Linezolid tablet containing coating layer and preparation method thereof

Abstract

The invention discloses a linezolid tablet containing a coating layer and a preparation method of the linezolid tablet, and relates to the technical field of pharmaceutical preparations, the linezolid tablet comprises a linezolid tablet core and a coating film layer wrapping the surface of the linezolid tablet core; the coating film layer is prepared from the following raw materials in percentage by mass: 5%-10% of acetic acid-cellulose butyrate, 2%-3% of glutamine, 0.5%-1% of carbodiimide, 3%-5% of cane sugar, 0.1%-0.5% of polyethylene glycol and the balance of an organic solvent. The linezolid tablet prepared by adopting the preparation method disclosed by the invention not only can slow down the release speed of a medicine, prolong the retention time of the medicine in a body and enable the medicine effect to be slowly and lastingly played, but also has a certain moisture-proof function due to the coating layer, and prolongs the shelf life of the medicine.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a linezolid tablet containing a coating layer and a preparation method thereof. Background Art

[0002] Linezolid is the first synthetic oxazolidinone antibacterial agent, which is a bacterial protein synthesis inhibitor and is mainly used for the treatment of infections caused by aerobic Gram-positive bacteria. Its novel mechanism of action avoids cross-resistance of linezolid with other antibacterial drugs, and it has been prepared into tablets and injections and widely used clinically. The chemical name of linezolid is (S)-N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide, and its structural formula is:

[0003]

[0004] The patent document with the publication number CN103505459B discloses a linezolid pharmaceutical composition and provides a preparation method of the linezolid pharmaceutical composition. The pharmaceutical composition includes linezolid, lactose, silicon dioxide, a disintegrant and a binder; wherein the disintegrant is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the binder is selected from hydroxypropyl methylcellulose or sodium carboxymethylcellulose; the preparation method of the pharmaceutical composition includes the following steps: a. Mix linezolid, lactose, silicon dioxide and the disintegrant evenly to obtain a mixture; b. Add a binder solution to the above mixture, granulate and dry; c. Add silicon dioxide and the disintegrant and mix evenly; d. Press into tablets or fill into capsules.

[0005] The patent document with the publication number CN105055354B discloses a linezolid tablet containing a coating layer and a preparation method thereof. Colloidal silicon dioxide is used as a disintegrant in the formulation, and a wet granulation one-step preparation process is adopted. The process has few steps and is easy to operate, and can obtain a crystalline linezolid tablet with qualified dissolution and good formability. Therefore, the crystalline linezolid tablet and the preparation method provided by the present invention are more suitable for industrial production compared with the prior art.

[0006] The current preparation process of linezolid tablets, like the patent documents disclosed above, usually mainly considers how to improve the dissolution of linezolid tablets. Although the current linezolid tablets have good dissolution, their drug release rate is relatively fast and they cannot maintain an effective blood drug concentration for a long time. Summary of the Invention

[0007] Based on the problem that the currently prepared linezolid tablets have a relatively fast drug release rate and cannot maintain an effective blood drug concentration for a long time, the object of the present invention is to provide a linezolid tablet containing a coating layer and a preparation method thereof. The linezolid tablet prepared by the preparation method of the present invention can not only slow down the drug release rate, prolong the residence time of the drug in the body, make the drug effect play slowly and lastingly, but also the provided coating layer has a certain moisture-proof function, prolonging the shelf life of the drug.

[0008] The present invention is achieved through the following technical solutions:

[0009] In the first aspect, the present application provides a linezolid tablet containing a coating layer, including a linezolid tablet core and a coating film layer wrapped on the surface of the linezolid tablet core;

[0010] The preparation raw materials of the coating film layer, calculated by mass percentage, include 5% - 10% of cellulose acetate butyrate, 2 - 3% of glutamine, 0.5% - 1% of carbodiimide, 3% - 5% of sucrose, 0.1% - 0.5% of polyethylene glycol, and the balance is an organic solvent.

