Preparation method of theophylline controlled release tablet and theophylline controlled release tablet

Abstract

The invention discloses a preparation method of a theophylline controlled-release tablet and the theophylline controlled-release tablet. The preparation method comprises the following steps: S1, dry granulation of a medicine layer: preparing medicine layer particles from theophylline, a slow-release hydrophilic polymer material, a moisture absorbent, a flow aid and a lubricant; s2, performing dry granulation on the boosting layer: preparing boosting layer particles from a coloring material, an expansive high polymer material, a moisture absorbent, a flow aid and a lubricant; s3, tabletting of double-layer tablets: adding the medicine layer particles and the boosting layer particles into a double-layer tablet press for tabletting; s4, semi-permeable membrane coating: adding the theophylline double-layer tablet chip and a semi-permeable membrane coating solution into a coating machine; and S5, laser drilling: drilling holes in the theophylline double-layer semi-permeable membrane coating tablets through a laser drilling machine. The osmotic pump controlled release technology is utilized to control the constant-speed release of the medicine, the medicine effect is more lasting, the plasma concentration is stable, the adverse reaction of the medicine is effectively reduced, the medicine taking frequency is reduced, the medicine taking compliance of a patient is improved, and the clinical treatment effect of the medicine is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing theophylline controlled-release tablets and the theophylline controlled-release tablets themselves. Background Technology

[0002] Theophylline is a medication used to treat asthma. It has a direct relaxing effect on respiratory smooth muscle. Its mechanism of action involves inhibiting phosphodiesterase, thereby increasing intracellular cAMP levels. The bronchodilatory effect of theophylline is partly due to the release of endogenous adrenaline and noradrenaline. Theophylline is a purine receptor blocker, which counteracts the constrictive effects of adenine and other substances on the respiratory tract. Theophylline can enhance diaphragmatic contractility, especially when diaphragmatic contraction is weak, thus benefiting respiratory function. Theophylline is effective in treating bronchitis. However, its drawbacks include a relatively small therapeutic index; its therapeutic window, i.e., the effective blood concentration range, is 5–10 μg / ml. When the blood concentration exceeds 15 μg / ml, the probability of adverse reactions is higher. In addition, theophylline has a short half-life, requiring patients to take the medication repeatedly to maintain an effective blood concentration and preserve a certain clinical therapeutic effect. Theophylline is clinically used to relieve wheezing symptoms in bronchial asthma, wheezing bronchitis, and obstructive emphysema, and can also be used for asthma caused by cardiogenic pulmonary edema.

[0003] Clinically, theophylline is commonly used in formulations such as sustained-release tablets and sustained-release capsules. Sustained-release tablets are typically taken twice daily, while sustained-release capsules are usually taken one to two times daily. Sustained-release tablets mainly come in several types: matrix-type, erosion-type, and a combination of both. Ordinary sustained-release formulations of theophylline generally employ matrix-type sustained-release technology, utilizing the insoluble matrix formed in water to control drug release. For example, a theophylline sustained-release formulation and its preparation method (CN106265576A) utilizes insoluble sustained-release excipient ethyl cellulose as a matrix and is prepared using matrix-type sustained-release technology; a theophylline sustained-release agent manufacturing method (CN85108712) utilizes insoluble sustained-release excipients ethyl cellulose and high-molecular-weight cellulose materials such as gum arabic as a matrix and is prepared using matrix-type and erosion-type sustained-release technologies; a high-content theophylline controlled-release agent preparation method (CN1060610A) utilizes insoluble sustained-release excipients ethyl cellulose, high-molecular-weight cellulose materials (hydroxypropyl methylcellulose), and higher fatty acid materials (fatty acids) as a matrix and is prepared using matrix-type and erosion-type sustained-release technologies. In ordinary theophylline sustained-release formulations, the insoluble matrix dissolves upon contact with water, forming channels. The drug releases through diffusion or erosion mechanisms. However, matrix disintegration is prone to occur in the mid-release phase. This sustained-release mechanism is susceptible to environmental media and external forces, resulting in significant intra- and inter-individual variability. All of the above types of theophylline sustained-release preparations suffer from uneven drug release control and incomplete drug release, which can easily lead to low bioavailability. Furthermore, the disintegration of the preparation can also easily cause gastrointestinal toxicity. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing theophylline controlled-release tablets and the theophylline controlled-release tablets themselves. By utilizing osmotic pump controlled-release technology to control the uniform release of the drug, the efficacy is more prolonged, the blood drug concentration is stable, the adverse drug reactions are effectively reduced, and the number of doses is reduced. A single dose can maintain the efficacy for 24 hours, increasing patient compliance and improving the clinical therapeutic effect of the drug. The preparation process of this invention is simple and easy to operate, the product quality is stable, and there is good reproducibility between batches.

