Anti-ulcer medicine and quality control method thereof

Abstract

The invention relates to the technical field of biological medicines, in particular to an anti-ulcer medicine and a quality control method thereof. Existing vitamin U belladonna aluminum dispersible tablets are improved, the problem that aluminum hydroxide in original dispersible tablets takes effect slowly is effectively solved by reasonably controlling the variety and dosage of auxiliary materials, the action time of neutralizing gastric acid is prolonged, and the vitamin U belladonna aluminum dispersible tablets have the advantages of being rapid in effect taking and more stable in acid making effect.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and particularly to anti-ulcer drugs and their quality control methods. Background Art

[0002] Compound Aluminum Hydroxide and Methylmethionine Sulfonium Chloride Dispersible Tablets are a compound oral preparation composed of vitamin UII (iodomethylmethionine), aluminum hydroxide, and belladonna extract. Vitamin UII has the effects of purifying the ulcer surface and promoting the healing of the ulcer surface. It is divided into two types: iodine type and chlorine type. This product is of the iodine type. When aluminum hydroxide is taken orally, the generated AlCl3 during the neutralization of gastric acid also has the effects of astringency and local hemostasis. It can relieve symptoms such as acid regurgitation caused by excessive gastric acid and is applicable to the treatment of gastric and duodenal ulcer diseases and reflux esophagitis; when belladonna extract is used in combination with antacids or H2 receptor antagonists, it can further reduce the gastric acid secretion of ulcer patients, and can also delay gastric emptying, which is beneficial to the healing of duodenal ulcers. It can be used as an antispasmodic to treat gastrointestinal dysfunction and irritable bowel syndrome, as well as biliary colic, dysmenorrhea, and nocturnal enuresis, etc.

[0003] Aluminum hydroxide is the main component of antacids. It can neutralize gastric acid and relieve discomfort symptoms such as stomachache and heartburn (i.e., heartburn) caused by excessive gastric acid secretion. However, the existing aluminum hydroxide in current aluminum hydroxide and compound aluminum hydroxide and methylmethionine sulfonium chloride dispersible tablets reacts with hydrochloric acid in gastric acid to generate water and insoluble aluminum salts, thereby neutralizing gastric acid and reducing the acidity of gastric contents. Since it proceeds through a chemical reaction step by step, this means that after the drug enters the human body, it cannot be quickly dispersed and fully contact with gastric acid to react. Usually, it takes a long time to start playing the role of neutralizing gastric acid, and it cannot relieve the symptoms of patients in a timely and effective manner. For patients who urgently need to relieve gastric acid discomfort, there is an urgent need to provide a drug in which aluminum hydroxide has a fast onset and can extend the time of neutralizing gastric acid.

[0004] In addition, compound aluminum hydroxide and methylmethionine sulfonium chloride dispersible tablets are not included in the Chinese Pharmacopoeia, the United States Pharmacopoeia, the European Pharmacopoeia, and the British Pharmacopoeia. The current quality standard for this variety is YBH03062009, and there is no determination of the content of vitamin UII and the detection of acid-neutralizing capacity. In the existing technical methods, the determination method of vitamin UII uses the silver nitrate residual titration method. This method has problems such as cumbersome operation, unreasonable sample pretreatment operation, and the use of nitrobenzene reagent during titration, which has relatively high toxicity. And in the existing technical methods, the acid-neutralizing capacity inspection item only controls the ability of the product to neutralize gastric acid and has no control over the process. Therefore, there is a need to provide an acid-neutralizing capacity determination method and a vitamin UII content determination method that can comprehensively control the product quality, and have good specificity and repeatability, which is beneficial to the quality control of the product. Summary of the Invention

[0005] In view of this, the present invention provides an anti-ulcer drug and its quality control method. The anti-ulcer drug has a rapid onset of action, a more stable acid-neutralizing effect, and a better anti-ulcer effect.

[0006] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0007] An anti-ulcer drug, calculated by mass parts, its raw materials include:

[0008]

[0009] The disintegrant includes croscarmellose sodium and / or crospovidone;

[0010] The binder includes hypromellose E5 and / or povidone K30.

