Theophylline sustained release tablet and its preparation method and application

Abstract

The application provides theophylline sustained-release tablets, a preparation method and application thereof, and belongs to the technical field of medicines.The theophylline sustained-release tablets comprise the following raw materials in parts by weight: theophylline derivatives or theophylline 90-110 parts;hydroxyethyl cellulose 10-20 parts;polyvinylpyrrolidone 1-2 parts;hexadecanol 3-5 parts;octadecanol 3-6 parts;talcum powder 0.2-0.6 parts;and magnesium stearate 0.2-0.6 parts.The preparation method is simple, the synthesis condition is mild, the yield is high, the theophylline derivatives have high selectivity, strong bronchodilating effect, quick effect, long maintenance time, small gastric irritation, slight cardiac side effect and good biological activities such as anti-tuberculosis, anti-convulsion and smooth muscle relaxation, and the theophylline derivatives are in a sustained-release dosage form, the drug action time is prolonged, and the theophylline derivatives have a wide application prospect.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of medicines, in particular to a theophylline sustained-release tablet and a preparation method and application thereof. BACKGROUND

[0002] Theophylline is a smooth muscle relaxant. It is mainly used for treating asthma and asthmatic bronchitis in clinic. Theophylline is easily absorbed after oral administration. The average half-life of an adult after administration is 5-6 hours, and the average half-life of a child is 3.5 hours. The therapeutic blood concentration of theophylline is narrow (5-20 mu g / mL), and the clearance rate and half-life vary from person to person. Ordinary theophylline tablets need to be taken three times a day. The use of theophylline at night affects sleep. After frequent administration, the blood concentration is prone to the "peak-valley" phenomenon, which causes headache, nausea, insomnia, convulsions and allergic reactions and other side effects. Theophylline controlled-release tablets can reduce the frequency of administration, effectively avoid the "peak-valley" phenomenon of blood concentration and reduce the side effects after administration. Theophylline sustained-release tablets, according to the requirements of the Japanese reference preparation (UNICON Tab. 100) instructions, are taken once a day after dinner, which does not affect the quality of sleep at night, especially the onset from night to early morning. There is no significant difference for patients with acute symptoms. Since the product has a slow peak time, the patient's compliance can be improved.

[0003] A theophylline sustained-release tablet with 24-hour drug release is provided in Chinese patent document CN10755088A. The main skeleton material used is cellulose, which is a material that swells in water. Theophylline is wrapped to achieve sustained release, but the release of theophylline in the sustained-release tablet is not complete.

[0004] Chinese patent document CN103239419A provides a preparation method of a theophylline sustained-release tablet, (1) adding a retarder to a wet granulator, preparing an adhesive by adding a solvent to the retarder, and stirring and shearing at room temperature; (2) adding theophylline, adhesive and filler to the wet granulator to prepare soft material; (3) replacing the granulator with a 16-20 mesh stainless steel screen, and granulating with the granulator; (4) drying the wet granules in a boiling bed using vacuum extraction, then using a crushing and granulating machine to granulate, adding a lubricant and mixing, and then pressing to obtain theophylline sustained-release tablets. This method can release at a constant speed, has stable quality, is safe, has a simple process and good process stability, but the release degree is not high, and the theophylline cannot be completely released. SUMMARY

[0005] The present application aims at providing theophylline sustained-release tablets, a preparation method and application thereof, and the theophylline sustained-release tablets are prepared by using theophylline or theophylline derivatives, and the preparation method is simple and has good sustained-release effect. The theophylline derivatives have high selectivity, strong bronchodilating effect, quick effect, long maintenance time, small gastric irritation, slight cardiac side effect and good biological activities such as anti-tuberculosis, anti-convulsion and smooth muscle relaxation, and the theophylline derivatives are prepared under mild synthesis conditions and have high yield, and the theophylline derivatives have wide application prospect as the sustained-release dosage form and long drug action time.

[0006] The technical scheme of the present application is implemented as follows:

[0007] The present application provides theophylline sustained-release tablets, which comprise the following raw materials by weight: theophylline derivatives or theophylline 90-110 parts, hydroxyethyl cellulose 10-20 parts, povidone 1-2 parts, cetyl alcohol 3-5 parts, stearyl alcohol 3-6 parts, talc 0.2-0.6 parts, and magnesium stearate 0.2-0.6 parts, and the structural formula of the theophylline derivatives is shown as formula I:

[0008] Formula I.

