An oral antagonist tablet composition and preparation method thereof

Abstract

The present application relates to the field of medical technology, and in particular to an oral antagonist tablet composition and its preparation process. The oral antagonist tablet composition, in parts by mass, comprises raw materials including: 35 to 45 parts of sodium alagrog, 20 to 30 parts of starch, 20 to 40 parts of tablet excipients, 2 to 8 parts of adhesives, 2 to 5 parts of lubricants, 10 to 15 parts of stabilizers, and 1 to 10 parts of adjuvants. The oral antagonist tablet composition prepared in the present application starts from the fundamental preparation of raw materials, effectively solves the problems of hygroscopicity, hydrolysis / degradation and low water solubility of the existing oral antagonist tablet composition, greatly improves the storage stability and effective storage time of the oral antagonist tablet composition, and avoids the excessive impurity generation and self-degradation of the oral antagonist tablet composition, effectively improves the safety of oral antagonist tablet composition, and has excellent medical application value.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to an oral antagonist tablet composition and a preparation process thereof. Background Art

[0002] Elagocin sodium is a gonadotropin-releasing hormone antagonist developed by AbbVie. In clinical use, it is mainly used to relieve moderate or severe pain symptoms in adult women caused by endometriosis, uterine fibroids and other diseases.

[0003] With the continuous development of its corresponding pharmaceutical agents, oral antagonist tablet compositions have become a more popular elagroc sodium preparation among patients. Existing oral antagonist tablet compositions are mostly prepared by dry granulation technology, which solves the problem of high hygroscopicity and has a dissolution curve similar to the original reference preparation, and the overall content uniformity is good, thereby having good patient compliance.

[0004] The process of dry granulation is mainly to mix the powders of materials and auxiliary materials evenly, compress them into large flakes or plates, and then crush and screen them into particles of the required size. This method relies on compression force to generate binding force between molecules. However, with the continuous application of oral antagonist tablet compositions, the technical problems they have also become more apparent. The first is the storage problem of tablets. The storage of oral antagonist tablet compositions faces a more obvious hygroscopic problem, which greatly affects the use time and storage life of oral antagonist tablet compositions; the second is the hydrolysis and degradation problem of tablets. The emergence of this problem will directly lead to the drug quality of the oral antagonist tablet composition and affect its effect; the last is solubility. Low water solubility will affect the absorption effect of the oral antagonist tablet composition in the human body.

[0005] In order to solve the above problems, the present application provides an oral antagonist tablet composition and a preparation process thereof. The oral antagonist tablet composition prepared in the present application starts from the fundamental preparation raw materials, effectively solves the problems of hygroscopicity, hydrolysis / degradation and low water solubility of the existing oral antagonist tablet composition, greatly improves the storage stability and effective storage time of the oral antagonist tablet composition, and avoids the excessive impurity generation and self-degradation of the oral antagonist tablet composition, effectively improves the safety of taking the oral antagonist tablet composition, and has very excellent medical application value. Summary of the invention

[0006] In order to solve the above problems, the first aspect of the present application provides an oral antagonist tablet composition, which includes, by mass, 35 to 45 parts of sodium alagrogol, 20 to 30 parts of starch, 20 to 40 parts of tablet excipients, 2 to 8 parts of adhesive, 2 to 5 parts of lubricant, 10 to 15 parts of stabilizer, and 1 to 10 parts of auxiliary agent.

[0007] As a preferred solution, the mass ratio of sodium ailagogine, starch material and tablet auxiliary materials is (40-45): (22-28): (25-30).

[0008] As a preferred solution, the mass ratio of sodium iragorcet, starch material and tablet auxiliary materials is (42-45): (25-26): (28-30).

[0009] As a preferred solution, the starch material is a composition of microcrystalline cellulose, sorbitol and complex starch.

[0010] As a preferred solution, the mass ratio of microcrystalline cellulose, sorbitol and composite starch is (1-1.5): (0.4-0.6): (4-5).

[0011] As a preferred solution, the mass ratio of the microcrystalline cellulose to the composite starch is (1-1.2):0.5:(4-4.5).

[0012] As a preferred solution, the composite starch is amylopectin and amylose.