[0005] To achieve the above and other related objectives, the present invention provides a method for preparing theophylline controlled-release tablets, comprising the following steps: S1. Dry granulation of drug layer: Theophylline, sustained-release hydrophilic polymer and hygroscopic agent are stirred and mixed evenly, and then the evenly mixed material is added to a dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with gliding agent and lubricant to obtain drug layer granules. S2. Dry granulation of the booster layer: The coloring material, the expandable polymer material and the hygroscopic agent are stirred and mixed evenly. Then, the evenly mixed material is added to the dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with the flow aid and lubricant to obtain the booster layer granules. S3, Bilayer tableting: The drug layer particles and the propulsion layer particles are added to a bilayer tableting machine for tableting to obtain theophylline bilayer tablet chips; S4, Semi-permeable membrane coating: (1) Preparation of semipermeable membrane coating solution: Add semipermeable membrane coating agent, plasticizer and pore-forming agent to acetone solution and stir evenly to obtain semipermeable membrane coating solution; (2) Semi-permeable membrane coating: The theophylline bilayer chip and the semi-permeable membrane coating solution are added to the coating machine. The semi-permeable membrane is uniformly coated on the outside of the theophylline bilayer chip in the form of thin film coating in the coating machine to obtain the theophylline bilayer semi-permeable membrane coated tablet. S5. Laser perforation: Perforation is made in the semi-permeable membrane coated tablets of theophylline double-layer tablets using a laser perforation machine to obtain theophylline controlled-release tablets.

[0006] In one example of the preparation method of theophylline controlled-release tablets of the present invention, the drug layer particles comprise the following components in parts by weight: 50-70 parts of theophylline, 20-40 parts of sustained-release hydrophilic polymer material, 2-8 parts of hygroscopic agent, 0.5-2 parts of flow aid, and 0.5-2 parts of lubricant. The booster layer particles comprise the following components in parts by weight: 1-2 parts coloring material, 70-90 parts expandable polymer material, 10-20 parts hygroscopic agent, 1-2 parts flow aid, and 1-2 parts lubricant. The semipermeable membrane coating solution comprises the following components in parts by weight: 80-90 parts of semipermeable membrane coating agent, 5-10 parts of plasticizer, and 5-10 parts of pore-forming agent.

[0007] In one example of the preparation method of theophylline controlled-release tablets of the present invention, the sustained-release hydrophilic polymer material includes one or more of povidone K90, povidone K30, hydroxypropyl methylcellulose, and carbomer. The desiccant includes one or both of sodium chloride and mannitol; The flow aid is silica or colloidal silica; The lubricant is magnesium stearate; The coloring material is red iron dioxide; The expandable polymer material includes one or two of copovidone S630 and sodium carboxymethyl starch; The semi-permeable membrane coating agent is cellulose acetate; The plasticizer includes one or both of diethyl phthalate and triethyl citrate; The pore-forming agent includes one or both of polyethylene glycol 3350 and polyethylene glycol 1500.

[0008] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S1, theophylline, sustained-release hydrophilic polymer material and hygroscopic agent are placed in a wet mixing granulator and stirred evenly. The stirring speed of the wet mixing granulator is controlled to be 80-150 rpm, the cutting speed is controlled to be 800-1200 rpm, the mixing time is controlled to be 250-450 s, the tableting pressure of the dry granulator is controlled to be 0.2-0.3 MPa, the tablet thickness is controlled to be 0.5-2.0 mm, and the granulation mesh is controlled to be 12-20 mesh.

[0009] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S1, the stirring speed of the wet mixing granulator is controlled to be 100 rpm, the cutting speed is controlled to be 1000 rpm, the mixing time is controlled to be 360 ​​s, the tableting pressure of the dry granulator is controlled to be 0.25 MPa, the tablet thickness is controlled to be 1.0 mm, and the granulation mesh is controlled to be 16 mesh.

[0010] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S2, the coloring material, the expandable polymer material and the hygroscopic agent are placed in a wet mixing granulator and stirred and mixed evenly. The stirring speed of the wet mixing granulator is controlled to be 100-300 rpm, the cutting speed is controlled to be 1000-2000 rpm, the mixing time is controlled to be 400-800 s, the tableting pressure of the dry granulator is controlled to be 0.2-0.3 MPa, the tablet thickness is controlled to be 1.0-2.5 mm, and the granulation mesh is controlled to be 8-16 mesh.

[0011] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S2, the stirring speed of the wet mixing granulator is controlled to be 200 rpm, the cutting speed is controlled to be 1500 rpm, the mixing time is controlled to be 600 s, the tableting pressure of the dry granulator is controlled to be 0.25 MPa, the tablet thickness is controlled to be 1.5 mm, and the granulation mesh is controlled to be 12 mesh.

[0012] In one example of the preparation method of theophylline controlled-release tablets of the present invention, step S3 includes: adding drug layer particles and propulsion layer particles into the hopper of a bilayer tablet press, controlling the mass ratio of drug layer particles to propulsion layer particles to be 2:1, first pressing the drug layer particles into drug layer tablets, and then pressing the drug layer tablets and propulsion layer particles into bilayer tablets, controlling the main compression pressure of the drug layer tablets to be 0.2-1.5KN, the hardness of the drug layer tablets to be 20-50N, the main compression pressure of the bilayer tablets to be 8-16KN, and the hardness of the bilayer tablets to be 50-100N.

[0013] In one example of the preparation method of theophylline controlled-release tablets of the present invention, the main compression pressure of the drug layer tablet is controlled to be 0.4-0.6KN, the hardness of the drug layer tablet is 30-40N, the main compression pressure of the double-layer tablet is 10-12KN, and the hardness of the double-layer tablet is 60-80N.

