Theophylline sustained-release tablet as well as preparation method and application thereof

Abstract

The invention provides a theophylline sustained-release tablet as well as a preparation method and application thereof, and belongs to the technical field of medicines. The theophylline sustained release tablet comprises the following raw materials in parts by weight: 90-110 parts of theophylline derivative or theophylline; 10 to 20 parts of hydroxyethyl cellulose; 1 to 2 parts of povidone; 3-5 parts of hexadecanol; 3 to 6 parts of octadecanol; 0.2 to 0.6 part of talcum powder; and 0.2 to 0.6 part of magnesium stearate. The preparation method is simple, the synthesis condition is mild, the yield is high, the prepared theophylline derivative has the advantages of high selectivity, strong bronchiectasis effect, quick response, long maintenance time, small stomach irritation, slight cardiac side effect and better biological activities of antituberculosis, anticonvulsion, smooth muscle relaxation and the like, meanwhile, the theophylline derivative is in a sustained-release dosage form, the medicine action time is prolonged, and the bioavailability of the theophylline derivative is improved. Wide application prospects are realized.

Description

Technical Field

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

[0002] Theophylline is a smooth muscle relaxant. Clinically, it is mainly used to treat asthma and asthmatic bronchitis. It is easily absorbed orally, with an average half-life of 5-6 hours in adults and 3.5 hours in children. Theophylline has a narrow therapeutic range (5-20 μg / mL), with significant individual variability; clearance and half-life also vary from person to person. Regular theophylline tablets need to be taken three times daily. Taking it during nocturnal attacks can disrupt sleep, and frequent dosing can lead to peak-and-trough fluctuations in blood concentration, causing side effects such as headache, nausea, insomnia, cramps, and allergies. Theophylline controlled-release tablets can reduce the frequency of dosing, effectively avoiding these peak-and-trough fluctuations and reducing side effects. Theophylline sustained-release tablets, according to the Japanese reference preparation (UNICONTab.100) instructions, are taken once daily after dinner without affecting sleep quality, especially during nighttime and early morning attacks. For patients with acute symptoms, there is no significant difference; the product's slower peak time also improves patient compliance.

[0003] Chinese patent document CN10755088A discloses a 24-hour theophylline sustained-release tablet. The main skeleton material used is cellulose, which is a water-swelling material. It encapsulates theophylline to achieve sustained release. However, the theophylline in this sustained-release tablet is not completely released.

[0004] Chinese patent document CN103239419A discloses a method for preparing theophylline sustained-release tablets: (1) adding a retarder to a wet granulator, and preparing a binder by adding a solvent to the retarder, and stirring and shearing at room temperature; (2) adding theophylline, binder and filler to the wet granulator to make a soft material; (3) replacing the granulator with a 16-20 mesh stainless steel mesh and granulating it using a granulator; (4) drying the wet granules by vacuum pumping them into a fluidized bed, then granulating them using a pulverizer and granulator, adding a lubricant and mixing, and then compressing them into tablets to obtain theophylline sustained-release tablets. This method can release theophylline at a constant rate, with stable quality, safety, simple process and good process stability, but the release degree is not high, and it cannot achieve complete release of theophylline. Summary of the Invention

[0005] The purpose of this invention is to provide a theophylline sustained-release tablet, its preparation method, and its application. The sustained-release tablet is prepared using theophylline or its derivatives. The preparation method is simple and yields good sustained-release effects. The theophylline derivatives are synthesized under mild conditions with high yield. The obtained theophylline derivatives exhibit high selectivity, strong bronchodilatory effect, rapid onset of action, long duration of action, low gastric irritation, mild cardiac side effects, and good biological activities such as anti-tuberculosis, anticonvulsant, and smooth muscle relaxant effects. Furthermore, as a sustained-release dosage form, it prolongs the duration of drug action and has broad application prospects.

