Preparation method of bismuth potassium citrate oral solid preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses a preparation process of a bismuth potassium citrate oral solid preparation. According to the preparation process of the bismuth potassium citrate oral solid preparation, the retention time of the medicine in the stomach is prolonged, the adhesion of the medicine in the stomach is improved, the curative effect of the medicine is improved, free bismuth of the product can be reduced, and the safety of the medicine is enhanced mainly by adding the biological adhesive material and the suspending aid.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing a bismuth potassium citrate oral solid preparation. Background Art

[0002] Potassium bismuth citrate is a bismuth-containing complex of indefinite composition, used for the treatment of digestive system diseases such as gastritis, duodenal ulcer and gastric ulcer associated with Helicobacter pylori pathogens. It is a gastric mucosal protective drug, and its mechanism of action is as follows: on the one hand, potassium bismuth citrate forms insoluble bismuth oxychloride and bismuth citrate precipitates in the acidic environment of the stomach, forming a chelate with a protein base layer, which serves as a protective film on the surface of ulcers and erosions; on the other hand, it can increase the synthesis of prostaglandin E, the production of mucus and the secretion of carbohydrates, effectively improve the stability of the gastrointestinal mucosa against pepsin, hydrochloric acid, bile acid enzymes and salts, promote the accumulation of epithelial factors in the defect area, and reduce the activity of pepsin and pepsinogen.

[0003] Potassium citrate preparations were first developed by Gist-Brocades (now Astellas Pharma), which launched a proprietary colloidal bismuth subcitrate (De-Nol) preparation for ulcer treatment in the 1970s. The original De-Nol formula was a colloidal suspension in ammonia water with a very pungent ammonia smell. After the dosage form was improved, potassium citrate tablets were launched in the Netherlands and Italy in August and September 1984, respectively, with the trade name De-Nol and a specification of 120 mg (in terms of bismuth oxide). In July 2015, Astellas announced that Astellas would stop supplying De-Nol from December 31, 2015. In July 1990, TORALABORATORIES SL was approved to market potassium citrate tablets in Spain, with the trade name GASTRODENOL and a specification of 120 mg. Currently, GASTRODENOL is the reference preparation announced by NMPA.

[0004] Bismuth exists in a complex state in potassium citrate, making it difficult to absorb. However, studies have shown that after taking potassium citrate tablets (De-Nol), a brief absorption of bismuth will occur in about 30 minutes, and the absorbed bismuth has no therapeutic effect, but has certain toxicity, such as abnormal gait, confusion, myoclonus and ataxia. The literature points out that the blood concentration of bismuth that shows neurotoxicity is 50-100ng / ml. If the blood concentration of bismuth is above 100ng / ml, treatment should be stopped.

[0005] Since potassium bismuth citrate APIs are all prepared by spray drying, the spray-dried APIs have the characteristics of low bulk density and poor fluidity, which is very unfavorable for the preparation of preparations; at the same time, there are two difficulties in producing oral solid preparations of potassium bismuth citrate: first, since potassium bismuth citrate requires a certain "ammonia" content, if the temperature is too high during drying, ammonia loss may occur, which may affect the efficacy or safety of the preparation; second, potassium bismuth citrate will form a colloidal substance when it meets water, which affects the granulation process of the oral solid preparation. Therefore, when preparing oral solid preparations of potassium bismuth citrate, organic solvents are basically selected as solvents.

[0006] CN114129532B discloses a method for preparing bismuth potassium citrate capsules. The method controls the amount of water-insoluble auxiliary materials, uses ethanol as a solvent for an adhesive, and prepares the bismuth potassium citrate capsules through conventional mixing-granulation-wet granulation-drying-dry granulation-total mixing-filling-inner packaging and other process flows. The method has conventional formula composition and preparation process, and has not conducted systematic research on in vitro quality research, and cannot prove the quality superiority and product effectiveness of the product.