[0014] In one example of the preparation method of theophylline controlled-release tablets of the present invention, step S4 includes: adding theophylline bilayer tablet chips into a coating machine, coating the outer layer of the theophylline bilayer tablet chips with a semi-permeable membrane coating solution by spraying, and drying at the same time to obtain theophylline bilayer semi-permeable membrane coated tablets. The rotation speed of the coating machine is controlled at 5-15 rpm, the tablet bed temperature is 20-40°C, the atomization pressure is 1-5 bar, the coating speed is 200-800 gpm, the coating weight gain is 15-25%, the content of semi-permeable membrane coating agent in the semi-permeable membrane coating solution is 0.06-0.1 g / ml, and the concentration of acetone aqueous solution is 90-100%.

[0015] In one example of the preparation method of theophylline controlled-release tablets of the present invention, the rotation speed of the coating machine is controlled at 7-10 rpm, the tablet bed temperature is controlled at 28-33°C, the atomization pressure is controlled at 1.5-2.5 bar, the coating speed is controlled at 400-600 gpm, and the concentration of the acetone aqueous solution is controlled at 95%.

[0016] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step 5, the laser frequency of the laser drilling machine is controlled to be 100W, the drilling working frequency is 10-30W, the drilling diameter is 0.4-0.8mm, and the drilling speed is 8-20 tablets / s.

[0017] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S5, the drilling frequency of the laser drilling machine is controlled to be 18-20W, the drilling diameter is 0.6mm, and the drilling speed is 12 tablets / s.

[0018] The present invention also discloses a method for preparing theophylline controlled-release tablets.

[0019] This invention relates to a method for preparing theophylline controlled-release tablets. The theophylline controlled-release tablets utilize a combination of a drug layer, a booster layer, and a semi-permeable membrane coating layer to achieve a balance between the drug release driving force and the drug release resistance, thereby realizing uniform drug release. In the formulation design of the drug layer and the booster layer, highly absorbent and expansive polymeric materials are used. An inorganic salt hygroscopic agent is added to the formulation to enhance the hygroscopic expansibility of the polymeric materials, thereby generating sufficient osmotic pressure driving force. The addition of the inorganic salt hygroscopic agent prevents the granulation material from becoming sticky and adherent to the mesh, making granulation easier, improving particle uniformity and compressibility, further streamlining the production process, and enhancing drug stability. The semi-permeable membrane component mainly uses cellulose acetate as the film-forming material. Through formulation experiments, plasticizers and pore-forming agents are added to ensure both the flexibility of the semi-permeable membrane and the rate of water penetration, thereby controlling the uniform release of the drug.

[0020] Compared with the prior art, the advantages of the present invention are: (1) The drug layer particles and the booster layer particles are granulated by dry granulation in the granulation process, which simplifies the process and makes it easy to operate. It reduces the steps of making soft materials and drying particles, avoids the safety problems caused by organic solvents as wetting agents, and makes large-scale production smoother, safer and easier. (2) Theophylline controlled-release tablets control drug release by using a combination of a booster layer to promote drug release and a drug layer itself to release the drug, which can effectively reduce the lag in drug release in the early stage and the phenomenon of empty release or no release in the middle and late stages. (3) Theophylline controlled-release tablets encapsulate the drug within an isolating semi-permeable membrane, avoiding the impact of differences in gastrointestinal motility and body fluid environment after oral administration on drug release. This ensures the stability and reproducibility of drug release and addresses the individual differences in therapeutic efficacy associated with conventional sustained-release formulations. (4) The theophylline controlled-release tablets can also push the residual liquid of the drug layer out of the tablet core in the later stage of drug release, avoiding the phenomenon that residual tablets or particles of ordinary skeleton-type sustained-release tablets will encapsulate the drug at the end of drug release, thus ensuring complete drug release and full utilization of the drug. Attached Figure Description

[0021] Figure 1 This is a dissolution curve of the theophylline controlled-release tablets produced in Example 1 of the present invention; Figure 2 This is a dissolution curve of theophylline controlled-release tablets produced in Example 2 of the present invention. Detailed Implementation

[0022] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, unless otherwise specified, the following embodiments and features can be combined with each other. It should also be understood that the terminology used in the embodiments of the present invention is for describing specific implementation schemes and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the respective manufacturers.

[0023] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention, as well as the prior art known to those skilled in the art and the description of the invention, may be implemented using any prior art methods, devices, and materials similar to or equivalent to the methods, devices, and materials in the embodiments of the present invention.

[0024] This invention provides a method for preparing theophylline controlled-release tablets, comprising the following steps: S1. Dry granulation of drug layer: Theophylline, sustained-release hydrophilic polymer and hygroscopic agent are stirred and mixed evenly, and then the evenly mixed material is added to a dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with gliding agent and lubricant to obtain drug layer granules. S2. Dry granulation of the booster layer: The coloring material, the expandable polymer material and the hygroscopic agent are stirred and mixed evenly. Then, the evenly mixed material is added to the dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with the flow aid and lubricant to obtain the booster layer granules. S3, Bilayer tableting: The drug layer particles and the propulsion layer particles are added to a bilayer tableting machine for tableting to obtain theophylline bilayer tablet chips; S4, Semi-permeable membrane coating: (1) Preparation of semipermeable membrane coating solution: Add semipermeable membrane coating agent, plasticizer and pore-forming agent to acetone aqueous solution and stir evenly to obtain semipermeable membrane coating solution; (2) Semi-permeable membrane coating: The theophylline bilayer chip and the semi-permeable membrane coating solution are added to the coating machine. The semi-permeable membrane is uniformly coated on the outside of the theophylline bilayer chip in the form of thin film coating in the coating machine to obtain the theophylline bilayer semi-permeable membrane coated tablet. S5. Laser perforation: Perforation is made in the semi-permeable membrane coated tablets of theophylline double-layer tablets using a laser perforation machine to obtain theophylline controlled-release tablets.

