Enteric layer and preparation method thereof, and oral preparation

Abstract

The present invention relates to an enteric layer and a preparation method thereof. The enteric layer is mainly composed of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talcum powder. The enteric layer is beneficial to reducing the ethanol residual amount of the enteric layer through reasonable proportioning. In addition, the preparation method provided by the present invention further reduces the ethanol residual amount in the enteric layer by controlling parameters such as the moisture content of the air intake during the coating process. It is not necessary to place the ethanol for a long time after coating to allow the ethanol to evaporate freely to reduce the ethanol residual, and the control of the ethanol residual is more stable. In addition, the enteric layer provided by the present invention and the preparation method thereof can also avoid the generation of white spots on the surface of the non-white enteric layer and avoid uneven color.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an enteric layer and a preparation method thereof, and an oral preparation. Background Art

[0002] Ulcerative colitis (UC) and Crohn's disease (CD) are chronic nonspecific intestinal inflammatory diseases with unclear etiology, collectively referred to as inflammatory bowel disease (IBD). The clinical manifestations of ulcerative colitis are persistent or recurrent diarrhea, bloody and mucous stools accompanied by abdominal pain, tenesmus, and varying degrees of systemic symptoms. The lesions are mainly in the large intestine, rectal mucosa and submucosa, and are distributed continuously in the intestinal mucosa. The clinical manifestations of Crohn's disease are diverse, including gastrointestinal manifestations, systemic manifestations, extraintestinal manifestations, and complications. The lesions can affect the entire digestive tract, usually in a discontinuous distribution, and the main site of onset is the terminal ileum and its adjacent colon.

[0003] Mesalamine (mesalazine) is a 5-aminosalicylic acid (5ASA) compound. Its anti-inflammatory mechanism is not fully understood. In vitro studies have shown that mesalamine has a certain effect on the content of intestinal mucosal prostaglandins, has the function of scavenging reactive oxygen free radicals, may inhibit lipoxygenase, and has a certain anti-inflammatory effect. It is commonly used in the treatment of ulcerative colitis (acute attack and prevention of recurrence) and Crohn's disease (acute attack).

[0004] Mesalazine is absorbed rapidly and completely in the upper gastrointestinal tract after oral administration, but is least absorbed in the intestinal end colon, and the absorption in the intestinal tract has a trend of gradually reducing from the proximal end to the distal end. Meanwhile, after 500mg of mesalazine is intravenously administered, the half-life is about 42 minutes, and the half-life is short. The anti-inflammatory effect of mesalazine in vivo is a local effect on the intestinal tract, a non-systemic effect, and what the blood drug concentration reflects is the total absorption of mesalazine, which is not entirely the absorption of the target intestinal tract site of action. In order to prevent mesalazine from being absorbed in the proximal small intestine, and to make it arrive at the terminal morbid small intestine (such as the terminal ileum) and the colon to play a role, it is necessary to be designed as an enteric-coated preparation so that the target treatment site obtains enough dosages.

[0005] Copolymer of methacrylic acid and methyl methacrylate (1:1), also known as methacrylic acid copolymer type A, has a Chinese trade name of Eudragit L and an English trade name of Eudragit L100. Eudragit L contains carboxyl groups, and the molar ratio of carboxyl groups to ester groups is about 1:1. It is easy to dissolve in water by forming salts with alkali. Eudragit L 100 dissolves in solutions with a pH greater than 6. Eudragit L100 is soluble in ethanol. For enteric-coated preparations released at the end of the small intestine of humans, ethanol solvents are preferably used for liquid coating to obtain better enteric layer coating films. In order to ensure the safety of drug administration, the ethanol residue in the preparation needs to be controlled below a certain limit, among which the enteric layer with low ethanol residue and its preparation method are very important.

[0006] Patent CN108348472A specification discloses that 500mg mesalazine enteric-coated tablets are prepared by coating three methacrylic acid and methyl methacrylate copolymers (1:1) with a total of 90.5mg on a non-functional hydroxypropyl methylcellulose layer isolation tablet core, with a weight gain of 13%, but no specific formula or control method for residual enteric layer solvent is disclosed. At the same time, the patent also discloses 700mg to 1500mg mesalazine enteric-coated preparations, which are composed of two enteric layers, and the enteric layers are added with a new enteric material methacrylic acid and methyl methacrylate copolymer (1:2), but no specific formula or control method for residual enteric layer solvent is disclosed.

[0007] Patent CN112315929B discloses a composition of a four-layer coating system mesalazine enteric-coated tablet (250mg, 500mg) and its preparation method. The composition is composed of a mesalazine tablet core and four layers of coating, and the coating layers are as follows from the inside to the outside: the first layer: an isolation layer; the second layer: a sustained-release enteric coating layer; the third layer: a positioning acid-resistant layer; and the fourth layer: a moisture-proof layer. The sustained-release enteric coating layer and the positioning acid-resistant layer constitute the enteric layer, which is prepared with about 80% ethanol, but the patent still does not describe how to control the ethanol residue.

