Oral antagonistic tablet composition and preparation method thereofTechnical Field
The application relates to the technical field of medicines, in particular to an oral antagonistic tablet composition and a preparation process thereof.
Background
The IgGo sodium is a gonadotrophin releasing hormone antagonist developed by Igo-vitamin company, and is mainly used for relieving moderate or severe pain symptoms caused by endometriosis, uterine fibroids and other diseases of adult females in clinical use.
With the continued development of their corresponding agents, oral antagonistic tablet compositions have become a popular formulation of sodium alagolide for patients. The existing oral antagonistic tablet composition is mostly prepared by adopting a dry granulation technology, solves the problem of high hygroscopicity, has a dissolution curve similar to that of an original reference preparation, has good content uniformity of the whole body, and further has good medication compliance of patients.
The dry granulating process is mainly to mix the powder of the materials and the auxiliary materials uniformly, compress the powder into big sheets or plates, and then crush and screen the powder into particles with the required size. However, with the continued use of oral antagonistic tablet compositions, the technical problems that exist are further revealed. Firstly, the storage of the tablet is subject to the problem of relatively obvious hygroscopicity, which greatly influences the service life and the storage life of the oral antagonistic tablet composition, secondly, the problem of hydrolysis and degradation of the tablet, which directly causes the quality of the oral antagonistic tablet composition to influence the action effect, and finally, the problem of solubility and relatively low water solubility can influence the absorption effect of the oral antagonistic tablet composition in human bodies.
In order to solve the problems, the application provides the oral antagonism tablet composition and the preparation process thereof, and the prepared oral antagonism tablet composition effectively solves the problems of hygroscopicity, hydrolysis/degradation and low water solubility of the traditional oral antagonism tablet composition from the fundamental preparation raw materials, greatly improves the storage stability and effective storage time of the oral antagonism tablet composition, avoids the phenomena of excessive impurity generation and self degradation of the oral antagonism tablet composition, effectively improves the administration safety of the oral antagonism tablet composition, and has very excellent medical application value.
Disclosure of Invention
In order to solve the problems, the first aspect of the application provides an oral antagonistic tablet composition, which comprises, by mass, 35-45 parts of Alagox sodium, 20-30 parts of starch, 20-40 parts of tablet auxiliary materials, 2-8 parts of binders, 2-5 parts of lubricants, 10-15 parts of stabilizers and 1-10 parts of auxiliary materials.
As a preferable scheme, the mass ratio of the sodium tarragon to the tablet auxiliary material is (40-45): 22-28): 25-30.
As a preferable scheme, the mass ratio of the sodium tarragon to the tablet auxiliary material is (42-45): 25-26): 28-30.
As a preferred embodiment, the starch material is a combination of microcrystalline cellulose, sorbitol and composite starch.
As a preferable scheme, the mass ratio of the microcrystalline cellulose, the sorbitol and the composite starch is (1-1.5): 0.4-0.6): 4-5.
As a preferable scheme, the mass ratio of the microcrystalline cellulose to the composite starch is (1-1.2) 0.5 (4-4.5).
As a preferred embodiment, the composite starch is amylopectin and amylose.
As a preferable scheme, the mass ratio of the amylopectin to the amylose is (0.8-1.4): 3-4.
As a preferred embodiment, the branched chain content of the amylopectin is more than or equal to 70%.
As a preferred embodiment, the branched chain content of the amylose is not less than 75%.
According to the application, by selecting the compounded starch material composition, the storage stability and dissolution rate of the tablet can be effectively improved, and the problem of hygroscopicity of the tablet can be effectively solved. By compounding the microcrystalline cellulose, the sorbitol and the composite starch, the supporting effect of a 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 compact internal multidimensional network, so that the uniform dispersion of active ingredients in the system is completed by matching with a preparation process, the uniformity of the system is greatly improved, the starch composition can play a good chain segment supporting effect in the network structure by matching with the microcrystalline cellulose and the sorbitol, thereby effectively stabilizing intermolecular steric hindrance, avoiding high system reactivity caused by the building of the compact network structure, and greatly reducing impurity reaction phenomenon in the storage process, and on the other hand, the formation of a complex compact system is also beneficial to improving the activity resistance of water molecules in the system and the resistance of external moisture entering the system, so that the connection effect of the internal moisture and the external moisture is effectively isolated, the excellent moisture absorption prevention effect is achieved, and the added sorbitol can accelerate the disintegration of the compact network structure of the tablet under the acidic environment after being taken, so that the tablet has excellent dissolution effect.