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

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

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

[0012] S1. 8-chlorotheophylline and pentaerythritol chloride are reacted to prepare an intermediate, and the structural formula is as follows: ;

[0013] S2. The intermediate is reacted with hydrazine hydrate, and sodium nitrite aqueous solution is added and stirred to prepare a product.

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

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

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

[0017] The present application further protects a preparation method of the theophylline sustained-release tablet, comprising the following steps:

[0018] (1) placing the theophylline or the theophylline derivative into an airflow mill for pretreatment;

[0019] (2) dissolving povidone into water to form a transparent solution to obtain a binder;

[0020] (3) mixing the pretreated theophylline or the theophylline derivative and hydroxyethyl cellulose, spraying into the binder, wet granulation, wet whole granulation, drying, dry whole granulation to obtain a dry whole granulation intermediate;

[0021] (4) heating cetyl alcohol and stearyl alcohol to complete melting to form a transparent solution to obtain a hot melt solvent;

[0022] (5) heating the dry whole granulation intermediate, adding the hot melt solvent and uniformly mixing, hot melt granulation, cooling, whole granulation to obtain hot melt granules;

[0023] (6) mixing the hot melt granules and talc, adding magnesium stearate and uniformly mixing to obtain a mixture;

[0024] (7) tabletting the mixture, packaging and obtaining the theophylline sustained-release tablet.

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

[0026] The present application further protects the use of the theophylline sustained-release tablet in the preparation of a drug for treating asthma, epilepsy and anticonvulsant.

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

[0028] The present application uses cetyl alcohol and stearyl alcohol as a sustained-release skeleton material, and combines with a binder and a lubricant to prepare the theophylline sustained-release tablet with a 24-hour release period, which significantly delays the dissolution of the theophylline or the theophylline derivative, can well control the release of the drug, has a long-term stability, a good release reproducibility, and the release degree of the drug at the 24th hour is more than 85%, the drug is completely released, the in-vitro dissolution behavior is consistent with that of the theophylline sustained-release tablet produced by Nichi-Iko Pharmaceutical Co., Ltd., improves the patient's medication compliance, overcomes the inconvenience and the large concentration fluctuation caused by multiple drug administration, provides convenience for patients, and has a high bioavailability.

[0029] However, theophylline belongs to methyl xanthine compounds, contains secondary amine structure in the molecule, and is weakly alkaline as a whole, so that it forms a hypertonic solution in the gastric acid environment, directly stimulates the gastric mucosa, and causes gastrointestinal reactions such as nausea, vomiting, stomach pain, etc. At the same time, theophylline has a similar molecular structure to adenosine (purine nucleosides), which makes theophylline act as a competitive antagonist, preferentially binds to adenosine receptors, thereby blocking the normal binding of adenosine to the receptors, antagonizing its physiological effects, and causing rapid heart rate, cardiac excitation, and central nervous system excitation.

[0030] From the analysis of the drug action mechanism and structure, it is indicated that the same substance molecule including two or more basic structures with the same pharmacological effect is a way to obtain a new drug with high therapeutic efficacy and low toxicity. According to the splicing principle in new drug design, theophylline derivatives are synthesized, the secondary amine structure is removed, the alkalinity is reduced, the molecular structure is increased, the binding efficiency to adenosine receptors is reduced to a certain extent, the side effects are reduced, in addition, the theophylline skeleton structure makes it have the characteristics of high selectivity, strong bronchodilating effect, fast onset, long maintenance time, small gastric irritation, and slight cardiac side effects, etc. Meanwhile, the tetrazole structure is added to the structure of the derivatives in the application, so that the compound has good antituberculosis, anticonvulsant, and smooth muscle relaxing biological activities.

[0031] The preparation method of the application is simple, the synthesis conditions are mild, the yield is high, the theophylline derivatives prepared have high selectivity, strong bronchodilating effect, fast onset, long maintenance time, small gastric irritation, slight cardiac side effects, and good anticonvulsant, smooth muscle relaxing biological activities, etc. At the same time, it is a sustained-release dosage form, prolongs the drug action time, and has a broad application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can be obtained by those skilled in the art without creative labor.