[0025] In one example of the preparation method of the theophylline controlled-release tablets of the present invention, the drug layer particles comprise the following components in parts by weight: 50-70 parts of theophylline, 20-40 parts of sustained-release hydrophilic polymer material, 2-8 parts of hygroscopic agent, 0.5-2 parts of flow aid, and 0.5-2 parts of lubricant; the propulsion layer particles comprise the following components in parts by weight: 1-2 parts of coloring material, 70-90 parts of swelling polymer material, 10-20 parts of hygroscopic agent, 1-2 parts of flow aid, and 1-2 parts of lubricant; the semi-permeable membrane coating liquid comprises the following components in parts by weight: 80-90 parts of semi-permeable membrane coating agent, 5-10 parts of plasticizer, and 5-10 parts of pore-forming agent.

[0026] In one example of the preparation method of theophylline controlled-release tablets of the present invention, the sustained-release hydrophilic polymer material includes one or more of povidone K90, povidone K30, hydroxypropyl methylcellulose, and carbomer; the hygroscopic agent includes one or two of sodium chloride and mannitol; the flow aid is silica or colloidal silica; the lubricant is magnesium stearate; the coloring material is red iron oxide; the swelling polymer material includes one or two of copovidone S630 and sodium carboxymethyl starch; the semi-permeable membrane coating agent is cellulose acetate; the plasticizer includes one or two of diethyl phthalate and triethyl citrate; and the pore-forming agent includes one or two of polyethylene glycol 3350 and polyethylene glycol 1500.

[0027] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S1, theophylline, sustained-release hydrophilic polymer material, and hygroscopic agent are placed in a wet granulation mixer and stirred until uniformly mixed. The stirring speed of the wet granulation mixer is controlled at 80-150 rpm, the cutting speed at 800-1200 rpm, and the mixing time at 250-450 s. The granulation pressure of the dry granulation machine is controlled at 0.2-0.3 MPa, the granulation thickness at 0.5-2.0 mm, and the granulation mesh size at 12-20 mesh. Preferably, the stirring speed of the wet granulation mixer is controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 360 s. The granulation pressure of the dry granulation machine is controlled at 0.25 MPa, the granulation thickness at 1.0 mm, and the granulation mesh size at 16 mesh.

[0028] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S2, the coloring material, the expandable polymer material, and the hygroscopic agent are placed in a wet mixing granulator and stirred until uniformly mixed. The stirring speed of the wet mixing granulator is controlled at 100-300 rpm, the cutting speed at 1000-2000 rpm, and the mixing time at 400-800 s. The granulation pressure of the dry granulator is controlled at 0.2-0.3 MPa, the granulation thickness at 1.0-2.5 mm, and the granulation mesh size at 8-16 mesh. Preferably, the stirring speed of the wet mixing granulator is controlled at 200 rpm, the cutting speed at 1500 rpm, and the mixing time at 600 s. The granulation pressure of the dry granulator is controlled at 0.25 MPa, the granulation thickness at 1.5 mm, and the granulation mesh size at 12 mesh.

[0029] In one example of the preparation method of theophylline controlled-release tablets of the present invention, step S3 includes: adding drug layer particles and propulsion layer particles into the hopper of a bilayer tablet press, controlling the mass ratio of drug layer particles to propulsion layer particles to be 2:1, first pressing the drug layer particles into drug layer tablets, and then pressing the drug layer tablets and propulsion layer particles into bilayer tablets, controlling the main compression pressure of the drug layer tablets to be 0.2-1.5 kN, the hardness of the drug layer tablets to be 20-50 N, the main compression pressure of the bilayer tablets to be 8-16 kN, and the hardness of the bilayer tablets to be 50-100 N. Preferably, the main compression pressure of the drug layer tablets is controlled to be 0.4-0.6 kN, the hardness of the drug layer tablets to be 30-40 N, the main compression pressure of the bilayer tablets to be 10-12 kN, and the hardness of the bilayer tablets to be 60-80 N.

[0030] In one example of the preparation method of theophylline controlled-release tablets of the present invention, step S4 includes: adding theophylline bilayer tablet chips into a coating machine, coating the outer layer of the theophylline bilayer tablet chips with a semi-permeable membrane coating solution by spraying, and simultaneously drying to obtain theophylline bilayer semi-permeable membrane coated tablets. The rotation speed of the coating machine is controlled at 5-15 rpm, the tablet bed temperature at 20-40°C, the atomization pressure at 1-5 bar, the coating speed at 200-800 gpm, the coating weight gain at 15-25%, the content of semi-permeable membrane coating agent in the semi-permeable membrane coating solution at 0.06-0.1 g / ml, and the concentration of acetone aqueous solution at 90-100%. Preferably, the rotation speed of the coating machine is controlled at 7-10 rpm, the tablet bed temperature at 28-33°C, the atomization pressure at 1.5-2.5 bar, the coating speed at 400-600 gpm, and the concentration of acetone aqueous solution at 95%.