[0006] The technical solution of this invention is implemented as follows:

[0007] This invention provides a theophylline sustained-release tablet, comprising the following raw materials in parts by weight: 90-110 parts of theophylline derivative or theophylline; 10-20 parts of hydroxyethyl cellulose; 1-2 parts of povidone; 3-5 parts of cetyl alcohol; 3-6 parts of octadecyl alcohol; 0.2-0.6 parts of talc; and 0.2-0.6 parts of magnesium stearate; wherein the structural formula of the theophylline derivative is shown in Formula I.

[0008] Formula I.

[0009] As a further improvement of the present invention, the polyvinylpyrrolidone is polyvinylpyrrolidone K29 and polyvinylpyrrolidone K32, with a mass ratio of (0.5-1):(0.5-1.5).

[0010] As a further improvement of the present invention, the hydroxyethyl cellulose is hydroxyethyl cellulose 250HX.

[0011] As a further improvement of the present invention, the preparation method of the theophylline derivative is as follows:

[0012] S1. An intermediate was prepared by reacting 8-chlorotheophylline with pentaerythritol tetrachloride, the structural formula of which is as follows: ;

[0013] S2. The intermediate is reacted with hydrazine hydrate, and an aqueous solution of sodium nitrite is added and stirred to obtain the product.

[0014] As a further improvement of the present invention, the mass ratio of 8-chlorotheophylline and pentaerythritol tetrachloride in step S1 is (4-4.2):1.

[0015] As a further improvement of the present invention, the reaction temperature in step S2 is 55-65°C.

[0016] As a further improvement of the present invention, the concentration of the sodium nitrite aqueous solution in step S2 is 5-15 wt%, and the stirring time is 1-3 h.

[0017] This invention further protects a method for preparing the above-mentioned theophylline sustained-release tablets, comprising the following steps:

[0018] (1) Pre-treat theophylline or its derivatives in an air jet mill;

[0019] (2) Dissolve povidone in water to form a transparent solution to obtain an adhesive;

[0020] (3) Mix the pretreated theophylline or theophylline derivative and hydroxyethyl cellulose, spray in the binder, wet granulate, wet granulate, dry, dry granulate to obtain the dry granulation intermediate;

[0021] (4) Take hexadecyl alcohol and octadecyl alcohol and heat them until they are completely melted into a transparent solution to obtain a hot-melt solvent;

[0022] (5) Heat the dry granulation intermediate, add hot melt solvent and mix evenly, hot melt granulate, cool, and granulate to obtain hot melt granules;

[0023] (6) Mix the hot melt particles and talc powder, add magnesium stearate, mix evenly to obtain a mixture;

[0024] (7) Compress the mixture into tablets, package them, and obtain theophylline sustained-release tablets.

[0025] As a further improvement of the present invention, the wet granulation time is 20-40s, and the hot melt granulation time is 15-25min.

[0026] This invention further protects the use of the above-mentioned theophylline sustained-release tablets in the treatment of asthma, epilepsy, and anticonvulsants.

[0027] The present invention has the following beneficial effects:

[0028] This invention uses cetyl alcohol and octadecyl alcohol as sustained-release matrix materials, combined with binders and lubricants, to prepare a theophylline sustained-release tablet with a 24-hour release cycle. This significantly delays the dissolution of theophylline or its derivatives, effectively controlling drug release, exhibiting long-term stability, and good reproducibility of release. The drug release rate exceeds 85% at 24 hours, ensuring complete release. The in vitro dissolution behavior is consistent with that of the theophylline sustained-release tablets produced by the reference formulation Nichi-Iko Pharmaceutical Co., Ltd., improving patient compliance, overcoming the inconvenience of multiple dosing and the drawbacks of large concentration fluctuations, providing convenience for patients, and demonstrating high bioavailability.

[0029] However, theophylline, being a methylxanthine compound, contains a secondary amine structure and is weakly alkaline overall. This causes it to form a hypertonic solution in the acidic environment of the stomach, directly irritating the gastric mucosa and triggering gastrointestinal reactions such as nausea, vomiting, and stomach pain. Simultaneously, theophylline shares structural similarities with adenosine (a purine nucleoside), allowing it to act as a competitive antagonist, preferentially binding to adenosine receptors. This blocks the normal binding of adenosine to its receptors, antagonizing its physiological effects and leading to increased heart rate, cardiac excitation, and central nervous system stimulation.

