Coating preparation and preparation method thereof

Abstract

The invention discloses a coating preparation and a preparation method thereof. The coating preparation comprises a quick-release layer, a slow-release layer and a coating material, wherein the quick-release layer and the slow-release layer are coated with the coating material; the coating preparation is prepared by the following steps: S1, preparing the quick release layer; s2, preparing a sustained-release layer; s3, preparing a coating material; and S4, preparing the coating preparation. The coating preparation provided by the invention can improve the position and speed of drug release, increase the stability of the drug, prevent the compatibility change of the drug, control the position of drug release, cover the bitter taste and bad smell of the drug, and improve the appearance of the drug. According to the method for preparing the coating preparation, the problems of migration of active pharmaceutical ingredients in the tabletting process, breakage of a coating film and crushing of the medicine in the transportation and storage processes can be avoided, the stability of the active pharmaceutical ingredients is further guaranteed, the production efficiency of the medicine can be improved, the product quality is guaranteed, and the production cost is reduced. The production cost is reduced; meanwhile, the environment-friendly requirement is met.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a coating preparation and a preparation method thereof. Background Art

[0002] Nonsteroidal anti-inflammatory drugs are a class of drugs that mainly inhibit the synthesis of prostaglandins by inhibiting cyclooxygenase COX-Ⅰ and COX-Ⅱ, and even by inhibiting COX-Ⅲ, thereby producing antipyretic, analgesic and anti-inflammatory effects. They have been widely used in clinical practice and have certain safety and effectiveness. They mainly include aspirin, ibuprofen, diclofenac, acetaminophen, etc. Most of the drugs on the market are immediate-release dosage forms, and a small number are sustained-release dosage forms. The immediate-release dosage form takes effect quickly, but the concentration of the main active drug ingredient also decreases quickly, and generally needs to be supplemented every 4 to 6 hours; the sustained-release dosage form can maintain effective blood concentration for a long time, and is generally taken once every 12 hours, but the drug takes effect more slowly. The double-layer tablet can achieve rapid release of the immediate-release layer at the beginning, so that the drug takes effect quickly, and then the sustained-release layer continues to slowly release the drug, so that the drug is maintained in the effective blood concentration range for a long time.

[0003] When considering the controlled release of existing bilayer tablets, most of them are coated. However, a series of problems may occur during the tableting and / or coating process, such as: rupture or cracking of the coating, chemical reaction between the coating material and the active drug ingredient, migration of the drug during the coating process, etc., which makes it impossible for the active drug ingredient to maintain the predetermined controlled release characteristics, and is easily affected by various factors in the body, resulting in problems such as the inability of the active drug ingredient to be stably and effectively exerted and low bioavailability. Summary of the invention

[0004] In order to solve at least one of the above technical problems, a preparation is developed in which the active pharmaceutical ingredient is stable, has high bioavailability, and can quickly and continuously exert antipyretic, analgesic and anti-inflammatory effects. The present application provides a coated preparation with good controlled release of active pharmaceutical ingredients and stable drugs and a preparation method thereof.

[0005] On the one hand, the present application provides a coating preparation, comprising a quick-release layer, a sustained-release layer and a coating material, wherein the quick-release layer and the sustained-release layer are wrapped with a coating material, and the coating material comprises a plasticizer and a polymer; the quick-release layer comprises an active pharmaceutical ingredient, a diluent, a disintegrant, a binder and a lubricant; the sustained-release layer comprises an active pharmaceutical ingredient, a diluent, a binder and a lubricant; wherein the effective dose of the active pharmaceutical ingredient is 50 mg to 700 mg, preferably 100 mg to 500 mg.

[0006] By adopting the above technical scheme, taking the rapid-release agent and the sustained-release agent at the same time can improve the patient's compliance with medication, and also help maintain the stability of blood drug concentration, which can improve the convenience and compliance of treatment; on this basis, the use of coating film can not only further improve the stability of the drug and control the release, but also effectively improve the palatability of the drug and cover up the unpleasant taste of the drug.

[0007] Optionally, the coating material includes, by mass, 1 to 16 parts of plasticizer and 20 to 500 parts of polymer; the immediate-release layer includes, by mass, 10 to 70 parts of active pharmaceutical ingredients, 20 to 40 parts of diluent, 5 to 20 parts of disintegrant, 1 to 5 parts of binder and 1 to 5 parts of lubricant; the sustained-release layer includes, by mass, 30 to 90 parts of active pharmaceutical ingredients, 20 to 30 parts of diluent, 1 to 10 parts of binder and 1 to 5 parts of lubricant.

[0008] By adopting the above technical solution, the stability of the drug can be improved, the drug release can be controlled, and the patient's medication experience can be improved, which has certain benefits on the drug treatment effect and quality; in addition, the drug can maintain a therapeutically effective concentration for a longer time, reduce the number of dosing times, and achieve effective treatment with small doses.

[0009] Optionally, the active pharmaceutical ingredient is sieved through an 80-100 mesh sieve, and the mass ratio of the active pharmaceutical ingredient in the immediate-release layer to the active pharmaceutical ingredient in the sustained-release layer is 1:(3-5).