[0031] In one example of the preparation method of theophylline controlled-release tablets of the present invention, in step S5, the laser frequency of the laser drilling machine is controlled to be 100W, the drilling frequency is 10-30W, the drilling diameter is 0.4-0.8mm, and the drilling speed is 8-20 tablets / s. Preferably, the drilling frequency of the laser drilling machine is controlled to be 18-20W, the drilling diameter is 0.6mm, and the drilling speed is 12 tablets / s.

[0032] The present invention will be further described below through several embodiments. It should be noted that, unless otherwise specified, the materials, reagents and equipment used in the embodiments can all be purchased through commercial means.

[0033] Example 1: A method for preparing a theophylline controlled-release tablet, comprising the following steps: S1. Drug laminar flow granulation

[0034] The theophylline, povidone K90, hydroxypropyl methylcellulose, and sodium chloride in the above-mentioned formula were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 360 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The granulation pressure of the dry granulation machine was controlled at 0.25 MPa, the granule thickness at 1.0 mm, and the granulation mesh at 16 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain drug layer granules.

[0035] S2, Dry Granulation with Booster Layer

[0036] The sodium carboxymethyl starch, sodium chloride, and red iron oxide in the above formula are placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator is controlled at 200 rpm, the cutting speed at 1500 rpm, and the mixing time at 600 s. Then, the evenly mixed material is added to a dry granulator to obtain granules. The granulation pressure of the dry granulator is controlled at 0.25 MPa, the granulation thickness at 1.5 mm, and the granulation mesh at 12 mesh. The granules are then mixed evenly with silica and magnesium stearate to obtain the booster layer granules.

[0037] S3, Double-layer tablet compression The drug layer granules and the propulsion layer granules are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer granules to propulsion layer granules is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer granules into a drug layer tablet first, and then the drug layer tablet and the propulsion layer granules are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 0.5KN, and the hardness of the drug layer tablet is 35N. The main compression pressure of the bilayer tablet is controlled at 11KN, and the hardness of the bilayer tablet is 70N.

[0038] S4, semi-permeable membrane coating

[0039] The above-mentioned amounts of cellulose acetate, diethyl phthalate, and polyethylene glycol 1500 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 8 rpm, the tablet bed temperature at 30°C, the atomization pressure at 2.0 bar, the coating speed at 500 gpm, and the coating weight gain at 20%.

[0040] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 20W, the perforation diameter at 0.6mm, and the perforation speed at 12 tablets / s.

[0041] Example 2: A method for preparing a theophylline controlled-release tablet, the steps of which are as follows: S1. Drug laminar flow granulation

[0042] The theophylline, povidone K30, carbomer, and sodium chloride in the above-mentioned formula were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 360 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The granulation pressure of the dry granulation machine was controlled at 0.25 MPa, the granule thickness at 1.0 mm, and the granulation mesh at 16 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain drug layer granules.

[0043] S2, Dry Granulation with Booster Layer

[0044] The copovidone S630, sodium chloride, and red iron oxide in the above formula were placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator was controlled at 200 rpm, the cutting speed at 1500 rpm, and the mixing time at 600 s. Then, the evenly mixed material was added to a dry granulator to obtain granules. The pelleting pressure of the dry granulator was controlled at 0.25 MPa, the pellet thickness at 1.5 mm, and the granulation mesh at 12 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain the booster layer granules.

[0045] S3, Double-layer tablet compression The drug layer granules and the propulsion layer granules are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer granules to propulsion layer granules is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer granules into a drug layer tablet first, and then the drug layer tablet and the propulsion layer granules are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 0.5KN, and the hardness of the drug layer tablet is 35N. The main compression pressure of the bilayer tablet is controlled at 11KN, and the hardness of the bilayer tablet is 70N.

[0046] S4, semi-permeable membrane coating

[0047] The above-mentioned amounts of cellulose acetate, diethyl phthalate, and polyethylene glycol 1500 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 8 rpm, the tablet bed temperature at 30°C, the atomization pressure at 2.0 bar, the coating speed at 500 gpm, and the coating weight gain at 20%.

[0048] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 20W, the perforation diameter at 0.6mm, and the perforation speed at 12 tablets / s.

[0049] Example 3: A method for preparing a theophylline controlled-release tablet, the steps of which are as follows: S1. Drug laminar flow granulation

[0050] The theophylline, povidone K90, and mannitol in the above-mentioned proportions were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 80 rpm, the cutting speed at 800 rpm, and the mixing time at 450 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The pelleting pressure of the dry granulation machine was controlled at 0.2 MPa, the pellet thickness at 0.5 mm, and the granulation mesh at 12 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain drug layer granules.

[0051] S2, Dry Granulation with Booster Layer

[0052] Sodium carboxymethyl starch, sodium chloride, and red iron oxide in the above formula are placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator is controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 800 s. Then, the evenly mixed material is added to a dry granulator to obtain granules. The granulation pressure of the dry granulator is controlled at 0.2 MPa, the granulation thickness at 1.0 mm, and the granulation mesh at 8 mesh. The granules are then mixed evenly with silica and magnesium stearate to obtain the booster layer granules.

[0053] S3, Double-layer tablet compression The drug layer particles and the booster layer particles are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer particles to booster layer particles is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer particles into a drug layer tablet first, and then the drug layer tablet and the booster layer particles are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 0.2KN and the hardness of the drug layer tablet is 20N. The main compression pressure of the bilayer tablet is controlled at 8KN and the hardness of the bilayer tablet is 50N.