[0011] In the present invention, the particle size of the aluminum hydroxide is d90 ≤ 6.0 μm.

[0012] Weiyou Dianqie Lv Dispersible Tablets is a common acid-neutralizing drug, composed of vitamin U II (iodomethyl methionine), aluminum hydroxide, and belladonna extract, and is used to relieve heartburn, stomachache caused by excessive gastric acid, and chronic gastritis. The therapeutic effect of acid-neutralizing drugs lies in combining and neutralizing gastric acid, reducing the reverse diffusion of gastric acid to the gastric mucosa, reducing the gastric acid entering the duodenum at the same time, increasing the pH value of gastric juice, and reducing the activity of pepsin, thereby relieving pain and promoting ulcer healing.

[0013] In the present invention, aluminum hydroxide with a particle size of d90 ≤ 6.0 μm is selected, combined with specific types of disintegrants, binders, and hypromellose K100M. The prepared anti-ulcer drug effectively improves the problem of slow onset of action of aluminum hydroxide and prolongs the action time of neutralizing gastric acid, thereby improving the healing of ulcers.

[0014] In the present invention, the filler includes at least one of microcrystalline cellulose, lactose, mannitol, starch, sorbitol, and sucrose. In specific embodiments, the filler is microcrystalline cellulose or lactose.

[0015] In the present invention, the lubricant includes at least one of magnesium stearate, calcium stearate, colloidal silicon dioxide, stearic acid, or talc powder. In specific embodiments, the lubricant is magnesium stearate.

[0016] In specific embodiments of the present invention, calculated by mass parts, the raw materials of the anti-ulcer drug include:

[0017]

[0018] In other embodiments, calculated by mass parts, the raw materials of the anti-ulcer drug include:

[0019]

[0020] The dosage forms of the anti-ulcer drug include granules, capsules, tablets, and so on.

[0021] In some specific embodiments, the anti-ulcer drug is a tablet, and its preparation method includes:

[0022] Step 1: Weigh the prescribed amount of binder and add it to purified water to obtain a binder solution;

[0023] Step 2: Mix 25% of the prescribed amount of filler, 50% of the prescribed amount of aluminum hydroxide, and hypromellose K100, granulate using the binder solution, and dry to obtain sustained-release granules;

[0024] Step 3: Mix aluminum hydroxide, vitamin U II, belladonna extract, disintegrant, and the remaining filler, granulate using the binder solution, and dry to obtain immediate-release granules;

[0025] Step 4: Mix the sustained-release granules and immediate-release granules and press them into tablets.

[0026] In Step 1 of the present invention, the mass concentration of the binder solution is 8% - 10%, specifically it can be 8%, 9%, or 10%. In specific embodiments of the present invention, the binder solution is an aqueous solution of hypromellose E5 with a mass concentration of 8% or an aqueous solution of povidone K30 with a mass concentration of 10%.

[0027] In the present invention, in Steps 2 and 3, after granulation, there is also a step of sizing with a 20 - 30 mesh sieve.

[0028] In the present invention, in Steps 2 and 3, the drying is carried out until the water content < 5%.

[0029] The present invention also provides an anti-ulcer drug prepared by the above preparation method.

[0030] The present invention also provides a quality control method for the anti-ulcer drug, including:

[0031] Step a: Grind the drug and add water for ultrasonic treatment; titrate with 0.1 mol / L silver nitrate titrant, and use potentiometry to indicate the end point; determine the content of vitamin U II according to the amount of silver nitrate consumed;

[0032] Step b: Grind the drug into fine powder and sieve it through No. 5 sieve to obtain fine powder. Weigh precisely 0.140 g of the fine powder based on the mass of aluminum hydroxide, add ethanol, adjust the pH to 3.5, slowly add water, stir at a speed of 200 revolutions per minute for 1 - 2 minutes, then add 1 mol / L hydrochloric acid titrant preheated to 36.5°C - 37.5°C, stir at a speed of 200 revolutions per minute, measure the pH value of the solution at 10 minutes, 20 minutes, and 30 minutes respectively, which shall not be lower than 1.8, 2.1, and 2.7 respectively, and shall not be higher than 4; then add 1 mol / L hydrochloric acid titrant preheated to 36.5°C - 37.5°C, continue stirring and reacting for 1 hour, and stop stirring; under the stirring condition, titrate the pH value to 3.5 with 1 mol / L sodium hydroxide titrant, calculate the volume of hydrochloric acid consumed per gram of the drug, and obtain the acid-neutralizing capacity of the drug.