[0030] Analysis of the drug's mechanism of action and structure shows that including two or more basic structures with the same pharmacological effects in the same molecule is often a way to obtain new drugs with high therapeutic efficacy and low toxicity. Based on the principle of combination in new drug design, this invention synthesizes theophylline derivatives. Structurally, the secondary amine structure is absent, reducing its basicity. At the same time, its molecular structure is enlarged, showing a significant difference from adenosine, which also reduces the binding efficiency with adenosine receptors to a certain extent, thereby reducing side effects. In addition, the multi-theophylline skeleton structure gives it high selectivity, strong bronchodilatory effect, rapid onset of action, long duration of action, low gastric irritation, and mild cardiac side effects. Furthermore, the addition of a tetrazolium structure to the derivative of this invention gives the compound good anti-tuberculosis, anticonvulsant, and smooth muscle relaxant biological activities.

[0031] The preparation method of this invention is simple, the synthesis conditions are mild, and the yield is high. The theophylline derivative obtained has high selectivity, strong bronchodilatory effect, rapid onset of action, long duration of action, low gastric irritation, mild cardiac side effects, and good anticonvulsant and smooth muscle relaxant biological activities. At the same time, it is a sustained-release dosage form, which prolongs the drug action time and has broad application prospects. Attached Figure Description

[0032] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 This is a schematic diagram of the structure of theophylline derivatives;

[0034] Figure 2 This is a flowchart illustrating the preparation process of theophylline sustained-release tablets.

[0035] Figure 3 For example, the cumulative release percentage-time curve in test example 2;

[0036] Figure 4The images show the structure of mouse lung tissue under a light microscope after HE staining. Detailed Implementation

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] Preparation Example 1: Theophylline Derivatives

[0039] The synthesis route is as follows:

[0040]

[0041] The preparation method is as follows:

[0042] S1. 0.4 mol 8-chlorotheophylline, 0.8 mol NaOH, and 0.1 mol pentaerythritol tetrachloride were added to 200 mL of toluene and the mixture was heated under reflux for 4 h to prepare the intermediate; ESI-MS calculated value: C 33 H 33 Cl4N 16 O8(M+H) + 923.52, measured value: 923.5, yield: 90%. NMR results: 1 H NMR (300MHz, CDCl3) δ3.67 (s, 8H), 2.72-2.75 (m, 24H). 13 C NMR (75MHz, CDCl3) δ154.9, 151.4, 150.5, 149, 107.4, 33.2, 32.3, 29.1, 25.7.

[0043] S2. Add 50 mL of hydrazine hydrate to 1 g of the intermediate, heat to 55 °C, stir until the reaction is complete as monitored by TLC, cool to room temperature, filter, wash with methanol, dissolve the product in 2 mol / L hydrochloric acid solution, add 5 wt% sodium nitrite aqueous solution, stir at room temperature for 3 h, filter, wash with ice water, separate by column chromatography, the eluent is a mixture of methanol and dichloromethane in a volume ratio of 1:30, to obtain the product, the structural formula of which is as follows. Figure 1 ESI-MS calculated value: C 33 H 33 N 28 O8(M+H) + 949.79, measured value: 949.8, yield: 59%. NMR results: 1H NMR (300MHz, CDCl3) δ3.89 (s, 8H), 2.92-2.97 (m, 24H). 13 C NMR (75MHz, CDCl3) δ157.8, 151.5, 120.4, 99.0, 54.3, 30.4, 29.4, 26.9.

[0044] Preparation Example 2: Theophylline Derivatives

[0045] The preparation method is as follows:

[0046] S1. 0.42 mol 8-chlorotheophylline, 0.8 mol NaOH, and 0.1 mol pentaerythritol tetrachloride were added to 200 mL of toluene and the mixture was heated under reflux for 6 h to obtain the intermediate; yield 92%.