[0054] S4, semi-permeable membrane coating

[0055] The above-mentioned amounts of cellulose acetate, triethyl citrate, and polyethylene glycol 3350 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 5 rpm, the tablet bed temperature at 20°C, the atomization pressure at 1.0 bar, the coating speed at 200 gpm, and the coating weight gain at 15%.

[0056] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 10W, the perforation diameter at 0.4mm, and the perforation speed at 8 tablets / s.

[0057] Example 4: A method for preparing a theophylline controlled-release tablet, the steps of which are as follows: S1. Drug laminar flow granulation

[0058] The theophylline, povidone K30, and mannitol in the above-mentioned proportions were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 150 rpm, the cutting speed at 1200 rpm, and the mixing time at 250 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The pelleting pressure of the dry granulation machine was controlled at 0.3 MPa, the pellet thickness at 2.0 mm, and the granulation mesh at 20 mesh. The granules were then mixed evenly with colloidal silica and magnesium stearate to obtain drug layer granules.

[0059] S2, Dry Granulation with Booster Layer

[0060] The sodium carboxymethyl starch, mannitol, and red iron oxide in the above formula were placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator was controlled at 300 rpm, the cutting speed at 2000 rpm, and the mixing time at 400 s. Then, the evenly mixed material was added to a dry granulator to obtain granules. The pelleting pressure of the dry granulator was controlled at 0.3 MPa, the pellet thickness at 2.5 mm, and the granulation mesh at 16 mesh. The granules were then mixed evenly with colloidal silica and magnesium stearate to obtain the booster layer granules.

[0061] S3, Double-layer tablet compression The drug layer particles and the booster layer particles are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer particles to booster layer particles is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer particles into a drug layer tablet first, and then the drug layer tablet and the booster layer particles are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 1.5KN and the hardness of the drug layer tablet is 50N. The main compression pressure of the bilayer tablet is controlled at 16KN and the hardness of the bilayer tablet is 100N.

[0062] S4, semi-permeable membrane coating

[0063] The above-mentioned amounts of cellulose acetate, triethyl citrate, and polyethylene glycol 3350 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 15 rpm, the tablet bed temperature at 40°C, the atomization pressure at 5.0 bar, the coating speed at 800 gpm, and the coating weight gain at 25%.

[0064] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 30W, the perforation diameter at 0.8mm, and the perforation speed at 20 tablets / s.

[0065] Example 5: A method for preparing a theophylline controlled-release tablet, comprising the following steps: S1. Drug laminar flow granulation

[0066] The theophylline, povidone K90, hydroxypropyl methylcellulose, and sodium chloride in the above-mentioned formula were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 360 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The granulation pressure of the dry granulation machine was controlled at 0.25 MPa, the granule thickness at 1.0 mm, and the granulation mesh at 16 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain drug layer granules.

[0067] S2, Dry Granulation with Booster Layer

[0068] The sodium carboxymethyl starch, sodium chloride, and red iron oxide in the above formula are placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator is controlled at 200 rpm, the cutting speed at 1500 rpm, and the mixing time at 600 s. Then, the evenly mixed material is added to a dry granulator to obtain granules. The granulation pressure of the dry granulator is controlled at 0.25 MPa, the granulation thickness at 1.5 mm, and the granulation mesh at 12 mesh. The granules are then mixed evenly with silica and magnesium stearate to obtain the booster layer granules.

[0069] S3, Double-layer tablet compression The drug layer granules and the propulsion layer granules are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer granules to propulsion layer granules is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer granules into a drug layer tablet first, and then the drug layer tablet and the propulsion layer granules are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 0.4KN and the hardness of the drug layer tablet is 30N. The main compression pressure of the bilayer tablet is controlled at 10KN and the hardness of the bilayer tablet is 60N.

[0070] S4, semi-permeable membrane coating

[0071] The above-mentioned amounts of cellulose acetate, diethyl phthalate, and polyethylene glycol 1500 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 7 rpm, the tablet bed temperature at 28°C, the atomization pressure at 1.5 bar, the coating speed at 400 gpm, and the coating weight gain at 20%.

[0072] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 18W, the perforation diameter at 0.6mm, and the perforation speed at 12 tablets / s.

[0073] Example 6: A method for preparing a theophylline controlled-release tablet, comprising the following steps: S1. Drug laminar flow granulation

[0074] The theophylline, povidone K90, hydroxypropyl methylcellulose, and sodium chloride in the above-mentioned formula were placed in a wet granulation machine and mixed evenly. The mixing speed of the wet granulation machine was controlled at 100 rpm, the cutting speed at 1000 rpm, and the mixing time at 360 s. Then, the evenly mixed material was added to a dry granulation machine to obtain granules. The granulation pressure of the dry granulation machine was controlled at 0.25 MPa, the granule thickness at 1.0 mm, and the granulation mesh at 16 mesh. The granules were then mixed evenly with silica and magnesium stearate to obtain drug layer granules.

[0075] S2, Dry Granulation with Booster Layer

[0076] The sodium carboxymethyl starch, sodium chloride, and red iron oxide in the above formula are placed in a wet granulator and mixed evenly. The mixing speed of the wet granulator is controlled at 200 rpm, the cutting speed at 1500 rpm, and the mixing time at 600 s. Then, the evenly mixed material is added to a dry granulator to obtain granules. The granulation pressure of the dry granulator is controlled at 0.25 MPa, the granulation thickness at 1.5 mm, and the granulation mesh at 12 mesh. The granules are then mixed evenly with silica and magnesium stearate to obtain the booster layer granules.