[0013] As a preferred solution, the mass ratio of amylopectin to amylose is (0.8-1.4):(3-4).

[0014] As a preferred solution, the branched chain content of the amylopectin is ≥ 70%.

[0015] As a preferred solution, the branch chain content of the amylose is ≥75%.

[0016] In this application, by selecting the above-mentioned compounded starch material composition, not only can the storage stability and dissolution of the tablets be effectively improved, but also the hygroscopicity problem of the tablets can be effectively solved. Through the compounding of the above-mentioned microcrystalline cellulose, sorbitol and composite starch, the supporting effect of the long straight-chain spiral structure in the composite starch and the multi-branched structure of the branched starch can be fully utilized to build a tight internal multidimensional network, so as to cooperate with the preparation process to complete the uniform dispersion of the effective ingredients in the system, greatly improve the uniformity of the system, and the starch composition with microcrystalline cellulose and sorbitol can play a good segment support role in the network structure, thereby effectively stabilizing the intermolecular steric hindrance, avoiding the high system reaction activity caused by the construction of the tight network structure, thereby greatly reducing the impurity reaction phenomenon that occurs during storage; on the other hand, the formation of a complex and tight system also helps to increase the activity resistance of water molecules in the system and the resistance of external water entering the system, thereby effectively isolating the connection between internal water and external water, thereby playing an excellent anti-hygroscopic effect, and the added sorbitol can accelerate the disintegration of the tablet's tight network structure in an acidic environment after taking, so that the tablet has an excellent dissolution effect.

[0017] As a preferred solution, the tablet auxiliary material is a combination of a colloid auxiliary agent and a sugar alcohol compound.

[0018] As a preferred solution, the mass ratio of the colloid auxiliary agent to the sugar alcohol compound is (8-10): (0.8-1).

[0019] As a preferred solution, the colloid auxiliary agent is at least one of gum arabic, xanthan gum, guar gum, konjac gum and gelatin.

[0020] As a preferred solution, the colloid auxiliary agent is gelatin.

[0021] As a preferred solution, the weight average molecular weight of the colloid auxiliary agent is 100,000 to 250,000.

[0022] As a preferred solution, the weight average molecular weight of the colloid auxiliary agent is 150,000 to 200,000.

[0023] As a preferred solution, the sugar alcohol compound is at least one of mannitol, maltitol, xylitol and lactitol.

[0024] As a preferred embodiment, the sugar alcohol compound is a combination of mannitol and lactitol.

[0025] As a preferred solution, the mass ratio of mannitol to lactitol is (3-5):(0.4-0.8).

[0026] As a preferred solution, the mass ratio of mannitol to lactitol is (4-4.5):(0.5-0.6).

[0027] In this application, the addition of a specific sugar alcohol compound and gelatin under a specific molecular weight greatly improves the stability and water resistance of the tablets. After the two are compounded, a good active group connection effect can be formed with the sugar alcohol compound through the gelatin multi-molecular chain structure, so that the two can be more in phase in the system. In the process of tableting, with the repeated extrusion process, gelatin will be more inclined to form an external wrapping structure for other ingredients, and the wrapping structure can form a gelatin colloid layer with a higher content purity in the tablet due to the presence of the sugar alcohol compound, thereby forming a smooth and lower surface energy tablet surface. When in contact with water, the surface can greatly increase the difficulty of forming a hydration layer on the surface in contact with water, thereby reducing the residence time of water on the surface, thereby causing a series of problems caused by the intrusion of surface water.

[0028] As a preferred solution, the binder is at least one of ethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, and methyl cellulose.

[0029] As a preferred solution, the binder is sodium carboxymethyl cellulose.

[0030] As a preferred solution, the mass ratio of the starch material to the adhesive is (22-28): (6-8).

[0031] As a preferred solution, the mass ratio of the starch material to the adhesive is (25-26):7.5.

[0032] As a preferred solution, the lubricant is at least one of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, and magnesium lauryl sulfate.

[0033] As a preferred solution, the lubricant is hydrogenated vegetable oil.

[0034] As a preferred solution, the stabilizer is at least one of ethylenediaminetetraacetic acid, vitamin C, vitamin E, butylated hydroxyanisole, and sodium citrate.