[0010] By adopting the above technical solution, the particle size of the active pharmaceutical ingredient is limited, which can ensure that the drug has good solubility, dissolution rate and clinical efficacy, thereby significantly improving the bioavailability of the drug; in addition, controlling the mass of the active pharmaceutical ingredient to 1: (3-5) is conducive to the rapid release of the drug in the immediate release layer to increase the blood drug concentration in a short time to reach the loading dose, giving the sustained-release layer a certain period of time to slowly release in order to maintain an effective blood concentration for a long time, and at the same time helps to reduce the adverse reactions of non-steroidal anti-inflammatory drugs to the gastrointestinal tract, and avoid the discomfort of patients after taking the medicine as much as possible.

[0011] Optionally, in the coating material, the plasticizer is triethyl citrate; the polymer is selected from polymers with an elongation at break of 200% to 800%, preferably a polymer with an elongation at break of 750%.

[0012] By adopting the above technical solution, the coating material has excellent disintegration and solubility properties, and can be taken normally by patients in the absence of water and still has good palatability.

[0013] Optionally, the polymer is a copolymer of ethyl acrylate and methyl methacrylate in any ratio.

[0014] Furthermore, in the copolymer, the ratio of the ethyl acrylate to the methyl methacrylate is 2:1.

[0015] By adopting the above technical solution, the release of active pharmaceutical ingredients can be effectively controlled, and it is ensured that the active pharmaceutical ingredients are not affected by various factors, such as pH value, enteric solubility of the active pharmaceutical ingredients, etc.

[0016] Optionally, the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug; the diluent is selected from one or more of starch, dextrin, pregelatinized starch, lactose or microcrystalline cellulose; the disintegrant is selected from one or more of sodium carboxymethyl starch, corn starch and hydroxypropyl methylcellulose; the binder is selected from one or more of polyvinyl pyrrolidone K30, polyethylene oxide, pectin and sodium alginate; the lubricant is selected from one or more of stearic acid, magnesium stearate, talc and methylcellulose.

[0017] Furthermore, the non-steroidal anti-inflammatory drug is selected from one of acetaminophen, ibuprofen, diclofenac sodium or aspirin; the diluent is microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch; and the lubricant is magnesium stearate and talc.

[0018] Furthermore, in the quick-release layer, the adhesive is polyvinyl pyrrolidone K30; in the sustained-release layer, the adhesive is a mixture of polyvinyl pyrrolidone K30 and polyethylene oxide, wherein, based on 100% by mass of the adhesive, the mass percentage of polyvinyl pyrrolidone K30 is 0 to 80%, and the mass percentage of polyethylene oxide is 20 to 100%.

[0019] By adopting the above technical solution, the coating preparation prepared in the present application can have better disintegration, palatability and solubility. In addition, the binder in the sustained-release layer is a composite of polyvinyl pyrrolidone and polyethylene oxide, which can ensure that the active pharmaceutical ingredients in the sustained-release layer will not migrate and provide a good and uniform matrix for subsequent spray coating.

[0020] On the other hand, the present application provides a method for preparing the above-mentioned coating preparation, comprising the following steps:

[0021] S1. Preparation of immediate release layer

[0022] After mixing the active pharmaceutical ingredient with the diluent and part of the disintegrant, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then the remaining disintegrant and lubricant are added, mixed, sieved and granulated to obtain the immediate release layer granules for later use;

[0023] S2. Preparation of sustained-release layer

[0024] After mixing the active pharmaceutical ingredient with the diluent, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then a lubricant is added, mixed, sieved and granulated to obtain sustained-release layer granules for later use;

[0025] S3. Preparation of coating materials

[0026] Under stirring conditions, the polymer, plasticizer and pure water are mixed, and the mixture is sieved to obtain a coating material for later use;

[0027] S4. Preparation of coating preparation

[0028] After pre-compressing the sustained-release granules of S2, the immediate-release layer granules of S1 are filled, and under certain conditions, the coating material of S3 is bottom-sprayed to obtain a coated preparation.

[0029] Optionally, in S1 and S2, the drying temperature is 50-60° C., and the drying time is 2-4 hours.

[0030] Optionally, in S3, the stirring is for 1 to 2 hours.

[0031] The adoption of the above technical solution is beneficial to maintaining the stability of active pharmaceutical ingredients, and can also avoid the migration of active pharmaceutical ingredients during tableting, the rupture of the coating film, and the breakage of the drug during transportation and storage, thereby further ensuring the quality of the coated preparation products.

[0032] Optionally, in S4, the bottom spraying conditions include: inlet air temperature 50°C, material temperature 42°C, atomization pressure 0.17mp, fluidization pressure 0.1mp, fan speed 2500rpm, coating weight gain 5%, aging temperature 55°C, and aging time 4h.

[0033] By adopting the above technical solution, the production efficiency of medicines can be further improved, the quality of products can be guaranteed, the production cost can be reduced and environmental protection requirements can be met.

[0034] In summary, the present invention includes at least one of the following beneficial technical effects:

[0035] 1. The coating preparation of the present invention can improve the location and speed of drug release, increase the stability of the drug, prevent changes in drug compatibility, control the location of drug release, and can also mask the bitter taste and bad smell of the drug and improve the appearance of the drug.