As a preferred embodiment, the tablet adjuvant is a combination of a colloid adjuvant and a sugar alcohol compound.
As a preferable scheme, the mass ratio of the colloid auxiliary agent to the sugar alcohol compound is (8-10): 0.8-1.
As a preferable scheme, the colloid auxiliary agent is at least one of acacia, xanthan gum, guar gum, konjak gum and gelatin.
As a preferred embodiment, the colloid auxiliary is gelatin.
As a preferable scheme, the weight average molecular weight of the colloid auxiliary agent is 100000-250000.
As a preferable scheme, the weight average molecular weight of the colloid auxiliary agent is 150000-200000.
As a preferred embodiment, the sugar alcohol compound is at least one of mannitol, maltitol, xylitol, lactitol.
As a preferred embodiment, the sugar alcohol compound is a combination of mannitol and lactitol.
As a preferable scheme, the mass ratio of mannitol to lactitol is (3-5) (0.4-0.8).
As a preferable scheme, the mass ratio of mannitol to lactitol is (4-4.5) (0.5-0.6).
The application adds specific sugar alcohol compound and gelatin with specific molecular weight to compound, which greatly improves the stability and water resistance of the tablet. After the two components are compounded, a good active group connecting effect can be formed by a gelatin multi-molecular chain structure and a sugar alcohol compound, so that the gelatin multi-molecular chain structure and the sugar alcohol compound can be more in phase in a system, gelatin can be more biased to form an external wrapping structure for other components along with the repeated extrusion process in the tabletting process, the wrapping structure can form a gelatin colloid layer with higher content and purity on the tablet due to the existence of the sugar alcohol compound, so that a tablet surface with smooth surface energy and lower surface energy is formed, and the surface can greatly improve the forming difficulty of a hydration layer on the surface in contact with moisture when the moisture is contacted, so that the retention time of the moisture on the surface is reduced, and the invasion of the surface moisture causes a plurality of problems.
As a preferred embodiment, the binder is at least one of ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, and methylcellulose.
As a preferred embodiment, the binder is sodium carboxymethyl cellulose.
As a preferable scheme, the mass ratio of the starch to the adhesive is (22-28) to (6-8).
As a preferable scheme, the mass ratio of the starch to the adhesive is (25-26) 7.5.
As a preferable scheme, the lubricant is at least one of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol and magnesium lauryl sulfate.
As a preferred embodiment, the lubricant is hydrogenated vegetable oil.
As a preferable scheme, the stabilizer is at least one of ethylenediamine tetraacetic acid, vitamin C, vitamin E, butyl hydroxy anisole and sodium citrate.
As a preferred embodiment, the stabilizer is a combination of ethylenediamine tetraacetic acid and sodium citrate.
As a preferable scheme, the mass ratio of the ethylenediamine tetraacetic acid to the sodium citrate is (1-2).
As a preferred embodiment, the auxiliary agent is sodium dodecyl sulfate or polyoxyethylated castor oil.
As a preferred embodiment, the auxiliary agent is sodium dodecyl sulfate.