[0011] On the one hand, in the present invention, the coating film layer adds glutamine to cellulose acetate butyrate, and under the cross-linking action of carbodiimide, the carboxyl group on cellulose acetate butyrate reacts with the amino group on glutamine to generate an amide group, and the formed amide group has hydrophobicity, which can achieve the moisture-proof effect and prolong the shelf life of the linezolid tablet. At the same time, a cross-linked structure with a three-dimensional space network is formed, making the coating film layer have strong stability and improving the hardness and friability of the linezolid tablet. On the other hand, the added sucrose will be dispersed in the reaction system in the form of particles during the amidation reaction of cellulose acetate butyrate and glutamine. When the formed suspension is wrapped on the surface of the linezolid tablet and dried, the sucrose dispersed in the suspension will change the surface tension of the coating film, resulting in the appearance of rich and poor phases on the coating film. After drying, voids will be formed in the poor phase region, that is, sieve holes for drug release are formed on the coating film, enabling the drug to be slowly released through the sieve holes in the body, so that the drug can maintain an effective blood drug concentration for a long time, achieving a sustained release effect, thereby improving the therapeutic effect of the linezolid tablet. At the same time, the coating film will gradually degrade in the later stage of drug release, so that the linezolid tablet is completely released, achieving a sustained release effect, and no harmful substances to the body will be generated after the coating film degrades.

[0012] In addition, on the one hand, the added polyethylene glycol will be inserted between the formed polymer chains during the amidation reaction of cellulose acetate butyrate glutamine, increasing the degree of freedom of movement of the polymer chains, thereby reducing the glass transition temperature of the polymer and making the formed coating film softer, improving the flexibility and ductility of the coating film. On the other hand, since the polyethylene glycol molecule contains very active hydroxyl functional groups, when coating the linezolid tablets, when the polyethylene glycol comes into contact with linezolid, these hydroxyl functional groups will form hydrogen bonds and ligand interactions with the surface of the linezolid tablets, thereby forming a stable affinity connection, enhancing the bonding effect between the coating film and linezolid, and improving the stability of the prepared linezolid tablets.

[0013] In a specific embodiment, the raw materials for preparing the linezolid tablet core include, by mass percentage, 70% - 72% of linezolid, 7% - 8% of corn starch, 2.5% - 3% of microcrystalline cellulose, 4.5% - 5.5% of sodium starch glycolate, 0.5% - 1.5% of magnesium stearate, and the balance is hydroxypropyl methyl cellulose.

[0014] In a specific embodiment, the preparation method of the linezolid tablet core includes the following steps:

[0015] Mix corn starch, microcrystalline cellulose, and sodium starch glycolate to obtain a mixture;

[0016] Mix the mixture with linezolid, add hydroxypropyl methyl cellulose, granulate and then dry to prepare drug granules;

[0017] Add magnesium stearate to the drug granules, mix evenly and then press into tablets to obtain the linezolid tablet core.

[0018] In a specific embodiment, when preparing the drug granules, the drying temperature is controlled at 40°C - 50°C.

[0019] In a specific embodiment, the organic solvent includes ethanol.

[0020] In a specific embodiment, the linezolid tablet core includes a type II crystalline linezolid tablet core or a type III crystalline linezolid tablet core.

[0021] In a specific embodiment, the thickness of the coating film layer is 200 - 300 μm.

[0022] In a second aspect, the present application provides a method for preparing a linezolid tablet containing a coating layer, including the following steps:

[0023] Dissolve cellulose acetate butyrate and glutamine into organic solvents respectively to obtain a cellulose acetate butyrate solution and a glutamine solution. Then mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, and add carbodiimide and polyethylene glycol, and react to obtain a coating suspension;

[0024] Coat the prepared coating suspension on the surface of the linezolid tablet core, and after drying, the linezolid tablet with a coating film layer is obtained.

[0025] In a specific embodiment, the reaction temperature during the preparation of the coating solution is controlled at 80°C to 120°C.

[0026] In a specific embodiment, the coating solution is coated on the surface of the linezolid tablet by the dipping coating method or the pan coating method.

[0027] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0028] (1) In the coating film layer of the present invention, by adding glutamine to cellulose acetate butyrate, under the cross-linking action of carbodiimide, the carboxyl group on cellulose acetate butyrate reacts with the amino group on glutamine to generate an amide group, and the formed amide group has hydrophobicity, which can achieve the effect of moisture-proofing, extend the shelf life of the linezolid tablet, and at the same time form a cross-linked structure with a three-dimensional space network, making the coating film layer have strong stability and improving the hardness and friability of the linezolid tablet.

