A preparation method of pentoxifylline sustained-release tablets

Abstract

The present application discloses a method for preparing pentoxifylline sustained-release tablets, comprising the following steps: premixing: mixing pentoxifylline with a sustained-release material to obtain a premixed powder; wet granulation: dissolving a binder in purified water, atomizing and adding it to the premixed powder for wet granulation, wherein the stirring speed of the wet granulation is 55 to 80 rpm, the shear speed is 1400 to 1800 rpm, the atomization pressure is 0.1 to 0.4 MPa, the liquid addition pressure is 0.05 to 0.3 MPa, and the granulation time is 5 to 15 min; wet granulation: making the particles reach a uniform and fine state; drying: drying the particles obtained by wet granulation to control the moisture content of the particles; dry granulation: granulating the dried particles through a sieve; total mixing: adding a flow aid and a lubricant to the particles after granulation and mixing; tableting; coating to obtain pentoxifylline sustained-release tablets. The preparation method of the present application improves the yield in the product production process, and the prepared pentoxifylline sustained-release tablets show dissolution characteristics close to those of the original drug in an in vitro dissolution test.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and in particular relates to a method for preparing a sustained-release tablet whose active ingredient is pentoxifylline. Background Art

[0002] Pentoxifylline is an alkaloid obtained by introducing a pentoxifylline group into theobromine extracted from cocoa beans. Its chemical name is 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione. It is a methylxanthine derivative and a non-selective phosphodiesterase inhibitor. It increases intracellular adenosine triphosphate by inhibiting phosphodiesterase, improves the deformability of red blood cells, reduces fibrinogen, and inhibits the aggregation of red blood cells and platelets.

[0003] Pentoxifylline sustained-release tablets are currently mainly used in China to improve cerebral circulation after ischemic cerebrovascular disease. They can also be used to treat peripheral vascular diseases, such as chronic occlusive vasculitis with intermittent claudication. In addition, there have been many literature reports on new uses of pentoxifylline in recent years. Studies have shown that pentoxifylline can be used to treat early renal failure caused by diabetes, increase red blood cell membrane compliance, reduce high blood viscosity in patients with type 2 diabetes, reduce urine series trace protein and 24-hour urine protein, treat diabetic nephropathy, and prevent the occurrence and development of renal failure; improve the microcirculation of blood vessels in the inner and outer membranes of peripheral nerves, increase the conduction velocity of peripheral nerves, and improve symptoms such as limb numbness and pain in patients with complications of diabetic peripheral neuropathy; inhibit liver fibrosis and be used to treat fatty liver and liver fibrosis.

[0004] In the preparation process of pentoxifylline sustained-release tablets, pentoxifylline has a certain water solubility and will dissolve prematurely during wet granulation, resulting in difficulty in granule formation, or problems such as unstable granule structure and too rapid disintegration may occur during the drying process, thereby affecting the hardness, friability and release characteristics of the final preparation.

[0005] On the other hand, the high content of pentoxifylline in the preparation will increase the difficulty of preparation design and production, requiring more precise process control to ensure uniform distribution and stable release of the drug in the sustained-release material. At the same time, the high content of pentoxifylline will increase the brittleness of the preparation, affecting the mechanical strength and yield of the preparation.

[0006] Chinese patent CN117084990A discloses a method for preparing a sustained-release tablet containing pentoxifylline using hydroxypropyl methylcellulose as a sustained-release skeleton material and an ethanol aqueous solution as a wetting agent. Although this method helps to control drug release, when the ethanol aqueous solution is used as a wetting agent, the particle state is relatively loose, and the particle size distribution at each stage of granulation is not studied, and the yield is very low. At the same time, this method requires strict control of the volatilization and residual amount of ethanol to avoid adverse reactions to patients, and the solvent residue problem that may be generated in the subsequent drying process, which has potential risks to drug quality and patient health.