[0033] In the present invention, in step b, the temperature of the added water and hydrochloric acid titrant is 36.5°C - 37.5°C.

[0034] According to the above method, conduct quality monitoring on the drug of the present invention. Taking the drug containing 0.14 g of aluminum hydroxide raw material per tablet as an example, each tablet of the drug consumes no less than 3.0 ml of hydrochloric acid titrant (1 mol / L). Meanwhile, when the content of vitamin U II is 90.0% - 110.0% of the labeled amount, determine that the drug is a qualified product.

[0035] The present invention provides an anti-ulcer drug and its quality control method. The present invention improves the existing dispersible tablets of vitamin U and belladonna aluminum. By reasonably controlling the types and dosages of excipients, it effectively improves the problem that the aluminum hydroxide in the original dispersible tablets has a slow onset, and prolongs the action time of neutralizing gastric acid, with the characteristics of rapid onset and more stable acid-neutralizing capacity effect. In addition, the quality control method provided by the present invention can comprehensively control the product quality, and has good specificity, which is beneficial to the quality control of the product. Description of the Drawings

[0036] Figure 1 It is the investigation result of the acid-neutralizing speed of each component in the prescription of the present invention;

[0037] Figure 2 It is the pH value - time curve of the aluminum hydroxide raw material;

[0038] Figure 3 It is the pH value - time curve of the influence of other components on the acid-neutralizing capacity;

[0039] Figure 4 It is the linear data of the sampling amount and titration volume during the determination of vitamin U II;

[0040] Figure 5 It shows the comparison result of the acid-neutralizing capacity of the drugs in Examples 1 - 2 and Comparative Examples 1 - 2. Detailed implementation manners

[0041] The present invention provides an anti-ulcer drug and a quality control method therefor. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those related can obviously make changes or appropriate alterations and combinations to the methods and applications in this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0042] The test materials used in the present invention are all ordinary commercially available products and can be purchased in the market.

[0043] The following further elaborates the present invention in conjunction with embodiments:

[0044] Example 1 Preparation of an anti-ulcer drug

[0045] The prescription composition is shown in Table 1:

[0046] Table 1

[0047] Composition Dosage (g) Vitamin U II 50 Aluminum hydroxide (d90 ≤ 6.0 μm) 140 Belladonna extract 10 Microcrystalline cellulose 70 Hypromellose K100M 50 Croscarmellose sodium 20 Hypromellose E5 5 Magnesium stearate 2

[0048] (1) Pretreatment of raw and auxiliary materials: Control the particle size of aluminum hydroxide to meet the requirements (d90 ≤ 6.0 μm);

[0049] (2) Preparation of binder: Weigh hypromellose E5 and add it to purified water to prepare an 8% aqueous solution of hypromellose E5 for standby;

[0050] (3) Mixing and granulation:

[0051] ① Preparation of sustained-release granules: Weigh 25% of the prescription amount of microcrystalline cellulose and 50% of the prescription amount of aluminum hydroxide (d90 ≤ 6.0 μm), mix for 3 min, and then add the prescription amount of hypromellose K100M in equal increments and mix for 10 min. Use an 8% aqueous solution of hypromellose E5 for wet granulation. The time for preparing the soft material is 3 - 5 min, and the granulation sieve is a 20 - 30 mesh steel mesh;