[0029] (2) The sucrose added in the present invention will be dispersed in the reaction system in the form of particles during the amidation reaction of cellulose acetate butyrate and glutamine. When the formed suspension is wrapped on the surface of the linezolid tablet and dried, the sucrose dispersed in the suspension will change the surface tension of the coating film, resulting in the appearance of rich and poor phases on the coating film. After drying, voids will be formed in the poor phase region, that is, drug-releasing sieve holes are formed on the coating film, enabling the drug to be slowly released through the sieve holes in the body, so that the drug can maintain an effective blood drug concentration for a long time, achieving a sustained-release effect, thereby improving the therapeutic effect of the linezolid tablet. At the same time, the coating film will gradually degrade in the later stage of drug release, so that the linezolid tablet is completely released, achieving a sustained-release effect, and the coating film will not produce substances harmful to the body after degradation.

[0030] (3) In the present invention, polyethylene glycol is added. On the one hand, during the amidation reaction of cellulose acetate butyrate glutamine, it will be inserted between the formed polymer chains, increasing the degree of freedom of movement of the polymer chains, thereby reducing the glass transition temperature of the polymer, making the formed coating film softer, and improving the flexibility and ductility of the coating film. On the other hand, since the polyethylene glycol molecule contains very active hydroxyl functional groups, when coating linezolid tablets, when polyethylene glycol comes into contact with linezolid, these hydroxyl functional groups will form hydrogen bonds and ligand interactions with the surface of the linezolid tablets, thereby forming a stable affinity connection, enhancing the bonding effect between the coating film and linezolid, and improving the stability of the prepared linezolid tablets. Detailed implementation manners

[0031] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the embodiments. The illustrative implementation manners and descriptions of the present invention are only used to explain the present invention and do not limit the present invention.

[0032] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is obvious to those of ordinary skill in the art that the present invention does not have to employ these specific details. In other embodiments, well-known materials or methods have not been described in detail in order to avoid obscuring the present invention.

[0033] Throughout the specification, the reference to "an embodiment", "embodiment", "an example" or "example" means that the specific features, structures or characteristics described in connection with the embodiment or example are included in at least one embodiment of the present invention. Thus, the phrases "an embodiment", "embodiment", "an example" or "example" appearing throughout the specification do not necessarily all refer to the same embodiment or example. In addition, the specific features, structures or characteristics can be combined in any suitable combination and / or sub-combination in one or more embodiments or examples. The term "and / or" used herein includes any and all combinations of one or more of the related listed items. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0034] The "ranges" disclosed in this application are defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of a particular range. The ranges defined in this way can include or exclude the end values, and can be combined arbitrarily, that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, ranges of 60-110 and 80-120 are also contemplated. In addition, if the minimum range values of 1 and 2 are listed, and if the maximum range values of 3, 4, and 5 are listed, the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise specified, the numerical range "a-b" represents an abbreviated representation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been fully listed herein, and "0-5" is only an abbreviated representation of these numerical combinations. In addition, when it is stated that a certain parameter is an integer ≥2, it is equivalent to disclosing that the parameter is, for example, the integers 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0035] If there is no special instruction, all steps of this application can be carried out sequentially or randomly, and preferably sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) carried out sequentially, or may include steps (b) and (a) carried out sequentially. For example, it is mentioned that the method may further include step (c), which means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b), and (c), or may include steps (a), (c), and (b), or may include steps (c), (a), and (b), etc.

[0036] Example 1

[0037] This example provides a method for preparing linezolid tablets containing a coating layer, wherein the linezolid tablets include a linezolid tablet core and a coating film layer wrapped on the surface of the linezolid tablet core;

[0038] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 2.5 g of glutamine, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0039] The raw materials for preparing the linezolid tablet core are: 600 mg of polymorph II linezolid, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0040] The specific preparation method is as follows:

[0041] S1. Prepare the linezolid tablet core

[0042] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0043] S1-2. After mixing the mixture with linezolid of Form II and adding hydroxypropyl methylcellulose, granulate and then dry at a temperature of 45 °C to prepare drug granules;

[0044] S1-3. Add magnesium stearate to the drug granules, mix evenly and then press tablets to obtain the linezolid tablet core of Form II.