[0036] 2. The method for preparing coated preparations of the present invention can not only avoid the migration of active pharmaceutical ingredients, the rupture of coating films and the breakage of medicines during the tableting process, thereby ensuring the stability of active pharmaceutical ingredients, but also improve the production efficiency of medicines, ensure the quality of products, reduce production costs and meet environmental protection requirements. DETAILED DESCRIPTION

[0037] The present application is further described in detail below with reference to the embodiments.

[0038] Prior to the present invention, certain solutions have been provided on the market for the above-mentioned problems, such as the controlled release of the drug. For example, patent CN101987081A mentions that the controlled release preparation, especially the controlled release preparation with zero-order release, is controlled by coating the controlled release film on the outer layer to achieve improved performance. However, the inventor found that the controlled release film is very likely to rupture or crack during the tableting process, which leads to problems such as uncontrolled release of active drug ingredients. Patent CN110037994A provides an ibuprofen rapid-release and sustained-release double-layer tablet and a preparation method thereof. The dosage form consists of an ibuprofen rapid-release layer and an ibuprofen sustained-release layer. Ibuprofen is dispersed in the rapid-release layer and the sustained-release layer in a certain proportion, which can provide rapid release and subsequent 12 hours of slow release, thereby achieving rapid onset and continuous maintenance of effective blood drug concentration. However, the excipients used in the two-layer tablets are different, and tableting is required after two wet granulations, and the process is relatively complicated and cumbersome.

[0039] In view of the fact that the existing technologies are not as good as the inventor's expectations, the inventor made the present invention through further research.

[0040] The present application designs a coating preparation, comprising a quick-release layer, a sustained-release layer and a coating material, wherein the quick-release layer and the sustained-release layer are wrapped with a coating material, and the coating material comprises a plasticizer and a polymer; the quick-release layer comprises an active pharmaceutical ingredient, a diluent, a disintegrant, a binder and a lubricant; the sustained-release layer comprises an active pharmaceutical ingredient, a diluent, a binder and a lubricant; wherein the effective dose of the active pharmaceutical ingredient is 50 mg to 700 mg, preferably 100 mg to 500 mg.

[0041] When designing the above-mentioned coating preparation, the present application passes the active drug ingredients through a 80-100 mesh sieve, and controls the mass ratio of the active drug ingredients in the immediate-release layer and the sustained-release layer to be 1:(3-5).

[0042] When designing the coating material, the preferred plasticizer is triethyl citrate, and the preferred polymer has an elongation at break of 750%.

[0043] On the basis of the above, the inventors further defined the polymer, and the polymer used was a copolymer of ethyl acrylate and methyl methacrylate in any ratio; in the copolymer, the ratio of ethyl acrylate to methyl methacrylate was 2:1.

[0044] The present application also provides a method for preparing the above-mentioned coating preparation, comprising the following steps:

[0045] S1. Preparation of immediate release layer

[0046] After mixing the active pharmaceutical ingredient with the diluent and part of the disintegrant, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then the remaining disintegrant and lubricant are added, mixed, sieved and granulated to obtain the immediate release layer granules for later use;

[0047] S2. Preparation of sustained-release layer

[0048] After mixing the active pharmaceutical ingredient with the diluent, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then a lubricant is added, mixed, sieved and granulated to obtain sustained-release layer granules for later use;

[0049] S3. Preparation of coating materials

[0050] Under stirring conditions, the polymer, plasticizer and pure water are mixed, and the mixture is sieved to obtain a coating material for later use;

[0051] S4. Preparation of coating preparation

[0052] After pre-compressing the sustained-release granules of S2, the immediate-release layer granules of S1 are filled, and under certain conditions, the coating material of S3 is bottom-sprayed to obtain a coated preparation.

[0053] The existing non-steroidal anti-inflammatory drugs for antipyretic, analgesic and anti-inflammatory effects on the market mainly include aspirin, ibuprofen, diclofenac and acetaminophen, etc. Their main dosage forms are immediate-release dosage forms, and a small number are sustained-release dosage forms. As the name suggests, immediate-release dosage forms have a rapid effect, but the effective blood concentration of the drug also decreases very quickly, and the drug needs to be replenished in time to ensure that the drug continues to work stably; while the sustained-release dosage form can maintain the effective blood concentration for a long time, the drug takes effect more slowly. Both have very poor controllable release and have certain defects.