[0033] Figure 1 It is a structural schematic diagram of theophylline derivatives;

[0034] Figure 2 It is a preparation process flow chart of theophylline sustained-release tablets;

[0035] Figure 3 It is a cumulative release percentage-time curve graph in test example 2;

[0036] Figure 4The structure of each group of mice lung tissue HE staining under light microscope. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work are within the protection scope of the present application.

[0038] Preparation Example 1 Theophylline Derivative

[0039] The synthetic route is as follows:

[0040]

[0041] The preparation method is as follows:

[0042] S1. 0.4 mol 8-chloro theophylline, 0.8 mol NaOH, 0.1 mol pentaerythritol chloride were added into 200 mL toluene, heated to reflux for 4 h to prepare an intermediate; ESI-MS calculated value: C 33 H 33 Cl4N 16 O8(M+H) + 923.52, actual value: 923.5, yield 90%. NMR results: 1 H NMR (300 MHz, CDCl3) δ 3.67 (s, 8H), 2.72-2.75 (m, 24H). 13 C NMR (75 MHz, CDCl3) δ 154.9, 151.4, 150.5, 149, 107.4, 33.2, 32.3, 29.1, 25.7.

[0043] S2. 1 g of the intermediate was added with 50 mL of hydrazine hydrate, heated to 55°C, and stirred until the intermediate was completely reacted as monitored by TLC. After cooling to room temperature, filtration was performed, and the product was washed with methanol. The product was dissolved in a 2 mol / L hydrochloric acid solution, 5 wt% sodium nitrite aqueous solution was added, and stirring was performed at room temperature for 3 h. Filtration was performed, and ice water washing was performed. Column chromatography separation was performed with methanol and dichloromethane as the eluent at a volume ratio of 1:30 to prepare the product, and the structural formula is as follows: Figure 1 ESI-MS calculated value: C 33 H 33 N 28 O8(M+H) + 949.79, actual value: 949.8, yield 59%. NMR results: 1H NMR (300 MHz, CDC13) δ 3.89 (s, 8H), 2.92-2.97 (m, 24H). 13 C NMR (75 MHz, CDC13) δ 157.8, 151.5, 120.4, 99.0, 54.3, 30.4, 29.4, 26.9.

[0044] Preparation Example 2 Theophylline Derivative

[0045] The preparation method is as follows:

[0046] S1. 0.42 mol 8-chloro theophylline, 0.8 mol NaOH, 0.1 mol pentaerythritol chloride were added into 200 mL toluene, heated to reflux for 6 h to prepare an intermediate; yield 92%.

[0047] S2. 1 g of the intermediate was added with 50 mL of hydrazine hydrate, heated to 65°C, and stirred until the intermediate was completely reacted as monitored by TLC. The mixture was cooled to room temperature, filtered, washed with methanol, and the product was dissolved in 2 mol / L hydrochloric acid solution. 15 wt% sodium nitrite aqueous solution was added, and the mixture was stirred at room temperature for 1 h, filtered, washed with ice water, and separated by column chromatography with methanol and dichloromethane (1:30 by volume) as eluent to obtain the product, which has the structural formula as shown in Figure 1 , yield 62%.

[0048] Preparation Example 3 Theophylline Derivative

[0049] The preparation method is as follows:

[0050] S1. 0.41 mol 8-chloro theophylline, 0.8 mol NaOH, 0.1 mol pentaerythritol chloride were added into 200 mL toluene, heated to reflux for 5 h to prepare an intermediate; yield 91%.

[0051] S2. 1 g of the intermediate was added with 50 mL of hydrazine hydrate, heated to 60°C, and stirred until the intermediate was completely reacted as monitored by TLC. The mixture was cooled to room temperature, filtered, washed with methanol, and the product was dissolved in 2 mol / L hydrochloric acid solution. 10 wt% sodium nitrite aqueous solution was added, and the mixture was stirred at room temperature for 2 h, filtered, washed with ice water, and separated by column chromatography with methanol and dichloromethane (1:30 by volume) as eluent to obtain the product, which has the structural formula as shown in Figure 1 , yield 61%.

[0052] Test Example 1

[0053] Kunming mice were selected, half male and half female, weighing 18-22 g, and the drug solvent was dimethyl sulfoxide, with a dosage of 0.1 mL per mouse. The pharmacological test method was determined by referring to the "Antiepileptic Drug Development Program" published by the National Institutes of Health.

