Aminophylline tablet for treating bronchial asthma and preparation method of aminophylline tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to aminophylline tablets for treating bronchial asthma and a preparation method of the aminophylline tablets, the tablets are composed of aminophylline, carnauba wax, poly N-isopropylacrylamide, glyceryl monostearate and other auxiliary materials, the finally prepared tablets can be slowly released, and the drug effect reaches 24 h. Acceleration tests prove that the content change of the active substance ammonia tea is slow, a certain drug effect can be kept, and the tablet is simple in preparation process and suitable for further expanded production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an aminophylline tablet for treating bronchial asthma and a preparation method thereof. Background Art

[0002] The chemical name of aminophylline is 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione-1,2-ethylenediamine hydrate, and its molecular formula is C 2 H 8 N 2 ·(C 7 H 8 N 4 O 2 ) 2 ·xH 2 O, and its structural formula is as follows:

[0003]

[0004] Aminophylline is a commonly used prescription made from a drug that relieves tracheal spasms in clinical practice. There are aminophylline tablets and aminophylline injections. Among them, intravenous injection of aminophylline has a fast anti-asthmatic effect and good curative effect, and is used clinically. However, the safety range is small, the therapeutic index is narrow, and the individual difference in the in vivo elimination rate is relatively large. If used improperly, it is often likely to cause serious toxic and side effects, and even endanger life. The aminophylline tablet is relatively flexible and convenient to use, so it is also a very common usage method.

[0005] Most of the aminophylline tablets disclosed in the prior art cannot play a role for a long time, which is a great disadvantage for drugs that act at night. Summary of the Invention

[0006] Based on the deficiencies of the prior art, a tablet containing aminophylline is provided, which solves the problem of 24-hour release of aminophylline and can effectively treat asthma, and is suitable for further clinical expansion and application.

[0007] Specifically, the inventors solved it through the following technical solutions:

[0008] A tablet containing aminophylline, the tablet is composed of the following raw materials in parts by weight:

[0009]

[0010]

[0011] Further preferably, the tablet is composed of the following raw materials in parts by weight:

[0012]

[0013] Furthermore, the skeleton material is selected from carnauba wax and poly (N-isopropylacrylamide), and the weight ratio of carnauba wax to poly (N-isopropylacrylamide) is 4:1.

[0014] Furthermore, the filler is selected from microcrystalline cellulose and one or a combination of sorbitol, xylitol, and lactose; preferably, the filler is selected from microcrystalline cellulose and lactose.

[0015] Furthermore, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone. More preferably, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose.

[0016] Furthermore, the lubricant is selected from one of talc, magnesium stearate, colloidal silicon dioxide, sodium lauryl sulfate, and sodium lauryl sulfonate; more preferably, the lubricant is selected from magnesium stearate.

[0017] More preferably, the tablet is composed of the following raw materials in parts by weight:

[0018]

[0019] Furthermore, the tablet preparation process comprises the following steps:

[0020] 1) heating the skeleton material to a molten state and maintaining the temperature above 85° C. to obtain a mixture 1 for standby use;

[0021] 2) heating ethanol to 50-60° C., then adding glyceryl monostearate and aminophylline, stirring until completely dissolved, to obtain mixture 2, which is set aside;

[0022] 3) Add mixture 2 to mixture 1, then condense, solidify and crush to obtain mixture 3 for later use

[0023] 4) Add filler and disintegrant to mixture 3 and mix evenly, add appropriate amount of binder to granulate, and dry;

[0024] 5) adding a lubricant, mixing evenly, and tableting to obtain aminophylline tablets.

[0025] Furthermore, the tablet is composed of the following raw materials in parts by weight:

[0026]

[0027] The preparation of the tablet comprises the following steps:

[0028] 1) Heat carnauba wax to a molten state, add poly (N-isopropylacrylamide) with stirring, and keep the temperature above 90° C. to obtain a mixture 1, which is set aside;

[0029] 2) heating ethanol to 50-60° C., then adding glyceryl monostearate and aminophylline, stirring until completely dissolved, to obtain mixture 2, which is set aside;

[0030] 3) Add mixture 2 to mixture 1, then condense, solidify and crush to obtain mixture 3 for later use

[0031] 4) Add microcrystalline cellulose, lactose and cross-linked sodium carboxymethyl cellulose to mixture 3 and mix well, add appropriate amount of 3% hydroxypropyl methylcellulose in 50% ethanol solution to granulate, and dry;

[0032] 5) adding magnesium stearate and mixing evenly, and tableting to obtain aminophylline tablets.

[0033] Furthermore, the tablet of the present invention is used in preparing bronchial asthma medicine.

[0034] Compared with the prior art, the present invention has achieved unexpected technical effects.