[0007] CN111214443A discloses a method for preparing potassium bismuth citrate granules, which uses water-insoluble excipients such as cross-linked polyvinylpyrrolidone and magnesium stearate. The water-insoluble excipients cannot be dissolved in water when the granules are taken, which affects the mouthfeel of the granules when taken and reduces the compliance of the medication. At the same time, the method has great limitations and cannot produce other oral solid dosage forms such as tablets and capsules.

[0008] CN112263553A discloses a method for preparing potassium bismuth citrate tablets. The method adopts a direct compression process based on the preparation process, which is a conventional formula composition and preparation process, and does not improve the safety and effectiveness of the product.

[0009] Therefore, it is very necessary to provide a preparation scheme for oral solid dosage forms with high efficiency, low cost, good safety and improved effective performance. Summary of the invention

[0010] In order to overcome the shortcomings of existing product designs, the purpose of the present invention is to provide a method for preparing a potassium bismuth citrate oral solid preparation, the potassium bismuth citrate preparation has a short preparation process, the produced preparation has good stability, the quality indicators meet the standards, the in vitro effectiveness simulation experiment proves that its effectiveness is improved, and the in vivo PK test proves that its safety is improved.

[0011] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing a bismuth potassium citrate oral solid preparation, the specific steps are as follows:

[0013] (1) Raw material modification

[0014] Weigh potassium bismuth citrate, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-50° C. (preferably, the upper and lower limits of the temperature are set to 30-40° C.), and ensure that the material is in a fluidized state in the fluidized bed; spray a suspending agent solution or suspension prepared with purified water into the fluidized bed to ensure that the material temperature is within the control range; continue to maintain the temperature fluidized drying until the material drying loss is 2% to 4%;

[0015] (2) adding a bioadhesive material, a disintegrant, a diluent and a lubricant to the modified raw material and mixing them uniformly to obtain a potassium bismuth citrate oral solid preparation;

[0016] (3) tableting or capsule filling as required;

[0017] The suspending agent is one or more of colloidal silicon dioxide, xanthan gum, sodium alginate, carboxymethyl cellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone;

[0018] The bioadhesive material is one or more of carbomer 971P, carbomer 974P, and polycarbophil;

[0019] Furthermore, the lubricant is at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, hydrogenated vegetable oil, and glyceryl behenate.

[0020] Furthermore, the diluent is pregelatinized starch and / or mannitol;

[0021] Furthermore, the disintegrant is one or more of sodium carboxymethyl starch, potassium polacrilin, and cross-linked sodium carboxymethyl cellulose;

[0022] Further, the amount of the bioadhesive added is 0.1% to 5%, preferably 3% to 4%, of the total amount of the potassium citrate oral solid preparation; and / or

[0023] The amount of the disintegrant added is 1% to 10% of the total amount of the potassium bismuth citrate oral solid preparation, preferably 2% to 5%; and / or

[0024] The amount of the diluent added is 0-20% of the total amount of the potassium citrate oral solid preparation, preferably 0%-15%; and / or

[0025] The amount of the lubricant added is 0.5% to 2% of the total amount of the potassium citrate oral solid preparation, preferably 1% to 2%; and / or

[0026] The amount of the suspending agent added is 0.5% to 5% of the total amount of the potassium bismuth citrate oral solid preparation, preferably 1% to 2%.

[0027] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0028] (1) In the granulation process of the present invention, the temperature of the material is controlled. Setting the upper and lower limits of the temperature of the material within the range of 30-50° C. is more conducive to the formation of the particles. The loose particle structure can better accommodate other auxiliary materials. The moisture content of the particles is controlled within a limit range (2% to 4%) during the granulation process, which can enhance the stability of the particles during storage. The moisture content of the particles can also affect the formability of the particles and alleviate the sticking effect.

[0029] (2) The present invention performs particle modification on the bismuth potassium citrate raw material before preparing the preparation. The purpose of the particle modification is to increase the proportion of particles in the material after the raw material and the solvent are granulated, thereby improving the fluidity, compressibility and stability of the particles, and providing basic conditions for adding other functional excipients.

