Composition containing acotiamide hydrochloride and preparation method thereof

Abstract

The invention relates to the field of medicine preparation, in particular to a composition containing acotiamide hydrochloride and a preparation method of the composition. The invention relates to a composition containing acotiamide hydrochloride. The composition is mainly prepared from active ingredients and auxiliary materials through dry granulation, the active component is acotiamide hydrochloride and / or a hydrate thereof. The acotiamide hydrochloride tablet provided by the invention is prepared by adopting a dry granulation process, so that the risk that active ingredients in wet granulation are easy to generate crystal form transformation in a drying process is avoided; the prepared acotiamide hydrochloride tablet is good in stability and good in dissolution rate.

Description

[0001] This application is a divisional application of application number 201810344310.3, invention name “A composition containing acotiamide hydrochloride and preparation method thereof”, and the application date of the parent case is 2018.04.17. Technical Field

[0002] The present invention relates to the field of drug preparation, and in particular to a composition containing acotiamide hydrochloride and a preparation method thereof. Background Art

[0003] Acotiamide Hydrochloride Tablets Jointly developed by Japan's Sawara Shinyaku Co., Ltd. and Astellas Pharma Group, it is used to treat functional dyspepsia (FD) symptoms such as upper abdominal bloating and premature fullness. The drug inhibits the degradation of acetylcholine by inhibiting the activity of peripheral acetylcholinesterase, thereby improving many FD symptoms.

[0004] The English name or Latin name of Acotiamide hydrochloride hydrate Tablets, the Chinese chemical name is N-[2-(isopropylamino)ethyl]-2-(2-hydroxy-4,5-dimethoxybenzamido)thiazole-4-carboxamide hydrochloride trihydrate, the chemical structure formula is:

[0005]

[0006] The molecular formula is C 21 H 30 N4O5S·HCl·3H2O, molecular weight is 541.06.

[0007] Acotiamide hydrochloride is slightly soluble in water and almost insoluble in a hydrochloric acid medium of pH 1.0, which results in the problem of low solubility and slow dissolution rate of acotiamide hydrochloride. At the same time, acotiamide hydrochloride is easy to lose water under low humidity conditions (<20% RH), and is converted from trihydrate to monohydrate, thereby affecting the stability of the tablets. At the same time, acotiamide hydrochloride itself has poor fluidity and a high proportion in the preparation, which cannot meet the requirements of the direct compression process.

[0008] Since the wet granulation process requires high-temperature drying, and the API easily loses bound water during the drying process, the stability risk of the final product is very high. At the same time, acotiamide hydrochloride itself has poor fluidity and a high proportion in the preparation, which cannot meet the requirements of the direct compression process.

[0009] In view of this, the present invention is proposed. Summary of the invention

[0010] The first object of the present invention is to provide a composition containing acotiamide hydrochloride, which has good stability and good solubility.

[0011] The second object of the present invention is to provide a method for preparing the acotiamide hydrochloride composition, which adopts a dry granulation process to avoid the risk of crystal transformation of the active ingredient during the drying process in wet granulation, and the prepared tablets have moderate hardness, smooth surface and fast disintegration speed.

[0012] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0013] A composition containing acotiamide hydrochloride, which is mainly obtained by dry granulation of active ingredients and auxiliary materials;

[0014] The active ingredient is acotiamide hydrochloride and / or its hydrate.

[0015] The composition containing acotiamide hydrochloride provided by the present invention is prepared by adopting a dry granulation process, thereby avoiding the risk of crystal transformation of the active ingredient in the drying process in wet granulation; the prepared acotiamide hydrochloride tablets have good stability and good solubility.

[0016] Furthermore, the active ingredient is acotiamide hydrochloride and / or its hydrate, preferably one or more of acotiamide hydrochloride monohydrate, acotiamide hydrochloride dihydrate and acotiamide hydrochloride trihydrate, more preferably acotiamide hydrochloride trihydrate.