[0054] When considering the controlled release of the drug, the inventors combined the actual test operation to further improve the stability of the drug. First, by making the drug into a double-layer tablet containing a coating material, wherein the double-layer tablet contains a quick-release layer and a sustained-release layer, taking the quick-release agent and the sustained-release agent at the same time can improve the patient's compliance with the medication, and also help maintain the stability of the blood drug concentration, which can improve the convenience and compliance of treatment, so as to basically achieve the controlled release effect; in addition, spraying the coating on the outside of the double-layer tablet can not only further improve the stability of the drug and control the release, but also effectively improve the palatability of the drug and cover up the unpleasant taste of the drug. Secondly, the inventors limit the particle size of the active pharmaceutical ingredient and determine the dosage ratio of the active pharmaceutical ingredient in the immediate-release layer and the sustained-release layer, which not only enables the drug to have good solubility, dissolution rate and clinical efficacy, but also facilitates the rapid release of the drug in the immediate-release layer to increase the blood drug concentration in a short time to reach the loading dose, giving the sustained-release layer a certain time to slowly release to maintain an effective blood concentration for a long time, and at the same time helps to reduce the adverse reactions of non-steroidal anti-inflammatory drugs to the gastrointestinal tract, and avoid the discomfort of patients after taking the medicine as much as possible. Finally, when preparing the immediate-release layer and the sustained-release layer, the raw materials of this application are basically the same, only the adhesive is specially designed when preparing the sustained-release layer. This design gives the sustained-release layer another protective barrier, which can not only delay the volatilization of the active pharmaceutical ingredient in the sustained-release layer, so that the blood drug concentration is maintained at a stable level for a long time, and the combination of the immediate-release layer maximizes the efficacy of the drug, but also effectively avoids the migration and rupture of the active pharmaceutical ingredient during the tableting process and reduces the effect of the pH value in the patient's body on the drug during the swallowing process, thereby reducing the number of dosing times, achieving effective treatment with a small dose, and further improving the bioavailability.

[0055] In addition, the inventors have also fully considered the compliance of patients. When selecting coating materials, the inventors selected a copolymer of ethyl acrylate and methyl methacrylate with a breaking elongation of 750%. In addition to ensuring that the drug is not easily broken during transportation and storage, thereby further improving the stability and safety of the product, the coating film formed by the material also has excellent disintegration and solubility properties. It can be taken normally by patients in the absence of water, reducing the swallowing conditions and difficulty of the preparation, and also helps the elderly and children swallow it, with excellent palatability.

[0056] The present application is further described below in conjunction with specific preparation examples, embodiments and comparative examples. Unless otherwise specified, the materials used in the examples are all commercially available conventional materials.

[0057] The following are the quick-release layer and the sustained-release layer prepared in this application.

[0058] Preparation Example 1

[0059] The immediate release layer of this preparation example is composed of the following raw materials, including:

[0060] Ibuprofen 20 servings

[0061] Microcrystalline cellulose 20 parts

[0062] 5 parts of sodium carboxymethyl starch

[0063] Polyvinylpyrrolidone K30 1 part

[0064] 1 part magnesium stearate

[0065] 1 part talcum powder

[0066] Some pure water;

[0067] The immediate release layer of this preparation example is prepared by the following steps:

[0068] According to the above formula ratio, ibuprofen, microcrystalline cellulose and 2 parts of sodium carboxymethyl starch are mixed, and then polyvinyl pyrrolidone K30 and pure water are added to mix to obtain a soft material, which is dried at 50° C. for 2 hours, sieved and granulated, and then the remaining 3 parts of sodium carboxymethyl starch, magnesium stearate and talc are added, mixed, sieved and granulated to obtain immediate-release layer granules for later use;

[0069] The sustained-release layer of this preparation example is composed of the following raw materials, including:

[0070] Ibuprofen 80 servings

[0071] Microcrystalline cellulose 40 parts

[0072] Polyvinylpyrrolidone K30 2 parts

[0073] 3 parts of polyethylene oxide

[0074] 2 parts of magnesium stearate

[0075] 3 parts talcum powder

[0076] Some pure water;

[0077] The sustained-release layer of this preparation example is prepared by the following steps:

[0078] According to the above formula ratio, after mixing ibuprofen and microcrystalline cellulose, polyvinyl pyrrolidone K30, polyethylene oxide and pure water are added, and the mixture is mixed to obtain a soft material. The mixture is dried at 50°C for 2 hours, sieved and granulated, and then a lubricant is added, mixed, sieved and granulated to obtain sustained-release layer granules for later use.

[0079] Preparation Example 2

[0080] The immediate release layer of this preparation example is composed of the following raw materials, including:

[0081] Acetaminophen 18 parts

[0082] Microcrystalline cellulose 20 parts

[0083] 10 parts of sodium carboxymethyl starch

[0084] Polyvinylpyrrolidone K30 2 parts

[0085] 2 parts of magnesium stearate

[0086] 2 parts talcum powder

[0087] Some pure water;

[0088] The immediate release layer of this preparation example is prepared by the following steps:

[0089] According to the above formula ratio, acetaminophen, microcrystalline cellulose and 5 parts of sodium carboxymethyl starch are mixed, and then polyvinyl pyrrolidone K30 and pure water are added to mix to obtain a soft material, which is dried at 50° C. for 2 hours, sieved and granulated, and then the remaining 5 parts of sodium carboxymethyl starch, magnesium stearate and talc are added, mixed, sieved and granulated to obtain immediate-release layer granules for later use;

[0090] The sustained-release layer of this preparation example is composed of the following raw materials, including:

[0091] Acetaminophen 90 parts

[0092] 30 parts of microcrystalline cellulose

[0093] Polyvinylpyrrolidone K30 4 parts

[0094] 1 part of polyethylene oxide

[0095] 2 parts of magnesium stearate

[0096] 3 parts talcum powder

[0097] Some pure water;

[0098] The sustained-release layer of this preparation example is prepared by the following steps:

[0099] After mixing acetaminophen and microcrystalline cellulose according to the above formula ratio, polyvinyl pyrrolidone K30, polyethylene oxide and pure water are added, and mixed to obtain a soft material. The mixture is dried at 50°C for 2 hours, sieved and granulated, and then a lubricant is added, mixed, and sieved to obtain granules to obtain sustained-release layer granules for later use.