[0047] S2. Add 50 mL of hydrazine hydrate to 1 g of the intermediate, heat to 65 °C, stir until the reaction is complete as monitored by TLC, cool to room temperature, filter, wash with methanol, dissolve the product in 2 mol / L hydrochloric acid solution, add 15 wt% sodium nitrite aqueous solution, stir at room temperature for 1 h, filter, wash with ice water, separate by column chromatography, the eluent is a mixture of methanol and dichloromethane at a volume ratio of 1:30, to obtain the product, the structural formula of which is as follows. Figure 1 Yield: 62%.

[0048] Preparation Example 3: Theophylline Derivatives

[0049] The preparation method is as follows:

[0050] S1. 0.41 mol 8-chlorotheophylline, 0.8 mol NaOH, and 0.1 mol pentaerythritol tetrachloride were added to 200 mL of toluene and the mixture was heated under reflux for 5 h to obtain the intermediate with a yield of 91%.

[0051] S2. Add 50 mL of hydrazine hydrate to 1 g of the intermediate, heat to 60 °C, stir until the reaction is complete as monitored by TLC, cool to room temperature, filter, wash with methanol, dissolve the product in 2 mol / L hydrochloric acid solution, add 10 wt% sodium nitrite aqueous solution, stir at room temperature for 2 h, filter, wash with ice water, separate by column chromatography, the eluent is a mixture of methanol and dichloromethane in a volume ratio of 1:30, to obtain the product, the structural formula of which is as follows. Figure 1 Yield: 61%.

[0052] Test Example 1

[0053] Kunming mice, half male and half female, weighing 18-22g, were selected. The drug solvent was dimethyl sulfoxide, and the dosage was 0.1mL per mouse. Pharmacological experiments were conducted according to the "Antiepileptic Drug Development Procedure" published by the National Institutes of Health (NIH).

[0054] Twenty-four hours prior to the experiment, mice were electrically stimulated using an electroconvulsive device (110V, 60Hz, 0.2s single stimulation). Mice exhibiting hind limb rigidity were suitable for the experiment. After intraperitoneal injection of the theophylline derivative prepared in Example 3, mice were electrically stimulated under the same conditions. Hind limb rigidity was observed in negative cases, indicating the compound had no anticonvulsant effect; conversely, the absence of hind limb rigidity indicated the compound had an anticonvulsant effect. Then, the median effective dose (ED) of the most active compound was determined. 50 (The dose that elicits a positive response in 50% of the experimental subjects) was used to evaluate the efficacy. The results are shown in Tables 1 and 2.

[0055] Table 1

[0056]

[0057] Note: a, Maximum electroconvulsive disorder (number of positive mice / number of test mice).

[0058] Table 2

[0059]

[0060] Note: a, 95% confidence interval.

[0061] As shown in the table above, the theophylline derivative prepared in the example of this invention has good anticonvulsant activity, which is significantly higher than that of the positive control drugs carbamazepine and sodium valproate.

[0062] Example 1

[0063] This embodiment provides a theophylline sustained-release tablet.

[0064] Raw material composition (parts by weight): theophylline 90 parts; hydroxyethyl cellulose 250HX 10 parts; povidone 1 part; cetyl alcohol 3 parts; octadecyl alcohol 3 parts; talc 0.2 parts; magnesium stearate 0.2 parts. The povidone is povidone K29 and povidone K32 in a mass ratio of 1:1.

[0065] For reference Figure 2 Process flow diagram, preparation process:

[0066] (1) Pretreatment

[0067] The raw materials received according to the production order are weighed.

[0068] The theophylline raw material is pretreated in an air jet mill.

[0069] (2) Weighing

[0070] Raw materials and auxiliary materials received according to production orders are moved into the weighing and mixing room for verification (name, specifications, code, warehouse entry number, batch number, weight, and quality status). The materials are confirmed to be consistent with the production orders. A double-checking system is implemented during the weighing process.

[0071] (3) Wet granulation and drying

[0072] Preparation of adhesive: Take a certain amount of purified water and put it in a stainless steel bucket, add a certain amount of povidone, and stir until completely dissolved into a transparent solution.