[0035] As a preferred solution, the stabilizer is a combination of ethylenediaminetetraacetic acid and sodium citrate.

[0036] As a preferred solution, the mass ratio of EDTA to sodium citrate is (1-2): (1-2).

[0037] As a preferred solution, the auxiliary agent is sodium lauryl sulfate or polyoxyethylene castor oil.

[0038] As a preferred solution, the auxiliary agent is sodium dodecyl sulfate.

[0039] The second aspect of the present application provides a preparation process of the above-mentioned oral antagonist tablet composition, and the preparation process comprises the following steps: S1: passing elagot sodium, starch material, tablet auxiliary materials and adhesive through a 1-2 mm sieve to obtain a mixed powder; S2: mixing the mixed powder with a lubricant and dry granulating the mixture, wherein the granulation parameters are a horizontal speed of 20-40 rpm, a roller speed of 25-40 rpm, a roller pressure of 10-15 bar, an extruded tablet thickness of 1-1.5 mm, a sieve aperture of 1.2-1.3 mm, and a whole granulation speed of 25-30 rpm; S3: continuing to add the remaining raw materials and mix, and performing tableting operation, wherein the tableting speed is 50-60 thousand tablets / h, the filling depth is 5-6.5 mm, the main tablet thickness is 1-2 mm, and the pre-compression tablet thickness is 1.3-3.25 mm, and the tablet is obtained after completion.

[0040] The beneficial effects of this application are:

[0041] 1. The oral antagonist tablet composition provided in the present application effectively solves the problems of hygroscopicity, hydrolysis / degradation and low water solubility of the existing oral antagonist tablet compositions, greatly improves the storage stability and effective storage time of the oral antagonist tablet composition, avoids the excessive impurity generation and self-degradation of the oral antagonist tablet composition, effectively improves the safety of oral antagonist tablet composition, and has excellent medical application value.

[0042] 2. An oral antagonist tablet composition provided in the present application can not only effectively improve the storage stability and dissolution rate of the tablets by selecting a specific compound starch material composition, but also effectively solve the hygroscopicity problem of the tablets; make full use of the supporting role of the long straight-chain spiral structure in the composite starch and the multi-branched structure of the amylopectin to build a tight internal multi-dimensional network, thereby coordinating the preparation process to complete the uniform dispersion of the effective ingredients in the system, greatly improving the uniformity of the system, and the starch composition combined with microcrystalline cellulose and sorbitol can play a good segment support role in the network structure, thereby effectively stabilizing the intermolecular steric hindrance, avoiding the high system reaction activity caused by the construction of a tight network structure, thereby greatly reducing the impurity reaction phenomenon that occurs during storage; on the other hand, the formation of a complex and tight system also helps to increase the activity resistance of water molecules in the system and the resistance of external water entering the system, thereby effectively isolating the connection between internal and external water.

[0043] 3. An oral antagonist tablet composition provided in the present application, which is compounded with a specific sugar alcohol compound and gelatin with a specific molecular weight, greatly improves the stability and water resistance of the tablet; after the two are compounded, they can form a good active group connection effect with the sugar alcohol compound through the gelatin multi-molecular chain structure, so that the two can be more in phase in the system, and in the process of tableting, with repeated extrusion, gelatin will be more inclined to form an external wrapping structure for other ingredients, and the wrapping structure can form a gelatin colloid layer with higher content purity on the tablet surface due to the presence of the sugar alcohol compound, thereby forming a smooth and lower surface energy tablet surface, when in contact with water, the surface can greatly increase the difficulty of forming a hydration layer on the surface in contact with water, thereby reducing the residence time of water on the surface, thereby preventing a series of problems caused by the invasion of surface water.

[0044] 4. The oral antagonist tablet composition provided in the present application has a raw material scheme that can effectively improve the stability and hygroscopicity of the tablets, thereby greatly simplifying the preparation process of the finished tablets. The use of tablet packaging materials and related processes can be gradually omitted, thereby reducing costs and process complexity while ensuring good tablet stability. DETAILED DESCRIPTION

[0045] The following will further explain and demonstrate the technical solutions in the above invention content of this application in the form of specific implementation schemes. The following embodiments are only practical examples used to illustrate and explain the contents of the technical solutions in the specification, and should not limit the scope of the claims to be protected by this application. All technical products based on the technical solutions described in the invention content of this application should be included in the scope to be protected by this application.

