the data of Example 5 and Comparative Examples 2-4 in Table 2, the redox gradient system formed by sodium sulfite and sodium metabisulfite has a significant synergistic effect on the stability of the preparation. In Example 2, sodium metabisulfite was used in the inner coating and sodium sulfite was used in the outer coating to construct a dynamic oxidation-reduction protection gradient. The outer sodium sulfite quickly removes permeable oxygen, and the inner sodium metabisulfite combines with residual oxygen to achieve spatial selective protection. In Comparative Examples 2 and 3, the distribution of antioxidants is unreasonable, which destroys the redox sequence and leads to insufficient antioxidant capacity or accelerated light degradation; in Comparative Example 4, although the dosage is adjusted to partially restore the gradient, the imbalance of the proportion may cause a local acidic environment and accelerate the deterioration of the coating. In Example 2, by precisely regulating the oxidation-reduction potential difference, the risk of oxidative degradation and photochromism is significantly reduced, and the chemical stability and appearance stability of the preparation are comprehensively improved.

[0089] As can be seen from the data of Example 5 and Comparative Example 5, L-ascorbyl palmitate has a significant synergistic protective effect on the stability of the preparation. This is mainly due to the formation of a synergistic protection system by L-ascorbyl palmitate, sodium sulfite and sodium metabisulfite in the redox gradient design. The introduction of L-ascorbyl palmitate during the preparation of the tablet core may form a primary antioxidant layer on the surface of the granules, while the secondary protection system is composed of sodium sulfite and sodium metabisulfite in the coating layer. In Comparative Example 5, the replacement of sodium sulfite leads to a decrease in light stability due to the lack of potential gradient regulation.

[0090] As can be seen from the data of Example 5 and Comparative Example 6, Example 2 exhibits more excellent performance in the stability test, which indicates that the layered design and independent process of the inner and outer coatings are of great significance to the stability and performance of the tablets.

[0091] Those skilled in the art should understand that the above discussion of any embodiment is only intended to be exemplary in nature and is not intended to suggest that the present application is limited to these examples; under the concept of the present application, the above embodiments or technical features among different embodiments can be combined, steps can be implemented in any order, and there are many other variations of different aspects of the present application as described above, which are not provided in details for the sake of brevity.

Claims

1. A coating composition, characterized in that The invention comprises an inner coating composition and an outer coating composition; the weight ratio of the inner coating composition to the outer coating composition is 4.5-5.5:8.5-9.5; The inner coating composition comprises the following components by weight: 2.4%-3.2% sodium metabisulfite, 8%-12% triethyl citrate, 3%-8% talc, 0.1%-0.3% caramel pigment, and the balance is hypromellose; The outer coating composition comprises the following components by weight: 3.8%-4.6% sodium sulfite, 8%-15% nano zinc oxide, 10%-20% nano titanium dioxide, 6%-10% polyethylene glycol, 1%-5% colloidal silicon dioxide and the balance being hypromellose; The viscosity of a 2 wt % aqueous solution of hypromellose in the inner coating composition at 20° C. is 2.5-3.5 mPa·s; The viscosity of a 2 wt % aqueous solution of hypromellose in the outer coating composition at 20° C. is 14-16 mPa·s; The coated pharmaceutical preparation prepared by the coating composition comprises a tablet core and a coating; the coating is obtained by coating the tablet core with an inner coating composition and then coating the tablet core with an outer coating composition; the weight ratio of the tablet core to the coating is 250:13-15; The tablet core is prepared from the following raw materials by weight: 10%-14% of agomelatine raw material, 14%-30% of lactose, 4%-14% of corn starch, 4%-8% of sodium starch glycolate, 2.4%-8% of povidone, 0.04%-0.4% of colloidal silicon dioxide, 0.4%-0.56% of L-ascorbyl palmitate, 0.8%-1.2% of stearic acid, 0.8%-2% of magnesium stearate, and the balance is microcrystalline cellulose.

2. The coating composition according to claim 1, characterized in that The particle size D50 of the nano zinc oxide is 10-30 nm; the nano titanium dioxide is rutile titanium dioxide, and the particle size D50 is 20-50 nm.

3. The coating composition according to claim 1, characterized in that The steps for preparing the core are as follows: S1: mixing agomelatine API, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate and povidone to obtain a mixed powder; S2: adding L-ascorbyl palmitate to an ethanol aqueous solution to obtain a spray solution; S3: spraying the spray liquid onto the surface of the mixed powder, fluidizing and drying to obtain dry particles; S4: Mix the dry granules, colloidal silicon dioxide, stearic acid and magnesium stearate and compress to obtain tablet cores.

4. A method for preparing a coated pharmaceutical preparation using the coating composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) adding the inner coating composition to pure water and homogenizing under high pressure to obtain an inner coating solution; (2) adding the outer coating composition to pure water and homogenizing under high pressure to obtain an outer coating solution; (3) Preheat the tablet cores to 38-42°C, set the fluidized bed inlet temperature to 50-55°C, the atomizing pressure to 0.15-0.22 MPa, and the spray rate to 6-8 mL / min, spray the inner coating solution from the bottom, and when the coating weight gain reaches 1.8%-2.2%, proceed to drying, dry at 50°C / 20% RH for 1 hour, and then dry at 45°C / 15% RH for 2 hours. Then adjust the fluidized bed inlet temperature to 46-50°C, the atomizing pressure to 0.14-0.16 MPa, and the spray rate to 8-10 mL / min, spray the outer coating solution from the bottom, and stop when the coating weight gain reaches 3.3%-3.7% to obtain coated tablets; (4) The coated tablets were dried using a gradient drying procedure: the first stage: 55°C / 5% RH drying for 4 h, the second stage: 40°C / 10% RH drying for 8 h to eliminate internal stress, and the third stage: 25°C / 40% RH equilibrium for 24 h to obtain a coated pharmaceutical preparation.

5. The method for preparing the coated pharmaceutical preparation according to claim 4, characterized in that: The amount of pure water added in step (1) is 5-6 times the weight of the inner coating composition.

6. The method for preparing the coated pharmaceutical preparation according to claim 4, characterized in that: The amount of pure water added in step (2) is 3.5-4.5 times the weight of the outer coating composition.

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