[0054] 24 hours before the experiment, the mice were electrically stimulated (110V, 60Hz, 0.2s single stimulus) by using an electric convulsion instrument. The mice that showed hind limb rigidity were used for the experiment. 0.5 hours after intraperitoneal injection of the theophylline derivative prepared in Preparation Example 3, the mice were electrically stimulated under the same conditions. The mice that showed hind limb rigidity were negative, indicating that the compound had no anticonvulsant effect, and vice versa. Then, the half effective dose ED50 (the dose that can cause 50% of the experimental subjects to show a positive reaction) of the compound with good activity was determined to evaluate the drug efficacy. The results are shown in Tables 1 and 2. 50

[0055] Table 1

[0056]

[0057] Note: a, maximum electric convulsion (number of positive mice / number of mice tested).

[0058] Table 2

[0059]

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

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

[0062] Example 1

[0063] This example 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; stearyl alcohol 3 parts; talc 0.2 parts; magnesium stearate 0.2 parts. The povidone is povidone K29 and povidone K32, with a mass ratio of 1:1.

[0065] Referring to the process flow chart as shown in Figure 2 , the preparation process is as follows:

[0066] (1) Pretreatment

[0067] The raw materials received according to the production instructions were weighed.

[0068] The theophylline raw material was pretreated in an airflow mill.

[0069] (2) Weighing

[0070] ​The raw and auxiliary materials taken according to the production instruction are moved into the weighing and mixing room, and the materials (name, specification, code, storage sequence number, batch number, weight, and quality state) are checked. The materials are consistent with the production instruction without error. The weighing process is executed by the double-checking system.

[0071] (3) Wet granulation and drying

[0072] Preparation of the binder: a certain amount of purified water is placed in a stainless steel bucket, and a certain amount of povidone is added and stirred to completely dissolve into a transparent solution.

[0073] Premixing: the theophylline (after being pulverized) and hydroxyethyl cellulose are sequentially put into the mixing granulator for premixing.

[0074] Binder addition: the binder is sprayed into the mixing granulator.

[0075] Wet granulation: granulation for 30 s.

[0076] Wet sizing: the wet sizing machine is started for wet sizing.

[0077] Drying: the stainless steel baking tray containing the granules is placed in the hot air circulating air tank, the tank door is closed, and drying is performed. The tray is turned over every one hour during the drying process, and the temperature condition is checked and recorded.

[0078] (4) Sizing

[0079] Sizing: the dried granules are sized on the sizing machine.

[0080] (5) Hot melt granulation and cooling

[0081] Preparation of the hot melt solvent: the prepared cetyl alcohol and stearyl alcohol are placed in a stainless steel bucket, heated in a water bath, and 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°C, and the material is preheated and maintained at a certain temperature by stirring.

[0083] Hot melt solvent addition: the hot melt solvent is added to the mixing granulator for stirring.

[0084] Hot melt granulation: granulation for 15 min. The granules are collected in a stainless steel baking tray.

[0085] Cooling: natural cooling for about 1 hour until the material temperature is lower than 30°C.

[0086] (6) Hot melt sizing

[0087] Hot melt sizing: the cooled granules are sized on the sizing machine.

[0088] (7) Mixing and total mixing

[0089] Mixing: Put the prepared hot melt granules and talc into a moving mixer and start mixing.

[0090] Total mixing: Put the prepared magnesium stearate into a moving mixer and start mixing. The total mixing intermediate is packaged in a double-layer polyethylene bag and placed in a stainless steel barrel in the intermediate station.

[0091] (8) Tabletting

[0092] Trial tabletting: Pour the granules into the hopper, set the target production speed of the tablet machine, and start trial tabletting. The operator takes 55 tablets (a total of 110 tablets) from the left and right discharge ports at the same time for detection. When the tablet weight, tablet thickness, and hardness meet the quality control requirements, fill in the batch production record in time. The QA personnel take a sample of 20 tablets from each of the left and right discharge ports before the formal tabletting starts, and detect the appearance (20 tablets), tablet weight (20 tablets), hardness (5 tablets), tablet thickness (5 tablets), and friability (about 6.5g) of each discharge port. If the requirements are met, formal tabletting can be started.