[0030] (3) The preparation method of the present invention improves the sedimentation volume ratio of the preparation in artificial gastric juice, but does not affect the colloid-precipitate conversion rate of the product. The free bismuth content of the preparation in vitro is reduced due to the adsorption of free bismuth by the bioadhesive material and the suspending agent. The in vitro free bismuth detection results show that the detection results are far lower than the 50ppm specified in the standard, and the free bismuth detection results of the samples with added bioadhesive material and suspending agent are even lower.

[0031] (4) The main effect of the present invention is also reflected in that the samples using bioadhesive materials and suspending agents have lower blood drug concentrations and drug-time curves in in vivo PK tests, and the amount of free bismuth absorbed by the human body will be less, therefore, it will have more advantages in safety.

[0032] (5) Using purified water as a solvent makes the production process safer, the production cost lower, and more environmentally friendly; the production process is simplified, and only the raw materials need to be modified and mixed and then the finished product can be obtained according to the conventional packaging procedures. DETAILED DESCRIPTION

[0033] The present invention is further described in detail below in conjunction with specific embodiments. The following embodiments are only for further illustrating the embodiments of the present invention, and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and replacements made by those skilled in the art on the basis of the present invention belong to the scope of protection claimed by the present invention.

[0034] Example 1

[0035] Table 1 Example 1 Formula composition

[0036] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 91.5％ Carbomer 974P Bioadhesives 4％ Povidone K90 Suspending Agents 1％ Sodium alginate Suspending Agents 0.5％ Sodium starch glycolate Disintegrants 2％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0037] Preparation process:

[0038] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the suspension of povidone K90 and sodium alginate prepared with purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material;

[0039] b. The components obtained in a are mixed evenly with carbomer 974P, sodium carboxymethyl starch and magnesium stearate;

[0040] c. half of the components obtained in b are compressed into tablets, and the other half are filled into capsules. The tableting and capsule filling in the present invention are carried out according to the basic operations in the art.

[0041] Example 2

[0042] The proportions of various substances and the preparation process in Example 2 are the same as those in Example 1, except that Carbomer 974P is replaced with Carbomer 971P.

[0043] Example 3

[0044] The proportions of various substances and the preparation process in Example 3 are the same as those in Example 1, except that Carbomer 974P is replaced with Polycarbophil.

[0045] Example 4

[0046] Table 2 Example 4 formulation composition

[0047] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 91.2％ Carbomer 974P Bioadhesives 3％ Xanthan gum Suspending Agents 0.6％ Sodium alginate Suspending Agents 1％ Polacrilin Potassium Disintegrants 3％ Magnesium Stearate Lubricants 1.2％ Purified water (ultimately removed) Solvents /

[0048] Preparation process:

[0049] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the xanthan gum and sodium alginate suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0050] b. Mix the components obtained in a with carbomer 974P, polacrilin potassium and magnesium stearate.

[0051] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0052] Example 5

[0053] Table 3 Example 5 formulation composition

[0054] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 90％ Polycarbophil Bioadhesives 3％ Colloidal Silica Suspending Agents 1％ Sodium alginate Suspending Agents 1％ Polacrilin Potassium Disintegrants 4％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0055] Preparation process:

[0056] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the colloidal silicon dioxide and sodium alginate suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0057] b. Mix the components obtained in a with polycarbophil, polacrilin potassium and magnesium stearate.

[0058] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0059] Example 6

[0060] Table 4 Example 6 formulation composition

[0061] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 93％ Polycarbophil Bioadhesives 3％ Hydroxypropyl cellulose (10mPa.s) Suspending Agents 1％ Cross-linked carboxymethyl cellulose sodium Disintegrants 2％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0062] Preparation process:

[0063] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the hydroxypropyl cellulose solution prepared by purified water into the fluidized bed, and after spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0064] b. The components obtained in a are mixed evenly with polycarbophil, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0065] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0066] Example 7

[0067] Table 5 Example 7 formulation composition

[0068] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 89％ Polycarbophil Bioadhesives 4％ Xanthan gum Suspending Agents 0.5％ Colloidal Silica Suspending Agents 0.5％ Polacrilin Potassium Disintegrants 5％ Polyethylene glycol 6000 Lubricants 0.5％ Calcium stearate Lubricants 0.5％ Purified water (ultimately removed) Solvents /

[0069] Preparation process:

[0070] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the xanthan gum and colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0071] b. Mix the components obtained in a with polycarbophil, polacrilin potassium, polyethylene glycol 6000 and calcium stearate.