[0008] Patent WO2017125856A1 discloses 500-2000 mg mesalazine enteric-coated preparations, the enteric layer of which is composed of one of methacrylic acid derivatives, anionic polymers of methacrylic acid, anionic copolymers of methacrylic acid and methyl acrylate, or a combination thereof, and the coating is made of an organic solvent. There is no description or control method for organic solvent residue.

[0009] Patent CN112315929B discloses a method for preparing an enteric layer of mesalazine enteric-coated tablets with a thickness of 0.6 mm to 1.2 mm, wherein the coating is performed using an ethanol-based liquid coating, and there is no description or control method related to ethanol residue.

[0010] The residual ethanol content in the enteric layer is related to the quality and safety of the drug. None of the above patents disclose how to obtain an enteric layer with low ethanol residue and its preparation method. Summary of the invention

[0011] In view of the problem in the prior art that the enteric layer has a high ethanol residue or has a large difference in ethanol residue between batches, the present invention provides an enteric layer with low ethanol residue and a preparation method thereof.

[0012] The first aspect of the present invention provides an enteric layer. The enteric layer comprises at least two layers of enteric layer films, each of which comprises the following components in parts by weight:

[0013] 100 parts of methacrylic acid and methyl methacrylate copolymer (1:1),

[0014] 8-15 parts of polyethylene glycol 6000,

[0015] 15 to 25 parts of talcum powder.

[0016] Among them, methacrylic acid and methyl methacrylate copolymer (1:1), namely Eudragit L100, is the main film-forming material of the enteric layer. It dissolves in a solution with a pH greater than 6 and is an excellent enteric film-forming material. Polyethylene glycol 6000 is a mixture formed by polycondensation of ethylene oxide and water. It is easily soluble in water and ethanol. In the enteric layer film, polyethylene glycol 6000 can improve the flexibility of the film, help the spray droplets to spread on the one side and combine with each other, which is conducive to the formation of a complete film; and can increase the permeability of the film and improve the drug dissolution rate. During the coating process, the coating liquid sprayed on the carrier of the preparation to be coated will become sticky as the solvent evaporates, so adding an appropriate amount of talcum powder to the coating liquid can reduce viscosity and avoid mutual adhesion between the carriers of the preparation to be coated. The present invention uses methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talcum powder as main components, and through reasonable proportioning, reduces the ethanol residual amount of the enteric layer and improves the safety of oral preparations.

[0017] The residual ethanol content of the enteric layer of the present invention can be as low as 5.5% by weight, preferably as low as 2.5% to 5.5% by weight, and even as low as below 3.80% by weight. In the present invention, the residual ethanol content refers to the weight proportion of residual ethanol in the enteric layer or preparation.

[0018] In some specific embodiments, the thickness of the enteric layer may be 170 μm to 310 μm, preferably 180 μm to 300 μm.

[0019] During the tablet coating process, the tablet tumbling degree fluctuates to a certain extent due to the tablet shape, and the thickness fluctuation of the enteric layer is the normal thickness fluctuation during the coating process. The thickness of the enteric layer in the present invention is the total thickness of all enteric layer films.

[0020] Enteric layers with a thickness of 170 μm to 310 μm are already considered thick films in the field of pharmaceutical preparations, and as the thickness increases, the ethanol residue is more likely to increase. However, the present application controls the ethanol residue of the high-thickness enteric layer within the range of 2.5 wt % to 5.5 wt % by controlling the content of each component of the enteric layer.

[0021] In some specific schemes, when the carrier of the preparation to be coated is a tablet, the thickness of the enteric layer wrapped on the side of the tablet may be 170μm to 250μm, preferably 180μm to 240μm, and most preferably 210μm to 240μm; the thickness of the enteric layer wrapped on the front of the tablet may be 200μm to 310μm, preferably 230μm to 300μm, and most preferably 240μm to 290μm.

[0022] In some specific embodiments, the enteric layer may include two to three enteric layer films.

[0023] In the present invention, the enteric layer membrane close to the preparation carrier to be coated is defined as the innermost layer, the enteric layer membrane far from the preparation carrier to be coated is defined as the outermost layer, and the enteric layer membrane between the innermost layer and the outermost layer is defined as the middle layer.

[0024] In some specific embodiments, in each enteric layer, the total weight of the methacrylic acid and methyl methacrylate copolymer (1:1), the polyethylene glycol 6000 and the talc accounts for ≥ 90%.

[0025] In some specific embodiments, the enteric layer film may also contain a small amount of other components, such as film-forming materials, plasticizers, colorants, opacifiers, anti-adhesive agents, and the like.

[0026] In some specific embodiments, the innermost enteric layer does not contain titanium dioxide.