[0007] Developing a simple and efficient production process for pentoxifylline sustained-release tablets is of great significance for achieving uniform dispersion of pentoxifylline in the sustained-release material to ensure stable release of the drug while ensuring drug yield. Summary of the invention

[0008] The present application provides a method for preparing a pentoxifylline sustained-release tablet, which improves the yield in the product production process by designing and optimizing the steps, ensures the effective utilization of resources and reduces the production cost. At the same time, the pentoxifylline sustained-release tablet prepared by this method shows a dissolution characteristic close to that of the original drug in an in vitro dissolution test.

[0009] In order to solve the above technical problems, the technical solutions provided by the present invention are as follows:

[0010] A method for preparing pentoxifylline sustained-release tablets comprises the following steps:

[0011] 1) Premixing: mixing pentoxifylline with a sustained-release material to obtain a premixed powder;

[0012] 2) Wet granulation: dissolve the binder in purified water, add it to the premixed powder by atomization for wet granulation, the stirring speed of the wet granulation is 55-80 rpm, the shear speed is 1400-1800 rpm, the atomization pressure is 0.1-0.4 MPa, the liquid addition pressure is 0.05-0.3 MPa, and the granulation time is 5-15 min;

[0013] 3) Wet granulation: wet granulation is performed on the granules obtained by wet granulation in 2) to make the granules uniform and fine;

[0014] 4) Drying: Dry the granules obtained in 3) to control the moisture content of the granules;

[0015] 5) Dry granulation: the granules obtained in 4) are granulated through a sieve;

[0016] 6) Total mixing: adding the glidant and lubricant to the granules after granulation and mixing;

[0017] 7) Tableting: tabletting is performed using a tablet press;

[0018] 8) Coating: Use a coating machine to coat to obtain pentoxifylline sustained-release tablets.

[0019] Furthermore, the granulation time is 7 to 15 minutes.

[0020] Furthermore, the atomization pressure is 0.15-0.3 MPa; the liquid addition pressure is 0.1-0.25 MPa.

[0021] Furthermore, after the wet granulation of the granules obtained by the wet granulation, the granules with different granulation times were selected, sampled and dried in an oven, and the particle size distribution data were checked as follows:

[0022]

[0023]

[0024] Furthermore, in the step 3), during the wet granulation process, the material is transferred to a swing granulator and wet granulated using a 14-mesh stainless steel screen.

[0025] Furthermore, during the drying step 4), the moisture content of the particles is controlled below 3.0%.

[0026] Furthermore, in the step 5) of dry granulation, the dried granules are transferred to a swing granulator and dry granulated using a 12-mesh nylon screen.

[0027] Furthermore, in the step 6), a hopper mixer is used for the total mixing, the mixing time is 15 minutes, and the mixer speed is 15 rpm.

[0028] Furthermore, the mass composition of the pentoxifylline sustained-release tablets is as follows:

[0029] 400 parts of pentoxifylline raw material, 140-160 parts of sustained-release material, 6-11 parts of binder, 2-3 parts of lubricant, 12-13 parts of glidant, the sustained-release material is hydroxyethyl cellulose, the binder is povidone, the glidant is talc, and the lubricant is magnesium stearate.

[0030] The invention also provides a pentoxifylline sustained-release tablet.

[0031] Compared with the prior art, the preparation method of the pentoxifylline sustained-release tablets of the present invention has the following advantages:

[0032] Dissolution curve consistency: The preparation process of the sustained-release tablets of the present invention makes the release curve of the drug in the dissolution test closer to that of the original drug, which ensures the stability and consistency of in vivo absorption, helps to maintain a stable blood drug concentration, thereby improving the therapeutic effect and reducing toxic side effects.

[0033] Improved yield: The present invention significantly optimizes the preparation process of pentoxifylline sustained-release tablets and successfully achieves a higher product yield.

[0034] Process optimization and cost control: Innovative preparation methods simplify the production process, potentially reduce raw material consumption and production costs, and improve the economy and sustainability of production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Comparison of dissolution curves of Examples 1-4 and the reference preparation

[0036] Figure 2 Comparison of dissolution curves of comparative examples 1-6 and reference preparations DETAILED DESCRIPTION

[0037] The following will be combined with the drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of this application.