[0072] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0073] Example 8

[0074] Table 6 Example 8 formulation composition

[0075] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 88％ Polycarbophil Bioadhesives 4％ Xanthan gum Suspending Agents 1％ Colloidal Silica Suspending Agents 0.5％ Polacrilin Potassium Disintegrants 5％ Sodium stearyl fumarate Lubricants 1.5％ Purified water (ultimately removed) Solvents /

[0076] Preparation process:

[0077] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the xanthan gum and colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0078] b. Mix the components obtained in a with polycarbophil, polacrilin potassium and sodium stearyl fumarate.

[0079] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0080] Example 9

[0081] Table 7 Example 9 formulation composition

[0082] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 87.5％ Polycarbophil Bioadhesives 4％ Xanthan gum Suspending Agents 1％ Colloidal Silica Suspending Agents 0.5％ Polacrilin Potassium Disintegrants 5％ Sodium Lauryl Sulfate Lubricants 1％ Hydrogenated vegetable oil Lubricants 1％ Purified water (ultimately removed) Solvents /

[0083] Preparation process:

[0084] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the xanthan gum and colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0085] b. Mix the components obtained in a with polycarbophil, polacrilin potassium, sodium lauryl sulfate and hydrogenated vegetable oil.

[0086] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0087] Example 10

[0088] The proportions of various substances and the preparation process in Example 10 are the same as those in Example 8, except that sodium stearyl fumarate is replaced by glyceryl behenate.

[0089] Embodiment 11

[0090] Table 8 Example 11 formulation composition

[0091]

[0092]

[0093] Preparation process:

[0094] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0095] b. Mix the components obtained in a with polycarbophil, polacrilin potassium and magnesium stearate.

[0096] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0097] Example 12

[0098] Table 9 Example 12 formulation composition

[0099] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 79％ Pregelatinized starch Thinner 10％ Polycarbophil Bioadhesives 4％ Colloidal Silica Suspending Agents 1％ Polacrilin Potassium Disintegrants 5％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0100] Preparation process:

[0101] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0102] b. The components obtained in a are mixed evenly with pregelatinized starch, polycarbophil, polacrilin potassium and magnesium stearate.

[0103] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0104] Embodiment 13

[0105] Table 10 Example 13 formulation composition

[0106] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 74％ Pregelatinized starch Thinner 5％ Mannitol Thinner 10％ Polycarbophil Bioadhesives 4％ Colloidal Silica Suspending Agents 1％ Polacrilin Potassium Disintegrants 5％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0107] Preparation process:

[0108] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0109] b. The components obtained in a are mixed evenly with mannitol, pregelatinized starch, polycarbophil, polacrilin potassium and magnesium stearate.

[0110] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0111] Embodiment 14

[0112] Table 11 Example 14 formulation composition

[0113] Material Name effect Composition ratio (weight percentage) Bismuth Potassium Citrate API 88％ Polycarbophil Bioadhesives 4％ Colloidal Silica Suspending Agents 2％ Sodium starch glycolate Disintegrants 5％ Magnesium Stearate Lubricants 1％ Purified water (ultimately removed) Solvents /

[0114] Preparation process:

[0115] a. Weigh the potassium bismuth citrate raw material according to the formula, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the upper and lower limits of the temperature to 30-40°C, and ensure that the material is fluidized in the fluidized bed; spray the colloidal silicon dioxide suspension prepared by purified water into the fluidized bed. After spraying, continue to maintain the temperature and dry for 10 minutes, control the drying loss to 2.0%-4.0%, stop the machine, and discharge the material.

