Theophylline sustained-release tablets and their preparation method

Abstract

This invention discloses a theophylline sustained-release tablet and its preparation method, belonging to the field of pharmaceutical formulation technology. The technical solution includes the following steps: 1) preparation of a pore-forming agent; 2) preparation of a blocking agent; 3) premixing: anhydrous theophylline and a hydrophilic gel framework material are premixed to obtain a premixed powder; 4) first granulation: the prepared pore-forming agent aqueous solution is added to the premixed powder, granulated, dried, and sized to obtain granules one; 5) second granulation: the prepared blocking agent ethanol solution is added to granules one, granulated, dried, and sized to obtain granules two; 6) tableting: a lubricant is added to granules two, and tablets are compressed using a tableting machine to obtain theophylline sustained-release tablets. This invention provides a theophylline sustained-release tablet and its preparation method with good sustained-release effect, long duration of action, and good batch-to-batch repeatability. The preparation method is simple and requires no heating; the prepared theophylline sustained-release tablets show good compatibility with the reference formulation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a theophylline sustained-release tablet and its preparation method. Background Technology

[0002] Currently, the prevalence and mortality rates of bronchial asthma are gradually increasing, making it a major chronic disease that seriously threatens people's health. Theophylline is a classic smooth muscle relaxant and diuretic. It increases the concentration of cyclic adenosine monophosphate (cAMP) in bronchial smooth muscle cells by inhibiting the destruction of cAMP by phosphodiesterase, thus relaxing bronchial and vascular smooth muscle. It also inhibits the reabsorption of sodium ions and water by the renal tubules, exhibiting a certain diuretic effect. It is mainly used for bronchial asthma. It can also be used for angina pectoris, biliary colic, and cardiac edema. However, theophylline has a very narrow effective blood concentration range (5-20 μg / ml), with the maximum effective blood concentration being only four times the minimum effective blood concentration, and a short half-life of approximately 5 hours. To maintain a certain blood drug concentration, medication must be taken every 5 hours. Such frequent medication is inconvenient for patients and results in fluctuating blood drug concentrations, sometimes exceeding the optimal therapeutic concentration and potentially causing toxic side effects, and sometimes falling far below the required concentration, failing to produce a therapeutic effect. Furthermore, bronchial asthma attacks often occur in the early morning, making nighttime medication extremely inconvenient. Taking medication only at bedtime cannot completely prevent asthma attacks during sleep. Sustained-release formulations can reduce peak blood drug concentrations and have a longer duration of effect, thus effectively reducing the adverse reactions of theophylline.

[0003] Chinese invention patent CN111202716A discloses a theophylline sustained-release tablet and its preparation method, comprising: 20-50% anhydrous theophylline; 5-15% matrix material; 3-7% lubricant; 2-6% pore-forming agent; 30-50% filler; and 4-8% disintegrant. The matrix material is composed of ethyl cellulose and hydrogenated vegetable oil in a mass ratio of 1-3:1. The above raw materials are prepared according to the following steps: (1) 40-50% of the total amount of anhydrous theophylline, matrix material, pore-forming agent, and lubricant are pulverized, sieved, and mixed evenly to obtain a mixture; (2) the mixture is hot-melt extruded; (3) cooled, cut into granules, and sieved; (4) the remaining lubricant, filler, and disintegrant are added, mixed evenly, and compressed into tablets. The theophylline sustained-release tablets prepared by this method not only require a high temperature for hot-melt extrusion, which poses a certain risk, but also the similarity factor F2 of the prepared theophylline sustained-release tablets is less than 65, resulting in poor fitting with the reference preparation. Summary of the Invention

[0004] This invention provides a theophylline sustained-release tablet and its preparation method, offering a theophylline sustained-release tablet with good sustained-release effect, long duration of action, and good batch-to-batch reproducibility, along with its preparation method. The preparation method is simple and requires no heating; the prepared theophylline sustained-release tablet shows good compatibility with the reference formulation.