[0027] In some specific embodiments, the enteric layer includes two layers of enteric layer films, wherein the outermost enteric layer film further includes a non-white colorant.

[0028] In some specific embodiments, the non-white colorant may be one or more of yellow iron oxide, red iron oxide, purple iron oxide, brown iron oxide, purple iron oxide, black iron oxide, sunset yellow, lemon yellow, brilliant blue, indigo, allura red, carmine, amaranth, etc. Preferably, the non-white colorant may be one or more of yellow iron oxide, red iron oxide, indigo, and carmine.

[0029] In some specific embodiments, the enteric layer film of the outermost layer further comprises titanium dioxide. In some specific embodiments, the enteric layer comprises three layers of enteric layer films, wherein the enteric layer film of the middle layer further comprises titanium dioxide, and the enteric layer film of the outermost layer further comprises a non-white colorant.

[0030] Preferably, in the outermost enteric layer film, the weight ratio of the non-white colorant to titanium dioxide is: 2.3-7.3:4.3-6.3.

[0031] In some specific embodiments, relative to 100 parts by weight of the methacrylic acid and methyl methacrylate copolymer (1:1), the amount of polyethylene glycol 6000 may be 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight or 15 parts by weight.

[0032] In some specific embodiments, relative to 100 parts by weight of the methacrylic acid and methyl methacrylate copolymer (1:1), the amount of talc may be 15 parts by weight, 16 parts by weight, 17 parts by weight, 18 parts by weight, 19 parts by weight, 20 parts by weight, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight or 25 parts by weight.

[0033] In some specific embodiments, the enteric layer film comprises the following components in parts by weight:

[0034] Methacrylic acid and methyl methacrylate copolymer (1:1) 100 parts,

[0035] 12 parts of polyethylene glycol 6000,

[0036] 20 parts of talcum powder.

[0037] The second aspect of the present invention provides a method for preparing an enteric layer, comprising the following steps:

[0038] Mixing 100 parts by weight of a copolymer of methacrylic acid and methyl methacrylate (1:1), 8 to 15 parts by weight of polyethylene glycol 6000, and 15 to 25 parts by weight of talc in a solvent to obtain a coating solution;

[0039] The coating liquid is sprayed on the carrier of the preparation to be coated to form an enteric layer.

[0040] In order to obtain a better enteric layer, methacrylic acid and methyl methacrylate copolymer (1:1) need to be completely dissolved in a solvent. The solvent selected in the present invention is preferably ethanol or ethanol aqueous solution. Preferably, the volume concentration of the ethanol aqueous solution can be 85-99.5% (v / v). The present invention selects a high concentration of ethanol aqueous solution to prepare the coating solution, which can completely dissolve the copolymer. The solid content of the coating solution can be 8% to 12%, preferably 8-10%. This solid content range takes into account solubility and prevents the coating solution from being too dilute, resulting in sedimentation of solid materials and uneven coating.

[0041] In the present invention, the concentration of ethanol aqueous solution refers to the volume percentage of ethanol in the mixed solvent of ethanol and water. The solid content of the coating solution refers to the weight percentage of the coating material in the coating solution. The coating solution is composed of the coating material and the solvent, wherein the coating material is the components constituting the enteric layer.

[0042] In some specific embodiments, during the coating process, the moisture content of the inlet air is controlled to be 8 g / kg to 20 g / kg. Preferably, the moisture content of the inlet air is controlled to be 8 g / kg to 14 g / kg.

[0043] In the present invention, the intake air moisture content represents the mass (grams) of water vapor mixed with each kilogram of dry air, and the unit is g / kg (dry air). It is the actual intake air moisture content and can be used to represent the absolute humidity of the intake air.

[0044] The carrier of the preparation to be coated of the present invention can be in the form of a tablet core, a granule or a capsule. For example, in the case where the carrier of the preparation to be coated is a tablet core, in order to prepare an enteric layer with low ethanol residue, a coating liquid prepared with ethanol can be sprayed on the carrier of the tablet to be coated by a tablet coating machine. The carrier of the tablet to be coated can be, for example, an elliptical biconvex mesalazine enteric-coated tablet core with a specification of 0.5g or 500mg. The carrier of the tablet to be coated can be, for example, a 17.3mm×8.8mm biconvex elliptical tablet. When the tablet coating machine is used for coating, the moisture content of the inlet air can range from 8g / kg to 20g / kg, and the moisture content of the inlet air can be adjusted and controlled by the inlet air unit of the coating machine, such as the surface cooling dehumidification, rotary dehumidification, humidification, etc. of the inlet air unit. When the air intake moisture content is 8g / kg to 20g / kg, when the air intake passes through the coating cavity and the tablet bed, the moisture in the air intake can quickly reduce the ethanol concentration in the surface layer of the enteric layer and the coating cavity through the dissolution effect, and on the other hand, it also increases the concentration gradient difference of ethanol volatilization, promoting the faster volatilization of ethanol on the surface layer of the enteric layer. The present invention also attempts to place the coating for a long time, and reduce the ethanol residue through ventilation at different temperatures and different moisture contents, but the effect is not ideal. At the same time, the range of air intake moisture content can effectively prevent the spray drying of the enteric material, and the obtained enteric layer has no white spots and uniform color.