[0045] S2. Prepare the coating film layer

[0046] S2-1. Dissolve cellulose acetate butyrate and glutamine into 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0047] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, then add carbodiimide and polyethylene glycol, and react at a temperature of 100 °C to obtain a coating suspension.

[0048] S3. Coat the coating film layer on the surface of the linezolid tablet core

[0049] Adopt the dipping coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet core, and dry at a temperature of 50 °C to form a 250-μm-thick coating film layer, that is, obtain the linezolid tablet containing the coating film layer.

[0050] Example 2

[0051] This example provides a preparation method of a linezolid tablet containing a coating layer, wherein the linezolid tablet includes a linezolid tablet core and a coating film layer wrapped on the surface of the linezolid tablet core; different from Example 1, the dosages of the raw materials for preparing the coating film layer in this example are different. Other process conditions are the same as those in Example 1.

[0052] The raw materials for preparing the coating film layer are: 5 g of cellulose acetate butyrate, 3 g of glutamine, 0.5 g of carbodiimide, 1 g of sucrose, 0.1 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0053] The raw materials for preparing the linezolid tablet core are: 600 mg of linezolid of Form II, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0054] The specific preparation method is as follows:

[0055] S1. Prepare the linezolid tablet core

[0056] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture.

[0057] S1-2. After mixing the mixture with polymorph II linezolid and adding hydroxypropyl methylcellulose, granulate and then dry at a temperature of 45 °C to prepare drug granules.

[0058] S1-3. Add magnesium stearate to the drug granules, mix evenly and then press tablets to obtain the polymorph II linezolid tablet core.

[0059] S2. Prepare the coating film layer

[0060] S2-1. Dissolve cellulose acetate butyrate and glutamine into 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution.

[0061] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, then add carbodiimide and polyethylene glycol, and react at a temperature of 100 °C to obtain a coating suspension.

[0062] S3. Coat the coating film layer on the surface of the linezolid tablet core

[0063] Adopt the dipping coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet core, and dry at a temperature of 50 °C to form a 250-μm-thick coating film layer, that is, obtain the linezolid tablet containing the coating film layer.

[0064] Example 3

[0065] This example provides a preparation method of a linezolid tablet containing a coating layer, wherein the linezolid tablet includes a linezolid tablet core and a coating film layer wrapped on the surface of the linezolid tablet core; different from Example 1, the dosage of the raw materials for preparing the coating film layer in this example is different. Other process conditions are the same as those in Example 1.

[0066] The raw materials for preparing the coating film layer are: 10 g of cellulose acetate butyrate, 3 g of glutamine, 1 g of carbodiimide, 2 g of sucrose, 0.5 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0067] The raw materials for preparing the linezolid tablet core are: 600 mg of polymorph II linezolid, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0068] The specific preparation method is as follows:

[0069] S1. Preparation of linezolid tablet cores

[0070] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0071] S1-2. After mixing the mixture with linezolid polymorph II, add hydroxypropyl methylcellulose, granulate, and dry at a temperature of 45°C to prepare drug granules;

[0072] S1-3. Add magnesium stearate to the drug granules, mix evenly, and press tablets to obtain linezolid polymorph II tablet cores.

[0073] S2. Preparation of the coating film layer

[0074] S2-1. Dissolve cellulose acetate butyrate and glutamine in 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0075] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, then add carbodiimide and polyethylene glycol, and react at a temperature of 100°C to obtain a coating suspension.

[0076] S3. Coating the coating film layer on the surface of the linezolid tablet core

[0077] Use the dip coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet core, and dry at a temperature of 50°C to form a 250-μm-thick coating film layer, that is, obtain linezolid tablets containing a coating film layer.

[0078] Example 4

[0079] This example provides a method for preparing linezolid tablets containing a coating layer, wherein the linezolid tablets include linezolid tablet cores and a coating film layer wrapped on the surface of the linezolid tablet cores; different from Example 1, the thickness of the coating film layer coated in this example is 200 μm. Other process conditions are the same as those in Example 1.

[0080] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 2.5 g of glutamine, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0081] The raw materials for preparing the linezolid tablet cores are: 600 mg of linezolid polymorph II, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0082] The specific preparation method is as follows:

[0083] S1. Preparation of linezolid tablet cores

[0084] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0085] S1-2. After mixing the mixture with linezolid of polymorph II, add hydroxypropyl methylcellulose. After granulation, dry at a temperature of 45°C to prepare drug granules;

[0086] S1-3. Add magnesium stearate to the drug granules, mix evenly and then press tablets to obtain linezolid tablet cores of polymorph II.

