A saxagliptin tablet containing a coating layer and its preparation process

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and discloses a saxagliptin tablet containing a coating layer and a preparation process thereof; the following operation steps are included: (1) uniformly mixing saxagliptin, a diluent, a disintegrant, and a lubricant, performing dry granulation and tabletting to obtain a tablet core; (2) adding hydroxypropyl methylcellulose phthalate, Eudragit, and diethyl phthalate into absolute ethanol, and uniformly mixing to obtain an enteric coating solution; (3) adding modified chitosan and hydroxypropyl methylcellulose into absolute ethanol and uniformly mixing to obtain a gastric-soluble coating solution; Step 2: (1) spraying the enteric coating solution on the surface of the tablet core and drying to form an enteric coating layer; (2) spraying the gastric-soluble coating solution on the enteric coating layer and drying to form a gastric-soluble coating layer, thereby obtaining the saxagliptin tablet.

Description

Technical Field

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

[0002] By selectively inhibiting DPP-4, saxagliptin can increase the levels of endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, thereby regulating blood glucose and being widely used in diabetic patients; however, saxagliptin itself has unstable chemical properties and is prone to degradation under solid or liquid conditions, especially prone to intramolecular cyclization in aqueous solution to generate an inactive degradation product "cyclic amidine"; in order to enhance the stability of saxagliptin in the preparation and avoid its destruction by gastric acid in the stomach or degradation during storage, a coating technology is required to isolate the drug from the external environment; in the prior art, an enteric coating layer is usually coated on the surface of the saxagliptin tablet core; however, the storage performance of the saxagliptin tablet containing only the enteric coating layer will decrease in a relatively harsh environment, thereby affecting its efficacy.

[0003] In summary, in order to solve this problem, it is of great significance to prepare a saxagliptin tablet containing a coating layer. Summary of the Invention

[0004] The purpose of the present invention is to provide a saxagliptin tablet containing a coating layer and a preparation process thereof to solve the problems raised in the prior art.

[0005] To achieve the above purpose, the present invention provides the following technical solutions:

[0006] A preparation process of a saxagliptin tablet containing a coating layer includes the following operation steps:

[0007] Step 1: (1) Uniformly mix saxagliptin, diluent, disintegrant, and lubricant, perform dry granulation and tabletting to obtain a tablet core; (2) Add hydroxypropyl methylcellulose phthalate, Eudragit, and diethyl phthalate to absolute ethanol and uniformly mix to obtain an enteric coating solution; (3) Add modified chitosan and hydroxypropyl methylcellulose to absolute ethanol and uniformly mix to obtain a gastric-soluble coating solution;

[0008] Step 2: (1) Spray the enteric coating solution on the surface of the tablet core and dry to form an enteric coating layer; (2) Spray the gastric-soluble coating solution on the enteric coating layer and dry to form a gastric-soluble coating layer to obtain the saxagliptin tablet.

[0009] Preferably, the enteric coating layer accounts for 5-7 wt% of the tablet core; the gastric-soluble coating layer accounts for 2.2-2.7 wt% of the tablet core.

[0010] More preferably, the raw materials of the enteric coating solution include the following components: by mass, 8 - 15 parts of hydroxypropyl methylcellulose phthalate, 5 - 7 parts of Eudragit, 2 - 3 parts of diethyl phthalate, and 50 - 60 parts of absolute ethanol; Eudragit includes one of the Eudragit L series and S series; the raw materials of the gastric - soluble coating solution include the following components: by mass, 8 - 12 parts of hydroxypropyl methylcellulose, 2 - 4 parts of modified chitosan, and 40 - 50 parts of absolute ethanol.