[0100] Preparation Example 3

[0101] The immediate release layer of this preparation example is composed of the following raw materials, including:

[0102] Aspirin 15

[0103] 30 parts of microcrystalline cellulose

[0104] 15 parts of sodium carboxymethyl starch

[0105] Polyvinylpyrrolidone K30 2 parts

[0106] 2 parts of magnesium stearate

[0107] 3 parts talcum powder

[0108] Some pure water;

[0109] The immediate release layer of this preparation example is prepared by the following steps:

[0110] According to the above formula ratio, aspirin, microcrystalline cellulose and 7 parts of sodium carboxymethyl starch are mixed, and then polyvinyl pyrrolidone K30 and pure water are added to mix to obtain a soft material, which is dried at 60° C. for 4 hours, sieved and granulated, and then the remaining 8 parts of sodium carboxymethyl starch, magnesium stearate and talc are added, mixed, sieved and granulated to obtain immediate-release layer granules for later use;

[0111] The sustained-release layer of this preparation example is composed of the following raw materials, including:

[0112] Aspirin 60 servings

[0113] Microcrystalline cellulose 20 parts

[0114] Polyvinylpyrrolidone K30 4 parts

[0115] 4 parts of polyethylene oxide

[0116] 2 parts of magnesium stearate

[0117] 3 parts talcum powder

[0118] Some pure water;

[0119] The sustained-release layer of this preparation example is prepared by the following steps:

[0120] According to the above formula ratio, after mixing aspirin and microcrystalline cellulose, polyvinyl pyrrolidone K30, polyethylene oxide and pure water are added, and the mixture is mixed to obtain a soft material. The mixture is dried at 50°C for 2 hours, sieved and granulated, and then a lubricant is added, mixed, sieved and granulated to obtain sustained-release layer granules for later use.

[0121] Preparation Example 4

[0122] The immediate release layer of this preparation example is composed of the following raw materials, including:

[0123] Diclofenac Sodium 10 parts

[0124] 30 parts of microcrystalline cellulose

[0125] 20 parts of sodium carboxymethyl starch

[0126] Polyvinylpyrrolidone K30 4 parts

[0127] 4 parts of magnesium stearate

[0128] 1 part talcum powder

[0129] Some pure water;

[0130] The immediate release layer of this preparation example is prepared by the following steps:

[0131] According to the above formula ratio, diclofenac sodium, microcrystalline cellulose and 10 parts of sodium carboxymethyl starch are mixed, and polyvinyl pyrrolidone K30 and pure water are added to mix to obtain a soft material, which is dried at 50° C. for 2 hours, sieved and granulated, and then the remaining 10 parts of sodium carboxymethyl starch, magnesium stearate and talc are added, mixed, sieved and granulated to obtain immediate-release layer granules for later use;

[0132] The sustained-release layer of this preparation example is composed of the following raw materials, including:

[0133] Diclofenac Sodium 30 parts

[0134] Microcrystalline cellulose 40 parts

[0135] Polyvinylpyrrolidone K30 5 parts

[0136] 3 parts of polyethylene oxide

[0137] 2 parts of magnesium stearate

[0138] 2 parts talcum powder

[0139] Some pure water;

[0140] The sustained-release layer of this preparation example is prepared by the following steps:

[0141] According to the above formula ratio, diclofenac sodium and microcrystalline cellulose are mixed, and then polyvinyl pyrrolidone K30, polyethylene oxide and pure water are added to mix to obtain a soft material, which is dried at 50°C for 2 hours and sieved to granulate. Subsequently, a lubricant is added, mixed, and sieved to granulate to obtain sustained-release layer granules for later use.

[0142] The following is the coating material prepared in this application

[0143] Preparation Example 5

[0144] The coating material of this preparation example is composed of the following raw materials, including:

[0145] 1 part of triethyl citrate,

[0146] Copolymer of ethyl acrylate and methyl methacrylate (1:1) 20 parts elongation at break 750%, some pure water;

[0147] The coating material of this preparation example is prepared by the following steps:

[0148] According to the above formula ratio, the copolymer of ethyl acrylate and methyl methacrylate, triethyl citrate and pure water were mixed with continuous stirring for 1 hour, and the mixture was sieved to obtain coating material A1 for later use.

[0149] Preparation Example 6

[0150] The coating material of this preparation example is composed of the following raw materials, including:

[0151] 8 parts of triethyl citrate,

[0152] Copolymer of ethyl acrylate and methyl methacrylate (1:2) 240 parts elongation at break 750%, some pure water;

[0153] The coating material of this preparation example is prepared by the following steps:

[0154] According to the above formula ratio, the copolymer of ethyl acrylate and methyl methacrylate, triethyl citrate and pure water were mixed with continuous stirring for 1 hour, and the mixture was sieved to obtain coating material A2 for later use.