[0093] Formal tabletting: Start tabletting according to the parameters adjusted during trial tabletting. During tabletting, add granules to the hopper in time, and the amount of material should not be less than the upper edge of the window. During the formal tabletting operation, the operator should record the tabletting process parameters every 15 minutes, and at the same time, take a sample of 20 tablets from the left and right discharge ports, and detect the appearance (20 tablets), tablet weight (20 tablets), hardness (5 tablets), tablet thickness (5 tablets); take a sample of about 6.5g at the beginning, middle, and end of tabletting for friability testing. The theophylline sustained-release tablets are packaged in a double-layer polyethylene bag and placed in a stainless steel barrel.

[0094] (9) Aluminum plastic packaging

[0095] The theophylline sustained-release tablets are packaged with an aluminum plastic blister packaging machine. During the blistering process, samples are taken at any time for appearance inspection; the air tightness is checked every 30 minutes, and 20 boards are taken for each sample and recorded.

[0096] (10) Outer packaging

[0097] The tablets packaged with aluminum plastic are outer packaged and labeled.

[0098] Example 2

[0099] Compared with Example 1, the difference is that the raw material ratio is different.

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

[0101] Example 3

[0102] The difference from 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; stearyl alcohol 5 parts; talc 0.5 parts; magnesium stearate 0.5 parts. The povidone is povidone K29 and povidone K32, mass ratio 1:1.

[0104] Example 4

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

[0106] Example 5

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

[0108] Example 6

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

[0110] Test Example 2

[0111] The test is divided into Example 1-3 and reference preparation groups, and 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.) are used respectively.

[0112] Using water 900 mL as the dissolution medium, the paddle method is used, the rotation speed is 100 r / min, at 1, 3, 4, 6, 8, 24 h, 5 mL of the solution is taken and filtered, and the same temperature and the same volume of dissolution medium is immediately supplemented; an appropriate amount of the filtrate is accurately taken, each is quantitatively diluted with purified water to prepare a solution containing about 7 μg of anhydrous theophylline per 1 mL, and the absorbance is measured at 271 nm by ultraviolet-visible spectrophotometry (general rule 0401); another appropriate amount of theophylline reference substance is accurately weighed, dissolved in water and quantitatively diluted to prepare a solution containing about 7 μg of anhydrous theophylline per 1 mL as the reference solution, and the absorbance is measured by the same method, and the cumulative dissolution amount of each tablet at different time points is calculated, and the results are shown in Figure 3 As can be seen from the figure, the dissolution curve of the sustained-release tablets prepared in Example 3 is most similar to that of the reference preparation, which is the optimal formula.

[0113] Test Example 3

[0114] The mice were randomly divided into 8 groups, 10 mice in each group. The negative control group, the model group, and the example 1-6 groups. Except for the negative control group, the other groups of mice were respectively sensitized with 0.2 mL of fresh prepared normal saline sensitizing solution containing 80 μg of chicken egg protein and 1 mg of aluminum hydroxide by intraperitoneal injection on the 1st day, the 8th day and the 15th day. From the 22nd day, the mice were put into the self-made organic glass box, and were inhaled 10 mL of 1 wt% chicken egg protein normal saline solution for 7 days, twice a day. 30 minutes before the excitation, the model group was given 10 mL of normal saline for atomization inhalation; the example 1-6 groups were given 120 mg of theophylline sustained-release tablets prepared in the corresponding manner, and were inhaled by using a dry powder atomization inhalation device.

[0115] 1. Bronchoalveolar lavage fluid collection and lung tissue collection: 24 hours after the last chicken egg protein excitation, the mice were anesthetized, the trachea was exposed, a disposable intravenous indwelling needle was inserted, the double lungs were lavaged, and the bronchoalveolar lavage fluid was collected. The recovery rate was 80-90% after 3 times of repeated collection. The lung tissue was collected immediately after the bronchoalveolar lavage fluid was collected, was fixed, and was subjected to HE staining and routine pathological examination. The results are shown in Figure 4 As shown in the figure, a large number of inflammatory cells, mainly neutrophils and lymphocytes, infiltrated around the small bronchus and the accompanying small blood vessels in the model group, the airway mucosa was edematous, and even the epithelium was shed, and the goblet cells proliferated. In the example 3 group and the example 6 group, the bronchial and lung tissue structures were basically normal, and the inflammatory cell infiltration around the bronchial wall was obviously reduced.