[0087] S2. Preparation of the coating film layer

[0088] S2-1. Dissolve cellulose acetate butyrate and glutamine in 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0089] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, then add carbodiimide and polyethylene glycol, and react at a temperature of 100°C to obtain a coating suspension.

[0090] S3. Coating the coating film layer on the surface of the linezolid tablet core

[0091] Adopt the dipping coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet core, and dry at a temperature of 50°C to form a 200-μm-thick coating film layer, that is, obtain linezolid tablets containing a coating film layer.

[0092] Example 5

[0093] This example provides a preparation method of linezolid tablets containing a coating layer, wherein the linezolid tablets include linezolid tablet cores and a coating film layer wrapped on the surface of the linezolid tablet cores; different from Example 1, the thickness of the coated coating film layer in this example is 300 μm. Other process conditions are the same as those in Example 1.

[0094] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 2.5 g of glutamine, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0095] The raw materials for preparing the linezolid tablet cores are: 600 mg of linezolid of polymorph II, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0096] The specific preparation method is as follows:

[0097] S1. Preparation of linezolid tablet cores

[0098] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0099] S1-2. After mixing the mixture with linezolid of polymorph II, add hydroxypropyl methylcellulose, granulate, and dry at a temperature of 45 °C to prepare drug granules;

[0100] S1-3. Add magnesium stearate to the drug granules, mix evenly, and press tablets to obtain linezolid tablet cores of polymorph II.

[0101] S2. Preparation of the coating film layer

[0102] S2-1. Dissolve cellulose acetate butyrate and glutamine in 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0103] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, add carbodiimide and polyethylene glycol, and react at a temperature of 100 °C to obtain a coating suspension.

[0104] S3. Coating the linezolid tablet cores with the coating film layer

[0105] Use the dip coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet cores, and dry at a temperature of 50 °C to form a 200-μm-thick coating film layer, that is, obtain linezolid tablets containing the coating film layer.

[0106] Example 6

[0107] This example provides a preparation method of linezolid tablets containing a coating layer, wherein the linezolid tablets include linezolid tablet cores and a coating film layer wrapped on the surface of the linezolid tablet cores; different from Example 1, in this example, linezolid tablet cores of polymorph III are used to replace linezolid tablet cores of polymorph II. Other process conditions are the same as those in Example 1.

[0108] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 2.5 g of glutamine, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0109] The raw materials for preparing the linezolid tablet cores are: 600 mg of linezolid of polymorph III, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0110] The specific preparation method is as follows:

[0111] S1. Preparation of linezolid tablet cores

[0112] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0113] S1-2. After mixing the mixture with linezolid of Form II, add hydroxypropyl methylcellulose, granulate, and dry at a temperature of 45°C to prepare drug granules;

[0114] S1-3. Add magnesium stearate to the drug granules, mix evenly, and press tablets to obtain linezolid tablet cores of Form III.

[0115] S2. Preparation of the coating film layer

[0116] S2-1. Dissolve cellulose acetate butyrate and glutamine in 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0117] S2-2. Mix the cellulose acetate butyrate solution with the glutamine solution and sucrose, add carbodiimide and polyethylene glycol, and react at a temperature of 100°C to obtain a coating suspension.

[0118] S3. Coating the coating film layer on the surface of the linezolid tablet core

[0119] Adopt the dipping coating method to coat the coating suspension prepared in step S2 on the surface of the linezolid tablet core, and dry at a temperature of 50°C to form a 250-μm-thick coating film layer, that is, obtain linezolid tablets containing the coating film layer.

[0120] Comparative Example 1

[0121] This comparative example provides a preparation method of linezolid tablets containing a coating layer, wherein the linezolid tablets include linezolid tablet cores; different from Example 1, the surface of the linezolid tablets in this comparative example is not coated with a coating film layer, and other processes are the same as those in Example 1.

[0122] The raw materials for preparing the linezolid tablet core are: 600 mg of linezolid of Form II, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0123] The specific preparation method is as follows:

[0124] S1. Preparation of linezolid tablet cores

[0125] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0126] S1-2. Mix the mixture with linezolid of Form II, add hydroxypropyl methylcellulose, granulate, and dry at 45°C to prepare drug granules.