The second aspect of the application provides a preparation process of the oral antagonistic tablet composition, which comprises the following steps of S1, sieving sodium tarragon, starch, tablet auxiliary materials and a binder with a screen of 1-2 mm to obtain mixed powder, S2, mixing the mixed powder with a lubricant, granulating by a dry method, wherein the granulating parameter is 20-40 rpm, the rotating speed of a roller is 25-40 rpm, the pressure of the roller is 10-15 bar, the thickness of an extruded tablet is 1-1.5 mm, the aperture of the screen is 1.2-1.3 mm, the finishing rotating speed of the screen is 25-30 rpm, S3, continuing adding the rest raw materials, mixing, tabletting, and obtaining tablets with a tabletting speed of 50-60 kilotablets/h, a filling depth of 5-6.5 mm, a main tablet thickness of 1-2 mm and a pre-pressed tablet thickness of 1.3-3.25 mm.
The application has the beneficial effects that:
1. the oral antagonistic tablet composition provided by the application effectively solves the problems of hygroscopicity, hydrolysis/degradation and low water solubility of the existing oral antagonistic tablet composition, greatly improves the storage stability and effective storage time of the oral antagonistic tablet composition, avoids the phenomena of excessive impurity generation and self degradation of the oral antagonistic tablet composition, effectively improves the administration safety of the oral antagonistic tablet composition, and has very excellent medical application value.
2. The oral antagonistic tablet composition provided by the application can effectively improve the storage stability and dissolution of tablets and effectively solve the problem of hygroscopicity of tablets by selecting a specific compounded starch material composition, and fully utilizes the supporting effect of a long straight-chain spiral structure in composite starch and the multi-branched structure of amylopectin to build a compact internal multidimensional network, so that the uniform dispersion of active ingredients in a system is completed by matching with a preparation process, the uniformity of the system is greatly improved, the starch composition, together with microcrystalline cellulose and sorbitol, can play a good chain segment supporting effect in the network structure, thereby effectively stabilizing intermolecular steric hindrance, avoiding high system reactivity caused by the building of the compact network structure, greatly reducing impurity reaction phenomenon caused in the storage process, and on the other hand, the formation of a complex compact system is also beneficial to improving the activity resistance of water molecules in the system and the resistance of external moisture entering the system, and further effectively isolating the connection effect of the internal moisture and the external moisture.
3. The oral antagonistic tablet composition provided by the application is compounded by adding the specific sugar alcohol compound and gelatin under the specific molecular weight, so that the stability and the waterproofness of the tablet are greatly improved, after the specific sugar alcohol compound and gelatin are compounded, a good active group connecting effect can be formed by a gelatin multi-molecular chain structure and the sugar alcohol compound, so that the two components can be more in phase in a system, gelatin can be more biased to form an external wrapping structure for other components along with repeated extrusion in the tabletting process, the wrapping structure can form a gelatin colloid layer with higher content and purity on the tablet due to the existence of the sugar alcohol compound, so that a smooth tablet surface with lower surface energy is formed, and when moisture contacts, the surface can greatly improve the difficulty of forming a moisture contact surface hydration layer, so that the retention time of moisture on the surface is reduced, and a plurality of problems caused by invasion of surface moisture are solved.
4. The oral antagonistic tablet composition provided by the application has the advantages that the raw material scheme can effectively improve the stability and hygroscopicity of the tablet, so that the preparation process flow of a finished tablet is greatly simplified, the use of a tablet wrapping material and related processes can be gradually omitted, and the cost and the process complexity are reduced on the premise of ensuring good tablet stability.
Detailed Description
The technical solutions in the above summary of the present application will be further described and illustrated in the following detailed description. And the following examples are merely practical examples for illustrating and explaining the technical aspects in the specification, and should not limit the scope of the claims to be protected by the present application. All technical products based on the technical proposal of the application are covered in the scope of the application.
In the examples which follow, the starting materials are commercially available products, unless otherwise specified, or may be prepared by methods well known to those skilled in the art.
Example 1
Example 1a first aspect provides an oral antagonistic tablet composition, comprising, by mass, 44 parts of elagose sodium, 25 parts of starch, 28 parts of tablet excipients, 7.5 parts of binders, 3 parts of lubricants, 12 parts of stabilizers and 3.5 parts of auxiliaries.
The starch is a composition of microcrystalline cellulose, sorbitol and composite starch, and the mass ratio of the microcrystalline cellulose, the sorbitol and the composite starch is 1:0.5:4.5.