[0017] The present invention takes acotiamide hydrochloride trihydrate as an example (confirmed by thermogravimetric analysis and moisture determination) to study the factors affecting the stability of the active ingredient crystal form. It is found that under relatively high temperature and humidity conditions, the moisture content of the acotiamide hydrochloride raw material does not change with the high temperature and humidity and the extension of the storage time. It shows that acotiamide hydrochloride trihydrate is its stable crystal form under relatively high temperature and humidity conditions.

[0018] Further, the storage temperature of the active ingredient is 40-60°C and the storage humidity is >25%;

[0019] Preferably, the storage humidity is 30%-35%.

[0020] Furthermore, the particle size of the active ingredient is D(v, 0.5)≤15 μm, D(v, 0.9)≤50 μm.

[0021] For example, in different embodiments, the particle size of the active ingredient is D(v, 0.5)≤12μm, D(v, 0.9)≤48μm; it can also be D(v, 0.5)≤10μm, D(v, 0.9)≤45μm; it can also be D(v, 0.5)≤10μm, D(v, 0.9)≤40μm; and so on.

[0022] The investigation of raw material particle size shows that when the raw material particle size is D(v,0.5)≤15μm and D(v,0.9)≤50μm, the preparation dissolves well, and when it exceeds this range, the dissolution becomes slower and lower.

[0023] Furthermore, the auxiliary materials include fillers, binders, disintegrants, glidants, lubricants and coating powders.

[0024] Preferably, the weight percentage of each raw material except the coating powder is: active ingredient 30%-50%, filler 30%-65%, binder 0.5%-15%, disintegrant 1%-15%, glidant 0.8%-10.5%, lubricant 0.12%-1.5%;

[0025] The coating powder accounts for 1%-5% of the weight of the above raw materials.

[0026] The various components work synergistically together to produce acotiamide hydrochloride tablets with excellent comprehensive performance.

[0027] Preferably, the active ingredient is 38%-45%, the filler is 40%-54%, the binder is 2%-8%, the disintegrant is 3%-10%, the glidant is 2%-5%, and the lubricant is 0.5%-1%;

[0028] The coating powder accounts for 2%-4% of the weight of the above raw materials.

[0029] For example, in different embodiments, the raw materials include: by weight percentage, active ingredient 30%, filler 65%, binder 3.08%, disintegrant 1%, glidant 0.8%, lubricant 0.12%;

[0030] The raw materials may also include: by weight percentage, active ingredient 50%, filler 30%, binder 15%, disintegrant 2%, glidant 1.5%, lubricant 1.5%;

[0031] The raw materials may also include: by weight percentage, active ingredient 33%, filler 40%, binder 0.5%, disintegrant 15%, glidant 10.5%, lubricant 1%;

[0032] The raw materials may also include: by weight percentage, active ingredient 38%, filler 54%, binder 2%, disintegrant 3%, glidant 2%, lubricant 1%;

[0033] The raw materials may also include: by weight percentage, active ingredient 40%, filler 45%, binder 8%, disintegrant 3%, glidant 3.5%, lubricant 0.5%;

[0034] The raw materials may also include: by weight percentage, active ingredient 45%, filler 40%, binder 4.8%, disintegrant 5%, glidant 5%, lubricant 0.2%;

[0035] The raw materials may also include: by weight percentage, active ingredient 40%, filler 41.2%, binder 5%, disintegrant 10%, glidant 3%, lubricant 0.8%; and the like.

[0036] Likewise, in different embodiments, the coating powder may be 1%, 2%, 3%, 4%, 5%, etc., of the total weight of the above-mentioned raw materials.

[0037] Further, the filler includes a hydrophilic fast-dissolving component and an insoluble component;

[0038] The hydrophilic fast-dissolving component includes one or more of lactose, sucrose, glucose and mannitol;

[0039] The insoluble components include one or more of microcrystalline cellulose, starch, pregelatinized starch, and dextrin.

[0040] Furthermore, the binder is one or more of hydroxypropyl cellulose, povidone, hydroxypropyl methyl cellulose, starch and sodium carboxymethyl cellulose, preferably hydroxypropyl cellulose.

[0041] Furthermore, the disintegrant includes one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, pregelatinized starch, starch and calcium carboxymethyl starch, preferably low-substituted hydroxypropyl cellulose.