[0011] More preferably, the preparation method of the modified chitosan is as follows: (1) Add succinic anhydride and EDC to deionized water and mix evenly to obtain a mixed solution; add gelatin to deionized water, mix evenly at 60 - 65 °C, adjust the pH to 4.3 - 5, add the mixed solution, react for 16 hours, and dialyze to obtain carboxylated gelatin; add the carboxylated gelatin to deionized water at 90 - 95 °C, keep it at 35 - 40 °C for heat preservation to obtain a carboxylated gelatin aqueous solution for standby; add chitosan to a 1 - 1.5 wt% acetic acid aqueous solution, mix evenly for 30 - 40 minutes, remove bubbles at low temperature for 40 - 60 minutes, add EDC and NHS and mix evenly, adjust the pH to 6.0 - 6.2, add the carboxylated gelatin aqueous solution and sodium alginate, react at 50 - 60 °C for 16 - 20 hours, purify and dry to obtain the modified chitosan.

[0012] More preferably, the raw materials of the carboxylated gelatin include the following components: by mass, 1 - 2 parts of gelatin, 0.3 - 0.5 parts of succinic anhydride, 0.18 - 0.2 parts of EDC, and 30 - 40 parts of deionized water; the raw materials of the modified chitosan include the following components: by mass, 1.2 - 1.5 parts of chitosan, 0.2 - 0.22 parts of EDC, 0.2 - 0.22 parts of NHS, 3 - 4 parts of carboxylated gelatin aqueous solution, 0.1 - 0.15 parts of sodium alginate, and 40 - 50 parts of acetic acid aqueous solution; the carboxylated gelatin accounts for 30 - 40 wt% of the carboxylated gelatin aqueous solution.

[0013] More preferably, the process conditions for spraying the enteric coating solution are: temperature 30 - 40 °C, spraying pressure 0.22 - 0.3 MPa, spraying speed 7 - 10 mL / min; the process conditions for spraying the gastric - soluble coating solution are: temperature 35 - 40 °C, spraying pressure 0.3 - 0.4 MPa, spraying speed 10 - 12 mL / min.

[0014] More preferably, the raw materials of the tablet core include the following components: 2 - 3 wt% of saxagliptin, 5 - 6 wt% of disintegrant, 0.6 - 1 wt% of lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct - compression lactose with a mass ratio of 1:(2 - 3).

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0016] In the present invention, saxagliptin, diluent, disintegrant, and lubricant are made into a tablet core, and then an enteric coating solution and a gastric coating solution are successively sprayed on the surface thereof to obtain saxagliptin tablets.

[0017] The efficacy of saxagliptin depends on its absorption in the small intestine. The enteric coating can ensure that the drug is not prematurely released in the stomach, thereby improving its absorption efficiency in the small intestine and further enhancing the bioavailability of the drug. Among them, the enteric coating layer is made of hydroxypropyl methylcellulose phthalate, Eudragit, and diethyl phthalate.

[0018] In the solution, hydroxypropyl methylcellulose phthalate and Eudragit (L series and S series) are insoluble in the gastric acid environment and can only dissolve in the alkaline environment of the small intestine, thus ensuring that the drug is released only at the appropriate site (small intestine); diethyl phthalate is used as a plasticizer, which helps to improve the flexibility of the enteric coating film, ensure the stability and integrity of the coating film, and enable the drug to be better released in the intestinal environment.

[0019] In the solution, the prepared enteric coating layer has poor light protection and moisture-proof effects; thus, it will affect the storage effect of the drug; on this basis, a gastric coating layer is added; among them, the gastric coating layer is made of modified chitosan and hydroxypropyl methylcellulose.

[0020] In the solution, hydroxypropyl methylcellulose (HPMC) has good light stability and moisture-proof property, and in the acidic environment of the stomach, HPMC can dissolve rapidly; while chitosan has good film-forming properties, can form a uniform film on the surface of the tablet, and has certain antibacterial properties, which can inhibit the growth of microorganisms, help to extend the shelf life of the drug, and reduce the contamination of the drug by microorganisms.