[0046] In the following examples, unless otherwise specified, the raw materials are all commercially available products, or can be prepared by methods well known to those skilled in the art.

[0047] Example 1

[0048] Example 1 The first aspect provides an oral antagonist tablet composition, in parts by mass, the raw materials include: 44 parts of sodium alagrogol, 25 parts of starch, 28 parts of tablet excipients, 7.5 parts of adhesive, 3 parts of lubricant, 12 parts of stabilizer, and 3.5 parts of auxiliary agent.

[0049] The starch material is a composition of microcrystalline cellulose, sorbitol and complex starch, and the mass ratio of the three is 1:0.5:4.5.

[0050] Microcrystalline cellulose was purchased from Hebei Runbu Biotechnology Co., Ltd. as a food-grade product.

[0051] The composite starch is amylopectin and straight-chain starch, and the mass ratio of the two is 1:3.8; the amylopectin is purchased from Wuhan Lanabai Pharmaceutical Chemical Co., Ltd., and the amylopectin content is 72%; the straight-chain starch is purchased from Wuhan Huaxiang Kejie Biotechnology Co., Ltd., and the straight-chain content is 76%.

[0052] The tablet auxiliary material is a composition of a colloid auxiliary agent and a sugar alcohol compound, and the mass ratio of the colloid auxiliary agent to the sugar alcohol compound is 8:1.

[0053] The colloid auxiliary agent is gelatin with a weight average molecular weight of 180,000, which was purchased from Guangzhou Huayu Biotechnology Co., Ltd.

[0054] The sugar alcohol compound is a composition of mannitol and lactitol, and the mass ratio of the two is 4.2:0.5.

[0055] The adhesive is sodium carboxymethyl cellulose; the lubricant is hydrogenated vegetable oil, which is a food-grade product purchased from Hebei Baipin Biotechnology Co., Ltd.

[0056] The stabilizer is a composition of ethylenediaminetetraacetic acid and sodium citrate, and the mass ratio of the two is 1:2.

[0057] The auxiliary agent is sodium lauryl sulfate.

[0058] The second aspect of this embodiment provides a preparation process of an oral antagonist tablet composition, and the preparation process comprises the following steps: S1: passing elagot sodium, starch material, tablet auxiliary materials and adhesive through a 1.8 mm sieve to obtain a mixed powder; S2: mixing the mixed powder with a lubricant and dry granulating the mixture, wherein the granulation parameters are a horizontal speed of 30 rpm, a roller speed of 35 rpm, a roller pressure of 15 bar, an extruded tablet thickness of 1.2 mm, a sieve aperture of 1.2 mm, and a whole granulation speed of 25 rpm; S3: continuing to add the remaining raw materials and mixing, and performing tableting operation, wherein the tableting speed is 55,000 tablets / h, the filling depth is 5.5 mm, the main tablet thickness is 1.5 mm, and the pre-compression tablet thickness is 2.25 mm, and the tablet is obtained after completion.

[0059] Example 2

[0060] Example 2 The first aspect provides an oral antagonist tablet composition, in which the raw materials include, by mass: 40 parts of sodium alagrogol, 22 parts of starch, 30 parts of tablet excipients, 6 parts of adhesive, 3 parts of lubricant, 12 parts of stabilizer, and 2.5 parts of auxiliary agent.

[0061] The starch material is a composition of microcrystalline cellulose, sorbitol and complex starch, and the mass ratio of the three is 1.5:0.4:4.

[0062] Microcrystalline cellulose was purchased from Hebei Runbu Biotechnology Co., Ltd. as a food-grade product.

[0063] The composite starch is amylopectin and straight-chain starch, and the mass ratio of the two is 1:3.8; the amylopectin is purchased from Wuhan Lanabai Pharmaceutical Chemical Co., Ltd., and the amylopectin content is 72%; the straight-chain starch is purchased from Wuhan Huaxiang Kejie Biotechnology Co., Ltd., and the straight-chain content is 76%.