[0052] ② Preparation of immediate-release granules: Weigh 75% of the prescription amount of microcrystalline cellulose and 50% of the prescription amount of aluminum hydroxide (d90 ≤ 6.0 μm), mix for 3 min, then add the prescription amount of vitamin UⅡ and mix for 3 min, add belladonna extract in equal increments and mix for 10 min, and then add 75% of the prescription amount of croscarmellose sodium and mix for 3 min. Use an 8% aqueous solution of hypromellose E5 for wet granulation. The time for preparing the soft material is 3 - 5 min, and the granulation sieve is a 20 - 30 mesh steel mesh;

[0053] (4) Drying: The granules obtained in step (3) were dried separately using a fluidized bed dryer, controlling the moisture content < 5%;

[0054] (5) Granule sizing: The dried granules obtained in step (4) were sized separately using a vibrating granulator, with a sizing screen of 20 - 30 mesh steel wire;

[0055] (6) Total mixing: The granules obtained in step (5) were added to a three - dimensional motion mixer, and cross - linked carboxymethyl cellulose sodium and magnesium stearate were added according to the external addition dosage, and mixed for 3 - 5 min;

[0056] (7) Tabletting: The mixed granules were tabletted using a special punch.

[0057] Example 2: Preparation of an anti - ulcer drug

[0058] The prescription composition is shown in Table 2:

[0059] Table 2

[0060] Composition Dosage (g) Vitamin U II 50 Aluminum hydroxide (d90 ≤ 6.0 μm) 140 Belladonna extract 10 Lactose 90 Hypromellose K100M 30 Crospovidone 20 Povidone K30 8 Magnesium stearate 3

[0061] (1) Granule preparation

[0062] ① Preparation of sustained - release granules: Lactose, aluminum hydroxide and hypromellose K100 were mixed and granulated using povidone K30, then dried;

[0063] ② Preparation of immediate - release granules: Lactose, aluminum hydroxide, vitamin U II, belladonna extract and cross - linked povidone were mixed evenly and granulated using povidone K30, then dried

[0064] (2) After sizing the granules, total mixing and tabletting were carried out to obtain the product.

[0065] For the specific steps and parameters involved in the preparation process, refer to Example 1.

[0066] Comparative Example 1: Preparation of an anti - ulcer drug

[0067] The prescription composition is shown in Table 3:

[0068] Table 3

[0069] Composition Dosage (g) Vitamin U II 50 Aluminum hydroxide (d90 ≥ 15 μm) 140 Belladonna extract 10 Microcrystalline cellulose 70 Hypromellose K100M 40 Croscarmellose sodium 20 Hypromellose E5 5 Magnesium stearate 2

[0070] (1) Granule preparation

[0071] ① Preparation of sustained - release granules: Microcrystalline cellulose, aluminum hydroxide and hypromellose K100 were mixed and granulated using hypromellose E5, then dried;

[0072] ② Preparation of immediate - release granules: Microcrystalline cellulose, aluminum hydroxide, vitamin U II, belladonna extract and cross - linked carboxymethyl cellulose sodium were mixed evenly and granulated using hypromellose E5, then dried

[0073] (2) Granulate the granules and then perform total mixing and tabletting.

[0074] Comparative Example 2: Preparation of anti-ulcer drug

[0075] The prescription composition is shown in Table 4:

[0076] Table 4

[0077]

[0078]

[0079] (1) Mix microcrystalline cellulose, aluminum hydroxide, vitamin U II, belladonna extract, and cross-linked carboxymethylcellulose sodium evenly, granulate with hypromellose E5, and dry

[0080] (2) Granulate the granules and then perform total mixing and tabletting to obtain the product.

[0081] Determination test of acid-neutralizing capacity in Example 3

[0082] 1.1 Instruments and experimental devices

[0083] Dissolution tester RC12AD, TianDa TianFa Technology Co., Ltd.