[0021] However, chitosan needs to stay in the gastric acid environment for a long time before being destroyed; in the case of rapid gastric emptying, chitosan may be discharged into the small intestine before it is completely dissolved, and if gastric emptying is slow, chitosan will have more time to dissolve in the stomach; the introduction of sodium alginate can enhance the light protection effect of chitosan, and introducing it into modified chitosan can enhance the resistance of the coating layer to environmental factor changes such as temperature and humidity, but the degradation of high-concentration sodium alginate in gastric acid is relatively slow. In order to reduce its impact on the drug dissolution rate, the addition amount of sodium alginate needs to be controlled.

[0022] In order to reduce the dissolution time of chitosan and sodium alginate in gastric acid without affecting the absorption of drugs in the small intestine; in the solution, chitosan is modified by gelatin and sodium alginate; gelatin is a natural polymer material that can dissolve rapidly in an acidic environment. Modifying it on chitosan can effectively reduce the dissolution time of chitosan in gastric acid, and it has good film-forming ability and flexibility, which can provide certain mechanical protection during the coating process; the modified chitosan and hydroxypropyl methylcellulose act synergistically to effectively improve the stability of drug storage; and there is good bonding between the gastric-soluble coating layer and the enteric-soluble coating layer, and it is not easy to fall off. Detailed implementation mode

[0023] The following will combine the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work belong to the protection scope of the present invention.

[0024] In the following detailed implementation modes, parts are parts by mass. In this embodiment, it should be noted that there are no special restrictions on the purchase manufacturers of all raw materials involved in the present invention. Exemplarily, they include: gelatin model food grade, purchased from Hefei Tanrun Biotechnology Co., Ltd.; the CAS number of succinic anhydride is 108-30-5; the CAS number of EDC is 1892-57-5; the CAS number of NHS is 6066-82-6; the model of chitosan is 26520, purchased from Hubei Shiteng Chemical Technology Co., Ltd.; sodium alginate model food grade, purchased from Jiangsu Aofu Biotechnology Co., Ltd.; microcrystalline cellulose model food grade, purchased from Shandong Yaheng Biotechnology Co., Ltd.; anhydrous direct compression lactose food grade, purchased from Zhengzhou Kangyuan Chemical Products Co., Ltd.; the product number of carboxymethyl starch sodium (disintegrant) is S30572, purchased from Shanghai Yuanye Biotechnology Co., Ltd.; the product number of magnesium stearate (lubricant) is 1, pharmaceutical grade, purchased from Shanxi Jinyang Pharmaceutical Excipients Co., Ltd.; hydroxypropyl methylcellulose model food grade, purchased from Sichuan Century Star Biotechnology Co., Ltd.; the product number of hydroxypropyl methylcellulose phthalate is 180-9187-4298, pharmaceutical grade, purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; the model of Eudragit is L100, purchased from Shanghai Dexiang Pharmaceutical Technology Co., Ltd.; the CAS number of diethyl phthalate is 84-66-2.

[0025] The preparation method of carboxylated gelatin is as follows: Add 0.4 parts of succinic anhydride and 0.2 parts of EDC to deionized water and mix evenly to obtain a mixed solution (prepared and used immediately); add 1.2 parts of gelatin to deionized water, mix evenly at 60 °C, adjust the pH to 4.5, add the mixed solution, react for 16 hours, and dialyze with a dialysis bag with a molecular weight of 3500 Dalton for 2 days to obtain carboxylated gelatin.

[0026] The preparation method of the modified chitosan is as follows: (1) Add carboxylated gelatin into deionized water at 90°C, keep it at 37°C for heat preservation to obtain a carboxylated gelatin aqueous solution (30wt%), and set it aside; (2) Add 1.2 parts of chitosan into 40 parts of acetic acid aqueous solution with a concentration of 1.2wt%, mix evenly for 30 minutes, remove bubbles at low temperature for 40 minutes, add 0.2 parts of EDC and 0.2 parts of NHS, mix evenly, adjust the pH to 6.0, add 3.5 parts of carboxylated gelatin aqueous solution and 0.15 parts of sodium alginate, react at 60°C for 18 hours, purify and dry to obtain the modified chitosan.