[0042] Furthermore, the glidant is one or both of silicon dioxide and talc.

[0043] Furthermore, the lubricant is one or more of magnesium stearate, talc, micro-powdered silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol, preferably magnesium stearate.

[0044] Furthermore, the coating powder is a film coating premix.

[0045] The present invention also provides a method for preparing the composition containing acotiamide hydrochloride, comprising the following steps:

[0046] Weigh the active ingredient, filler, glidant, disintegrant and binder and mix;

[0047] The mixture is placed in a dry granulator for granulation to obtain granules;

[0048] A lubricant is added to the granules, mixed evenly, tableted, and coated to obtain the acotiamide hydrochloride tablets.

[0049] Studies have shown that the acotiamide hydrochloride raw material is easy to lose crystal water under low humidity (<20% RH) conditions, resulting in changes in crystal form. The present invention adopts a dry granulation process to avoid the risk of crystal transformation that is prone to occur during the drying process of the active ingredient in wet granulation. At the same time, the direct compression process cannot meet the needs of the direct compression process because the product has large specifications, a high proportion of active ingredients, and poor fluidity, especially after crushing, the particle size is reduced, and the fluidity is further deteriorated. The process of dry granulation is selected to overcome this problem.

[0050] The disintegrant was tested in three ways: internal addition, external addition, and internal and external addition. It was found that the internal and external addition had a better effect. Further, the disintegrant was added twice, once before dry granulation, and once together with the lubricant.

[0051] Furthermore, the weight ratio of the disintegrant added twice is 1:0.8-1.5.

[0052] For example, in different embodiments, the weight ratio of the disintegrant added twice can be 1:0.8, 1:1, 1:1.2, 1:1.5, etc.

[0053] Furthermore, the granulation pressure is 0.2-2 MPa, preferably 0.2-1 MPa.

[0054] When the granulation pressure is high, the granules are harder, the tablet surface is rough, the tablet disintegration time is prolonged, and the dissolution curve is slowed down; when the dry granulation pressure is reduced and controlled at 0.2-1Mpa, the tablet disintegration and dissolution are accelerated.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] (1) The present invention adopts a dry granulation process, thereby avoiding the risk of crystal transformation that is prone to occur during the API drying process in wet granulation; at the same time, it overcomes the problem that wet granulation cannot meet the requirements of direct compression process.

[0057] (2) Controlling the particle size of the raw material drug improves the solubility of the drug.

[0058] (3) Control the pressure of the dry granulation process so that the prepared tablets have moderate hardness, smooth surface and fast disintegration rate.

[0059] (4) The specific addition method of disintegrant effectively promotes the disintegration rate of the drug.

[0060] (5) The storage temperature and humidity of the acotiamide hydrochloride raw material are provided so that the acotiamide hydrochloride is a stable trihydrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the description of the embodiments or the prior art are briefly introduced below.

[0062] Figure 1 It is a scatter diagram of the change of moisture content at different storage times under 20°C / 18%RH conditions in Example 1 of the present invention;

[0063] Figure 2 It is a scatter diagram of the change of moisture content at different storage times under 40°C / 35%RH conditions in Example 1 of the present invention;

[0064] Figure 3 It is a scatter diagram of the change of moisture content at different storage times under the conditions of 60°C / 35%RH in Example 1 of the present invention;

[0065] Figure 4 The dissolution curves of tablets prepared from acotiamide hydrochloride trihydrate with different particle sizes in Example 2 of the present invention;

[0066] Figure 5 The dissolution curves of tablets prepared by different disintegrant addition methods in Example 3 of the present invention;

[0067] Figure 6 The dissolution curves of tablets prepared at different granulation pressures in Example 4 of the present invention;

[0068] Figure 7 The dissolution curves of the tablets prepared in Examples 5 and 6 and other examples of the present invention are shown. DETAILED DESCRIPTION

[0069] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0070] Example 1

[0071] The effects of temperature and humidity on the stability of acotiamide hydrochloride crystals were studied. The API, i.e., the active ingredient, was placed under humidity conditions of 18% RH and 35% RH to examine the changes in its moisture content.