[0155] Preparation Example 7

[0156] The coating material of this preparation example is composed of the following raw materials, including:

[0157] 16 parts of triethyl citrate,

[0158] 500 parts of copolymer of ethyl acrylate and methyl methacrylate (2:1) with elongation at break of 750%, some pure water;

[0159] The coating material of this preparation example is prepared by the following steps:

[0160] According to the above formula ratio, the copolymer of ethyl acrylate and methyl methacrylate, triethyl citrate and pure water are mixed with continuous stirring for 2 hours, and the mixture is sieved to obtain coating material A3 for later use.

[0161] Preparation Example 8

[0162] The coating material of this preparation example is composed of the following raw materials, including:

[0163] 16 parts of triethyl citrate,

[0164] 500 parts of copolymer of ethyl acrylate and methyl methacrylate (2:1) with elongation at break of 800%, some pure water;

[0165] The coating material of this preparation example is prepared by the following steps:

[0166] According to the above formula ratio, the copolymer of ethyl acrylate and methyl methacrylate, triethyl citrate and pure water are mixed with continuous stirring for 2 hours, and the mixture is sieved to obtain coating material A4 for later use.

[0167] Preparation Example 9

[0168] The coating material of this preparation example is composed of the following raw materials, including:

[0169] 16 parts of triethyl citrate,

[0170] 500 parts of copolymer of ethyl acrylate and methyl methacrylate (2:1) with elongation at break of 700%, some pure water;

[0171] The coating material of this preparation example is prepared by the following steps:

[0172] According to the above formula ratio, the copolymer of ethyl acrylate and methyl methacrylate, triethyl citrate and pure water are mixed with continuous stirring for 2 hours, and the mixture is sieved to obtain coating material A5 for later use.

[0173] The following are examples and comparative examples of the present application.

[0174] Example 1

[0175] The coating preparation of this embodiment is prepared by preparing Example 4 and Example 5 together, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Example 4, quickly filling the immediate-release layer of Example 4 to obtain a 19*10 mm tablet;

[0176] Place the above-mentioned tablets in a coating pan, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17 mp, fluidization pressure at 0.1 mp, fan speed at 2500 rpm, aging temperature at 55°C, and aging time at 4 h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B1.

[0177] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B1 of this example was tested to be 4.28±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.37%.

[0178] Example 2

[0179] The coating preparation of this embodiment is prepared by preparing Example 3 and Example 6, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Preparation Example 3, quickly filling the immediate-release layer of Preparation Example 3 to obtain a 19*10 mm tablet;

[0180] Place the above-mentioned tablets in a coating pan, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17mp, fluidization pressure at 0.1mp, fan speed at 2500rpm, aging temperature at 55°C, and aging time at 4h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B2.

[0181] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B2 of this example was tested to be 4.22±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.30%.

[0182] Example 3

[0183] The coating preparation of this embodiment is prepared by preparing Example 2 and Example 7 together, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Preparation Example 2, quickly filling the immediate-release layer of Preparation Example 2 to obtain a 19*10 mm tablet;

[0184] Place the above-mentioned tablets in a coating pan, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17mp, fluidization pressure at 0.1mp, fan speed at 2500rpm, aging temperature at 55°C, and aging time at 4h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B3.

[0185] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B3 of this example was tested to be 4.18±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.21%.

[0186] Example 4

[0187] The coating preparation of this embodiment is prepared by preparing Example 1 and Example 8, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Example 1, quickly filling the immediate-release layer of Example 1 to obtain a 19*10 mm tablet;

[0188] Place the above-mentioned tablets in a coating pan, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17mp, fluidization pressure at 0.1mp, fan speed at 2500rpm, aging temperature at 55°C, and aging time at 4h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B4.

[0189] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B4 of this example was tested to be 4.20±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.29%.

[0190] Example 5

[0191] The coating preparation of this embodiment is prepared by preparing Example 1 and Example 9, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Example 1, quickly filling the immediate-release layer of Example 1 to obtain a 19*10 mm tablet;

[0192] Place the above-mentioned tablets in a coating pan, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17mp, fluidization pressure at 0.1mp, fan speed at 2500rpm, aging temperature at 55°C, and aging time at 4h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B5.

[0193] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B5 of this example was tested to be 4.16±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.31%.

[0194] Example 6

[0195] The coating preparation of this embodiment is prepared by preparing Example 1 and Example 7 together, and specifically comprises the following steps: after pre-compressing the sustained-release layer of Preparation Example 1, quickly filling the immediate-release layer of Preparation Example 1 to obtain a 19*10 mm tablet;

[0196] Place the above-mentioned tablets in a coating pot, control the inlet air temperature at 50°C, material temperature at 42°C, atomization pressure at 0.17mp, fluidization pressure at 0.1mp, fan speed at 2500rpm, aging temperature at 55°C, and aging time at 4h, until the coating weight increases by 5% and it is visually observed that the drug has been evenly coated with a film coating, and dry to obtain the coating preparation B6.

[0197] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B6 of this example was tested to be 4.12±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.18%.

[0198] Comparative Example 1

[0199] The difference from Example 1 is that: Preparation Example 1 is directly tableted without coating, and other steps are kept unchanged to obtain Agent B7.