[0073] Premix: Theophylline (crushed) and hydroxyethyl cellulose are added sequentially into a mixing granulator for premixing.

[0074] Add binder: Spray the binder into the mixing granulator.

[0075] Wet granulation: granulation for 30 seconds.

[0076] Wet granulation: Start the granulator to perform wet granulation.

[0077] Drying: Place the stainless steel baking tray containing the granules into a hot air circulating box, close the box door, and dry. During the drying process, turn the tray over every hour and check and record the temperature.

[0078] (4) Whole grains

[0079] Granulation: The dried granules are granulated on a granulator.

[0080] (5) Hot melt granulation and cooling

[0081] Preparation of hot melt solvent: Place the prepared cetyl alcohol and octadecyl alcohol in a stainless steel container and heat in a water bath until completely melted into a transparent solution.

[0082] Premixing: The dry granulation intermediate is put into the mixing granulator, the water bath temperature is set to 80℃, and the material is stirred to preheat and maintain a certain temperature.

[0083] Heating the melting solvent: Add the hot melt solvent to the mixing granulator and stir.

[0084] Hot melt granulation: Granulate for 15 minutes. Serving in a stainless steel baking pan.

[0085] Cooling: Allow to cool naturally for about 1 hour until the material temperature is below 30°C.

[0086] (6) Hot melt granulation

[0087] Hot melt granulation: The cooled granules are granulated on a granulator.

[0088] (7) Mixing and total mixing

[0089] Mixing: Place the prepared hot melt granules and talc powder into the motion mixer and start the machine to mix.

[0090] Final mixing: Place the prepared magnesium stearate into a motion mixer and start mixing. The intermediate mixture is packaged in double-layer polyethylene bags, placed in a stainless steel drum, and stored in the intermediate station.

[0091] (8) Tableting

[0092] Start-up test compression: Pour the granules into the hopper, set the target production speed of the tablet press to begin test compression, and the operator simultaneously takes 55 tablets (110 tablets in total) from the left and right discharge ports for testing. When the tablet weight, thickness, and hardness meet the quality control requirements, the batch production record should be filled out promptly. Before formal tableting begins, QA personnel take 20 tablets from each of the left and right discharge ports, and test the appearance (20 tablets), weight (20 tablets), hardness (5 tablets), thickness (5 tablets), and friability (approximately 6.5g) of each discharge port. Once the requirements are met, formal tableting can begin.

[0093] Formal tableting: Begin tableting according to the parameters adjusted during trial tableting. During tableting, add granules to the hopper promptly, ensuring the material level is not lower than the upper edge of the viewing window. During formal tableting, operators should record the tableting process parameters every 15 minutes and simultaneously take samples from both the left and right discharge ports, 20 tablets each time, to test appearance (20 tablets), tablet weight (20 tablets), hardness (5 tablets), and tablet thickness (5 tablets). At the beginning, middle, and end of tableting, take approximately 6.5g samples to check for brittleness. The resulting theophylline sustained-release tablets are packaged in double-layer polyethylene bags and placed in stainless steel drums.

[0094] (9) Aluminum-plastic packaging

[0095] Theophylline sustained-release tablets were packaged using an aluminum-plastic blister packaging machine. During the blister packaging process, the appearance was checked at any time; the airtightness was checked every 30 minutes, and 20 blister packs were sampled and recorded each time.

[0096] (10) Outer packaging

[0097] The tablets, which are already in aluminum-plastic packaging, are then repackaged and labeled.

[0098] Example 2

[0099] The difference compared to Example 1 is that the raw material ratio is different.

[0100] Raw material composition (parts by weight): theophylline 110 parts; hydroxyethyl cellulose 250HX 20 parts; povidone 2 parts; cetyl alcohol 5 parts; octadecyl alcohol 6 parts; talc 0.6 parts; magnesium stearate 0.6 parts. The povidone is povidone K29 and povidone K32 in a mass ratio of 1:1.5.

[0101] Example 3

[0102] The difference compared to Example 1 is that the raw material ratio is different.