[0072] (1) 20℃ / 18%RH moisture test

[0073] Under the condition of 20℃ / 18%RH, the moisture content of the samples was tested at different storage times. The results are shown in Table 1. The corresponding scatter plot is shown in Figure 1shown.

[0074] Table 1 20℃ / 18%RH moisture survey data

[0075] Storage time (h) Moisture (%) 0 9.98 2 9.65 4 9.18 6 8.98 8 8.51 10 7.24 12 6.35 24 5.47 32 4.72 40 4.39 48 4.35 60 4.38

[0076] The data show that under low humidity conditions, acotiamide hydrochloride trihydrate is an unstable crystalline form; as the storage time increases, the original trihydrate (water content: 9.98%) loses two molecules of water and eventually becomes a monohydrate (water content: 4.38%).

[0077] (2) 40℃ / 35%RH moisture test

[0078] Under the condition of 40℃ / 35%RH, the moisture content of the samples was tested at different storage times. The results are shown in Table 2. The corresponding scatter plot is shown in Figure 2 shown.

[0079] Table 2 40℃ / 35%RH moisture investigation data

[0080]

[0081]

[0082] The data show that under the conditions of 40°C / 35%RH, the moisture content of acotiamide hydrochloride trihydrate was maintained at about 9.97% from 9.98% before storage, that is, the moisture content did not change with the extension of storage time. This shows that acotiamide hydrochloride trihydrate is a stable crystalline form under high humidity conditions.

[0083] (3) 60℃ / 35%RH moisture test

[0084] Under the condition of 60℃ / 35%RH, the moisture content of the samples was tested at different storage times. The results are shown in Table 3. The corresponding scatter plot is shown in Figure 3 shown.

[0085] Table 3 60℃ / 35%RH moisture investigation data

[0086] Storage time (h) Moisture (%) 0 9.98 2 9.94 4 9.98 6 9.97 8 9.98 10 9.94 12 9.92 24 9.98 36 10.01 48 9.96 60 10.02

[0087] The data showed that under relatively high temperature and humidity conditions, the moisture content of the acotiamide hydrochloride API was maintained at about 10.02% from 9.96% before placement, and the moisture content did not change with the higher temperature and humidity and the extension of the placement time. This indicates that the trihydrate of acotiamide hydrochloride is its stable crystalline form under relatively high temperature and humidity conditions.

[0088] The results of the crystal stability of the acotiamide hydrochloride API showed that humidity is the main factor affecting the crystal form of the active ingredient. Further experiments found that under higher humidity conditions (>25% RH), acotiamide hydrochloride is a stable trihydrate; under lower humidity conditions (<20% RH), acotiamide hydrochloride trihydrate eventually converts to a monohydrate through dehydration.

[0089] Therefore, the storage temperature of the active ingredient is 40-60° C., and the storage humidity is >25%; preferably, the storage humidity is 30%-35%.

[0090] Example 2

[0091] Raw material particle size: Acotiamide hydrochloride is slightly soluble in water and almost insoluble in a pH 1.0 hydrochloric acid medium, which results in the problem of low solubility and slow dissolution rate of acotiamide hydrochloride tablets.

[0092] Table 4 Raw materials

[0093] Drugs / Excipients Dosage(g) Acotiamide hydrochloride trihydrate* 100* lactose 78 Microcrystalline Cellulose PH101 32 Hydroxypropyl Cellulose 10 Low substituted hydroxypropyl cellulose 10 internal plus 10 external Silicon dioxide 7.5 Magnesium Stearate 2.5 Film coating premix 7.5 Made 257g / 1000 pieces

[0094] Note: * refers to the feed amount calculated based on anhydrous substance

[0095] Weigh the prescribed amount of acotiamide hydrochloride trihydrate, filler, glidant, disintegrant (internal part), and binder and mix them in a three-dimensional mixer for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Add lubricant and external disintegrant to the granules, mix well, press into tablets, and coat until the tablet core weight increases by 3%.

[0096] The effects of acotiamide hydrochloride trihydrate with different particle sizes on tablets were investigated, as shown in Table 5.