[0005] The technical solution of this invention is as follows:

[0006] In the first aspect, a method for preparing theophylline sustained-release tablets is disclosed, comprising the following steps:

[0007] 1) Preparation of porogen: Add the porogen to purified water, stir and dissolve to obtain an aqueous solution of the porogen;

[0008] 2) Preparation of the inhibitor: Add the inhibitor to ethanol and dissolve it in a water bath to obtain an ethanol solution of the inhibitor;

[0009] 3) Premixing: Anhydrous theophylline and hydrophilic gel framework material are premixed to obtain premixed powder;

[0010] 4) First granulation: Add the prepared pore-forming agent aqueous solution to the premixed powder, granulate, dry, and sizing to obtain granules.

[0011] 5) Second granulation: Add the prepared ethanol solution of the inhibitor to granules one, granulate, dry, and sizing to obtain granules two;

[0012] 6) Mixing and tableting: Add lubricant to granules 2 and use a tableting machine to compress the theophylline sustained-release tablets.

[0013] Preferably, the raw materials include the following components: 70-90 parts of anhydrous theophylline; 0.5-6 parts of hydrophilic gel skeleton material; 0.5-5 parts of pore-forming agent; 10-15 parts of inhibitor; and 0.1-3 parts of lubricant.

[0014] Preferably, the premixing in step 3) specifically involves placing anhydrous theophylline and hydrophilic gel skeleton material in a wet granulator, with a stirring speed of 100-300 rpm, preferably 300 rpm; a cutting speed of 800-1000 rpm, preferably 1000 rpm; and a mixing time of 100-300 s, preferably 300 s.

[0015] Preferably, in step 4), the prepared pore-forming agent aqueous solution is added to the premixed powder and granulated in a wet granulator. The pore-forming agent is added while granulating, the stirring speed is 300-600 rpm, preferably 500 rpm; the cutting speed is 1500-2000 rpm, preferably 2000 rpm; the granulation time is 90-150 s, preferably 120 s; in step 4), the drying is carried out by placing the granulated particles in a fluidized bed for drying at a temperature of 30-50℃, preferably 40℃; the moisture content is ≤2%, preferably ≤1%; after drying, the particles are granulated using a high-speed finishing machine with a sieve mesh of 20-24 mesh, preferably 24 mesh.

[0016] Preferably, in step 5), the prepared ethanol solution of the inhibitor is added to the granulated particles in the wet granulator. The inhibitor is preferably added while granulating. The stirring speed is 300-600 rpm, preferably 500 rpm. The cutting speed is 1500-2000 rpm, preferably 2000 rpm. The granulation time is 90-150 s, preferably 120 s. In step 5), the drying is carried out by placing the granulated particles in a fluidized bed for drying at a temperature of 30-50℃, preferably 40℃. The moisture content is ≤2%, preferably ≤1%. After drying, the particles are granulated using a high-speed finishing machine with a sieve mesh of 16-24 mesh, preferably 16 mesh.

[0017] Preferably, the pore-forming agent is one or both of polyvinylpyrrolidone K25 and polyvinylpyrrolidone K30, with polyvinylpyrrolidone K30 being the most preferred.

[0018] Preferably, the hydrophilic gel skeleton is one or both of hydroxyethyl cellulose 250M and hydroxyethyl cellulose 250HX.

[0019] Preferably, the retardant is hexadecanoic acid alcohol.

[0020] Preferably, the lubricant is one or more of magnesium stearate, talc, and silicon dioxide, and more preferably magnesium stearate or talc.

[0021] Secondly, the method for preparing theophylline sustained-release tablets disclosed herein is presented.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] 1. This invention stabilizes the release rate and avoids the "peak and trough" phenomenon of drug release, thereby ensuring the stable efficacy of the drug while guaranteeing patient safety.

[0024] 2. This invention employs a method of first granulation with a pore-forming agent to ensure uniform distribution of the pore-forming agent around anhydrous theophylline, followed by secondary granulation by dissolving a prepared inhibitor to ensure that the inhibitor adheres to each particle. This ensures the slow and stable release of theophylline sustained-release tablets. In this application, the pore-forming agent used is povidone. On the one hand, considering the adhesive effect during granulation, the pore-forming agent also acts as a binder, causing the materials to adhere together to form particles. On the other hand, considering that povidone is soluble in water, after the tablets are formed, over time, the povidone dissolves in water to form pores, allowing the raw material to be slowly released through these pores.