[0064] The tablet auxiliary material is a composition of a colloid auxiliary agent and a sugar alcohol compound, and the mass ratio of the colloid auxiliary agent to the sugar alcohol compound is 9:1.

[0065] The colloid auxiliary agent is gelatin with a weight average molecular weight of 180,000, which was purchased from Guangzhou Huayu Biotechnology Co., Ltd.

[0066] The sugar alcohol compound is a composition of mannitol and lactitol, and the mass ratio of the two is 3.5:0.8.

[0067] The adhesive is sodium carboxymethyl cellulose; the lubricant is hydrogenated vegetable oil, which is a food-grade product purchased from Hebei Baipin Biotechnology Co., Ltd.

[0068] The stabilizer is a composition of ethylenediaminetetraacetic acid and sodium citrate, and the mass ratio of the two is 1:2.

[0069] The auxiliary agent is sodium lauryl sulfate.

[0070] The second aspect of this embodiment provides a preparation process of an oral antagonist tablet composition, and the preparation process comprises the following steps: S1: passing elagot sodium, starch material, tablet auxiliary materials and adhesive through a 1.8 mm sieve to obtain a mixed powder; S2: mixing the mixed powder with a lubricant and dry granulating the mixture, wherein the granulation parameters are a horizontal speed of 30 rpm, a roller speed of 35 rpm, a roller pressure of 15 bar, an extruded tablet thickness of 1.2 mm, a sieve aperture of 1.2 mm, and a whole granulation speed of 25 rpm; S3: continuing to add the remaining raw materials and mixing, and performing tableting operation, wherein the tableting speed is 55,000 tablets / h, the filling depth is 5.5 mm, the main tablet thickness is 1.5 mm, and the pre-compression tablet thickness is 2.25 mm, and the tablet is obtained after completion.

[0071] Comparative Example 1

[0072] The specific implementation method of this comparative example is basically the same as that of Example 1, except that: the oral antagonist tablet composition, in parts by mass, comprises: 50 parts of sodium alagrogol, 15 parts of starch, 15 parts of tablet excipients, 5 parts of adhesive, 2 parts of lubricant, 8 parts of stabilizer, and 2.5 parts of auxiliary agent.

[0073] Comparative Example 2

[0074] The specific implementation of this comparative example is basically the same as that of Example 1, except that the starch material is a composition of microcrystalline cellulose, sorbitol and composite starch, and the mass ratio of the three is 0.5:0.2:6.

[0075] Comparative Example 3

[0076] The specific implementation of this comparative example is basically the same as that of Example 1, except that the starch material is a composition of microcrystalline cellulose, sorbitol and composite starch, and the mass ratio of the three is 2.5:1:4.

[0077] Comparative Example 4

[0078] The specific implementation of this comparative example is basically the same as that of Example 1, except that the composite starch is amylopectin and amylose, and the mass ratio of amylopectin to amylose is 1:1.

[0079] Comparative Example 5

[0080] The specific implementation of this comparative example is basically the same as that of Example 1, except that the colloidal auxiliary agent is gelatin with a weight average molecular weight of 80,000, which is purchased from Guangzhou Huayu Biotechnology Co., Ltd.

[0081] Comparative Example 6

[0082] The specific implementation of this comparative example is basically the same as that of Example 1, except that the tablet auxiliary material is a composition of a colloid auxiliary agent and a sugar alcohol compound, and the mass ratio of the colloid auxiliary agent to the sugar alcohol compound is 15:1.

[0083] Comparative Example 7

[0084] The specific implementation of this comparative example is basically the same as that of Example 1, except that the sugar alcohol compound is a combination of mannitol and lactitol, and the mass ratio of the two is 5:0.2.

[0085] Performance Evaluation

[0086] Stability test: The oral antagonist tablet compositions prepared in the examples and comparative examples were placed in a constant temperature and humidity chamber at 60±2°C and 75% humidity for 10 days. After 10 days, samples were taken for HPLC analysis to test the total impurity content. The test values ​​were taken as the average of 10 tests and recorded in Table 1.