[0200] The friability of the coating preparation B7 of this comparative example was measured (n=20, Roche denier, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) to be 1.10%.

[0201] Comparative Example 2

[0202] The difference from Example 3 is that in the sustained-release layer of Preparation Example 1, the adhesive is only polyvinyl pyrrolidone K30, and the other steps are kept unchanged to obtain Agent B8.

[0203] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B8 of this comparative example was tested to be 4.28±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.45%.

[0204] Comparative Example 3

[0205] The difference from Example 3 is that in Preparation Example 1, the mass ratio of the active pharmaceutical ingredients contained in the immediate-release layer and the sustained-release layer is 1:1, and the other steps are kept unchanged to obtain Agent B9.

[0206] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B9 of this comparative example was 4.17±0.1 mm and the friability (n=20, Roche denier, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.25%.

[0207] Comparative Example 4

[0208] The difference from Example 6 is that in Preparation Example 7, the polymer is only ethyl acrylate, and the other steps are kept unchanged to obtain Agent B10.

[0209] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B10 of this comparative example was 4.10±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.26%.

[0210] Comparative Example 5

[0211] The difference from Example 6 is that in Preparation Example 7, the polymer is only methyl methacrylate, and the remaining steps are kept unchanged to obtain Agent B11.

[0212] The coating film thickness (n=20, electronic digital micrometer, PalMe) of the coating preparation B11 of this comparative example was 4.13±0.1 mm, and the friability (n=20, Roche micrometer, 25 rpm, 4 min, Sotax model F1 Friabilator, Basel, Switzerland) was 0.24%.

[0213] Combining the basic test results of the above embodiments and comparative embodiments, the coating preparations produced by the formula and preparation method of the present application have a moderate coating film thickness and a friability of less than 0.5%, which is much smaller than that of the uncoated medicine. This shows that the coating preparations of the present application have better product quality and stronger stability.

[0214] The inventors also conducted the following performance tests on the above-mentioned Examples 1 to 6 and Comparative Examples 1 to 5, and recorded the test results in the following Tables 1 to 2. Including:

[0215] 1) Hardness test

[0216] The hardness of the coating preparations obtained in Examples 1 to 4 and Comparative Example 1 was measured by a tablet hardness tester (MultiTest 50), and each group was measured 3 times, and the average value was taken and recorded in the following table.

[0217] 2) Dissolution rate test

[0218] According to the Japanese Pharmacopoeia Dissolution Test, Method 2, the preparations of Examples 1 to 6 and Comparative Example 1 were subjected to a dissolution test using 0.1 N HCl (500 mL) at 100 rpm for 2 hours, and the drug dissolution rate was calculated.

[0219] 3) Release and dissolution determination

[0220] The test was conducted in accordance with the provisions of the first method of dissolution and release determination method in Part IV of the 2015 edition of the Pharmacopoeia of the People's Republic of China. The temperature was set at (37±0.5)°C, the speed was 100r / min, and 900ml of degassed pH 5.8 phosphate buffer and distilled water were used as release media. The release amounts of the preparations of Examples 1 to 6 and Comparative Examples 1 to 5 were measured for 5, 10, 30, 60, 120, and 180 minutes, respectively, and the final results were averaged.

[0221] Table 1 Hardness and dissolution rate of the drugs prepared in Examples 1 to 6 and Comparative Example 1

[0222]

[0223] It can be seen from the test results in Table 1 that the coating preparations prepared by the formulation and preparation method of the present application have better hardness and acid resistance, among which Examples 3 and 6 have the best hardness and acid resistance. This is due to the fact that Examples 3 and 6 have more suitable coating films and their thicknesses, indicating that the amount and proportion of the raw materials of the coating film of the present application, and the selection of the elongation at break of the coating film, when the two are compounded, have a crucial impact on the coating material and even the coating preparation.

[0224] Table 2 Release and dissolution test results of Examples 1 to 6 and Comparative Examples 1 to 5

[0225]

[0226]

[0227] From the experimental results in Table 2, it can be seen that the dissolution rate of the coated preparation is not only affected by the coating material, but also closely related to the thickness of the coating film. The conclusions are as follows:

[0228] Combining Example 1 with Comparative Example 1, the uncoated drug showed that the drug dissolution rate was fast in the early stage, and the dissolution was too slow in the later stage. The dissolution rate fluctuated greatly in the early stage and was too slow in the later stage. The drug dissolution rate of Example 1 was relatively stable, indicating that the coating film of the present application can effectively and reasonably control the release of the drug for a long time, thereby achieving excellent drug efficacy and duration of action;

[0229] Combining Example 3 with Comparative Example 2, the dissolution rate of Example 3 is relatively high, and the drug dissolution in the later stage is relatively stable. The inventors speculate that the reason for this phenomenon may be that: the inventors gave a certain protective barrier to the surface of the sustained-release layer when preparing the sustained-release layer. The protective barrier is formed by polyvinyl pyrrolidone and polyethylene oxide, and is used in combination with the outermost coating film formed by the copolymer, which can better achieve the drug release effect;

[0230] Combining Example 3 with Comparative Example 3, since the content of the active pharmaceutical ingredient in the immediate-release layer is increased, the dissolution rate of the drug is affected to a certain extent, thereby causing the blood drug concentration to quickly reach a peak value in a short period of time, which is not conducive to the stable effect of the drug compared with Example 3;

[0231] Combining Example 6 with Comparative Example 4 and Comparative Example 5, the effect of the coating material on the drug dissolution rate is fully confirmed, which shows that the coating material selected in this application has better controlled release.