[0077] S3, Double-layer tablet compression The drug layer particles and the booster layer particles are added separately into the hopper of the bilayer tableting machine. The mass ratio of drug layer particles to booster layer particles is controlled at 2:1. Based on a tablet weight of 252mg, a shallow arc punch with a diameter of 8.5mm is used to compress the drug layer particles into a drug layer tablet first, and then the drug layer tablet and the booster layer particles are compressed into a bilayer tablet. The main compression pressure of the drug layer tablet is controlled at 0.6KN and the hardness of the drug layer tablet is 40N. The main compression pressure of the bilayer tablet is controlled at 12KN and the hardness of the bilayer tablet is 80N.

[0078] S4, semi-permeable membrane coating

[0079] The above-mentioned amounts of cellulose acetate, diethyl phthalate, and polyethylene glycol 1500 were added to an acetone aqueous solution and stirred until homogeneous to obtain a semi-permeable membrane coating solution. The theophylline bilayer tablets were then added to a coating machine, and the semi-permeable membrane coating solution was sprayed onto the outer layer of the theophylline bilayer tablets. Simultaneously, the solution was dried to obtain theophylline bilayer semi-permeable membrane coated tablets. The coating machine speed was controlled at 10 rpm, the tablet bed temperature at 33°C, the atomization pressure at 2.5 bar, the coating speed at 600 gpm, and the coating weight gain at 20%.

[0080] S5, Laser Drilling The theophylline double-layer semi-permeable membrane coated tablets were perforated using a laser perforation machine to obtain theophylline controlled-release tablets. The laser frequency of the laser perforation machine was controlled at 100W, the perforation working frequency at 20W, the perforation diameter at 0.6mm, and the perforation speed at 12 tablets / s.

[0081] Detection and quality stability analysis of theophylline controlled-release tablets prepared in Examples 1 and 2 Dissolution testing: Following the release determination method in the Chinese Pharmacopoeia (2025 edition), the second method of dissolution determination was used. 900 ml of water was used as the release medium, the basket rotation speed was 50 r / min, and the temperature was (37±0.5) ℃. Samples of 5 ml were taken at 2, 4, 6, 8, 12, 16, and 24 hours, filtered, and the corresponding 5 ml of release medium was replenished promptly. An appropriate amount of the filtrate was taken and quantitatively diluted with water to prepare a solution containing approximately 7 μg of theophylline per ml as the test solution. An appropriate amount of theophylline reference standard was accurately weighed, dissolved in water, and quantitatively diluted to prepare a solution containing approximately 7 μg of theophylline per ml as the reference solution. The absorbance of both the reference solution and the test solution was measured at 272 nm using ultraviolet-visible spectrophotometry, and the drug dissolution rate at each time point was calculated.

[0082] The methods for detecting related substances are as follows: (1) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material; acetate buffer-acetonitrile (93:7) was used as the mobile phase. The preparation steps of the acetate buffer were as follows: take 1.36g of sodium acetate, add 100ml of water to dissolve it, add 5ml of glacial acetic acid, and then add water to dilute to 1000ml and shake well; the detection wavelength was 271nm; the injection volume was 20µl.

[0083] (2) System applicability requirements: In the system applicable solution chromatogram, the theoretical plate number calculated based on theophylline should not be less than 5000, and the separation degree between the theobromine peak and the theophylline peak should be greater than 2.0.

[0084] If impurity peaks are present in the chromatogram of the test solution, the individual impurity shall not exceed 0.1%, and the total impurities shall not exceed 0.5%.

[0085] Figure 1 and Figure 2 The dissolution curves of theophylline controlled-release tablets prepared in Examples 1 and 2 are shown below. The dissolution test results of theophylline controlled-release tablets prepared in Examples 1 and 2 are as follows: Table 1 shows the dissolution test results of the theophylline controlled-release tablets prepared in Example 1.

[0086] Table 2 shows the dissolution test results of the theophylline controlled-release tablets prepared in Example 2.

[0087] Following the above dissolution test method and related substance analysis method, the samples of Example 1 and Example 2 were subjected to an accelerated test for 6 months (humidity 75%±5%, temperature 40℃±2℃) and a long-term stability test for 6 months (humidity 60%±5%, temperature 25℃±2℃). The test results are shown in Tables 3 to 6.

[0088] Table 3 shows the accelerated test results of the theophylline controlled-release tablets prepared in Example 1 over 6 months.

[0089] Table 4 shows the results of a 6-month long-term test on the theophylline controlled-release tablets prepared in Example 1.

[0090] Table 5 shows the accelerated test results of the theophylline controlled-release tablets prepared in Example 2 over 6 months.

[0091] Table 6 shows the results of a 6-month long-term test on the theophylline controlled-release tablets prepared in Example 2.

[0092] Accelerated and long-term trials were conducted using commercially available packaging. The results showed that under these packaging conditions, none of the product's indicators changed significantly, meeting the requirements for storage and transportation of pharmaceuticals. This invention, the theophylline controlled-release tablets and its preparation method, produces products with stable quality and low impurity content. The formulation is simple, the process is straightforward, and it also ensures product quality and clinical therapeutic effects, achieving significant social and economic benefits.