[0116] b. Mix the components obtained in a with sodium carboxymethyl starch, magnesium stearate and polycarbophil.

[0117] c. Half of the component obtained in b is compressed into tablets, and the other part is filled into capsules.

[0118] The flowability and compressibility parameters of the particles obtained in step b of Example 1-14 were tested:

[0119] (1) Representative parameters of fluidity, determination method of angle of repose: add an excess of the powder to be tested into a container with a fixed diameter bottom plate. When the powder flows out from the central hole at the bottom of the container, a sliding slope (vertical shear plane is a triangle) is formed at the orifice of the bottom plate inside the container for the powder to flow out. The angle formed by the sliding slope and the horizontal bottom is the angle of repose.

[0120] (2) Representative parameters of compressibility, Hausner ratio determination method: that is, by measuring the apparent volume (Vo) of the loose powder and the tapped volume (V F ) is used to calculate. The Hausner ratio is calculated according to the following formula: Hausner ratio = Vo / V F .

[0121] The results are shown in Tables 12 and 13.

[0122] Table 12 Evaluation of the fluidity and compressibility of the sample particles produced in Examples 1-7 (1)

[0123]

[0124] Table 13 Evaluation of the fluidity and compressibility of the sample particles produced in Examples 8-14 (2)

[0125]

[0126] The tablets and capsules prepared in Examples 1-14 were subjected to in vitro quality comparison studies using GASTRODENOL as a reference preparation. The research items were labeled content, related substances, free bismuth, disintegration time, sedimentation volume ratio, and sedimentation wall phenomenon. The labeled content referred to the bismuth potassium citrate tablets of the Chinese Pharmacopoeia 2020 edition, and the disintegration time referred to the appendix of Part IV of the Chinese Pharmacopoeia 2020 edition. The detection methods of other items are as follows:

[0127] (1) Free bismuth: Take an appropriate amount of this product (equivalent to 120 mg of bismuth oxide), grind it into powder (take the contents of the capsule), accurately weigh it, put it into a volumetric flask, accurately add 50 ml of anhydrous ethanol, seal it and shake it for 10 minutes, filter it, accurately measure 20 ml of the filtrate, evaporate it to dryness, cool it, add an appropriate amount of 2% (volume concentration, the same below) nitric acid solution to dissolve it, transfer it and dilute it to a 20 ml volumetric flask, filter it with a 0.45 μm microporous filter membrane, and take the filtrate as the test solution; take 2% nitric acid solution as the blank solution; separately accurately measure an appropriate amount of bismuth single element standard solution (1000 μg / ml), dilute it with 2% nitric acid solution to prepare a series of bismuth standard solutions containing 0.1 μg to 2.0 μg bismuth per 1 ml. According to the atomic absorption spectrophotometry (Method 1 of Part IV of the Chinese Pharmacopoeia 2020 Edition, General Rules 0406), the absorbance value is measured at a wavelength of 223.06 nm, and the content of free bismuth is calculated. The free bismuth content shall not exceed 50 ppm.

[0128] (2) Sedimentation volume ratio and sedimentation wall phenomenon: Grind the product (take the contents of the capsule), weigh an appropriate amount (equivalent to 120 mg of bismuth oxide), place it in a 50 ml stoppered measuring cylinder, add 50 ml of artificial gastric juice (prepared according to the method in the Chinese Pharmacopoeia), seal it, shake vigorously for 1 minute, and record the initial volume of the suspension H. 0 , let it stand for half an hour, record the final volume H of the suspension, and calculate it according to the formula: sedimentation volume ratio = H / H 0 .

[0129] After the above-mentioned sedimentation test is completed, observe the inner wall of the stoppered measuring cylinder to see if there is any white substance hanging on the wall. The substance is insoluble in water. The above phenomenon is recorded as sedimentation hanging on the wall phenomenon.