[0232] In summary, the coating film of the present invention can greatly improve the controlled release of drugs, thereby increasing the stability of drugs, improving the production efficiency of drugs, and ensuring the quality of products.

[0233] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. A coating preparation, characterized in that: The coating preparation comprises a quick-release layer, a sustained-release layer and a coating material, wherein the quick-release layer and the sustained-release layer are coated with a coating material, and the coating material comprises a plasticizer and a polymer; the quick-release layer comprises an active pharmaceutical ingredient, a diluent, a disintegrant, a binder and a lubricant; the sustained-release layer comprises an active pharmaceutical ingredient, a diluent, a binder and a lubricant; Wherein, the effective dose of the active pharmaceutical ingredient is 50mg to 700mg, preferably 100mg to 500mg.

2. The coating preparation according to claim 1, characterized in that The coating material comprises, by weight, 1 to 16 parts of a plasticizer and 20 to 500 parts of a polymer; The immediate-release layer comprises, by weight, 10 to 70 parts of active pharmaceutical ingredients, 20 to 40 parts of diluents, 5 to 20 parts of disintegrants, 1 to 5 parts of binders, and 1 to 5 parts of lubricants; The sustained-release layer includes, by weight, 30 to 90 parts of active pharmaceutical ingredients, 20 to 30 parts of diluents, 1 to 10 parts of binders, and 1 to 5 parts of lubricants.

3. The coating preparation according to claim 2, characterized in that The active pharmaceutical ingredient is sieved through 80-100 meshes, and the mass ratio of the active pharmaceutical ingredient in the immediate-release layer to the active pharmaceutical ingredient in the sustained-release layer is 1:(3-5).

4. The coating preparation according to claim 2, characterized in that In the coating material, the plasticizer is triethyl citrate; The polymer is selected from polymers having an elongation at break of 200% to 800%, preferably a polymer having an elongation at break of 750%.

5. The coating preparation according to claim 4, characterized in that The polymer is a copolymer of ethyl acrylate and methyl methacrylate in any ratio; Preferably, in the copolymer, the ratio of the ethyl acrylate to the methyl methacrylate is 2:

1.

6. The coating preparation according to claim 2, characterized in that The active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug; the diluent is selected from one or more of starch, dextrin, pregelatinized starch, lactose or microcrystalline cellulose; the disintegrant is selected from one or more of sodium carboxymethyl starch, corn starch and hydroxypropyl methylcellulose; the binder is selected from one or more of polyvinyl pyrrolidone K30, polyethylene oxide, pectin and sodium alginate; the lubricant is selected from one or more of stearic acid, magnesium stearate, talc and methylcellulose; Preferably, the nonsteroidal anti-inflammatory drug is selected from one of acetaminophen, ibuprofen, diclofenac sodium or aspirin; the diluent is microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch; the lubricant is magnesium stearate and talc; Preferably, in the immediate-release layer, the binder is polyvinyl pyrrolidone K30; In the sustained-release layer, the binder is a mixture of polyvinyl pyrrolidone K30 and polyethylene oxide, wherein, based on 100% by mass of the binder, the mass percentage of the polyvinyl pyrrolidone K30 is 0-80%, and the mass percentage of the polyethylene oxide is 20-100%.

7. A method for preparing the coating preparation according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Preparation of immediate release layer After mixing the active pharmaceutical ingredient with the diluent and part of the disintegrant, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then the remaining disintegrant and lubricant are added, mixed, sieved and granulated to obtain the immediate release layer granules for later use; S2. Preparation of sustained-release layer After mixing the active pharmaceutical ingredient with the diluent, a binder and pure water are added, mixed to obtain a soft material, dried under certain conditions, sieved and granulated, and then a lubricant is added, mixed, sieved and granulated to obtain sustained-release layer granules for later use; S3. Preparation of coating materials Under stirring conditions, the polymer, plasticizer and pure water are mixed, and the mixture is sieved to obtain a coating material for later use; S4. Preparation of coating preparation After pre-compressing the sustained-release granules of S2, the immediate-release layer granules of S1 are filled, and under certain conditions, the coating material of S3 is bottom-sprayed to obtain a coated preparation.

8. The method for preparing the coating preparation according to claim 7, characterized in that: In S1 and S2, the drying temperature is 50-60° C., and the drying time is 2-4 hours.

9. The method for preparing the coating preparation according to claim 7, characterized in that: In S3, the stirring is for 1 to 2 hours.

10. The method for preparing the coating preparation according to claim 7, characterized in that: In S4, the bottom spraying conditions include: inlet air temperature 50°C, material temperature 42°C, atomization pressure 0.17mp, fluidization pressure 0.1mp, fan speed 2500rpm, coating weight gain 5%, aging temperature 55°C, and aging time 4h.

Images