[0038] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0039] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0040] The inventors have found that by controlling the key steps in the preparation method of pentoxifylline sustained-release tablets, not only the f2 similarity of the release curve of the pentoxifylline sustained-release tablets is improved, but also the yield of the pentoxifylline sustained-release tablets can be maintained at a high level, wherein the entire process includes the following main steps:

[0041] 1) Premixing: 400 parts of pentoxifylline and 140-160 parts of hydroxyethylcellulose were mixed in a wet mixing granulator for 5 minutes at a stirring speed of 50 rpm and a shearing speed of 1000 rpm;

[0042] 2) Wet granulation: 10 parts of povidone are dissolved in 206 parts of purified water, and the mixture is placed in a wet mixer granulator at a stirring speed of 55 to 65 rpm, a shearing speed of 1400 to 1800 rpm, and an atomization pressure of 0.1 to 0.4 MPa. Preferably, the atomization pressure is 0.15 to 0.3 MPa, such as 0.15 MPa, 0.2 MPa, 0.25 MPa or 0.3 MPa, but is not limited to the values ​​listed, and other values ​​not listed within the numerical range are also applicable;

[0043] The liquid adding pressure is 0.05 to 0.3 MPa, preferably, the liquid adding pressure is 0.1 to 0.25 MPa, such as 0.1 MPa, 0.15 MPa, 0.2 MPa or 0.25 MPa, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable;

[0044] The granulation time is 5 to 15 minutes, preferably, the granulation time is 7 to 15 minutes, for example, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes or 15 minutes, but it is not limited to the listed values, and other values ​​not listed in the numerical range are also applicable;

[0045] 3) Wet granulation: The granules obtained by wet granulation in 2) are transferred to a swing granulator and wet granulated using a screen, for example, a 13-mesh, 14-mesh, 15-mesh, 16-mesh, 17-mesh, 18-mesh or 19-mesh stainless steel screen, but not limited to the screens listed above, as long as the granules can be made uniform and fine. Granules with different granulation times are selected, sampled and dried in an oven, and the particle size distribution data are checked as follows:

[0046]

[0047] 4) Drying: Drying the particles obtained in 3) by a common drying method such as atmospheric pressure drying, boiling drying, vacuum drying, spray drying, drum drying, fluidized bed drying, infrared drying, etc., but not limited to the listed drying methods, as long as the moisture content of the particles can be controlled to be below 3.0%;

[0048] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a nylon screen, such as 10 mesh, 11 mesh, 12 mesh or 13 mesh, but not limited to the listed screens;

[0049] 6) Total mixing: 12.5 parts of talc and 2.5 parts of magnesium stearate are added to the granulated particles, and mixed in a hopper mixer for 15 minutes at a mixer speed of 15 rpm. The mixer can be selected from common mixing machines such as three-dimensional motion mixers, two-dimensional motion mixers, trough mixers, fluidized bed mixers, etc., but is not limited to the listed mixing machines, as long as the materials can be fully mixed;

[0050] 7) Tableting: tabletting is performed using a tablet press, which can be selected from common tableting methods such as single punch tableting method, rotary tableting method or multi-layer tableting method;

[0051] 8) Coating: Coating is performed using a coating machine, which can be selected from common coating methods such as tumble coating, fluidized bed coating, compression coating or spray coating, to finally obtain pentoxifylline sustained-release tablets.

[0052] The inventors found that, although the principle is not clear, changes in actual experimental conditions in the preparation process of the entire system have a very large impact on the effect of the invention.

[0053] When the atomization pressure is too high during wet granulation, the adhesive may impact the API and sustained-release material at too fast a speed, causing the material to splash everywhere, which not only wastes the raw materials but also may pollute the working environment. At the same time, the strong atomization impact may cause the material in the local area to absorb too much adhesive, forming an overly wet agglomerate, while other areas may not absorb enough, thus affecting the overall uniformity of the material. In addition, too high atomization pressure may cause the particles to be destroyed during the formation process, resulting in uneven particle size distribution of the prepared particles, further affecting the dissolution behavior and in vivo absorption of the preparation.