[0027] Example 1: The preparation process of a saxagliptin tablet containing a coating layer includes the following operation steps:

[0028] Step 1: (1) Uniformly mix saxagliptin, diluent, disintegrant, and lubricant, granulate and press tablets at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 8 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate into 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution; (3) Add 8 parts of hydroxypropyl methylcellulose and 2 parts of modified chitosan into 40 parts of absolute ethanol, mix evenly to obtain a gastric-soluble coating solution;

[0029] Among them, the raw materials of the tablet core include the following components: 2wt% saxagliptin, 6wt% disintegrant, 0.6wt% lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct compression lactose with a mass ratio of 1:3;

[0030] Step 2: (1) Set the temperature at 35°C, the spraying pressure at 0.25 MPa, and the spraying speed at 8 mL / min, spray the enteric coating solution on the surface of the tablet core, and dry to form an enteric coating layer (the enteric coating layer accounts for 7wt% of the tablet core); (2) Set the temperature at 40°C, the spraying pressure at 0.3 MPa, and the spraying speed at 10 mL / min, spray the gastric-soluble coating solution on the enteric coating layer, and dry to form a gastric-soluble coating layer (the gastric-soluble coating layer accounts for 2.5wt% of the tablet core) to obtain the saxagliptin tablet.

[0031] Example 2: The preparation process of a saxagliptin tablet containing a coating layer includes the following operation steps:

[0032] Step 1: (1) Mix saxagliptin, diluent, disintegrant, and lubricant evenly, granulate and table press at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 10 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution; (3) Add 10 parts of hydroxypropyl methylcellulose and 4 parts of modified chitosan to 40 parts of absolute ethanol, mix evenly to obtain a gastric-soluble coating solution;

[0033] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct compression lactose with a mass ratio of 1:3;

[0034] Step 2: (1) Set the temperature to 35 °C, the spraying pressure to 0.25 MPa, and the spraying speed to 8 mL / min. Spray the enteric coating solution on the surface of the tablet core and dry to form an enteric coating layer (the enteric coating layer accounts for 6 wt% of the tablet core); (2) Set the temperature to 40 °C, the spraying pressure to 0.3 MPa, and the spraying speed to 10 mL / min. Spray the gastric-soluble coating solution on the enteric coating layer and dry to form a gastric-soluble coating layer (the gastric-soluble coating layer accounts for 2.2 wt% of the tablet core) to obtain saxagliptin tablets.

[0035] Example 3: A preparation process of saxagliptin tablets containing a coating layer, including the following operating steps:

[0036] Step 1: (1) Mix saxagliptin, diluent, disintegrant, and lubricant evenly, granulate and table press at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 15 parts of hydroxypropyl methylcellulose phthalate, 6 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution; (3) Add 12 parts of hydroxypropyl methylcellulose and 3 parts of modified chitosan to 40 parts of absolute ethanol, mix evenly to obtain a gastric-soluble coating solution;

[0037] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct compression lactose with a mass ratio of 1:3;

[0038] Step 2: (1) Set the temperature at 35°C, the spraying pressure at 0.25 MPa, and the spraying speed at 8 mL / min. Spray the enteric coating solution on the surface of the tablet core and dry it to form an enteric coating layer (the enteric coating layer accounts for 7 wt% of the tablet core); (2) Set the process conditions for spraying the gastric-soluble coating solution as follows: temperature at 40°C, spraying pressure at 0.3 MPa, and spraying speed at 10 mL / min. Spray the gastric-soluble coating solution on the enteric coating layer and dry it to form a gastric-soluble coating layer (the gastric-soluble coating layer accounts for 2.7 wt% of the tablet core), thus obtaining the saxagliptin tablets.

[0039] Comparative Example 1 is based on Example 2, with hydroxypropyl methylcellulose introduced singly.