[0127] S1-3. Add magnesium stearate to the drug granules, mix evenly and press into tablets to obtain linezolid tablets of Form II.

[0128] Comparative Example 2

[0129] This comparative example provides a method for preparing linezolid tablets with a coating layer, wherein the linezolid tablets include a linezolid tablet core; different from Example 1, the coating film preparation material in this comparative example does not contain glutamine, and other processes are the same as those in Example 1.

[0130] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 50 ml of absolute ethanol.

[0131] The raw materials for preparing the linezolid tablet core are: 600 mg of linezolid of Form II, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0132] The specific preparation method is as follows:

[0133] S1. Prepare the linezolid tablet core

[0134] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture.

[0135] S1-2. Mix the mixture with linezolid of Form II, add hydroxypropyl methylcellulose, granulate, and dry at 45°C to prepare drug granules.

[0136] S1-3. Add magnesium stearate to the drug granules, mix evenly and press into tablets to obtain the linezolid tablet core of Form II.

[0137] S2. Prepare the coating film layer

[0138] S2-1. Dissolve cellulose acetate butyrate in 50 ml of absolute ethanol to obtain a cellulose acetate butyrate solution.

[0139] S2-2. Mix the cellulose acetate butyrate solution with sucrose, then add carbodiimide and polyethylene glycol, and react at 100°C to obtain a coating suspension.

[0140] S3. Coat the coating film layer on the surface of the linezolid tablet core

[0141] The coating suspension prepared in step S2 was coated on the surface of the linezolid tablet core by the dipping coating method, and after drying at a temperature of 50 °C, a coating film layer with a thickness of 250 μm was formed, thus obtaining linezolid tablets containing the coating film layer.

[0142] Comparative Example 3

[0143] This comparative example provides a method for preparing linezolid tablets containing a coating layer, wherein the linezolid tablets include a linezolid tablet core; different from Example 1, the coating film preparation material in this comparative example does not contain cellulose acetate butyrate, and other processes are the same as those in Example 1.

[0144] The raw materials for preparing the coating film layer are: 2.5 g of glutamine, 0.7 g of carbodiimide, 1.5 g of sucrose, 0.3 g of polyethylene glycol, and 50 ml of absolute ethanol.

[0145] The raw materials for preparing the linezolid tablet core are: 600 mg of polymorph II linezolid, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0146] The specific preparation method is as follows:

[0147] S1. Prepare the linezolid tablet core

[0148] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0149] S1-2. Mix the mixture and polymorph II linezolid, then add hydroxypropyl methylcellulose. After granulation, dry at a temperature of 45 °C to prepare drug granules;

[0150] S1-3. Add magnesium stearate to the drug granules, mix evenly and then press into tablets to obtain polymorph II linezolid tablet cores.

[0151] S2. Prepare the coating film layer

[0152] S2-1. Dissolve glutamine in 50 ml of absolute ethanol to obtain a glutamine solution;

[0153] S2-2. Mix the glutamine solution and sucrose, then add carbodiimide and polyethylene glycol, and react at a temperature of 100 °C to obtain a coating suspension.

[0154] S3. Coat the coating film layer on the surface of the linezolid tablet core

[0155] The coating suspension prepared in step S2 was coated on the surface of the linezolid tablet core by the dipping coating method, and dried at a temperature of 50 °C to form a coating film layer with a thickness of 250 μm, thus obtaining the linezolid tablets containing the coating film layer.

[0156] Comparative Example 4

[0157] This comparative example provides a method for preparing linezolid tablets containing a coating layer, wherein the linezolid tablets include a linezolid tablet core; different from Example 1, the coating film preparation material in this comparative example does not contain sucrose, and other processes are the same as those in Example 1.

[0158] The raw materials for preparing the coating film layer are: 7 g of cellulose acetate butyrate, 2.5 g of glutamine, 0.7 g of carbodiimide, 0.3 g of polyethylene glycol, and 100 ml of absolute ethanol.

[0159] The raw materials for preparing the linezolid tablet core are: 600 mg of polymorph II linezolid, 60 mg of corn starch, 24 mg of microcrystalline cellulose, 42 mg of sodium starch glycolate, 8.4 mg of magnesium stearate, and 106 mg of hydroxypropyl methylcellulose.