[0097] Table 5 Results of different particle sizes

[0098]

[0099] The mechanical crushing in group 3 is: high-grade crushing by universal crusher.

[0100] In addition, commercial products were tested and the results were as follows: Figure 4 shown.

[0101] The particle size of acotiamide hydrochloride trihydrate is investigated in the present invention, and it is shown that when the particle size of the raw material is D(v, 0.5) ≤ 15 μm and D(v, 0.9) ≤ 50 μm, the preparation dissolves well, and when the particle size exceeds this range, the dissolution becomes slower and lower.

[0102] Example 3

[0103] Methods of adding disintegrants: Investigate the methods of adding all disintegrants internally, externally, and internally and externally (internal and external ratio 1:1).

[0104] The raw materials used are shown in Table 6.

[0105] Table 6 Raw materials

[0106] Drugs / Excipients Dosage(g) Acotiamide hydrochloride trihydrate* 100* lactose 78 Microcrystalline Cellulose PH101 32 starch 10 Low substituted hydroxypropyl cellulose 20 talcum powder 7.5 Magnesium Stearate 2.5 Film coating premix 7.5 Made 257g / 1000 pieces

[0107] Note: * refers to the feed amount calculated based on anhydrous substance

[0108] Group 1:

[0109] Disintegrant addition: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the active ingredient, filler, glidant, disintegrant, and binder in the same amount as in Example 3, and mix them in a three-dimensional mixer for 20 minutes. The above mixture is granulated in a dry granulator with a pressure of 0.2-1 MPa and a screen size of 20 meshes. Add a lubricant to the granules, mix evenly, press into tablets, and coat until the tablet core weight increases by 3%.

[0110] Group 2:

[0111] Disintegrant addition: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the active ingredient, filler, glidant, and binder in the same amount as in Example 3, and place them in a three-dimensional mixer for mixing for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Lubricant and disintegrant are added to the granules, mixed evenly, tableted, and coated until the tablet core weight increases by 3%.

[0112] Group 3:

[0113] Disintegrant is added internally and externally: Acotiamide hydrochloride trihydrate is mechanically crushed, and the active ingredient, filler, glidant, disintegrant (internal addition part), and binder in the prescribed amount are weighed and placed in a three-dimensional mixer for mixing for 20 minutes as in Example Group 3. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Lubricant and external disintegrant are added to the granules, mixed evenly, tableted, and coated until the tablet core weight increases by 3%.

[0114] The tablets prepared in each group were subjected to dissolution testing, and the results are shown in Table 7.

[0115] Table 7 Effects of different disintegrant addition methods on tablets

[0116]

[0117] The curves corresponding to different groups are shown in Figure 5 shown.

[0118] It is proved that when disintegrants are added internally or externally, the product disintegrates fastest and has a higher solubility.

[0119] From the above results, it can be seen that the disintegrant can be added entirely internally, entirely externally, or both internally and externally, among which internally and externally addition is preferred.

[0120] Example 4

[0121] Dry granulation pressure control: Investigate the effect of dry granulation pressure on the appearance, hardness and dissolution of the final tablets.

[0122] Table 8 Raw materials

[0123] Drugs / Excipients Dosage(g) Acotiamide hydrochloride trihydrate* 100* lactose 78 Microcrystalline Cellulose PH101 32 Hydroxypropyl Cellulose 10 Low substituted hydroxypropyl cellulose 10 internal plus 10 external Silicon dioxide 7.5 Magnesium Stearate 2.5 Film coating premix 7.5 Made 257g / 1000 pieces

[0124] Note: * refers to the feed amount calculated based on anhydrous substance

[0125] Group 1:

[0126] Preparation method: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the prescribed amount of active ingredients, fillers, glidants, disintegrants (internal addition part), and binders in a three-dimensional mixer and mix for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 1-2Mpa and a screen mesh of 20 meshes. Lubricants and external disintegrants are added to the granules, mixed evenly, tableted, and coated until the tablet core weight increases by 3%.