[0045] In some specific schemes, when the preparation carrier to be coated is a tablet, an average of 110 to 135 mg of enteric layer is added to each tablet of the preparation carrier to be coated. Preferably, the preparation carrier to be coated may be composed of mesalazine tablets and a non-functional isolation layer. An enteric layer may be formed by spraying a coating liquid on the preparation carrier to be coated. After coating, an average of 110 to 135 mg of weight is added to each tablet, which is the total weight of the enteric layer. The tablet specification may be, for example, 0.5 g.

[0046] In order to obtain a better enteric layer, the coating process needs to control the coating tablet bed temperature to 25°C to 45°C, preferably 25°C to 35°C.

[0047] The third aspect of the present invention provides an oral preparation, comprising the enteric layer of the first aspect of the present application or the enteric layer obtained by the preparation method of the second aspect of the present application.

[0048] Preferably, the oral preparation may be mesalazine enteric-coated tablets with a specification of 0.5 g.

[0049] Compared with the prior art, the present invention has the following technical effects:

[0050] 1. The present invention provides an enteric layer, which is mainly composed of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talcum powder. Through reasonable proportioning, the ethanol residual amount of the enteric layer is reduced, thereby reducing the ethanol residual amount of the oral preparation and improving the safety of oral preparation. Polyethylene glycol 6000 can be inserted between the molecular chains of the high molecular polymer to weaken the attraction between the polymer molecular chains, that is, weaken the aggregation effect between the molecular chains, and increase the mobility and softness of the molecular chains. Therefore, an appropriate amount of polyethylene glycol 6000 is conducive to the effective volatilization of ethanol. However, an excessively high content of polyethylene glycol 6000 will reduce the glass transition temperature Tg of the film, resulting in an increase in the film viscosity and an increase in the compactness of the film during the film forming process, which is not conducive to the effective volatilization of ethanol. An excessively low content of polyethylene glycol 6000 will result in a poor film forming effect and easily cause white spots to form on the film surface.

[0051] 2. The present invention also provides a method for preparing an enteric layer. By controlling parameters such as the moisture content of the incoming air during the coating process, the residual ethanol in the enteric layer is significantly reduced. There is no need to leave the coating for a long time to allow the ethanol to evaporate freely to reduce the residual ethanol, and the control of the residual ethanol is more stable.

[0052] In addition, the enteric layer and preparation method provided by the present invention can also prevent white spots from forming on the surface of the non-white enteric layer and avoid uneven color. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1This is a scanning electron microscope image of the cross section of the elliptical mesalazine enteric-coated tablets prepared in Example 2 along the short diameter direction. DETAILED DESCRIPTION

[0054] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0055] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments and equipment used in the following examples, etc., can all be purchased on the market or can be obtained by existing methods; the amounts of the experimental reagents, unless otherwise specified, are the amounts of reagents used in conventional experimental operations; the experimental methods, unless otherwise specified, are all conventional methods.

[0056] The present invention is further described by the following examples. It should be correctly understood that the examples of the present invention are made to illustrate the present invention, rather than to limit the present invention, so simple modifications of the present invention under the premise of the method of the present invention also belong to the scope of the present invention.

[0057] First, prepare the tablet carrier for coating in the embodiment, i.e., the tablet carrier to be coated. The preparation method of the tablet carrier to be coated is conventional wet granulation, drying, mixing, tableting, etc. The prescription of the tablet carrier to be coated is shown in Table 1.

[0058] Table 1 Prescription of the carrier for the tablet to be coated

[0059]

[0060] Preparation method:

[0061] 1. Add mesalazine, anhydrous sodium carbonate, glycine, povidone and microcrystalline cellulose into a wet mixing granulator for mixing, add an appropriate amount of ethanol as a binder for wet granulation, and then use a fluidized bed to dry until the drying loss is not more than 2%, and then granulate to obtain dry granules.

[0062] 2. Mix the dry granules, cross-linked sodium carboxymethyl cellulose and silicon dioxide in a mixer for 15 minutes, and finally add calcium stearate and mix for 5 minutes.

[0063] 3. Use 17.3mm×8.8mm oval punch to press tablets, the tablet thickness range is 5.5mm~6.1mm, and the tablet friability is not more than 0.5%, and broken, cracked and crushed tablets shall not be detected. The ethanol residue of the plain tablet is 0%.