[0040] Step 1: (1) Uniformly mix saxagliptin, diluent, disintegrant, and lubricant, granulate and table the mixture at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 10 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, and mix them uniformly to obtain an enteric coating solution; (3) Add 10 parts of hydroxypropyl methylcellulose to 40 parts of absolute ethanol and mix them uniformly to obtain a gastric-soluble coating solution;

[0041] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct compression lactose with a mass ratio of 1:3;

[0042] Step 2: (1) Set the temperature at 35°C, the spraying pressure at 0.25 MPa, and the spraying speed at 8 mL / min. Spray the enteric coating solution on the surface of the tablet core and dry it to form an enteric coating layer (the enteric coating layer accounts for 6 wt% of the tablet core); (2) Set the temperature at 40°C, the spraying pressure at 0.3 MPa, and the spraying speed at 10 mL / min. Spray the gastric-soluble coating solution on the enteric coating layer and dry it to form a gastric-soluble coating layer (the gastric-soluble coating layer accounts for 2.2 wt% of the tablet core), thus obtaining the saxagliptin tablets.

[0043] Comparative Example 2 is based on Example 2, with gelatin not introduced into the modified chitosan.

[0044] Step 1: (1) Mix saxagliptin, diluent, disintegrant, and lubricant evenly, granulate and press tablets at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain tablet cores; (2) Add 10 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution; (3) Add 1.2 parts of chitosan to 40 parts of acetic acid aqueous solution with a concentration of 1.2 wt%, mix evenly for 30 minutes, remove bubbles at low temperature for 40 minutes, add 0.2 parts of EDC and 0.2 parts of NHS, mix evenly, adjust the pH to 6.0, add 0.15 parts of sodium alginate, react at 60 °C for 18 hours, purify and dry to obtain modified chitosan; Add 10 parts of hydroxypropyl methylcellulose and 4 parts of modified chitosan to 40 parts of absolute ethanol, mix evenly to obtain a gastric soluble coating solution;

[0045] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; The diluent includes microcrystalline cellulose and anhydrous direct compression lactose with a mass ratio of 1:3;

[0046] Step 2: (1) Set the temperature to 35 °C, the spraying pressure to 0.25 MPa, and the spraying speed to 8 mL / min, spray the enteric coating solution on the surface of the tablet core, and dry to form an enteric coating layer (the enteric coating layer accounts for 6 wt% of the tablet core); (2) Set the temperature to 40 °C, the spraying pressure to 0.3 MPa, and the spraying speed to 10 mL / min, spray the gastric soluble coating solution on the enteric coating layer again, and dry to form a gastric soluble coating layer (the gastric soluble coating layer accounts for 2.2 wt% of the tablet core) to obtain saxagliptin tablets.

[0047] Comparative Example 3 is based on Example 2, and sodium alginate is not introduced into the modified chitosan;

[0048] Step 1: (1) Mix saxagliptin, diluent, disintegrant, and lubricant evenly, granulate and tablet at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 10 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution; (3) Add carboxylated gelatin to deionized water at 90 °C, keep it at 37 °C, and obtain a carboxylated gelatin aqueous solution (30 wt%) for standby; Add 1.2 parts of chitosan to 40 parts of acetic acid aqueous solution at 1.2 wt%, mix evenly for 30 minutes, remove bubbles at low temperature for 40 minutes, add 0.2 parts of EDC and 0.2 parts of NHS, mix evenly, adjust the pH to 6.0, add 3.5 parts of carboxylated gelatin aqueous solution, react at 60 °C for 18 hours, purify and dry to obtain modified chitosan; Add 10 parts of hydroxypropyl methylcellulose and 4 parts of modified chitosan to 40 parts of absolute ethanol, mix evenly to obtain a gastric-soluble coating solution;

[0049] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; The diluent includes microcrystalline cellulose and direct compression lactose anhydrous with a mass ratio of 1:3;

[0050] Step 2: (1) Set the temperature at 35 °C, the spraying pressure at 0.25 MPa, and the spraying speed at 8 mL / min, spray the enteric coating solution on the surface of the tablet core, and dry to form an enteric coating layer (the enteric coating layer accounts for 6 wt% of the tablet core); (2) Set the temperature at 40 °C, the spraying pressure at 0.3 MPa, and the spraying speed at 10 mL / min, spray the gastric-soluble coating solution on the enteric coating layer again, and dry to form a gastric-soluble coating layer (the gastric-soluble coating layer accounts for 2.2 wt% of the tablet core) to obtain saxagliptin tablets.