[0127] Group 2:

[0128] Preparation method: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the active ingredient, filler, glidant, disintegrant (internal part), and binder in the same manner as in Example 2 Group 3, and mix them in a three-dimensional mixer for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Add lubricant and external disintegrant to the granules, mix evenly, press into tablets, and coat until the tablet core weight increases by 3%.

[0129] Table 9 Test results

[0130]

[0131] The corresponding curve diagram of Table 9 is as follows Figure 6 shown.

[0132] The results show that the greater the dry granulation pressure, the lower the tablet hardness, and the slower the tablet dissolution. The granulation pressure is 0.2-2Mpa, and can be further selected from 0.2-1Mpa.

[0133] In addition, when the granulation pressure is high, the granules are harder, the tablet surface is rough, the tablet disintegration time is prolonged, and the dissolution curve slows down; when the dry granulation pressure of Group 2 is reduced and controlled at 0.2-1Mpa, the tablet disintegration and dissolution are accelerated.

[0134] Example 5

[0135] Effect of changing the hydrophobic filler on tablet formulation.

[0136] Table 10 Raw materials

[0137]

[0138]

[0139] Note: * refers to the feed amount calculated based on anhydrous substance

[0140] Preparation method: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the active ingredient, filler, glidant, disintegrant (internal part), and binder in the same manner as in Example 2 Group 3, and mix them in a three-dimensional mixer for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Add lubricant and external disintegrant to the granules, mix evenly, press into tablets, and coat until the tablet core weight increases by 3%.

[0141] Example 6

[0142] Effect of adjusting the hydrophilic / hydrophobic filler ratio on tablet formulation.

[0143] Table 11 Raw materials

[0144]

[0145]

[0146] Note: * refers to the feed amount calculated based on anhydrous substance

[0147] Preparation method: Mechanically crush acotiamide hydrochloride trihydrate, and weigh the active ingredient, filler, glidant, disintegrant (internal part), and binder in the same manner as in Example 2 Group 3, and mix them in a three-dimensional mixer for 20 minutes. The above mixture is placed in a dry granulator for granulation, with a pressure of 0.2-1Mpa and a screen mesh of 20 meshes. Add lubricant and external disintegrant to the granules, mix evenly, press into tablets, and coat until the tablet core weight increases by 3%.

[0148] The dissolution curves of tablets prepared in different embodiments and commercially available products are shown in FIG. Figure 7 shown.

[0149] The dissolution method was determined using the following steps:

[0150] 1) Method: Dissolution method (Chinese Pharmacopoeia 2015 edition, Part IV, General Chapter "0931 Dissolution and Release Determination Method", Method 2 (Paddle Method)).

[0151] 2) Dissolution medium: 0.1 mol / L HCl, 900 ml

[0152] 3) Speed: 50 rpm

[0153] 4) Sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min, 120min

[0154] 5) Detection method: UV-visible spectrophotometry, detection wavelength: 330nm

[0155] 6) Preparation of test solution: Take 10 ml of solution at each time point, filter, accurately measure 2 ml of the filtrate, place it in a 10 ml volumetric flask, dilute to the scale with 0.1 mol / L HCl, and shake well.

[0156] 7) Preparation of reference solution: Take about 20 mg of acotiamide hydrochloride reference substance, place it in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, dilute to the scale with 0.1 mol / L HCl, and shake well.

[0157] 8) Calculation formula:

[0158]

[0159] Wr: The weight of the reference substance (mg) Vr: The dilution factor of the reference substance

[0160] As: absorbance of the test solution Ar: absorbance of the reference solution

[0161] Specification: 100mg

[0162] Note: 1.1110 = M 盐酸阿考替胺三水合物 / M 盐酸阿考替胺无水物 Since the content of the reference substance is calculated based on the anhydrous substance, the solubility needs to be converted into a coefficient.

[0163] Instrument Model:

[0164] Intelligent dissolution tester (model: ZRS-8G, manufacturer: Tianjin Tianda Tianfa Technology Co., Ltd.)

[0165] The information of commercially available products is as follows:

[0166] Product Name: Tablets

[0167] Chinese name: Acotiamide hydrochloride tablets

[0168] English Name: Acotiamide Hydrochloride Hydrate Tablets

[0169] Manufacturer: Japan Sawasaki Pharmaceuticals Co., Ltd. and Astellas Pharma Group

[0170] Research batch: E317

[0171] It can be seen that the preparation prepared by the present invention has a significantly better dissolution rate than the commercially available product and has a higher bioavailability.