[0130] (3) Related substances: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0131] Test solution: Take the contents of 20 tablets or 20 capsules of this product, grind them into powder, take an appropriate amount (equivalent to 120 mg of bismuth oxide), accurately weigh, put into a 20 ml volumetric flask, add about 10 ml of water, dissolve the potassium citrate by ultrasonication, then add 1 ml of dilute nitric acid and 5 ml of 0.05 mol / L disodium ethylenediaminetetraacetic acid solution, dilute to the scale with water, shake well, filter and take the filtrate.

[0132] Reference solution Take appropriate amounts of impurity A (cis-aconitic acid) reference, impurity B (trans-aconitic acid) reference and impurity C (itaconic acid) reference (all provided by CATO, with contents of 97.8%, 95.3% and 99.2%, respectively), accurately weigh, dissolve in water and quantitatively dilute to prepare a mixed solution containing approximately 12 μg each of impurity A, impurity B and impurity C per 1 ml.

[0133] Chromatographic conditions: A chromatographic column with octadecylsilane bonded silica as filler; 50 mM potassium phosphate (pH adjusted to 2.5 with 0.5 mol / L phosphoric acid solution)-acetonitrile (95:5) as mobile phase; flow rate of 1.0 ml per minute; column temperature of 25°C; detection wavelength of 210 nm; injection volume of 20 μl.

[0134] System suitability requires that impurity A, impurity B and impurity C appear in sequence in the chromatogram of the reference solution, and the separation between the peaks of each component must not be less than 3.0.

[0135] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the impurity content by the reference external standard method.

[0136] The results are shown in Tables 14 and 15.

[0137] Table 14 Comparison of the quality of samples produced in Examples 1-6 and the reference preparation - Tablets (1)

[0138]

[0139] Table 15 Comparison of the quality of samples produced by Examples 7-14 and the reference preparation - Tablets (2)

[0140]

[0141] The capsules prepared in Examples 1-14 were subjected to in vitro quality comparison studies using GASTRODENOL as a reference preparation. The results are shown in Tables 16 and 17.

[0142] Table 16 Comparison results of quality of production samples of Example 1-6 and reference preparation - Capsule (1)

[0143]

[0144]

[0145] Table 17 Quality comparison results of production samples of Examples 7-14 and reference preparations - capsules (2)

[0146]

[0147] It can be seen from Tables 14-17 that the quality of the homemade preparation is consistent with that of the reference preparation, and the indicators related to safety and efficacy such as free bismuth level, sedimentation coefficient and wall adhesion test are better than those of the reference preparation.

[0148] Among them, free bismuth is an important testing indicator that reflects the in vitro safety of the preparation. The free bismuth level of the preparation in vitro is correlated with the free bismuth in the blood. The lower the free bismuth level, the more conducive it is to lowering the bismuth level in the blood and improving safety.

[0149] The sedimentation volume ratio and the wall hanging phenomenon reflect the volume of the protective layer formed by potassium bismuth citrate in gastric juice. The larger the volume, the wider the distribution range in the gastric mucosa. The wall hanging phenomenon indicates the degree of transformation of potassium bismuth citrate from a colloid state to a protective film in artificial gastric juice. The more obvious the phenomenon is, the more significant the effect of the protective film formation is, the faster the speed is, and it is beneficial to the efficacy of the drug.

[0150] The tablets and capsules prepared in Example 11 were subjected to stability study, with GASTRODENOL as the reference preparation. The results of the stability study are shown in Table 18.

[0151] Table 18 Results of stability study of samples produced in Example and reference preparations (test conditions: 40°C, RH=75%, simulating commercial packaging)

[0152]

[0153] As can be seen from Table 18, the tablets and capsules produced in Example 11 have stable properties, and there are no significant changes in the various inspection indicators, which meet the quality standards.