[0087] Moisture absorption resistance test: The oral antagonist tablet compositions prepared in the examples and comparative examples were placed in a constant temperature and humidity chamber at 25±2°C and 75% humidity for 21 days. After 21 days, the tablets were observed to see whether they showed obvious moisture absorption, powder cracking, or hydration. If so, they were deemed unqualified, otherwise, they were qualified. A total of 50 samples were tested, and the qualified rate was calculated and recorded in Table 1.

[0088] Dissolution: The dissolution of the tablets prepared in the Examples and Comparative Examples was tested at 38°C and 1.2 pH. The test values ​​were averaged from 10 tests and recorded in Table 1.

[0089] Table 1 Performance test results

[0090]

[0091] It can be seen from the examples and comparative examples of the present application and the data results in Table 1 that examples 1 and 2 of the present application have obvious performance advantages over comparative examples 1 to 7 in terms of dissolution, moisture absorption resistance and stability. The specific technical scheme adopted in examples 1 and 2 fully utilizes the supporting effect of the long straight-chain spiral structure in the composite starch and the multi-branched structure of the amylopectin to build a tight internal multidimensional network, thereby coordinating the preparation process to complete the uniform dispersion of the effective ingredients in the system and greatly improve the uniformity of the system. The starch composition combined with microcrystalline cellulose and sorbitol can play a good segment supporting role in the network structure, thereby effectively stabilizing the intermolecular steric hindrance and avoiding the high system reaction activity caused by the construction of a tight network structure, thereby greatly reducing the impurity reaction phenomenon occurring during the storage process; on the other hand, the formation of a complex and tight system also helps to increase the activity resistance of water molecules in the system and the resistance of external water entering the system, thereby effectively isolating the connection between internal water and external water.

Claims

1. An oral antagonist tablet composition, characterized in that: The oral antagonist tablet composition comprises, by weight, 35-45 parts of ailagogine sodium, 20-30 parts of starch material, 20-40 parts of tablet auxiliary materials, 2-8 parts of adhesive, 2-5 parts of lubricant, 10-15 parts of stabilizer, and 1-10 parts of auxiliary agent; The starch material is a composition of microcrystalline cellulose, sorbitol and composite starch; The mass ratio of microcrystalline cellulose, sorbitol and composite starch is (1-1.5): (0.4-0.6): (4-5); The composite starch is amylopectin and amylose; the mass ratio of amylopectin to amylose is 1:3.8; The branch chain content of the amylopectin is ≥72%; the straight chain content of the amylose is ≥76%; The tablet auxiliary material is a composition of a colloid auxiliary agent and a sugar alcohol compound; The mass ratio of the colloidal auxiliary agent to the sugar alcohol compound is (8-9):1; The weight average molecular weight of the colloid additive is 180,000; The colloid auxiliary agent is gelatin; The sugar alcohol compound is a combination of mannitol and lactitol; the mass ratio of mannitol to lactitol is (3.5-4.2): (0.5-0.8); The binder is sodium carboxymethyl cellulose; The lubricant is hydrogenated vegetable oil; The stabilizer is a combination of ethylenediaminetetraacetic acid and sodium citrate, and the mass ratio of the two is 1:2; The auxiliary agent is sodium lauryl sulfate.

2. The oral antagonist tablet composition according to claim 1, characterized in that: The mass ratio of the sodium alagrogol, starch material and tablet auxiliary materials is (40-45): (22-28): (25-30).

3. The oral antagonist tablet composition according to claim 2, characterized in that: The mass ratio of the starch material to the adhesive is (22-28): (6-8).

4. A process for preparing the oral antagonist tablet composition according to any one of claims 1 to 3, characterized in that: Preparation process The following steps are involved: S1: Pass 1~2mm sieve through elaigog sodium, starch, tablet auxiliary materials and adhesive to obtain mixed powder; S2: Mix the mixed powder with lubricant and dry granulate, the granulation parameters are horizontal speed 20~40rpm, roller speed 25~40rpm, roller pressure, 10~15bar, extruded sheet thickness 1~1.5mm, sieve aperture 1.2~1.3mm, granulation speed 25~30rpm; S3: Continue to add the remaining raw materials and mix, and perform tableting operation, the tableting speed is 50~60 thousand tablets / h, the filling depth is 5~6.5mm, and the main tablet thickness is 1~2mm; The pre-compressed tablet is 1.3~3.25mm thick and is ready after completion.

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