[0025] 3. This invention ensures the uniformity of material mixing by mixing after two granulation processes. The theophylline sustained-release tablets prepared by this invention have good release rate and batch reproducibility, which effectively solves the problem of poor reproducibility in traditional processes and is suitable for industrial production.

[0026] 4. This invention optimizes the ratio of the hydrophilic gel skeleton and the blocking agent, as well as the method of adding the blocking agent, thereby achieving the same sustained-release effect as the marketed reference formulation. Detailed Implementation

[0027] The raw materials used in the embodiments of this invention are as follows:

[0028] The hydrophilic gel skeleton is at least one of hydroxyethyl cellulose 250M and hydroxyethyl cellulose 250HX, manufactured by Ashland Corporation. In the examples, hydroxyethyl cellulose 250HX is used.

[0029] The pore-forming agent is at least one of polyvinylpyrrolidone K25 and polyvinylpyrrolidone K30, and polyvinylpyrrolidone K30 is used in the examples;

[0030] The retardant is hexadecanoic acid;

[0031] The lubricant is at least one of magnesium stearate, talc, and silicon dioxide; magnesium stearate and talc are used in the examples.

[0032] The proportions of each raw material are as follows:

[0033] Anhydrous theophylline 70-90 parts; hydrophilic gel skeleton material: 0.5-6 parts; pore-forming agent: 0.5-5 parts; inhibitor: 10-15 parts; lubricant: 0.1-3 parts.

[0034] Reference formulation information:

[0035] Product Name UNICON English name Theophylline Sustained-release Tablets Specification 100mg (calculated as anhydrous theophylline) Holder Nichi-Iko Pharmaceutical Co.,Ltd

[0036] Example 1

[0037] The specific steps for preparing the theophylline sustained-release tablets are as follows:

[0038] 1) Add 1.785g of povidone K30 to 33.915g of purified water, stir and dissolve to obtain an aqueous solution of the porogen povidone K30;

[0039] 2) Add 42.66g of cetearyl alcohol to 28.44g of 95% ethanol, heat in a water bath at 60°C until completely dissolved, to obtain a cetearyl alcohol ethanol solution as an inhibitor.

[0040] 3) Place 300g of anhydrous theophylline and 7.13g of hydroxyethyl cellulose 250HX into a wet granulator, turn on the stirring speed of 300rpm and the cutting speed of 1000rpm, and premix for 300s.

[0041] 4) Add the prepared pore-forming agent polyvinyl ketone K30 aqueous solution from step 1) to the premixed material from step 3), and granulate while adding the polyvinyl ketone K30 aqueous solution; the stirring speed is 500 rpm; the cutting speed is 2000 rpm; the granulation time is 120 s; place the granulated particles in a fluidized bed for drying at a temperature of 40℃; the moisture content is reduced to ≤1%; after drying, use a high-speed granulator to granulate the particles, with a sieve mesh of 24 mesh;

[0042] 5) Place the granulated particles from step 4) into a wet granulator, add the prepared cetearyl alcohol ethanol solution from step 2) into the wet granulator while granulating; the stirring speed is 500 rpm; the cutting speed is 2000 rpm; the granulation time is 120 s; place the granulated particles in a fluidized bed for drying at a temperature of 40℃; the moisture content is reduced to ≤1%; after drying, use a high-speed granulator to granulate the particles, with a sieve mesh of 16 mesh.

[0043] 6) Add 3.57g of talc and 1.785g of magnesium stearate to the granules in step 5) and mix evenly. Compress the granules using a tablet press. The tablet hardness should be 2-4 kp. Produce three batches of samples in parallel.

[0044] Example 2

[0045] Compared with Example 1, the difference is that in step 2), the amount of cetearyl alcohol used is 42.625g and the amount of ethanol used is 28.41g; in step 3), the amount of hydroxyethyl cellulose is 5.355g. The other components and steps of this example are the same as those of Example 1.

[0046] Example 3

[0047] Compared with Example 1, the difference is that in step 2), the amount of cetearyl alcohol is 39.27g and the amount of ethanol is 26.18g; in step 3), the mass of hydroxyethyl cellulose is 10.71g. The other components and steps of this example are the same as those of Example 1.