[0051] Comparative Example 4 is based on Example 2, with only an enteric layer;

[0052] Step 1: (1) Mix saxagliptin, diluent, disintegrant, and lubricant evenly, granulate and tablet at a roller speed of 16 rpm, a pressure of 45 bar, and a screen of 1.0 mm to obtain a tablet core; (2) Add 10 parts of hydroxypropyl methylcellulose phthalate, 5 parts of Eudragit, and 2 parts of diethyl phthalate to 50 parts of absolute ethanol, mix evenly to obtain an enteric coating solution;

[0053] Among them, the raw materials of the tablet core include the following components: 2 wt% saxagliptin, 6 wt% disintegrant, 0.6 wt% lubricant, and the rest is diluent; The diluent includes microcrystalline cellulose and direct compression lactose anhydrous with a mass ratio of 1:3;

[0054] Step 2: (1) Set the temperature at 35 °C, the spraying pressure at 0.25 MPa, and the spraying speed at 8 mL / min. Spray the enteric coating solution on the surface of the tablet core and dry it to form an enteric coating layer (the enteric coating layer accounts for 6 wt% of the tablet core); obtain saxagliptin tablets.

[0055] Detection test: (1) Place the saxagliptin tablets (2.5 mg) of Examples 1 to 3 and Comparative Examples 1 to 4 at a temperature of 30 °C ± 2 °C and a relative humidity of 70% ± 5% for 10 days, then place them in simulated gastric acid for 2 hours and in simulated intestinal fluid for 20 minutes. Sample and detect every 5 minutes, calculate the cumulative dissolution degree in 20 minutes, and detect the total impurities by high performance liquid chromatography (HPLC); as shown in Table 1;

[0056] (2) Use the gastric-soluble coating solutions prepared in Example 2 and Comparative Examples 1 to 3 as the coating layers of the tablet cores, place them in simulated gastric acid for 40 minutes respectively, sample and detect every 5 minutes, and calculate the cumulative dissolution degree in 40 minutes; analyze the dissolution effect of the gastric-soluble coating layer by detecting the dissolution degree of the drug; as shown in Table 2.

[0057]

[0058] Table 1

[0059]

[0060] Table 2

[0061] Conclusion: As shown in Table 1, based on Example 2, in Comparative Example 1, the gastric-soluble coating layer is hydroxypropyl methylcellulose; this leads to a deterioration in the stability of the coating layer, thus increasing the impurities; as can be seen from Table 2, the dissolution degree of the enteric coating layer in Comparative Example 1 is higher than that in Example 2 because the enteric coating layer in Example 2 contains chitosan and sodium alginate, which takes a long time to be destroyed in simulated gastric acid; based on Example 2, in Comparative Example 2, gelatin is not introduced into the modified chitosan; this leads to a decrease in the dissolution degree because the introduction of gelatin can increase the dissolution speed of chitosan and sodium alginate in simulated gastric acid and reduce the influence of its gastric-soluble coating layer in intestinal fluid; based on Example 2, in Comparative Example 3, sodium alginate is not introduced into the modified chitosan; this leads to a reduction in the stability of the saxagliptin tablets, thus increasing the total impurity content in Table 1; since sodium alginate is not easily destroyed in gastric acid, in Table 2, the dissolution degree of Example 2 is slightly lower than that of Comparative Example 3; based on Example 2, in Comparative Example 4, there is only an enteric coating layer; this leads to a reduction in the stability of the saxagliptin tablets, thus increasing the content of total impurities.

[0062] It is obvious to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention.