[0054] When the atomization pressure is too low, the particle cohesion may be insufficient, resulting in the particle size being too small or too large, or the particle structure being loose, which not only affects the physical properties of the preparation (such as hardness and disintegration), but also has a negative impact on the dissolution rate and release characteristics of the drug.

[0055] When the liquid addition pressure is too low, the binder may not be able to effectively penetrate and mix into the material, and it is easy to form a dry core, affecting the dissolution and bioavailability of the preparation. When the liquid addition pressure is too high, the sprayed binder may cause the material to absorb water too quickly, forming an overly wet soft material, thereby reducing the mechanical strength of the particles and increasing the difficulty of subsequent processes such as drying and granulation.

[0056] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0057] Embodiment 1:

[0058] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0059] Preparation process:

[0060] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixing granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0061] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 15 min;

[0062] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0063] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0064] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0065] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0066] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0067] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0068] Finally, 537.2 g of pentoxifylline sustained-release tablets were obtained.

[0069] Determining dissolution similarity

[0070] The dissolution curve of the pentoxifylline sustained-release tablets in the aqueous medium of Example 1 was measured, and the specific measurement method was as follows:

[0071] Dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2)

[0072] Dissolution conditions: prepare the dissolution medium at a speed of 50 revolutions per minute. Operate according to the law. Take 10 ml of the dissolution solution after 1 h, 4 h, 8 h, 12 h and 24 h respectively, and immediately replenish the dissolution medium with the same temperature and volume.

[0073] Test solution: Take the dissolution amount at 1h, 4h, 8h, 12h and 24h respectively, filter, accurately measure 3.0ml, 1.0ml, 1.0ml and 1.0ml of the filtrate respectively, put it into a 25ml volumetric flask, add the dissolution medium to dilute to the scale, and shake well.

[0074] Reference solution: Take an appropriate amount of pentoxifylline reference substance, weigh it accurately by UV-visible spectrophotometry, dissolve it in a dissolution medium and quantitatively dilute it to make a solution containing approximately 17.8 μg per 1 ml.

[0075] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 273nm according to (General Rules 0401 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia), and calculate the dissolution amount of each tablet at different times.

[0076] Then, the dissolution curve was drawn and the dissolution similarity f2 value was determined.

[0077] The f2 value ranges from 0 to 100:

[0078] When f2 ≥ 50, the dissolution curves are generally considered to be similar.

[0079] When f2<50, the dissolution curves of the two are considered to be dissimilar.

[0080] The larger the f2 value, the more similar the dissolution curves are.

[0081] The dissolution curves of the pentoxifylline sustained-release tablets obtained in Example 1 under different conditions were measured, and the results are shown in Table 3 described below.

[0082] Determination of sustained-release tablet yield

[0083] The yield of the pentoxifylline sustained-release tablets of Example 1 was measured to measure the efficiency of converting the raw materials into the target drug product, and the calculation formula is as follows:

[0084] Yield (%) = (actual amount of target product obtained / theoretical amount of target product obtained) × 100%

[0085] The yield of the pentoxifylline sustained-release tablets of Example 1 is shown in Table 4 described below.

[0086] Embodiment 2:

[0087] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0088] Preparation process:

[0089] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0090] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 10 min;

[0091] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0092] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0093] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0094] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0095] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0096] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0097] Finally, 550.0 g of pentoxifylline sustained-release tablets were obtained.

[0098] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Example 2 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0099] Embodiment 3:

[0100] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0101] Preparation process:

[0102] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0103] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.15 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 7 min;

[0104] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0105] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0106] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0107] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0108] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0109] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0110] Finally, 539.5 g of pentoxifylline sustained-release tablets were obtained.

[0111] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Example 3 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0112] Embodiment 4:

[0113] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0114] Preparation process:

[0115] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0116] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.3 MPa, and a liquid addition pressure of 0.2 MPa, and the granulation was continued for 7 min;

[0117] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0118] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0119] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0120] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0121] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0122] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0123] Finally, 545.9 g of pentoxifylline sustained-release tablets were obtained.