[0064] 4. Preparation of isolation layer liquid: The solid content of the coating liquid is 5%. Add hydroxypropyl methylcellulose and polyethylene glycol 6000 to 50% ethanol aqueous solution, stir until completely dissolved, then add talcum powder and stir and disperse for 1 hour for use.

[0065] 5. Use a coating machine to coat the isolation layer. Coating is performed when the tablet bed temperature is preheated to 40°C. After the coating liquid is sprayed, the tablet bed temperature will drop to the predetermined temperature range. The inlet air temperature is 50°C to 60°C, and the inlet air volume is 50 to 70 m 3 / h, the coating pan speed is 3rpm-20rpm, the liquid supply pump speed is 8rpm, the atomization pressure is 1bar-3.5bar, and the tablet bed temperature is controlled at 30-40°C. After reaching the target weight gain, the coating is stopped to obtain a tablet carrier for enteric layer coating, and the ethanol residue is detected to be 0%.

[0066] Embodiment 1 to Embodiment 3

[0067] Examples 1 to 3 were prepared by increasing the amount of different enteric layers to provide three different weights of enteric layers, and the formulations are shown in Table 2. The percentage within the layer is the percentage of each material in each enteric layer film to Eudragit L100.

[0068] Table 2 Formulations of enteric layers of different weights

[0069]

[0070]

[0071] Preparation method: Prepare each layer of coating solution separately, and the solid content of the coating solution is 10%. Add Eudragit L100 and polyethylene glycol 6000 into 90% ethanol aqueous solution and stir for 2 hours, then add the remaining materials, stir / high shear dispersion for 1 hour, and set aside.

[0072] The tablet carrier to be coated is preheated to a tablet bed temperature of 35°C before coating. After the coating liquid is sprayed, the tablet bed temperature will drop to a predetermined temperature range. The inlet air moisture content is 8g / kg to 14g / kg, the inlet air temperature is 35°C to 45°C, and the inlet air volume is 50 to 70m 3 / h, the coating pan speed is 3-25rpm, the liquid supply pump speed is 8rpm-14rpm, the atomization pressure is 1bar-3.5bar, and the tablet bed temperature is controlled to be 25℃-35℃. After each layer reaches the target weight gain, the coating of that layer is stopped, and then the coating of the next layer is continued until the coating is completed, and an enteric layer with three layers of enteric layer membranes is obtained, wherein the inner layer is enteric layer membrane 1, the middle layer is enteric layer membrane 2, and the outer layer is enteric layer membrane 3. The scanning electron microscope image of the cross section of the elliptical mesalazine enteric-coated tablets prepared in Example 2 along the short diameter direction is as shown in Figure 1 shown.

[0073] Embodiment 4 to Embodiment 7

[0074] The difference between Examples 4 to 7 and Example 2 is that four different enteric layers with different ratios of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talc are provided. In Example 2, the ratio of Eudragit L100, polyethylene glycol 6000 and talc in each enteric layer film is 100:12:20, in Example 4, the ratio of Eudragit L100, polyethylene glycol 6000 and talc in each enteric layer film is 100:8:15, in Example 5, the ratio of Eudragit L100, polyethylene glycol 6000 and talc in each enteric layer film is 100:15:25, in Example 6, the ratio of Eudragit L100, polyethylene glycol 6000 and talc in each enteric layer film is 100:5:13, and in Example 7, the ratio of Eudragit L100, polyethylene glycol 6000 and talc in each enteric layer film is 100:5:13. The ratio of Eudragit L100, polyethylene glycol 6000 and talc is 100:20:28. The detailed prescriptions of Examples 4-7 are shown in Tables 3 and 4. The intra-layer percentage is the percentage of each material in each enteric layer of Eudragit L100.

[0075] Table 3 Enteric layer formulations with different ratios of Eudragit L100, polyethylene glycol 6000 and talc

[0076]

[0077]

[0078] Table 4 Enteric layer formulations with different ratios of Eudragit L100, polyethylene glycol 6000 and talc

[0079]

[0080]

[0081] The preparation methods of Examples 4 to 7 refer to Example 2.

[0082] Example 8 and Example 9

[0083] The difference between Example 8 and Example 9 and Example 2 is that different numbers of enteric layers are provided, and the prescriptions of Example 8 and Example 9 are shown in Table 5. The percentage within the layer is the percentage of each material in each enteric layer film to Eudragit L100.

[0084] Table 5 Prescriptions of different enteric layers

[0085]

[0086] The preparation methods of Examples 8 and 9 refer to those of Example 2.

[0087] Example 10 to Example 12

[0088] The enteric layer formulations of Examples 10 to 12 are the same as those of Example 2. Examples 2, 10, 11 and 12 use different inlet air moisture contents to prepare the enteric layers.