Claims

1. A preparation process of saxagliptin tablets containing a coating layer, characterized in that: The steps include: Step 1: (1) Saxagliptin, a diluent, a disintegrant, and a lubricant are uniformly mixed, dry granulated, and tableted to obtain tablet cores; (2) Hydroxypropyl methylcellulose phthalate, Eudragit, and diethyl phthalate are added to anhydrous ethanol, and uniformly mixed to obtain an enteric coating solution; (3) Modified chitosan and hydroxypropyl methylcellulose are added to anhydrous ethanol, and uniformly mixed to obtain a gastric coating solution; Step 2: (1) spraying an enteric coating liquid on the surface of the tablet core, drying, and forming an enteric coating layer; (2) spraying a gastric coating liquid on the enteric coating layer, drying, and forming a gastric coating layer to obtain saxagliptin tablets; The raw materials of the tablet core include the following components: 2-3wt% saxagliptin, 5-6wt% disintegrant, 0.6-1wt% lubricant, and the rest is diluent; the diluent includes microcrystalline cellulose and anhydrous direct compression lactose in a mass ratio of 1:(2-3); The raw materials of the enteric coating solution include the following components: by weight, 8-15 parts of hydroxypropyl methylcellulose phthalate, 5-7 parts of Eudragit, 2-3 parts of diethyl phthalate, and 50-60 parts of anhydrous ethanol; Eudragit includes one of the Eudragit L series and S series; the raw materials of the gastric coating solution include the following components: by weight, 8-12 parts of hydroxypropyl methylcellulose, 2-4 parts of modified chitosan, and 40-50 parts of anhydrous ethanol; The preparation method of the modified chitosan is as follows: (1) adding succinic anhydride and EDC to deionized water and mixing them uniformly to obtain a mixed solution; adding gelatin to deionized water, mixing them uniformly at 60-65° C., adjusting the pH to 4.3-5, adding the mixed solution, reacting for 16 hours, dialyzing, and obtaining carboxylated gelatin; adding carboxylated gelatin to deionized water at 90-95° C., keeping the temperature at 35-40° C., obtaining a carboxylated gelatin aqueous solution for later use; adding chitosan to a 1-1.5wt% acetic acid aqueous solution and mixing them uniformly for 30-40 minutes, degassing at low temperature for 40-60 minutes, adding EDC and NHS and mixing them uniformly, adjusting the pH to 6.0-6.2, adding the carboxylated gelatin aqueous solution and sodium alginate, reacting at 50-60° C. for 16-20 hours, purifying, and drying to obtain modified chitosan; The raw materials of the carboxylated gelatin include the following components: by weight, 1-2 parts of gelatin, 0.3-0.5 parts of succinic anhydride, 0.18-0.2 parts of EDC, and 30-40 parts of deionized water; the raw materials of the modified chitosan include the following components: by weight, 1.2-1.5 parts of chitosan, 0.2-0.22 parts of EDC, 0.2-0.22 parts of NHS, 3-4 parts of carboxylated gelatin aqueous solution, 0.1-0.15 parts of sodium alginate, and 40-50 parts of acetic acid aqueous solution; the carboxylated gelatin accounts for 30-40wt% of the carboxylated gelatin aqueous solution.

2. The preparation process of a saxagliptin tablet containing a coating layer according to claim 1, characterized in that: The enteric coating layer accounts for 5-7 wt % of the tablet core; the gastric coating layer accounts for 2.2-2.7 wt % of the tablet core.

3. The preparation process of a saxagliptin tablet containing a coating layer according to claim 1, characterized in that: The process conditions for spraying enteric-coated liquid are as follows: the temperature is 30~40°C, the spraying pressure is 0.22~0.3 MPa, and the spraying speed is 7~10 mL / min; the process conditions for spraying gastric-soluble coated liquid are as follows: the temperature is 35~40°C, the spraying pressure is 0.3~0.4 MPa, and the spraying speed is 10~12 mL / min.

4. Saxagliptin tablets prepared by the preparation process of a saxagliptin tablet containing a coating layer according to any one of claims 1 to 3.

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