[0093] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for preparing theophylline controlled-release tablets, characterized in that, Includes the following steps: S1. Dry granulation of drug layer: Theophylline, sustained-release hydrophilic polymer and hygroscopic agent are stirred and mixed evenly, and then the evenly mixed material is added to a dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with gliding agent and lubricant to obtain drug layer granules. S2. Dry granulation of the booster layer: The coloring material, the expandable polymer material and the hygroscopic agent are stirred and mixed evenly. Then, the evenly mixed material is added to the dry granulation machine to obtain granules. The granules are then stirred and mixed evenly with the flow aid and lubricant to obtain the booster layer granules. S3, Bilayer tableting: The drug layer particles and the propulsion layer particles are added to a bilayer tableting machine for tableting to obtain theophylline bilayer tablet chips; S4, Semi-permeable membrane coating: (1) Preparation of semipermeable membrane coating solution: Add semipermeable membrane coating agent, plasticizer and pore-forming agent to acetone solution and stir evenly to obtain semipermeable membrane coating solution; (2) Semi-permeable membrane coating: The theophylline bilayer chip and the semi-permeable membrane coating solution are added to the coating machine. The semi-permeable membrane is uniformly coated on the outside of the theophylline bilayer chip in the form of thin film coating in the coating machine to obtain the theophylline bilayer semi-permeable membrane coated tablet. S5. Laser perforation: Perforation is made in the semi-permeable membrane coated tablets of theophylline double-layer tablets using a laser perforation machine to obtain theophylline controlled-release tablets.

2. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, The drug layer particles comprise the following components in parts by weight: 50-70 parts theophylline, 20-40 parts sustained-release hydrophilic polymer, 2-8 parts hygroscopic agent, 0.5-2 parts flow aid, and 0.5-2 parts lubricant; the propulsion layer particles comprise the following components in parts by weight: 1-2 parts coloring material, 70-90 parts expandable polymer, 10-20 parts hygroscopic agent, 1-2 parts flow aid, and 1-2 parts lubricant; the semi-permeable membrane coating solution comprises the following components in parts by weight: 80-90 parts semi-permeable membrane coating agent, 5-10 parts plasticizer, and 5-10 parts pore-forming agent.

3. The method for preparing theophylline controlled-release tablets as described in claim 2, characterized in that, The sustained-release hydrophilic polymer material includes one or more of povidone K90, povidone K30, hydroxypropyl methylcellulose, and carbomer; the hygroscopic agent includes one or two of sodium chloride and mannitol; the flow aid is silica or colloidal silica; the lubricant is magnesium stearate; the coloring material is red iron oxide; the swelling polymer material includes one or two of copovidone S630 and sodium carboxymethyl starch; the semi-permeable membrane coating agent is cellulose acetate; the plasticizer includes one or two of diethyl phthalate and triethyl citrate; and the pore-forming agent includes one or two of polyethylene glycol 3350 and polyethylene glycol 1500.

4. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, In step S1, theophylline, slow-release hydrophilic polymer material and hygroscopic agent are placed in a wet mixing granulator and stirred until uniform. The stirring speed of the wet mixing granulator is controlled at 80-150 rpm, the cutting speed at 800-1200 rpm, and the mixing time at 250-450 s. The granulation pressure of the dry granulator is controlled at 0.2-0.3 MPa, the granulation thickness at 0.5-2.0 mm, and the granulation mesh at 12-20 mesh.

5. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, In step S2, the coloring material, the expandable polymer material, and the hygroscopic agent are placed in a wet mixing granulator and stirred until uniform. The stirring speed of the wet mixing granulator is controlled at 100-300 rpm, the cutting speed at 1000-2000 rpm, and the mixing time at 400-800 s. The pelleting pressure of the dry granulator is controlled at 0.2-0.3 MPa, the pellet thickness at 1.0-2.5 mm, and the pellet mesh at 8-16 mesh.

6. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, Step S3 includes: adding drug layer particles and booster layer particles into the hopper of the bilayer tableting machine, controlling the mass ratio of drug layer particles to booster layer particles to be 2:1, first compressing the drug layer particles into drug layer tablets, and then compressing the drug layer tablets and booster layer particles into bilayer tablets, controlling the main compression pressure of the drug layer tablets to be 0.2-1.5KN, the hardness of the drug layer tablets to be 20-50N, the main compression pressure of the bilayer tablets to be 8-16KN, and the hardness of the bilayer tablets to be 50-100N.

7. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, Step S4 includes: adding the theophylline bilayer tablet chip into a coating machine, coating the outer layer of the theophylline bilayer tablet chip with a semi-permeable membrane coating solution by spraying, and drying simultaneously to obtain theophylline bilayer semi-permeable membrane coated tablets. The rotation speed of the coating machine is controlled at 5-15 rpm, the tablet bed temperature at 20-40℃, the atomization pressure at 1-5 bar, the coating speed at 200-800 gpm, the coating weight gain at 15-25%, the content of semi-permeable membrane coating agent in the semi-permeable membrane coating solution at 0.06-0.1 g / ml, and the concentration of acetone aqueous solution at 90-100%.

8. The method for preparing theophylline controlled-release tablets as described in claim 1, characterized in that, In step S5, the laser frequency of the laser drilling machine is controlled to be 100W, the drilling working frequency is 10-30W, the drilling diameter is 0.4-0.8mm, and the drilling speed is 8-20 pieces / s.

9. A theophylline controlled-release tablet, characterized in that, It is prepared by the method of preparing theophylline controlled-release tablets according to any one of claims 1 to 8.

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