[0089] The preparation methods of Example 10, Example 11 and Example 12 refer to Example 2. The difference is that the inlet air moisture content of Example 2 is 8g / kg to 14g / kg, the inlet air moisture content of Example 10 is <8g / kg (dynamically adjusted within the range of 3g / kg to 7g / kg), the inlet air moisture content of Example 11 is 14g / kg to 20g / kg, and the inlet air moisture content of Example 12 is >20g / kg (dynamically adjusted within the range of 21 to 27g / kg).

[0090] The enteric coated tablets prepared in Example 10 were placed in a ventilated straight exhaust oven at 25°C and 40°C for 5 days to reduce the ethanol residue. The inlet air moisture content was set to <8g / kg (dynamically adjusted within the range of 3g / kg to 7g / kg), 8g / kg to 14g / kg, and 14g / kg to 20g / kg at each temperature.

[0091] Example 13 and Example 14

[0092] The enteric layer formulations of Example 13 and Example 14 are the same as that of Example 2. Examples 2, 13 and 14 provide three methods for preparing the enteric layer at different tablet bed temperatures.

[0093] Preparation method: Prepare each layer of coating solution separately, and the solid content of the coating solution is 10%. Add Eudragit L100 and polyethylene glycol 6000 into 90% ethanol aqueous solution and stir for 2 hours, then add the remaining materials, stir / high shear dispersion for 1 hour, and set aside.

[0094] In Example 2, Example 13 and Example 14, the tablet carrier to be coated is preheated to a tablet bed temperature of 35°C, 45°C and 55°C respectively before coating. After the coating liquid is sprayed, the tablet bed temperature will drop to a predetermined temperature range. The inlet air moisture content is 8g / kg to 14g / kg, and the inlet air volume is 50 to 70m 3 / h, the coating pan speed is 3-25rpm, the liquid supply pump speed is 8rpm-14rpm, and the atomization pressure is 1bar-3.5bar. Example 2 The inlet air temperature is 35℃-45℃, and the tablet bed temperature is controlled at 25℃-35℃; Example 13 The inlet air temperature is 45℃-55℃, and the tablet bed temperature is controlled at 35℃-45℃; Example 14 The inlet air temperature is 55.5℃-65℃, and the tablet bed temperature is controlled at 45.5℃-55℃. After each layer reaches the target weight gain, stop coating that layer, and then continue coating the next layer until the coating is completed, to obtain an enteric layer with three enteric layer membranes, wherein the inner layer is enteric layer membrane 1, the middle layer is enteric layer membrane 2, and the outer layer is enteric layer membrane 3.

[0095] Example 15 to Example 18

[0096] The enteric layer formulations of Examples 15 to 18 are the same as those of Example 4. Examples 4, 15, 16, 17, and 18 provide five methods for preparing the enteric layer using ethanol aqueous solutions of different concentrations.

[0097] The preparation methods of Examples 15 to 18 refer to Example 4. The difference is that Example 4, Example 15, Example 16, Example 17, and Example 18 respectively use 90%, 85%, 95%, 80%, and 99.5% (v / v) ethanol aqueous solution for liquid preparation.

[0098] Example 19 and Example 20

[0099] The enteric layer formulations of Example 19 and Example 20 are the same as that of Example 5. Example 5, Example 19 and Example 20 provide three methods for preparing enteric layers with different solid contents.

[0100] The preparation methods of Example 19 and Example 20 refer to Example 5. The difference is that the solid contents of the coating solutions of Example 5, Example 19 and Example 20 are 10%, 8% and 12% respectively.

[0101] Example 21 to Example 23

[0102] In Example 21, the colorant yellow iron oxide was replaced with indigo, in Example 22, the proportion of the colorant yellow iron oxide was increased, and in Example 23, the colorant yellow iron oxide was replaced with carmine. Attempts were made to improve the appearance by adjusting the prescription under the condition that the inlet air moisture content was <8 g / kg (dynamically adjusted within the range of 3 g / kg to 7 g / kg), and the prescription is shown in Table 6. The percentage within the layer is the percentage of each material in each enteric layer film in Eudragit L100.

[0103] Table 6 Prescriptions of different enteric layers

[0104]

[0105]

[0106] Preparation method: Prepare each layer of coating solution separately, and the solid content of the coating solution is 10%. Add Eudragit L100 and polyethylene glycol 6000 into 90% ethanol and stir for 2 hours, then add the remaining materials, stir / high shear dispersion for 1 hour, and set aside.

[0107] The tablet carrier to be coated is preheated to a tablet bed temperature of 35°C before coating. After the coating liquid is sprayed, the tablet bed temperature will drop to a predetermined temperature range. The inlet air moisture content is <8g / kg (dynamically adjusted within the range of 3g / kg to 7g / kg), the inlet air temperature is 35°C to 45°C, and the inlet air volume is 50 to 70m 3 / h, the coating pan speed is 3-25rpm, the liquid supply pump speed is 8rpm-14rpm, the atomization pressure is 1bar-3.5bar, the tablet bed temperature is controlled at 25℃-35℃, and the coating of each layer is stopped after the target weight gain is achieved, and then the coating of the next layer is continued until the coating is completed, thereby obtaining an enteric layer having three enteric layer films, wherein the inner layer is enteric layer film 1, the middle layer is enteric layer film 2, and the outer layer is enteric layer film 3.