[0084] pH meter C3060, Consort

[0085] Electronic balance XS205DU, Mettler

[0086] 1.2 Investigation of acid-neutralizing capacity of raw materials and excipients

[0087] (I) Investigation of the acid-neutralizing speed of each component in the prescription of the present invention

[0088] Weigh an appropriate amount of aluminum hydroxide raw material according to the prescription amount in Example 1, accurately weigh it, place it in a 250 ml dissolution cup, add 2 ml of ethanol (adjust the pH value to 3.5 with 0.1 mol / L hydrochloric acid solution), measure 198 ml of preheated water at 37 °C, and then slowly add the remaining amount of water while shaking. After stirring at 200 revolutions per minute for 1 minute, accurately add 2 ml of hydrochloric acid titrant (1.0 mol / L) preheated to 37 ± 0.5 °C, and start timing accurately. Measure the pH value of the solution every 1 minute. Taking time as the abscissa and the pH value of the solution as the ordinate, plot the acid-neutralizing curve (see Figure 1 Investigation of the acid-neutralizing speed of each component in the prescription).

[0089] Weigh appropriate amounts of vitamin UII, belladonna extract and excipients according to the prescription amount of Example 1, and accurately weigh them. Place them in a 250 ml dissolution cup, add 2 ml of ethanol (adjust the pH value to 3.5 with 0.1 mol / L hydrochloric acid solution), measure 199.5 ml of water preheated to 37 °C, and then slowly add the remaining water while shaking. After stirring at 200 revolutions per minute for 1 minute, accurately add 0.5 ml of hydrochloric acid titrant (1.0 mol / L) preheated to 37 ± 0.5 °C, and start timing accurately. Measure the pH value of the solution every 1 minute. Taking time as the abscissa and the pH value of the solution as the ordinate, draw an acid-neutralizing curve (see details in Figure 1 Investigation of the acid-neutralizing speed of each component in the prescription), then accurately add 20 ml of hydrochloric acid titrant (1 mol / L) preheated to 37 ± 0.5 °C, continue stirring for 1 hour, and titrate the pH value to 3.5 with sodium hydroxide titrant (1 mol / L) (the acid-neutralizing power results are shown in Table 5).

[0090] From Figure 1 and the results in Table 5, it can be seen that the acid-neutralizing power of the drug of the present invention is mainly contributed by aluminum hydroxide, and other components basically have no antacid power.

[0091] Table 5 Acid-neutralizing power of each component in the prescription

[0092]

[0093] (2) Investigation of the acid-neutralizing power of aluminum hydroxide raw materials in different proportions

[0094] Investigate the acid-neutralizing power of aluminum hydroxide raw drug (batch number 21030801). Weigh 1 tablet prescription amount of aluminum hydroxide raw material, 90% of the aluminum hydroxide raw material in 1 tablet prescription amount, 80% of the aluminum hydroxide raw material in 1 tablet prescription amount, and 70% of the aluminum hydroxide raw material in 1 tablet prescription amount respectively, and accurately weigh them. Place them in 4 250 ml dissolution cups respectively, add 2 ml of ethanol (adjust the pH value to 3.5 with 0.1 mol / L hydrochloric acid solution), measure 198 ml of water preheated to 37 °C, and then slowly add the remaining water while shaking. Stir at a speed of 200 revolutions per minute for 1 - 2 minutes. Accurately add 2 ml of hydrochloric acid titrant (1 mol / L) preheated to 37 ± 0.5 °C, and start timing accurately. Measure the pH value of the solution every 1 minute. Taking time as the abscissa and the pH value of the solution as the ordinate, draw an acid-neutralizing curve (see details in Figure 2 pH value-time curve of aluminum hydroxide raw materials from different manufacturers). Then accurately add 20 ml of hydrochloric acid titrant (1 mol / L) preheated to 37 ± 0.5 °C, continue stirring for 1 hour, and titrate the pH value to 3.5 with sodium hydroxide titrant (1 mol / L) (the acid-neutralizing power results are shown in Table 6).

[0095] From Figure 2As can be seen from Table 6 results, when 2 ml of hydrochloric acid titrant (1 mol / L) is added, the change in the reaction rate between the sample and the acid can be clearly observed. The curves of aluminum hydroxide raw materials with different ratios show that the plateau is basically reached in 30 minutes, and the pH value of the solution at the plateau is stable at 3.5.