[0160] The specific preparation method is as follows:

[0161] S1. Prepare the linezolid tablet core

[0162] S1-1. Mix corn starch, microcrystalline cellulose, and sodium starch glycolate according to the dosage to obtain a mixture;

[0163] S1-2. Mix the mixture and polymorph II linezolid, then add hydroxypropyl methylcellulose, granulate, and dry at a temperature of 45 °C to prepare drug granules;

[0164] S1-3. Add magnesium stearate to the drug granules, mix evenly, and press into tablets to obtain the polymorph II linezolid tablet core.

[0165] S2. Prepare the coating film layer

[0166] S2-1. Dissolve cellulose acetate butyrate and glutamine in 50 ml of absolute ethanol respectively to obtain a cellulose acetate butyrate solution and a glutamine solution;

[0167] S2-2. Mix the cellulose acetate butyrate solution and the glutamine solution, then add carbodiimide and polyethylene glycol, and react at a temperature of 100 °C to obtain a coating suspension.

[0168] S3. Coat the coating film layer on the surface of the linezolid tablet core

[0169] The coating suspension prepared in step S2 was coated on the surface of the linezolid tablet core by the dipping coating method, and dried at a temperature of 50°C to form a coating film layer with a thickness of 250 μm, thus obtaining the linezolid tablets containing the coating film layer.

[0170] The properties of the linezolid tablets prepared by the methods of Examples 1-6 and Comparative Examples 1-4 were detected.

[0171] 1. The content uniformity of the samples was determined according to the content uniformity determination method under the linezolid tablet standard in the Chinese Pharmacopoeia, and the test results are shown in Table 1.

[0172] Table 1

[0173]

[0174]

[0175] From the test results in the table, it can be seen that the content uniformity of the linezolid tablets prepared by the preparation method of the present application is higher than that of the comparative examples. Therefore, it is proved that the preparation method of the present application can also improve the content uniformity of the linezolid tablets.

[0176] 2. The sustained-release behavior of the linezolid tablets prepared in the above examples and comparative examples was detected in vitro according to the standards of the Chinese Pharmacopoeia, using 0.1N hydrochloric acid medium. The test results are shown in Table 2.

[0177] Table 2

[0178]

[0179] From the test results in Table 2, it can be seen that the linezolid tablets prepared by the method of the present application have good sustained-release effects, and through comparative experiments, it is verified that there is a synergistic effect between cellulose acetate butyrate and glutamine in the formula for preparing the coating film layer. From Comparative Example 2 and Comparative Example 3, it can be seen that whether cellulose acetate butyrate or glutamine is lacking, the sustained-release effect is not good, and there is a situation of burst release resulting in too high local concentration. From Comparative Example 4, it can be seen that when sucrose is not contained in the formula for preparing the coating film layer, the effect of forming pores on the coating film layer cannot be achieved, which results in too slow drug release and requires more than 15 hours to have a certain effect.

[0180] 3. According to the relevant regulations of the guiding principles for drug stability tests in the Chinese Pharmacopoeia, the stability of the linezolid tablets prepared by the above method was detected, including high-temperature test detection, high-humidity test detection and light test detection.

[0181] Among them, for the high-temperature test, the samples are placed in petri dishes, kept at 60 °C for 10 days, then sampled for determination, and detected according to the key stability investigation items. The test results are compared with those on day 0.

[0182] Among them, for the high-humidity test, the samples are placed in petri dishes, kept at 25 °C with a relative humidity of 70% ± 5% for 10 days, then sampled for determination, and detected according to the key stability investigation items. The test results are compared with those on day 0.

[0183] Among them, for the light test, the samples are placed in petri dishes and put into a light box with an illuminance of 4500 Lx, kept for 10 days, then sampled for determination, and detected according to the key stability investigation items. The test results are compared with those on day 0.

[0184] The test results are shown in Table 3.

[0185] Table 3

[0186]

[0187]

[0188]

[0189] It can be seen from the above test results that the linezolid tablets prepared by the method of the embodiment of the present application have good stability in the environments of light, high temperature and high humidity, and are more stable than the linezolid tablets prepared by the methods in Comparative Examples 1-3. Although the linezolid tablets prepared in Comparative Example 4 have good stability, their drug release rate is too slow and the therapeutic effect is not good.