[0124] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Example 4 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0125] Comparative Example 1:

[0126] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0127] Preparation process:

[0128] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0129] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 5 min;

[0130] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0131] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0132] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0133] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0134] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0135] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0136] Finally, 397.5 g of pentoxifylline sustained-release tablets were obtained.

[0137] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 1 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0138] Comparative Example 2:

[0139] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0140] Preparation process:

[0141] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0142] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.4 MPa, and a liquid addition pressure of 0.2 MPa, and the granulation was continued for 7 min;

[0143] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0144] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0145] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0146] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0147] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0148] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0149] Finally, 422.0 g of pentoxifylline sustained-release tablets were obtained.

[0150] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 2 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0151] Comparative Example 3:

[0152] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0153] Preparation process:

[0154] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0155] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.3 MPa, and the granulation was continued for 10 min;

[0156] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0157] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0158] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0159] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0160] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0161] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0162] Finally, 410.3 g of pentoxifylline sustained-release tablets were obtained.

[0163] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 3 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0164] Comparative Example 4:

[0165] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0166] Preparation process:

[0167] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0168] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.4 MPa, and a liquid addition pressure of 0.3 MPa, and the granulation was continued for 10 min;

[0169] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0170] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0171] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0172] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0173] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0174] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0175] Finally, 415.0 g of pentoxifylline sustained-release tablets were obtained.

[0176] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 4 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0177] Comparative Example 5:

[0178] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0179] Preparation process:

[0180] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0181] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 15 min;

[0182] 3) Drying: Vacuum extract the granules obtained in 2) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0183] 4) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0184] 5) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0185] 6) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0186] 7) Coating: Use a high-efficiency coating machine for tumbling coating.

[0187] Finally, 403.9 g of pentoxifylline sustained-release tablets were obtained.

[0188] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 5 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0189] Comparative Example 6:

[0190] Pretreatment of raw and auxiliary materials: the feeding frequency of the air flow mill is 200HZ, the feeding pressure is 0.5Mpa, and the grinding pressure is 0.2Mpa. The pentoxifylline is crushed and the particle size is controlled to be D90≤22μm; the hydroxyethyl cellulose is sieved with a 40-mesh rotary vibrating screen and set aside.

[0191] Preparation process:

[0192] 1) Premixing: 400 g of pentoxifylline and 140 g of hydroxyethylcellulose were mixed in a wet mixer granulator for 5 min at a stirring speed of 50 rpm and a shear speed of 1000 rpm;

[0193] 2) Wet granulation: 10 g of povidone was dissolved in 206 g of purified water, and the mixture was placed in a wet mixer granulator at a stirring speed of 60 rpm, a shear speed of 1500 rpm, an atomization pressure of 0.2 MPa, and a liquid addition pressure of 0.1 MPa, and the granulation was continued for 20 min;

[0194] 3) Wet granulation: transfer the material to a swing granulator, use a 14-mesh stainless steel screen for wet granulation, take a sample and dry it in an oven, check the particle size distribution, and make the particles uniform and fine;

[0195] 4) Drying: Vacuum extract the granules obtained in 3) to the boiling granulator; turn on each control button in turn, start heating, and control the air volume at 2000±500m 3 / h, the air inlet temperature is set at 65±5℃; when the material temperature is about 40~42℃, stop heating and start measuring moisture, and the particle moisture is controlled below 3.0%;

[0196] 5) Dry granulation: The dried granules are transferred to a swing granulator and granulated using a 12-mesh nylon screen;

[0197] 6) Total mixing: add 12.5 g of talc and 2.5 g of magnesium stearate to the granulated particles, and mix in a hopper mixer for 15 min at a mixer speed of 15 rpm;

[0198] 7) Tablet pressing: Use a double-discharge high-speed tablet press for tablet pressing;

[0199] 8) Coating: Use a high-efficiency coating machine for tumble coating.

[0200] Finally, 411.5 g of pentoxifylline sustained-release tablets were obtained.

[0201] The dissolution data and yield of the pentoxifylline sustained-release tablets obtained in Comparative Example 6 were measured in the same manner as in Example 1, and the results are shown in Tables 3 to 4 described below.