[0096] Table 6 Acid-neutralizing capacity of aluminum hydroxide raw materials

[0097]

[0098] (III) Influence of other components on the acid-neutralizing curve

[0099] Since only aluminum hydroxide in the prescription of the present invention has an acid-neutralizing effect, and other components have almost no acid-neutralizing effect, other components except aluminum hydroxide and excipients in the prescription are uniformly defined as other components herein to study the influence of other components on the acid-neutralizing curve of the product.

[0100] Weigh 0.14 g of aluminum hydroxide raw material in the prescription amount of 1 tablet, weigh 3 portions in parallel and weigh accurately, place them in a 250 ml dissolution cup, add 2 ml of ethanol (adjust the pH to 3.5 with 0.1 mol / L hydrochloric acid solution), measure 198 ml of preheated water at 37 °C, and then slowly add the remaining water while shaking. After stirring at 200 revolutions per minute for 1 minute, accurately add 2 ml of hydrochloric acid titrant (1.0 mol / L) preheated to 37 ± 0.5 °C, and start timing accurately. Measure the pH value of the solution every 1 min. Using time as the abscissa and the pH value of the solution as the ordinate, draw the acid-neutralizing curve (see Figure 3 ).

[0101] Weigh the fine powder of the simulated prescription in the amount of 1 tablet according to the prescription, weigh 3 portions in parallel and weigh accurately, place them in a 250 ml dissolution cup, add 2 ml of ethanol (adjust the pH value to 3.5 with 0.1 mol / L hydrochloric acid solution), measure 198 ml of preheated water at 37 °C, and then slowly add the remaining water while shaking. After stirring at 200 revolutions per minute for 1 minute, accurately add 2 ml of hydrochloric acid titrant (1.0 mol / L) preheated to 37 ± 0.5 °C, and start timing accurately. Measure the pH value of the solution every 1 min. Using time as the abscissa and the pH value of the solution as the ordinate, draw the acid-neutralizing curve (see Figure 3 ). As Figure 3 shown: The influence of other components on the acid-neutralizing curve is relatively significant. After mixing the powder according to the prescription, the acid-neutralizing speed of the product shows a downward trend, and the time to reach the plateau of the acid-neutralizing curve is prolonged.

[0102] Example 4 Determination of vitamin U II content

[0103] 2.1 Method 1:

[0104] Take the drug of Example 1 of the present invention, grind it into fine powder, take an appropriate amount of the fine powder (equivalent to about 250 mg of iodomethyl methionine), weigh it accurately, place it in a 50 ml volumetric flask, add an appropriate amount of water, shake to dissolve the vitamin UII, dilute it to the mark with water, shake well, filter, accurately measure 25 ml of the continuous filtrate, place it in a conical flask, shake well, accurately add 20 ml of silver nitrate titrant (0.1 mol / L), add 3 ml of dilute nitric acid and 5 ml of ammonium ferric sulfate indicator solution, shake well, titrate with ammonium thiocyanate titrant (0.1 mol / L), and correct the titration result with a blank test. Each 1 ml of silver nitrate titrant (0.1 mol / L) is equivalent to 29.12 mg of C6H14INO2S.

[0105] The results of the methodological verification of Method 1 showed that: the negative sample consumed silver nitrate titrant, which interfered with the determination of the content of vitamin UII, and there was a problem with the method specificity; the recovery rate of the method was 105% - 110%, and the accuracy was poor; taking the sample of batch number 211105 and repeating the determination 6 times, the average content was 107.6%, and the RSD was 2.8%, and the repeatability could not meet the requirements either.

[0106] Through the decoction test, it was found through analysis that: there was sodium chloride impurity in the excipient sodium carboxymethyl starch, which would react with silver nitrate to form silver chloride precipitate; the excipient polyvinylpyrrolidone K30 formed a light blue precipitate during the titration process, interfering with the judgment of the titration end point.

[0107] In view of the above results, referring to the literature, it is proposed to use potentiometric titration for determination.