[0035] In the present invention, aminophylline is creatively mixed with glyceryl monostearate to ensure that the tablets will not stick together during the tableting process, and at the same time help to improve the hardness and stability of the tablets. By combining with a waxy skeleton excipient, the sustained release and long-term control of the drug can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 : Comparison of the content of aminophylline in Examples 1-3 and Comparative Examples 1-5 at 0, 1, 2, 3, and 6 months.

[0037] Figure 2 : The cumulative dissolution rate of aminophylline in water at 1h, 2h, 4h, 8h, 12h, 16h, 20h and 24h was compared between Examples 1-3 and Comparative Examples 1-5.

[0038] Specific embodiment

[0039] The present invention discloses an aminophylline tablet for treating bronchial asthma and a preparation method thereof. Those skilled in the art can refer to the content of this article and appropriately change the process parameters. It should be particularly noted that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through relatively specific embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0040] Example 1: An aminophylline tablet for treating bronchial asthma and its preparation method: 1000 tablets

[0041]

[0042] The preparation process is as follows:

[0043] 1) Heat carnauba wax to a molten state, add poly (N-isopropylacrylamide) with stirring, and keep the temperature above 90° C. to obtain a mixture 1, which is set aside;

[0044] 2) heating ethanol to 50-60° C., then adding glyceryl monostearate and aminophylline, stirring until completely dissolved, to obtain mixture 2, which is set aside;

[0045] 3) adding mixture 2 to mixture 1, followed by condensation, solidification and crushing to obtain mixture 3 for later use;

[0046] 4) Add microcrystalline cellulose, lactose and cross-linked sodium carboxymethyl cellulose to mixture 3 and mix well, add an appropriate amount of 3% hydroxypropyl methylcellulose in 50% ethanol solution to granulate, and dry; wherein the stirring speed of the wet granulator is 200 rpm, the cutting speed is 250 rpm, and the mixing is performed for 3 minutes;

[0047] 5) adding magnesium stearate and mixing evenly, and tableting to obtain aminophylline tablets.

[0048] Example 2: An aminophylline tablet for treating bronchial asthma and its preparation method: 1000 tablets

[0049]

[0050] The preparation process is the same as that of Example 1.

[0051] Example 3: An aminophylline tablet for treating bronchial asthma and its preparation method: 1000 tablets

[0052]

[0053] The preparation process is the same as that of Example 1.

[0054] Example 4: An aminophylline tablet for treating bronchial asthma and its preparation method: 1000 tablets

[0055]

[0056] The preparation process is the same as that of Example 1.

[0057] The dissolution performance and the aminophylline content of the accelerated test were similar to those of Example 2.

[0058] Example 5: An aminophylline tablet for treating bronchial asthma and its preparation method: 1000 tablets

[0059]

[0060] The preparation process is the same as that of Example 1.

[0061] The dissolution performance and the aminophylline content of the accelerated test were similar to those of Example 2.

[0062] Comparative Example 1: Aminophylline tablets for treating bronchial asthma and preparation method thereof: 1000 tablets

[0063]

[0064]

[0065] The preparation process is the same as that of Example 1.

[0066] Comparative Example 2: Aminophylline tablets for treating bronchial asthma and preparation method thereof: 1000 tablets

[0067]

[0068] The preparation process is the same as that of Example 1.

[0069] Comparative Example 3: Aminophylline tablets for treating bronchial asthma and preparation method thereof: 1000 tablets

[0070]

[0071] The preparation process is the same as that of Example 1.

[0072] Comparative Example 4: Aminophylline tablets for treating bronchial asthma and preparation method thereof: 1000 tablets

[0073]

[0074] The preparation process is the same as that of Example 1.

[0075] Comparative Example 5: Aminophylline tablets for treating bronchial asthma and preparation method thereof: 1000 tablets

[0076]

[0077] The preparation process is the same as that of Example 1.

[0078] 1. Physical performance testing

[0079] Table 1 Physical properties test results of each embodiment

[0080]

[0081]

[0082] Reference for dissolution and related substances testing (General Rules of Part Four of the 2020 Edition of the Chinese Pharmacopoeia)

[0083] [Dissolution] According to the dissolution and release determination method in accordance with the 2020 edition of the Chinese Pharmacopoeia (General Rule 0931 Method 1), take this product, use 800 ml of water as the dissolution medium, and rotate at 100 revolutions per minute. Operate according to the method. After 10 minutes, take 10 ml of the solution for filtration, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with 0.01 mol / L sodium hydroxide solution to make a solution containing approximately 10 μg of aminophylline per 1 ml. According to the UV-Vis spectrophotometry (General Rule 0401), the absorbance is measured at a wavelength of 275 nm, and detection is carried out at 1h, 2h, 4h, 8h, 12h, 16h, 20h, and 24h respectively.