[0048] Comparative Example 1

[0049] Compared with Example 3, the difference is that in step 2), 39.27g of cetearyl alcohol is divided into two parts, one part is 7.854g (20%), which is premixed with anhydrous theophylline and hydroxyethyl cellulose in step 3), and the other part is 31.416g (80%), which is added to a wet granulator together with the inhibitor in step 5) for granulation. Other components and steps are the same as in Example 3.

[0050] Comparative Example 2

[0051] Compared with Example 3, the difference is that in step 2), 39.27g of cetearyl alcohol is divided into two parts, one part accounting for 15.708g (40%), which is premixed with anhydrous theophylline and hydroxyethyl cellulose in step 3), and the other part accounting for 23.562g (60%), which is added to a wet granulator together with the inhibitor in step 5) for granulation. Other components and steps are the same as in Example 3.

[0052] Comparative Example 3

[0053] Compared with Example 3, the difference is that in step 2), 39.27g of cetearyl alcohol is divided into two parts. One part, accounting for 23.562g (60%), is premixed with anhydrous theophylline and hydroxyethyl cellulose in step 3). The other part, accounting for 15.708g (40%), is added to a wet granulator together with the inhibitor in step 5) for granulation. The other components and steps are the same as in Example 3.

[0054] Example 4

[0055] The difference between this embodiment and Example 1 is that in step 2), the amount of cetearyl alcohol used is 35.7g and the amount of ethanol used is 23.8g; and in step 3), the amount of hydroxyethyl cellulose used is 14.28g. The other components and steps in this embodiment are the same as in Example 1.

[0056] To better compare the experimental conditions of Examples 1-4 and Comparative Examples 1-3, the key contents are listed in Table 1.

[0057] Table 1

[0058]

[0059] According to the dissolution method provided in the "Japanese Medical Pharmaceutical Quality Information Collection", the theophylline sustained-release tablets prepared in Examples 1-4 and Comparative Examples 1-3, as well as the reference formulation, were subjected to release tests. The specific dissolution test methods are as follows:

[0060] Dissolution apparatus: slurry method, 100 rpm;

[0061] Dissolution medium: water;

[0062] Media volume: 900ml;

[0063] Medium temperature: 37℃;

[0064] Sampling time: 4, 8, 24 hours, solvent replenishment;

[0065] Detection conditions: UV, 271nm;

[0066] The specific results are shown in Table 2.

[0067] Table 2

[0068]

[0069]

[0070] The release rate results show that all Examples 1-4 and Comparative Examples 1-3 in this invention meet the release rate requirements of the "Japanese Medical Pharmaceutical Quality Information Collection": 15%-45% at 4 hours, 35%-65% at 8 hours, and ≥70% at 24 hours. To accurately determine the fit between this invention and the reference preparation, this invention further investigated the release rate at multiple time points, such as 1 hour, 2 hours, 6 hours, and 12 hours, as shown in Table 2. The similarity factor of all examples and comparative examples in this invention is greater than 50, and the difference between Example 1 and the reference preparation at each detection point is less than 5, with a very small RSD and a similarity factor reaching 75, indicating that Example 1 has a good fit with the reference preparation.

[0071] As shown in Table 1, this invention has conducted a refined study on the preparation method of theophylline sustained-release tablets. The ratio of hydroxyethyl cellulose to cetearyl alcohol, and the internal and external addition of cetearyl alcohol, all affect the release of theophylline sustained-release tablets. In this invention, the various process parameters must be coordinated to achieve a better release effect.

[0072] In Example 3 and Comparative Examples 1, 2, and 3, although the similarity factors were all high, the RSD was larger and the intra-batch dissolution effect was poor due to the different methods and proportions of adding hexadecanoic acid. This demonstrates that the method and proportion of adding hexadecanoic acid are among the important performance characteristics of theophylline sustained-release tablets. This invention, through two granulation processes and two drying processes, yields a method for obtaining a theophylline sustained-release tablet with good sustained-release effect, intra-batch stability, and good repeatability. Furthermore, this invention optimizes the addition methods and proportions of relevant raw materials and excipients, resulting in a theophylline sustained-release tablet that highly matches the effects of commercially available theophylline sustained-release tablets.