[0108] 2.2 Method 2:

[0109] Take an appropriate amount of the fine powder of this product (equivalent to about 500 mg of vitamin UII), weigh it accurately, place it in a 100 ml volumetric flask, add an appropriate amount of water, ultrasonically shake to dissolve and dilute to the mark, shake well, filter, accurately measure 50 ml of the continuous filtrate, and titrate with silver nitrate titrant (0.1 mol / L) according to the potentiometric titration method (General Chapter 0701, Part IV of the Chinese Pharmacopoeia 2020 Edition). Each 1 ml of silver nitrate titrant (0.1 mol / L) is equivalent to 29.12 mg of C6H14INO2S.

[0110] 2.3 Specificity

[0111] Weigh each component and excipient except vitamin UII equivalent to 100 tablets according to the prescription amount, place them in a 1000 ml volumetric flask, add an appropriate amount of water, ultrasonically shake to dissolve and dilute to the mark, shake well, filter, and use it as the negative solution.

[0112] Accurately measure 50 ml of the negative solution, place it in a potentiometric titration cup, and determine it according to the proposed method. About 1 ml of silver nitrate titrant is consumed.

[0113] Accurately weigh about 250 mg of vitamin U II raw material, place it in a potentiometric titration cup, accurately add 50 ml of negative solution, and perform the determination according to the proposed method. As a result, there are 2 inflection points in the potentiometric titration curve. The difference in the titration volumes of the two inflection points is equivalent to the volume of silver nitrate titrant consumed by the negative solution. Calculated according to the titration volume of the first inflection point, the content of vitamin U II is 99.1%.

[0114] Accurately weigh another about 250 mg of vitamin U II raw material, place it in a potentiometric titration cup, add 50 ml of water, and perform the determination according to the proposed method. Calculate the content of vitamin U II to be 99.4%.

[0115] From the above test results, it is shown that the proposed potentiometric titration method can effectively avoid the interference of Cl ions and has good method specificity.

[0116] 2.4 Linearity and range

[0117] Accurately weigh about 300 mg, 400 mg, 500 mg, 600 mg, and 700 mg of vitamin U II raw material respectively, perform the test according to the proposed method. The f value of the AgNO3 titrant (0.1 mol / L) is 1.0288. Perform linear regression with the volume of titrant consumed (Y) against the sampling amount of vitamin U II (X), as shown in Table 7. Figure 4 The linear equation is obtained as Y = 0.0166X - 0.0437, r = 1.000. The results show that there is a good linear relationship between the sampling amount of vitamin U II in the range of 285.2 mg to 707.8 mg and the volume of silver nitrate titrant (0.1 mol / L) consumed.

[0118] Table 7 Linear data of vitamin U II

[0119]

[0120]

[0121] 2.5 Accuracy

[0122] Take 6 portions of 500 mg (corresponding to 100%) of vitamin U II raw material with known content (the average content determined by the legal standard is 99.7%), accurately weigh, add an appropriate amount of blank excipients without vitamin U II according to the prescription ratio, grind evenly, and operate according to the proposed method. The average recovery rate is 98.7% and the RSD is 0.3%, as shown in Table 8. This method has good accuracy.

[0123] Table 8 Recovery test data

[0124]

[0125] 2.6 Precision

[0126] Six samples of batch number 211105 (average tablet weight 0.3039 g) were subjected to a repeatability test according to the proposed method. The average content of vitamin U II was 97.6%, and the RSD value was 0.3%, as shown in Table 9. The precision of this method is good.

[0127] Table 9 Repeatability test data

[0128] Sampling amount / g Titration volume / ml Vitamin U II content 2.9578 7.899 97.3％ 2.9350 7.883 97.8％ 2.7896 7.480 97.7％ 2.9116 7.797 97.5％ 3.0024 8.052 97.7％ 2.9867 8.035 98.0％

[0129] Example 5

[0130] The drugs of Examples 1-2 and Comparative Examples 1-2 were taken respectively, and the acid-neutralizing capacity was measured according to the method in Part (1) of Example 3, and the content of vitamin U II was measured according to Method 1 in Example 4. The results are shown in Table 10 and Figure 5 .