[0103] Raw material composition (parts by weight): theophylline 100 parts; hydroxyethyl cellulose 250HX 15 parts; povidone 1.5 parts; cetyl alcohol 4 parts; octadecyl alcohol 5 parts; talc 0.5 parts; magnesium stearate 0.5 parts. The povidone is povidone K29 and povidone K32 in a mass ratio of 1:1.

[0104] Example 4

[0105] The difference from Example 1 is that theophylline was replaced by the theophylline derivative obtained in Preparation Example 1.

[0106] Example 5

[0107] The difference from Example 2 is that theophylline was replaced by the theophylline derivative obtained in Preparation Example 2.

[0108] Example 6

[0109] The difference from Example 3 is that theophylline was replaced by the theophylline derivative obtained in Preparation Example 3.

[0110] Test Example 2

[0111] The experiment was divided into Examples 1-3 and a reference preparation group, which used the theophylline sustained-release tablets prepared in Examples 1-3 and the commercially available reference preparation (theophylline sustained-release tablets produced by Nichi-Iko Pharmaceutical Co., Ltd).

[0112] Using 900 mL of water as the dissolution medium, a paddle method was employed at a rotation speed of 100 r / min. At 1, 3, 4, 6, 8, and 24 hours, 5 mL of solution was collected and filtered, with the same volume and temperature of dissolution medium replenished immediately. A precise amount of the filtrate was then precisely measured and quantitatively diluted with purified water to prepare a solution containing approximately 7 μg of anhydrous theophylline per mL. The absorbance was measured at 271 nm using UV-Vis spectrophotometry (General Rule 0401). Separately, a precise amount of theophylline reference standard was weighed, dissolved in water, and quantitatively diluted to prepare a solution containing approximately 7 μg of anhydrous theophylline per mL. The absorbance was measured using the same method. The cumulative dissolution amount of each tablet at different time points was calculated. The results are as follows: Figure 3 As shown in the figure, the dissolution curve of the sustained-release tablets prepared in Example 3 is most similar to that of the reference formulation, indicating that it is the optimal formulation.

[0113] Test Example 3

[0114] Mice were randomly divided into 8 groups, with 10 mice in each group: a negative control group, a model group, and groups 1-6. Except for the negative control group, mice in the other groups were intraperitoneally injected with 0.2 mL of freshly prepared physiological saline sensitization solution (containing 80 μg of chicken egg white and 1 mg of aluminum hydroxide) on days 1, 8, and 15. From day 22, mice were placed in a self-made plexiglass box and challenged by nebulizing 10 mL of 1 wt% chicken egg white saline solution twice daily for 7 days. Thirty minutes before challenge, the model group received 10 mL of physiological saline via nebulization; groups 1-6 received 120 mg of the corresponding prepared theophylline sustained-release tablets via dry powder nebulizer.

[0115] 1. Collection of bronchoalveolar lavage fluid and preservation of lung tissue: 24 hours after the last nebulized inhalation of chicken egg protein to challenge mice, they were anesthetized, the trachea was exposed, a disposable intravenous catheter was inserted, and both lungs were lavaged. Bronchoalveolar lavage fluid was collected, repeated three times, with a recovery rate of 80-90%. Lung tissue was immediately harvested after bronchoalveolar lavage fluid collection, fixed, and subjected to routine HE staining for pathological examination. Results are as follows: Figure 4 As shown in the figure, the model group exhibited extensive inflammatory cell infiltration around the small bronchi and accompanying small blood vessels, mainly composed of neutrophils and lymphocytes. Airway mucosal edema and even epithelial shedding were observed, along with goblet cell proliferation. In Examples 3 and 6, the bronchial and lung tissue structures were essentially normal, with a significant reduction in inflammatory cell infiltration around the bronchial walls.

[0116] 2. Cell counting and differential analysis in bronchoalveolar lavage fluid: The bronchoalveolar lavage fluid was centrifuged, and 20 μL of physiological saline was added to the precipitate. The total white blood cell count and differential cell count were performed using an automated blood analyzer. The supernatant was frozen for later use in the analysis of cytokines and total protein. The results are shown in Table 3.