[0108] Enteric layer properties testing

[0109] Appearance of enteric layer: Visually inspect the enteric layer of coated tablets.

[0110] Method for detecting the thickness of the enteric layer: Cut the enteric-coated tablet in the middle horizontally and measure the thickness of the enteric layer using a microscope.

[0111] Ethanol residue detection method: hydrogen flame ionization detector (FID), detector temperature 200°C, injection port temperature 200°C, headspace injection, carrier gas is nitrogen, flow rate 1.0 ml / min, split ratio 3: 1. In the present invention, except for the special case description in the embodiment, the ethanol residue detection of the sample is carried out after the corresponding experiment is completed.

[0112] In Examples 1 to 3, the thickness of the enteric layer is within the range of 170 μm to 310 μm, the thickness of the enteric layer on the side of the tablet is within the range of 170 μm to 250 μm, and the thickness of the enteric layer on the front of the tablet is within the range of 200 μm to 310 μm. There are no white spots on the surface of the enteric layer, the color is uniform, and the ethanol residue in the enteric layer is within the range of 2.5% to 5.5%. See Table 7 for details.

[0113] Table 7 Test results of different enteric layer film thickness

[0114]

[0115] In Example 2, Example 4 and Example 5, the ratio of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talc is in the range of 100:8-15:15-25, there are no white spots on the surface of the enteric layer, the color is uniform, and the ethanol residue in the enteric layer is in the range of 2.5%-5.5%.

[0116] In Example 6, the ratio of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talc was 100:5:13, and the enteric layer had white spots on the surface and uneven color. In Example 7, the ratio of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talc was 100:20:28, and the enteric layer ethanol residue was 5.64%, which was greater than 5.5%. See Table 8 for details.

[0117] Table 8 Enteric layer test results of different ratios of Eudragit L100, polyethylene glycol 6000 and talc

[0118]

[0119] In Example 2, Example 8 and Example 9, the enteric layer is composed of 2 to 3 layers; each enteric layer has a fixed ratio of methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000 and talcum powder; the proportion of the three components (methacrylic acid and methyl methacrylate copolymer (1:1), polyethylene glycol 6000, talcum powder) in each enteric layer is not less than 90%. There are no white spots on the surface of the enteric layer, the color is uniform, and the ethanol residue in the enteric layer is within the range of 2.5% to 5.5%. See Table 9 for details.

[0120] Table 9 Test results of enteric layer with different numbers of layers

[0121]

[0122]

[0123] The inlet air moisture content of the enteric layer coating of Example 2 and Example 11 ranges from 8g / kg to 20g / kg, and there are no white spots on the surface of the enteric layer, the color is uniform, and the enteric layer ethanol residue is within the range of 2.5% to 5.5%. The inlet air moisture content of the enteric layer coating of Example 10 is less than 8g / kg (dynamically adjusted within the range of 3g / kg to 7g / kg), there are obvious white spots on the surface of the enteric layer, the color is uneven, and the enteric layer ethanol residue is greater than 5.5%. The inlet air moisture content of Example 12 is greater than 20g / kg (dynamically adjusted within the range of 21g / kg to 27g / kg), the inlet air humidity is too high, and during the coating process, the enteric layer sheet sticks to the sheet, the enteric layer film is uneven, and the coating cannot be performed. See Table 10 for details.

[0124] Table 10 Test results of enteric layer with different air humidity content

[0125]

[0126]

[0127] The enteric-coated tablets prepared in Example 10 were subjected to the inlet air temperature of 25°C and 40°C for 5 days to reduce the ethanol residue. The effect of each inlet air moisture content on reducing the ethanol residue in the enteric layer was not obvious. At the inlet air moisture content of 14g / kg to 20g / kg, moisture invaded the inside of the plain tablets, and the raw and auxiliary materials of the plain tablets turned black when exposed to moisture, and expanded at the same time, destroying the enteric film. The effect of removing ethanol residue during the coating process at the inlet air moisture content of 8g / kg to 20g / kg was more obvious than that of leaving the tablets to stand after coating, and the efficiency was higher. In addition, the removal of ethanol residue during the coating process would not cause the plain tablets and the enteric film to turn black, and damage the plain tablets and the enteric layer. See Table 11 for details.

[0128] Table 11 Test results of Example 10 Enteric-coated tablets for reducing ethanol residue under different conditions

[0129]

[0130] Examples 2 and 13 show that when the tablet bed temperature is within the range of 25°C to 45°C, the surface of the enteric layer has no white spots, the color is uniform, and the ethanol residue in the enteric layer is within the range of 2.5% to 5.5%. Example 14 shows that when the tablet bed temperature is within the range of 45.5°C to 55°C, the surface of the enteric layer has white spots, the color is uneven, and the ethanol residue in the enteric layer is greater than 5.5%.