[0202] The comparison of the conditions of the embodiments and comparative examples is shown in Table 1:

[0203] Table 1 Examples and Comparative Examples Conditions

[0204]

[0205] After wet granulation of the granules obtained by the wet method, samples of different granulation times were taken out and dried in an oven, and the particle size distribution data were checked as shown in Table 2:

[0206] Table 2 Particle size distribution

[0207]

[0208] As can be seen from Table 2, when the granulation time is 7 to 15 minutes, the atomization pressure is 0.15 to 0.3 MPa and the liquid addition pressure is 0.1 to 0.25 MPa, as in Examples 1 to 4, the proportion of the preparation particles between 50 mesh and 100 mesh is relatively large (63.5% to 76.24%), which effectively removes the overly coarse or overly fine particles and achieves the effect of uniform overall particle size. When other conditions are the same, the granulation time is too short (Comparative Example 1) and too long (Comparative Example 6), the proportion of overly large and overly small particles is too large, and the particles cannot reach a uniform and fine state; when other conditions are the same, such as Example 4 and Comparative Example 2, the atomization pressure is not in the range of 0.15 to 0.3 MPa, the proportion of overly large and overly small particles is too large (54.17%), and the particles cannot reach a uniform and fine state; when other conditions are the same, such as Example 2 and Comparative Example 3, the liquid addition pressure is not in the range of 0.1 to 0.25 MPa. In Comparative Example 3 within the range of a, the proportion of oversized and undersized particles is too large (51.47%), and the particles cannot reach a uniform and fine state; when the atomization pressure and the liquid addition pressure are not within the limits of the present invention, such as Comparative Example 4, the proportion of oversized and undersized particles is too large (52.05%), and the particles cannot reach a uniform and fine state; when other conditions are the same, such as Example 1 and Comparative Example 5, which lacks the wet granulation step, the proportion of oversized and undersized particles is too large (55.74%), and the particles cannot reach a uniform and fine state.

[0209] Therefore, the granulation time, atomization pressure, liquid addition pressure and whether there is a wet granulation step work together to make the overall particle size uniform and small.

[0210] The dissolution data are shown in Table 3:

[0211] Table 3 Dissolution

[0212]

[0213] It can be seen from Table 3 that when the granulation time is 7 to 15 minutes, the atomization pressure is 0.15 to 0.3 MPa and the liquid addition pressure is 0.1 to 0.25 MPa, as in Examples 1 to 4, f2 is greater than 50 and the dissolution curves are similar to those of the reference preparation. When other conditions are the same, the granulation time is too short (Comparative Example 1) and too long (Comparative Example 6), f2 is less than 50, and the dissolution rate cannot be similar to that of the reference preparation; when other conditions are the same, such as Example 4 and Comparative Example 2, the atomization pressure is not in the range of 0.15-0.3Mpa, and f2 is 46, which is less than 50, and the dissolution rate cannot be similar to that of the reference preparation; when other conditions are the same, such as Example 2 and Comparative Example 3, the liquid addition pressure is not in the range of 0.1-0.25Mpa, and f2 is 47, which is less than 50, and the dissolution rate cannot be similar to that of the reference preparation; when both the atomization pressure and the liquid addition pressure are not within the limits of the present invention, such as Comparative Example 4, its f2 is 46, which is less than 50, and the dissolution rate cannot be similar to that of the reference preparation; when other conditions are the same, such as Example 1 and Comparative Example 5, Comparative Example 5 lacking the wet granulation step, f2 is 46, which is less than 50, and the dissolution rate cannot be similar to that of the reference preparation.