[0084] [Content Determination] Anhydrous theophylline Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 100 mg of aminophylline), place in a 200ml volumetric flask, add 20ml of 0.1mol / L sodium hydroxide solution and 60ml of water, shake for 10 minutes to dissolve the aminophylline, dilute to the scale with water, shake well, filter, accurately measure 5ml of the filtrate, place in a 250ml volumetric flask, dilute to the scale with 0.01mol / L sodium hydroxide solution, shake well, and measure the absorbance at a wavelength of 275nm according to the UV-Vis spectrophotometry (General Rule 0401).

[0085] result

[0086] Figure 1 : Comparison of the content of aminophylline in Examples 1-3 and Comparative Examples 1-5 at 0, 1, 2, 3, and 6 months.

[0087] Figure 2 : The cumulative dissolution rate of aminophylline in water at 1h, 2h, 4h, 8h, 12h, 16h, 20h and 24h was compared between Examples 1-3 and Comparative Examples 1-5.

[0088] 2. Exploration of preparation technology

[0089] A single factor experimental method was adopted, and the best solvent for dissolving aminophylline and glyceryl monostearate was selected. During the experiment, ethanol, chloroform, tert-butyl alcohol, methanol and water were selected under room temperature, and the results showed that impurities or precipitation were generated in all of them. The inventor accidentally discovered that under heating conditions, aminophylline and glyceryl monostearate were added to ethanol to clarify the solution, and then quickly added to the mixture, and the final prepared product had stable dissolution and good content, which was detected at the 0th month and was above 99%; other solvents such as tert-butyl alcohol and water could not achieve this effect, and other solvents such as methanol could not be heated because ethanol was selected as the solvent in the final process.

Claims

1. A tablet containing aminophylline, characterized in that: The tablet is composed of the following raw materials in parts by weight:

2. The tablet according to claim 1, characterized in that The tablet is composed of the following raw materials in parts by weight:

3. The tablet according to claim 1 or 2, characterized in that The skeleton material is selected from carnauba wax and poly (N-isopropylacrylamide), and the weight ratio of carnauba wax to poly (N-isopropylacrylamide) is 4:

1.

4. The tablet according to claim 1 or 2, characterized in that The filler is selected from microcrystalline cellulose and one or a combination of sorbitol, xylitol, and lactose; preferably, the filler is selected from microcrystalline cellulose and lactose.

5. The tablet according to claim 1 or 2, characterized in that The disintegrant is selected from cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone. More preferably, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose.

6. The tablet according to claim 1 or 2, characterized in that The lubricant is selected from one of talc, magnesium stearate, colloidal silicon dioxide, sodium lauryl sulfate, and sodium lauryl sulfonate; more preferably, the lubricant is selected from magnesium stearate.

7. The tablet according to claim 1 or 2, characterized in that The tablet is composed of the following raw materials in parts by weight:

8. The tablet according to claim 1, characterized in that The tablet preparation process comprises the following steps: Steps: 1) heating the skeleton material to a molten state and maintaining the temperature above 85° C. to obtain a mixture 1 for standby use; 2) heating ethanol to 50-60° C., then adding glyceryl monostearate and aminophylline, stirring until completely dissolved, to obtain mixture 2, which is set aside; 3) Adding mixture 2 to mixture 1, followed by condensation, solidification and crushing to obtain mixture 3 for later use; 4) Adding filler and disintegrant to mixture 3, mixing evenly, adding appropriate amount of binder to granulate, and drying; 5) adding a lubricant, mixing evenly, and tableting to obtain aminophylline tablets.

9. A tablet according to claim 7, characterized in that The tablet is composed of the following raw materials in parts by weight: The preparation of the tablet comprises the following steps: 1) Heat carnauba wax to a molten state, add poly (N-isopropylacrylamide) with stirring, and keep the temperature above 90° C. to obtain a mixture 1, which is set aside; 2) heating ethanol to 50-60° C., then adding glyceryl monostearate and aminophylline, stirring until completely dissolved, to obtain mixture 2, which is set aside; 3) Adding mixture 2 to mixture 1, and then condensing, solidifying, and crushing to obtain mixture 3, which is set aside. 4) Adding microcrystalline cellulose, lactose, and cross-linked sodium carboxymethyl cellulose to mixture 3, mixing evenly, adding an appropriate amount of 3% hydroxypropyl methylcellulose in 50% ethanol solution to granulate, and drying; 5) adding magnesium stearate and mixing evenly, and tableting to obtain aminophylline tablets.

10. Use of the tablet according to any one of claims 1 to 9 in the preparation of bronchial asthma medicines.

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