[0131] Table 12 Enteric layer test results at different tablet bed temperatures

[0132]

[0133] In Examples 4, 15, 16 and 18, the ethanol aqueous solution with a concentration of 85% to 99.5% (v / v) was used for the preparation, and there were no white spots on the surface of the enteric layer, the color was uniform, and the residual ethanol in the enteric layer was within the range of 2.5% to 5.5%. In Example 17, the ethanol with a concentration of 80% (v / v) was used for the preparation, and there were white spots on the surface of the enteric layer, and the color was uneven.

[0134] Table 13 Enteric layer test results of different ethanol concentrations

[0135]

[0136]

[0137] In Example 5, Example 19 and Example 20, the solid content of the coating solution was in the range of 8% to 12%, there were no white spots on the surface of the enteric layer, the color was uniform, and the ethanol residue in the enteric layer was in the range of 2.5% to 5.5%.

[0138] Table 14 Enteric layer test results with different liquid solid content

[0139]

[0140] In Example 21, the colorant yellow iron oxide is replaced by indigo, in Example 22, the proportion of the colorant yellow iron oxide is increased, and in Example 23, the colorant yellow iron oxide is replaced by carmine. When the moisture content of the incoming air is less than 8g / kg (dynamically adjusted within the range of 3g / kg to 7g / kg), there are obvious white spots on the surface of the enteric layer, the color is uneven, and the ethanol residue in the enteric layer is greater than 5.5%. This shows that when the moisture content of the incoming air is less than 8g / kg, it is difficult to obtain an enteric layer with low ethanol residue, no white spots, and uniform color by adjusting the proportion of the colorant or increasing the proportion of the colorant through the prescription.

[0141] Table 15 Test results of enteric layer in different prescriptions

[0142]

[0143] It can be concluded from the above tests that the low ethanol residual enteric layer of the mesalazine enteric-coated tablets provided by the present invention and the preparation method thereof can significantly reduce the ethanol residual amount in the enteric layer during the coating process, and there is no need to place the ethanol for a long time after coating to allow the ethanol to evaporate freely to reduce the ethanol residual amount, and the control of the ethanol residual amount is more stable. In addition, the generation of white spots on the surface of the non-white enteric layer, resulting in uneven color, is also avoided.

[0144] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be based on the protection scope of the claims.

Claims

1. A method for preparing an oral preparation, characterized in that: The oral preparation is a mesalazine enteric-coated tablet, which comprises a tablet carrier to be coated and an enteric layer, wherein the thickness of the enteric layer wrapped on the front of the tablet carrier to be coated is 200 μm to 310 μm; and the enteric layer is composed of three layers of enteric layer films by weight: The innermost enteric layer is composed of 100 parts of methacrylic acid and methyl methacrylate copolymer, 12 parts of polyethylene glycol 6000 and 20 parts of talc; The middle enteric layer film is composed of 100 parts of methacrylic acid and methyl methacrylate copolymer, 12 parts of polyethylene glycol 6000, 20 parts of talc and titanium dioxide; The outermost enteric layer is composed of 100 parts of methacrylic acid and methyl methacrylate copolymer, 12 parts of polyethylene glycol 6000, 20 parts of talc, titanium dioxide and yellow iron oxide; The ratio of carboxyl group to ester group in the copolymer of methacrylic acid and methyl methacrylate is 1:1; in each enteric layer, the total weight of the copolymer of methacrylic acid and methyl methacrylate, the polyethylene glycol 6000 and the talc accounts for ≥90%; The preparation method comprises the following steps: (1) mixing the components of each enteric layer film in an ethanol aqueous solution to form a coating solution, wherein the volume concentration of the ethanol aqueous solution is 85-99.5%; (2) Spraying the coating liquid onto the tablet carrier to be coated for coating; during the coating process, controlling the moisture content of the incoming air to be 8 g / kg-14 g / kg; controlling the temperature of the coated tablet bed to be 35° C.-45° C.; and the ethanol residual content of the formed enteric layer to be 2.5 wt %-5.5 wt %.

2. The preparation method according to claim 1, characterized in that: The thickness of the enteric layer wrapped on the side of the tablet carrier to be coated is 170 μm to 250 μm.

3. The preparation method according to claim 1, characterized in that: The solid content of the coating solution is 8% to 12%.

4. The preparation method according to claim 1, characterized in that: The solid content of the coating solution is 8% to 10%.

5. The preparation method according to claim 1, characterized in that: On average, each tablet to be coated has a total enteric layer weight of 110-135 mg of carrier.

6. The preparation method according to claim 1, characterized in that: The specification of the oral preparation is 0.5g.

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