[0116] 2. Cell counting and classification in the bronchoalveolar lavage fluid: the bronchoalveolar lavage fluid was centrifuged, 20 μL of normal saline was added to the precipitate, and the total number of white blood cells and the cell classification count were counted by using an automatic blood analyzer; the supernatant was frozen for the determination of cytokines and total protein. The results are shown in Table 3.

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

[0118]

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

[0120] As shown in the above table, the number of eosinophils, neutrophils, lymphocytes and macrophages in the theophylline sustained-release tablets prepared in the example 1-6 groups was obviously decreased.

[0121] 3. Determination of cytokine concentration and total protein content in the supernatant of the bronchoalveolar lavage fluid: the frozen supernatant of the bronchoalveolar lavage fluid was taken, the IL-4 and TNF-α in the bronchoalveolar lavage fluid were determined by using the ELISA method, and the total protein concentration in the bronchoalveolar lavage fluid was determined by using an automatic biochemical analyzer. The results are shown in Table 4.

[0122] Table 4

[0123]

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

[0125] From the above table, it can be seen that the theophylline sustained-release tablets prepared in Examples 1-6 can obviously reduce the contents of total protein, IL-4 and TNF-α.

[0126] The above merely describes the preferred embodiments of the present application and is not used to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A theophylline sustained release tablet, characterized by, The preparation method comprises the following steps: (1) preparing the theophylline derivative; (2) dissolving the polyvinylpyrrolidone in water to obtain a transparent solution; (3) mixing the theophylline derivative and the hydroxyethyl cellulose, and spraying the mixture into the transparent solution to obtain wet granules; (4) heating the wet granules to add the hot melt solvent, and uniformly mixing the wet granules and the hot melt solvent to obtain hot melt granules; (5) mixing the hot melt granules and the talc, and adding the magnesium stearate to obtain a mixture; and (6) tabletting the mixture, and packaging to obtain the theophylline sustained-release tablets. Formula I.

2. The theophylline sustained release tablet according to claim 1, wherein The polyvinylpyrrolidone is polyvinylpyrrolidone K29 and polyvinylpyrrolidone K32, and the mass ratio is (0.5-1):(0.5-1.5).

3. The theophylline sustained release tablet according to claim 1, wherein The hydroxyethyl cellulose is hydroxyethyl cellulose 250HX.

4. The theophylline sustained release tablet according to claim 1, wherein The theophylline derivative is prepared by the following method: S1. reacting 8-chlorotheophylline and pentaerythritol chloride to obtain an intermediate, and the structure of the intermediate is as shown in the following formula: ； S2. reacting the intermediate and hydrazine hydrate, adding an aqueous sodium nitrite solution to stir to obtain a product.

5. The theophylline sustained release tablet according to claim 4, wherein The mass ratio of the 8-chlorotheophylline and the pentaerythritol chloride in step S1 is (4-4.2):

1.

6. The theophylline sustained release tablet according to claim 4, wherein The reaction temperature in step S2 is 55-65°C.

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

8. A process for the preparation of the sustained release theophylline tablet according to any one of claims 1 to 7, characterized in that, The preparation method comprises the following steps: (1) pretreating the theophylline derivative in an airflow mill; (2) dissolving the polyvinylpyrrolidone in water to obtain a transparent solution; (3) mixing the pretreated theophylline derivative and the hydroxyethyl cellulose, spraying the mixture into the transparent solution, wet granulating, wet whole granulating, drying, dry whole granulating to obtain dry whole granules; (4) heating the cetyl alcohol and the stearyl alcohol to completely melt into a transparent solution to obtain a hot melt solvent; (5) heating the dry whole granules, adding the hot melt solvent, uniformly mixing, hot melt granulating, cooling, and whole granulating to obtain hot melt granules; (6) mixing the hot melt granules and the talc, adding the magnesium stearate, and uniformly mixing to obtain a mixture; (7) tabletting the mixture, packaging, and obtaining the theophylline sustained-release tablets.

9. The production method according to claim 8, characterized by, The wet granulating time is 20-40s, and the hot melt granulating time is 15-25min.

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