Microcrystalline cellulose is purchased from Hebei's Biotechnology Inc. as a food grade product.
The composite starch is amylopectin and amylose, the mass ratio of the amylopectin to the amylose is 1:3.8, the amylopectin is purchased from the pharmaceutical chemical company of Wuhan and the white pharmaceutical industry Co, the branched chain content is 72%, the amylose is purchased from the biological technology company of Wuhan Hua Xiangke, and the linear chain content is 76%.
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.
The colloid auxiliary agent is gelatin, the weight average molecular weight is 180000, and the colloid auxiliary agent is purchased from Guangzhou Hua Yu biotechnology Co.
The sugar alcohol compound is a composition of mannitol and lactitol, and the mass ratio of the mannitol to the lactitol is 4.2:0.5.
The binder is sodium carboxymethyl cellulose and the lubricant is hydrogenated vegetable oil, which is a food grade product sold by Hebei Bai Biotechnology Co.
The stabilizer is a composition of ethylenediamine tetraacetic acid and sodium citrate, and the mass ratio of the two is 1:2.
The auxiliary agent is sodium dodecyl sulfate.
The second aspect of the embodiment provides a preparation process of an oral antagonistic tablet composition, which comprises the following steps of S1, sieving sodium tarragon, starch, tablet auxiliary materials and a binder with a 1.8mm screen to obtain mixed powder, S2, mixing the mixed powder with a lubricant, granulating by a dry method, wherein the granulating parameter is 30rpm, the roller is 35rpm, the roller is pressed at 15bar, the thickness of an extruded tablet is 1.2mm, the aperture of the screen is 1.2mm, the rotational speed of the whole granule is 25rpm, S3, continuously adding the rest raw materials, mixing, tabletting, wherein the tabletting speed is 55 kilo tablets/h, the filling depth is 5.5mm, the main tabletting thickness is 1.5mm, and the pre-pressed tablet thickness is 2.25 mm.
Example 2
Example 2 a first aspect provides an oral antagonistic tablet composition comprising, by mass, 40 parts of sodium elagose, 22 parts of starch, 30 parts of tablet excipients, 6 parts of binders, 3 parts of lubricants, 12 parts of stabilizers, 2.5 parts of adjuvants.
The starch is a composition of microcrystalline cellulose, sorbitol and composite starch, and the mass ratio of the microcrystalline cellulose, the sorbitol and the composite starch is 1.5:0.4:4.
Microcrystalline cellulose is purchased from Hebei's Biotechnology Inc. as a food grade product.
The composite starch is amylopectin and amylose, the mass ratio of the amylopectin to the amylose is 1:3.8, the amylopectin is purchased from the pharmaceutical chemical company of Wuhan and the white pharmaceutical industry Co, the branched chain content is 72%, the amylose is purchased from the biological technology company of Wuhan Hua Xiangke, and the linear chain content is 76%.
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.
The colloid auxiliary agent is gelatin, the weight average molecular weight is 180000, and the colloid auxiliary agent is purchased from Guangzhou Hua Yu biotechnology Co.
The sugar alcohol compound is a composition of mannitol and lactitol, and the mass ratio of the mannitol to the lactitol is 3.5:0.8.
The binder is sodium carboxymethyl cellulose and the lubricant is hydrogenated vegetable oil, which is a food grade product sold by Hebei Bai Biotechnology Co.
The stabilizer is a composition of ethylenediamine tetraacetic acid and sodium citrate, and the mass ratio of the two is 1:2.
The auxiliary agent is sodium dodecyl sulfate.
The second aspect of the embodiment provides a preparation process of an oral antagonistic tablet composition, which comprises the following steps of S1, sieving sodium tarragon, starch, tablet auxiliary materials and a binder with a 1.8mm screen to obtain mixed powder, S2, mixing the mixed powder with a lubricant, granulating by a dry method, wherein the granulating parameter is 30rpm, the roller is 35rpm, the roller is pressed at 15bar, the thickness of an extruded tablet is 1.2mm, the aperture of the screen is 1.2mm, the rotational speed of the whole granule is 25rpm, S3, continuously adding the rest raw materials, mixing, tabletting, wherein the tabletting speed is 55 kilo tablets/h, the filling depth is 5.5mm, the main tabletting thickness is 1.5mm, and the pre-pressed tablet thickness is 2.25 mm.