[0073] Although the present invention has been described in detail by way of preferred embodiments, the invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A process for the preparation of sustained release theophylline tablets, characterized in that, Includes the following steps: 1) Preparation of porogen: Add the porogen to purified water, stir and dissolve to obtain an aqueous solution of the porogen; The porogen is povidone K30, the amount of porogen is 1.785g, and the amount of purified water is 33.915g. 2) Preparation of the inhibitor: Add the inhibitor to ethanol and dissolve it in a water bath to obtain an ethanol solution of the inhibitor; The inhibitor is cetearyl alcohol, and the amount of the inhibitor is 42.66g; the ethanol is 95% ethanol, and the amount of ethanol is 28.44g. 3) Premixing: Anhydrous theophylline and hydrophilic gel framework material are premixed to obtain premixed powder; The amount of anhydrous theophylline used is 300g; The hydrophilic gel skeleton material is hydroxyethyl cellulose 250HX, and the amount of hydrophilic gel skeleton material used is 7.13g; 4) First granulation: Add the prepared pore-forming agent aqueous solution to the premixed powder, granulate, dry, and sizing to obtain granules. 5) Second granulation: Add the prepared ethanol solution of the inhibitor to granules one, granulate, dry, and sizing to obtain granules two; 6) Mixing and tableting: Add lubricant to granules II and compress using a tableting machine to obtain theophylline sustained-release tablets; The lubricant is talc and magnesium stearate; the amounts of talc and magnesium stearate are 3.57g and 1.785g, respectively.

2. The process for preparing the theophylline sustained release tablet according to claim 1, wherein The premixing in step 3) specifically involves placing anhydrous theophylline and hydrophilic gel skeleton material in a wet granulator, with a stirring speed of 100-300 rpm and a cutting speed of 800-1000 rpm; the mixing time is 100-300 s.

3. The method for preparing theophylline sustained-release tablets as described in claim 1, characterized in that, The premixing in step 3) specifically involves placing anhydrous theophylline and hydrophilic gel skeleton material in a wet granulator, with a stirring speed of 300 rpm, a cutting speed of 1000 rpm, and a mixing time of 300 s.

4. The method for preparing theophylline sustained-release tablets as described in claim 1, characterized in that, In step 4), the prepared pore-forming agent aqueous solution is added to the premixed powder and granulated in a wet granulator. The pore-forming agent is added while granulating, and the stirring speed is 300-600 rpm; the cutting speed is 1500-2000 rpm; and the granulation time is 90-150 s. In step 4), the granulated particles are dried in a fluidized bed at a temperature of 30-50℃ with a moisture content of ≤2%. After drying, the particles are granulated using a high-speed granulator with a sieve mesh of 20-24 mesh.

5. The method for preparing theophylline sustained-release tablets as described in claim 1, characterized in that, In step 4), the prepared pore-forming agent aqueous solution is added to the premixed powder and granulated in a wet granulator. The pore-forming agent is added while granulating, the stirring speed is 500 rpm, the cutting speed is 2000 rpm, and the granulation time is 120 s. In step 4), the granulated particles are dried in a fluidized bed at a temperature of 40℃ with a moisture content of ≤1%. After drying, the particles are granulated using a high-speed granulator with a sieve mesh of 24 mesh.

6. The method for preparing theophylline sustained-release tablets as described in claim 1, characterized in that, In step 5), the prepared ethanol solution of the inhibitor is added to the granulated particles in the wet granulator. The inhibitor is added while granulating. The stirring speed is 300-600 rpm. The cutting speed is 1500-2000 rpm. The granulation time is 90-150 s. In step 5), the granulated particles are dried in a fluidized bed at a temperature of 30-50℃. The moisture content is ≤2%. After drying, the particles are granulated using a high-speed finishing machine with a sieve mesh of 16-24 mesh.

7. The method for preparing theophylline sustained-release tablets as described in claim 1, characterized in that, In step 5), the prepared ethanol solution of the inhibitor is added to the granulated particles in the wet granulator. The inhibitor is added while granulating. The stirring speed is 500 rpm, the cutting speed is 2000 rpm, and the granulation time is 120 s. In step 5), the granulated particles are dried in a fluidized bed at a temperature of 40°C. The moisture content is reduced to ≤1%. After drying, the particles are granulated using a high-speed finishing machine with a 16-mesh sieve.

8. The theophylline sustained-release tablet prepared by the method described in claim 1.

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