[0117] Table 3 Comparison of cell classification and count (×10) 7 (pieces / L)

[0118]

[0119] Note: * indicates P<0.05 compared with the negative control group; # indicates P<0.05 compared with the model group.

[0120] As shown in the table above, the number of eosinophils, neutrophils, lymphocytes and macrophages in the theophylline sustained-release tablets prepared in Examples 1-6 of this invention decreased significantly.

[0121] 3. Determination of cytokine concentration and total protein content in bronchoalveolar lavage fluid supernatant: Frozen bronchoalveolar lavage fluid supernatant was collected, and IL-4 and TNF-α in the bronchoalveolar lavage fluid were determined by ELISA. The total protein concentration in the bronchoalveolar lavage fluid was determined by a fully automated biochemical analyzer. The results are shown in Table 4.

[0122] Table 4

[0123]

[0124] Note: * indicates P<0.05 compared with the negative control group; # indicates P<0.05 compared with the model group.

[0125] As shown in the table above, the theophylline sustained-release tablets prepared in Examples 1-6 of this invention can significantly reduce the content of total protein, IL-4 and TNF-α.

[0126] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A theophylline sustained-release tablet, characterized in that, The raw materials include the following parts by weight: 90-110 parts of theophylline derivative or theophylline; 10-20 parts of hydroxyethyl cellulose; 1-2 parts of povidone; 3-5 parts of cetyl alcohol; 3-6 parts of octadecyl alcohol; 0.2-0.6 parts of talc; and 0.2-0.6 parts of magnesium stearate. The structural formula of the theophylline derivative is shown in Formula I. Formula I.

2. The theophylline sustained-release tablet according to claim 1, characterized in that, The povidone is povidone K29 and povidone K32, with a mass ratio of (0.5-1):(0.5-1.5).

3. The theophylline sustained-release tablet according to claim 1, characterized in that, The hydroxyethyl cellulose is hydroxyethyl cellulose 250HX.

4. The theophylline sustained-release tablet according to claim 1, characterized in that, The preparation method of the theophylline derivative is as follows: S1. An intermediate was prepared by reacting 8-chlorotheophylline with pentaerythritol tetrachloride, the structural formula of which is as follows: ； S2. The intermediate is reacted with hydrazine hydrate, and an aqueous solution of sodium nitrite is added and stirred to obtain the product.

5. The theophylline sustained-release tablet according to claim 4, characterized in that, The mass ratio of 8-chlorotheophylline to pentaerythritol tetrachloride in step S1 is (4-4.2):

1.

6. The theophylline sustained-release tablet according to claim 4, characterized in that, The reaction temperature in step S2 is 55-65℃.

7. The theophylline sustained-release tablet according to claim 4, characterized in that, The concentration of the sodium nitrite aqueous solution in step S2 is 5-15 wt%, and the stirring time is 1-3 h.

8. A method for preparing theophylline sustained-release tablets as described in any one of claims 1-7, characterized in that, Includes the following steps: (1) Pre-treat theophylline or its derivatives in an air jet mill; (2) Dissolve povidone in water to form a transparent solution to obtain an adhesive; (3) Mix the pretreated theophylline or theophylline derivative and hydroxyethyl cellulose, spray in the binder, wet granulate, wet granulate, dry, dry granulate to obtain the dry granulation intermediate; (4) Take hexadecyl alcohol and octadecyl alcohol and heat them until they are completely melted into a transparent solution to obtain a hot-melt solvent; (5) Heat the dry granulation intermediate, add hot melt solvent and mix evenly, hot melt granulate, cool, and granulate to obtain hot melt granules; (6) Mix the hot melt particles and talc powder, add magnesium stearate, mix evenly to obtain a mixture; (7) Compress the mixture into tablets, package them, and obtain theophylline sustained-release tablets.

9. The preparation method according to claim 8, characterized in that, The wet granulation time is 20-40 seconds, and the hot melt granulation time is 15-25 minutes.

10. The use of the theophylline sustained-release tablet as described in any one of claims 1-7 in a medicament for treating asthma, epilepsy, and anticonvulsants.

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