[0190] 4. Detect the friability and hardness of the linezolid tablets prepared in the above examples and comparative examples, and the results are shown in Table 4.

[0191] Table 4

[0192] sample Friability (fragmentation) Hardness(Kg) Example 1 No splinters 36.2 Example 2 No splinters 35.3 Example 3 No splinters 35.4 Example 4 No splinters 36.0 Example 5 No splinters 36.2 Example 6 No splinters 36.1 Comparative Example 1 More lobes 13.2 Comparative Example 2 Splinters appear 25.3 Comparative Example 3 Splinters appear 26.1 Comparative Example 4 No splinters 36.3

[0193] It can be seen from the test data in the above table that the friability and hardness of the linezolid tablets prepared by the preparation method of the present application are also very high.

[0194] To sum up, the linezolid tablets prepared by the preparation method of the present invention can not only slow down the drug release rate, prolong the residence time of the drug in the body, make the drug effect play slowly and lastingly, but also the provided coating layer has a certain moisture-proof function, prolong the shelf life of the drug, improve the stability of the drug. At the same time, using the preparation method of the present application can also improve the content uniformity of the linezolid tablets, and improve the hardness and friability of the linezolid tablets.

[0195] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the various embodiments of the present invention, and they should all be covered within the scope of the claims and the description of the present invention.

Claims

1. A linezolid tablet containing a coating layer, characterized in that: It comprises a linezolid tablet core and a coating film layer wrapped on the surface of the linezolid tablet core; The raw materials for preparing the coating film layer include, by mass percentage, 5% to 10% of cellulose acetate-butyrate, 2% to 3% of glutamine, 0.5% to 1% of carbodiimide, 1% to 2% of sucrose, 0.1% to 0.5% of polyethylene glycol, and the balance is an organic solvent.

2. The linezolid tablet containing a coating layer according to claim 1, characterized in that: The raw materials for preparing the linezolid tablet core include, by mass percentage, 70% to 72% of linezolid, 7% to 8% of corn starch, 2.5% to 3% of microcrystalline cellulose, 4.5% to 5.5% of sodium starch glycolate, 0.5% to 1.5% of magnesium stearate, and the balance is hydroxypropyl methylcellulose.

3. The linezolid tablet containing a coating layer according to claim 2, characterized in that: The preparation method of the linezolid tablet core comprises the following steps: Mix corn starch, microcrystalline cellulose, and sodium starch glycolate to obtain a mixture; The mixture and linezolid are mixed, and then hydroxypropyl methylcellulose is added, and the mixture is granulated and dried to prepare drug granules; Magnesium stearate is added to the drug particles, mixed evenly, and then tableted to obtain linezolid tablet cores.

4. The linezolid tablet containing a coating layer according to claim 3, characterized in that: When preparing the drug particles, the drying temperature is controlled at 40°C to 50°C.

5. The linezolid tablet containing a coating layer according to claim 1, characterized in that: The organic solvent includes ethanol.

6. The linezolid tablet containing a coating layer according to claim 1, characterized in that: The linezolid tablet core includes a II crystal linezolid tablet core or a III crystal linezolid tablet core.

7. The linezolid tablet containing a coating layer according to claim 1, characterized in that: The thickness of the coating film layer is 200-300 μm.

8. A method for preparing a linezolid tablet containing a coating layer, characterized in that: The following steps are involved: Dissolving cellulose acetate-butyrate and glutamine in an organic solvent respectively to obtain a cellulose acetate-butyrate solution and a glutamine solution, then mixing the cellulose acetate-butyrate solution with the glutamine solution and sucrose, and then adding carbodiimide and polyethylene glycol to react to obtain a coating suspension; The prepared coating suspension is coated on the surface of the linezolid tablet core, and after drying, the linezolid tablet containing the coating film layer is obtained.

9. The method for preparing a linezolid tablet containing a coating layer according to claim 8, characterized in that: The reaction temperature when preparing the coating solution is controlled at 80°C to 120°C.

10. The method for preparing a linezolid tablet containing a coating layer according to claim 8, characterized in that: The coating liquid is coated on the surface of the linezolid tablets by a dip coating method or a pan coating method.

Images