Comparative example 1
The specific embodiment of this comparative example is substantially the same as in example 1 except that the oral antagonistic tablet composition comprises, in parts by mass, 50 parts of sodium elego, 15 parts of starch, 15 parts of tablet adjuvants, 5 parts of binders, 2 parts of lubricants, 8 parts of stabilizers, and 2.5 parts of adjuvants.
Comparative example 2
The specific embodiment of this comparative example was substantially the same as in example 1, except that the starch was a combination of microcrystalline cellulose, sorbitol and composite starch, in a mass ratio of 0.5:0.2:6.
Comparative example 3
The specific embodiment of this comparative example is substantially the same as example 1, except that the starch is a combination of microcrystalline cellulose, sorbitol and composite starch in a mass ratio of 2.5:1:4.
Comparative example 4
The specific embodiment of this comparative example is substantially the same as in example 1, except that the composite starch is amylopectin and amylose, and the mass ratio of amylopectin to amylose is 1:1.
Comparative example 5
The specific embodiment of this comparative example was essentially the same as example 1, except that the colloidal auxiliary was gelatin, having a weight average molecular weight of 80000, purchased from Yan Hua Biotechnology Co., ltd.
Comparative example 6
The specific embodiment of this comparative example is substantially the same as example 1 except that the tablet formulation is a combination of a colloidal adjuvant and a sugar alcohol compound in a mass ratio of 15:1.
Comparative example 7
The specific embodiment of this comparative example is substantially the same as example 1 except that the sugar alcohol compound is a composition of mannitol and lactitol in a mass ratio of 5:0.2.
Evaluation of Performance
Stability test the oral antagonistic tablet compositions prepared in examples and comparative examples were placed in a constant temperature and humidity cabinet at 60.+ -. 2 ℃ and 75% humidity for 10 days, and after 10 days were sampled and analyzed for total impurity amount by HPLC test, and the average value of 10 tests was recorded in Table 1.
Moisture absorption resistance test the oral antagonistic tablet compositions prepared in examples and comparative examples were placed in a constant temperature and humidity cabinet at 25.+ -. 2 ℃ and 75% humidity for 21 days, and after 21 days, whether the tablets had obvious moisture absorption and powdering and hydration phenomena or not was observed, if so, the tablets were judged to be unacceptable, otherwise, 50 samples were tested, and the yield was calculated and reported in Table 1.
Dissolution degree the dissolution degree of the tablets prepared in examples and comparative examples was measured at 38℃and 1.2pH, and the average of 10 measurements was recorded in Table 1.
Table 1 results of performance test table
According to the embodiment of the application, the comparative example and the data result in Table 1 show that the embodiment 1 and the embodiment 2 of the application have obvious performance advantages in terms of dissolution, moisture absorption resistance and stability compared with the comparative examples 1-7, the embodiment 1 and the embodiment 2 adopt a specific technical scheme, the supporting effect of a long straight-chain spiral structure in composite starch and the multi-branched structure of amylopectin are fully utilized to build a compact internal multidimensional network, so that the uniform dispersion of active ingredients in the system is completed by matching with the preparation process, the uniformity of the system is greatly improved, the starch composition and microcrystalline cellulose and sorbitol can play a good chain segment supporting effect in the network structure, thereby effectively stabilizing intermolecular steric hindrance, avoiding high system reactivity caused by the building of the compact network structure, greatly reducing impurity reaction phenomenon in the storage process, and on the other hand, the formation of a complex compact system is also beneficial to improving the activity resistance of water molecules in the system and the resistance of external moisture entering the system, thereby effectively isolating the connection effect of the internal moisture and the external moisture.