[0172] Experimental example

[0173] Preparation stability test

[0174] 1. Stability study program test items

[0175] Table 12 Stability test conditions

[0176]

[0177]

[0178] 2. Stability data

[0179] 2.1 Influencing factors test

[0180] Table 13 Test results of factors affecting the preparation of Acotiamide Hydrochloride Tablets in Group 3 of Example 3

[0181]

[0182]

[0183] Note: / / indicates undetermined

[0184] Other embodiments such as Example 5 and Example 6 were also tested using the same method, and the results were consistent with the above results, so they are not listed one by one.

[0185] 2.2 Accelerated test

[0186] Example 4 Accelerated test of tablets prepared in Group 2, Example 5 and Example 6.

[0187] Accelerated conditions: 40℃±2℃, RH75%±5%. Packaging: Aluminum-plastic blister.

[0188] Table 14 Results of accelerated test of acotiamide hydrochloride tablets

[0189]

[0190]

[0191]

[0192] Note: / / indicates undetermined

[0193] 2.3 Long-term trials

[0194] Example 4 Long-term test of tablets prepared from Group 2, Example 5 and Example 6.

[0195] Long-term conditions: 25℃±2℃, RH60%±5%. Packaging: Aluminum-plastic blister.

[0196] Table 15 Results of long-term study on acotiamide hydrochloride tablets

[0197]

[0198]

[0199] Note: / / indicates undetermined

[0200] In addition, the stability test results of other groups such as Group 3 in Example 3 are consistent with the above and are not listed one by one.

[0201] Stability conclusion: The test results of influencing factors show that:

[0202] ① Under high humidity conditions of 75% and 92.5%, the weight gain of the samples was less than 5% (the weight gain was between 2.96% and -4.62%); under high temperature conditions of 40°C and 60°C, the weight loss of the samples was small (the weight loss was between 1.13% and -2.66%).

[0203] ② Under each condition, the properties, related substances, solubility and content did not change significantly;

[0204] The results of accelerated and long-term stability tests show that:

[0205] ① After being placed under accelerated conditions for 6 months, there was no obvious change trend in the properties, related substances, solubility and content of the three batches of samples in the pilot test.

[0206] ② After being placed under long-term conditions for 6 months, the properties, related substances, solubility and content of the three batches of samples in the pilot test showed no obvious change trend.

[0207] This indicates that the acotiamide hydrochloride tablets provided by the present invention have excellent stability.

[0208] In addition, the following tests were performed:

[0209] The active ingredient is selected from acotiamide hydrochloride monohydrate or acotiamide hydrochloride dihydrate or a mixture thereof or a mixture thereof with acotiamide hydrochloride trihydrate, and the remaining ingredients are the same as those in Example 5. The preparation is prepared by the same method as in Example 5, and the measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0210] The hydrophilic fast-dissolving component is selected from any one or more of sucrose, glucose, mannitol and a mixture of sucrose and lactose. The remaining ingredients are the same as those in Example 5 and are prepared by the same method as in Example 5. The measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0211] The insoluble component is selected from dextrin or a combination thereof with any one or more of microcrystalline cellulose, starch, and pregelatinized starch. The remaining ingredients are the same as those in Example 5 and are prepared by the same method as in Example 5. The measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0212] The binder is selected from one or more of hydroxypropyl cellulose, povidone, hypromellose and sodium carboxymethyl cellulose and a mixture thereof with starch. The remaining ingredients are the same as those in Example 5 and are prepared by the same method as in Example 5. The measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0213] The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, pregelatinized starch, starch and calcium carboxymethyl starch and a mixture thereof with low-substituted hydroxypropyl cellulose. The remaining ingredients are the same as those in Example 5 and are prepared by the same method as in Example 5. The measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0214] The lubricant is selected from one or more of talc, micropowdered silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol, and a mixture thereof with magnesium stearate. The remaining ingredients are the same as those in Example 5. The preparation is prepared by the same method as in Example 5, and the measurement parameters of the obtained preparation are basically the same as those in Example 5.