[0131] Table 10 Results of determination of vitamin U II content

[0132] Sample batch number Vitamin U II content Example 1 97.6％ Example 2 97.9％ Comparative Example 1 98.0％ Comparative Example 2 97.1％

[0133] The results showed that the drugs of Examples 1-2 of the present invention could reach the plateau in about 10 minutes, and the pH value of the solution at the plateau was stable at 3.5. The drug of Comparative Example 1 reached the plateau in 25 minutes, and the acid-neutralizing capacity of Comparative Example 2 was unstable and decreased rapidly later. It is indicated that the drugs of Examples 1-2 of the present invention are prepared by controlling the particle size of aluminum hydroxide d90≤6 μm, reasonably matching each auxiliary material, preparing sustained-release granules and immediate-release granules respectively and then tabletting, and the prepared products have a rapid onset and a more stable acid-neutralizing capacity effect.

[0134] The above is only the preferred embodiment of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. An anti-ulcer drug, characterized in that, In parts by mass, its raw materials include: The disintegrant includes sodium croscarmellose and / or crospovidone; The binder includes hypromellose E5 and / or povidone K30.

2. The anti-ulcer drug according to claim 1, characterized in that, The particle size of the aluminum hydroxide is d90 ≤ 6.0 μm.

3. The anti-ulcer drug according to claim 1 or 2, characterized in that, The filler includes at least one of microcrystalline cellulose, lactose, mannitol, starch, sorbitol, and sucrose.

4. The anti-ulcer drug according to any one of claims 1 to 3, characterized in that, The lubricant includes at least one of magnesium stearate, calcium stearate, colloidal silicon dioxide, stearic acid, or talc powder.

5. The anti-ulcer drug according to any one of claims 1 to 4, characterized in that, It includes the following raw materials in parts by mass: Or, 6. The preparation method of the anti-ulcer drug according to any one of claims 1 to 5, characterized in that, Includes: Step 1: Weigh the prescribed amount of binder and add it to purified water to obtain a binder solution; Step 2: Mix 25% of the prescribed amount of filler, 50% of the prescribed amount of aluminum hydroxide, and hypromellose K100, granulate using the binder solution, and dry to obtain sustained-release granules; Step 3: Mix aluminum hydroxide, vitamin U II, belladonna extract, disintegrant, and the remaining filler, granulate using the binder solution, and dry to obtain immediate-release granules; Step 4: Mix the sustained-release granules and immediate-release granules and press into tablets.

7. The preparation method according to claim 6, characterized in that, In Step 1, the mass concentration of the binder solution is 8% - 10%.

8. The preparation method according to claim 6, characterized in that, In Steps 2 and 3, After granulation, it further includes the step of sizing with a 20 - 30 mesh sieve; Dry until the water content < 5%.

9. The quality control method of the anti-ulcer drug according to any one of claims 1 to 5, characterized in that, Includes: Step a: Grind the drug and add water for ultrasonic treatment; Titrate with 0.1 mol / L silver nitrate titrant, and use potentiometry to indicate the end point; Determine the content of vitamin U II according to the amount of silver nitrate consumed; Step b: Grind the drug finely and pass through a No. 5 sieve to obtain fine powder; accurately weigh 0.140 g of the fine powder based on the mass of aluminum hydroxide, add ethanol, adjust the pH to 3.5, slowly add water, stir at a speed of 200 revolutions per minute for 1 - 2 minutes, then add 1 mol / L hydrochloric acid titrant preheated to 36.5°C - 37.5°C, stir at a speed of 200 revolutions per minute, measure the pH value of the solution at 10 minutes, 20 minutes, and 30 minutes respectively, which shall not be lower than 1.8, 2.1, 2.7, and shall not be higher than 4; then add 1 mol / L hydrochloric acid titrant preheated to 36.5°C - 37.5°C, continue to stir and react for 1 hour, stop stirring; under stirring conditions, titrate the pH value to 3.5 with 1 mol / L sodium hydroxide titrant, calculate the volume of hydrochloric acid consumed per gram of the drug, and obtain the acid-neutralizing capacity of the drug.

10. The quality control method according to claim 9, characterized in that, In Step b, the temperature of the added water and hydrochloric acid titrant is 36.5°C - 37.5°C.

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