[0214] Product yield data are shown in Table 4:

[0215] Table 4 Product yield

[0216] sample Yield (%) Example 1 92.3 Example 2 94.5 Example 3 92.7 Example 4 93.8 Comparative Example 1 68.3 Comparative Example 2 72.5 Comparative Example 3 70.5 Comparative Example 4 71.3 Comparative Example 5 69.4 Comparative Example 6 70.7

[0217] It can be seen from Table 4 that when the granulation time is 7 to 15 minutes, the atomization pressure is 0.15 to 0.3 MPa and the liquid addition pressure is 0.1 to 0.25 MPa, as in Examples 1 to 4, the product yield is between 92.3% and 94.5%, which is relatively high. When other conditions are the same, the granulation time is too short, such as in Comparative Example 1, the product yield is 68.3%, and the granulation time is too long, such as in Comparative Example 6, the product yield is 70.7%, and the product yield is low; when other conditions are the same, such as in Example 4 and Comparative Example 2, the atomization pressure is not in the range of 0.15 to 0.3 MPa, the product yield is 72.5%, and the product yield is low; when other conditions are the same, such as in Example 2 and Comparative Example 3, the liquid addition pressure is not in the range of 0.1 to 0.25 MPa, the product yield is 70.5%, and the product yield is low; when both the atomization pressure and the liquid addition pressure are not within the limits of the present invention, such as in Comparative Example 4, the product yield is 71.3%, and the product yield is low; when other conditions are the same, such as in Example 1 and Comparative Example 5, the product yield of Comparative Example 5 lacking the wet granulation step is 69.4%, and the product yield is low.

[0218] It can be seen that in the preparation process, the granulation time, atomization pressure, liquid addition pressure and whether there is a wet granulation step work together to ensure that the solubility of the pentoxifylline sustained-release tablets can achieve a better yield.

[0219] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing pentoxifylline sustained-release tablets, characterized in that: The steps include: 1) Premixing: mixing pentoxifylline with a sustained-release material to obtain a premixed powder; 2) Wet granulation: The binder is dissolved in purified water, and atomized and added to the premixed powder for wet granulation. The stirring speed of the wet granulation is 55-80 rpm, the shear speed is 1400-1800 rpm, the atomization pressure is 0.15-0.3 MPa, the liquid addition pressure is 0.1-0.25 MPa, and the granulation time is 7-15 min; 3) Wet granulation: wet granulation is performed on the granules obtained by wet granulation in 2) to make the granules uniform and fine; 4) Drying: Dry the granules obtained in 3) to control the moisture content of the granules; 5) Dry granulation: the granules obtained in 4) are granulated through a sieve; 6) Total mixing: adding the glidant and lubricant to the granules after granulation and mixing; 7) Tablet pressing: tablet pressing is performed using a tablet press; 8) Coating: coating with a coating machine to obtain pentoxifylline sustained-release tablets; Wherein, the sustained-release material is hydroxyethyl cellulose, and the binder is povidone.

2. A method for preparing pentoxifylline sustained-release tablets according to claim 1, characterized in that: After the wet granulation of the granules obtained by the wet granulation, the granules with different granulation times were selected, sampled and dried in an oven, and the particle size distribution data were checked as follows: 。 3. A method for preparing pentoxifylline sustained-release tablets according to claim 2, characterized in that: In the step 3), the material is transferred to a swing granulator during wet granulation and wet granulated using a 14-mesh stainless steel screen.

4. A method for preparing pentoxifylline sustained-release tablets according to claim 3, characterized in that: In the step 4) of drying, the moisture content of the particles is controlled below 3.0%.

5. A method for preparing pentoxifylline sustained-release tablets according to claim 4, characterized in that: In the step 5) dry granulation, the dried granules are transferred to a swing granulator and dry granulated using a 12-mesh nylon screen.

6. A method for preparing pentoxifylline sustained-release tablets according to claim 5, characterized in that: In the step 6), a hopper mixer is used for the total mixing, the mixing time is 15 minutes, and the mixer speed is 15 rpm.

7. A method for preparing pentoxifylline sustained-release tablets according to any one of claims 1 to 6, characterized in that: The mass composition of the pentoxifylline sustained-release tablets is as follows: 400 parts of pentoxifylline raw material, 140-160 parts of sustained-release material, 6-11 parts of binder, 2-3 parts of lubricant, 12-13 parts of glidant, the sustained-release material is hydroxyethyl cellulose, the binder is povidone, the glidant is talc, and the lubricant is magnesium stearate.

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