[0215] By changing the ratio of the raw materials, as exemplified in the content of the invention, the types of ingredients are the same as in Examples 5-6, and the same method as in Example 5 is adopted for preparation, the measurement parameters of the obtained preparation are basically the same as those of Examples 5 and 6.

[0216] Although the present invention has been illustrated and described with specific embodiments, it will be appreciated that many other changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, it is intended to include all such changes and modifications within the scope of the present invention in the appended claims.

Claims

1. A composition containing acotiamide hydrochloride, characterized in that: It is mainly obtained by dry granulation of active ingredients and excipients; The active ingredient is acotiamide hydrochloride and / or its hydrate; Preferably, the active ingredient is one or more of acotiamide hydrochloride monohydrate, acotiamide hydrochloride dihydrate and acotiamide hydrochloride trihydrate, more preferably acotiamide hydrochloride trihydrate; Preferably, the storage temperature of the active ingredient is 40-60°C and the storage humidity is >25%; Preferably, the storage humidity is 30%-35%.

2. The composition containing acotiamide hydrochloride according to claim 1, characterized in that The particle size of the active ingredient is D(v, 0.5)≤15 μm, D(v, 0.9)≤50 μm.

3. The composition containing acotiamide hydrochloride according to claim 2, characterized in that: The auxiliary materials include fillers, binders, disintegrants, glidants, lubricants and coating powders; Preferably, the weight percentage of each raw material except the coating powder is: active ingredient 30%-50%, filler 30%-65%, binder 0.5%-15%, disintegrant 1%-15%, glidant 0.8%-10.5%, lubricant 0.12%-1.5%; The coating powder accounts for 1%-5% of the weight of the above raw materials.

4. The composition containing acotiamide hydrochloride according to claim 3, characterized in that Active ingredient 38%-45%, filler 40%-54%, binder 2%-8%, disintegrant 3%-10%, glidant 2%-5%, lubricant 0.5%-1%; The coating powder accounts for 2%-4% of the weight of the above raw materials.

5. The composition containing acotiamide hydrochloride according to claim 3 or 4, characterized in that: The filler includes a hydrophilic fast-dissolving component and an insoluble component; The hydrophilic fast-dissolving component includes one or more of lactose, sucrose, glucose and mannitol; The insoluble components include one or more of microcrystalline cellulose, starch, pregelatinized starch, and dextrin; Furthermore, the binder is one or more of hydroxypropyl cellulose, povidone, hydroxypropyl methyl cellulose, starch and sodium carboxymethyl cellulose, preferably hydroxypropyl cellulose.

6. The composition containing acotiamide hydrochloride according to claim 3 or 4, characterized in that: The disintegrant comprises one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, pregelatinized starch, starch and calcium carboxymethyl starch, preferably low-substituted hydroxypropyl cellulose; Furthermore, the glidant is one or both of silicon dioxide and talc; Further, the lubricant is one or more of magnesium stearate, talc, micro-powdered silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol, preferably magnesium stearate; Furthermore, the coating powder is a film coating premix.

7. A method for preparing a composition containing acotiamide hydrochloride according to any one of claims 3 to 6, characterized in that: The following steps are involved: Weigh the active ingredient, filler, glidant, disintegrant and binder and mix; The mixture is placed in a dry granulator for granulation to obtain granules; A lubricant is added to the granules, mixed evenly, tableted, and coated to obtain the acotiamide hydrochloride tablets.

8. The method for preparing a composition containing acotiamide hydrochloride according to claim 7, characterized in that: The disintegrant is added twice, once before dry granulation, and once together with the lubricant.

9. The method for preparing a composition containing acotiamide hydrochloride according to claim 8, characterized in that: The weight ratio of the disintegrant added twice is 1:0.8-1.

5.

10. The method for preparing a composition containing acotiamide hydrochloride according to claim 7, characterized in that: The granulation pressure is 0.2-2 MPa, preferably 0.2-1 MPa.

Images