[0154] The tablets and capsules prepared in Example 11 were used as the reference preparation. A single-center, randomized, open, single-dose, three-preparation, three-period, three-sequence crossover design of bismuth pharmacokinetics was conducted with GASTRODENOL as the reference preparation. Healthy subjects were randomly assigned to three dosing sequence groups in a ratio of 1:1:1 according to the screening number sequence. The subjects took the tablets, capsules or reference preparation orally once to ensure the compliance of the subjects in taking medicine, eating and drinking. Blood samples were drawn at intervals (5, 10, 20, 30, 40, 50 min, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0 h, respectively). The collected blood samples were centrifuged at 2-8° C. for 10 min to separate plasma samples, and transported at -20° C. for detection. The bismuth content in plasma was detected by inductively coupled plasma mass spectrometry (ICP-MS), the in vivo concentration was calculated, and then the peak blood concentration (C max ), the area under the drug curve 0-t (AUC 0-t ), the area under the drug curve 0-∞ (AUC 0-∞ ), the results are shown in Table 19.

[0155] Table 19 PK comparison study results of production samples and reference preparations in Example 11 (n=6)

[0156] Pharmacokinetic parameters Reference preparation Example 11 Tablets Example 11 Capsules Label content 97.9％ 98.5％ 98.9％ <![CDATA[C max (ng / ml)]]> 53.45 28.69 6.65 <![CDATA[AUC 0-t (mg / ml)]]> 116.13 55.14 17.01 <![CDATA[AUC 0-∞ (mg / ml)]]> 148.33 75.04 22.90

[0157] Table 19C max The results showed that the blood concentration of bismuth in the tablets and capsules produced in Example 11 was much lower than that of the reference preparation, and the peak concentration of free bismuth in the body and the drug-time curve AUC 0-t and AUC 0-∞ The results show that the total amount of bismuth absorbed by the tablets and capsules produced in Example 11 is much lower than that of the reference preparation, and the safety of the oral solid preparation produced in Example 11 is better than that of the reference preparation.

[0158] Compared with the published research data, the peak concentration of free bismuth in vivo and the AUC of the drug-time curve of the homemade capsules 0-t and AUC 0-∞ The results are lower than those of the marketed capsule products, the peak concentration of which is not less than 15 ng / ml, and the AUC of the drug-time curve 0-t Not less than 50h·ng / ml, AUC 0-∞Not less than 60 h·ng / ml. The safety of the oral solid preparation produced in Example 11 is better than similar marketed products.

Claims

1. A method for preparing a solid oral preparation of potassium bismuth citrate, the specific steps are as follows: (1) Raw material modification Weigh potassium bismuth citrate, place it in a multifunctional fluidized bed coating machine, turn on the heating and fan, set the temperature to 30-50°C, and ensure that the material is in a fluidized state in the fluidized bed; spray the suspending agent solution or suspension prepared with purified water into the fluidized bed; continue to maintain the temperature and fluidize and dry until the material has a drying loss of 2% to 4%; (2) adding a bioadhesive material, a disintegrant, a diluent and a lubricant to the modified raw material and mixing them evenly to obtain a potassium bismuth citrate oral solid preparation; (3) Compress tablets or fill capsules as needed; The suspending agent is one or more of colloidal silicon dioxide, xanthan gum, sodium alginate, carboxymethyl cellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone; The bioadhesive material is one or more of carbomer 971P, carbomer 974P, and polycarbophil.

2. The preparation method according to claim 1, characterized in that: The lubricant is at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, hydrogenated vegetable oil, and glyceryl behenate.

3. The preparation method according to claim 1, characterized in that: The diluent is pregelatinized starch and / or mannitol.

4. The preparation method according to claim 1, characterized in that: The disintegrant is one or more of sodium starch glycolate, polacrilin potassium, and cross-linked sodium carboxymethyl cellulose.

5. The preparation method according to claim 1, characterized in that: The amount of the bioadhesive added is 0.1% to 5% of the total amount of the potassium bismuth citrate oral solid preparation; and / or The amount of the disintegrant added is 1% to 10% of the total amount of the potassium bismuth citrate oral solid preparation; and / or The amount of the diluent added is 0-20% of the total amount of the oral solid preparation of potassium bismuth citrate; and / or The amount of the lubricant added is 0.5% to 2% of the total amount of the potassium bismuth citrate oral solid preparation; and / or The amount of the suspending agent added accounts for 0.5% to 5% of the total amount of the potassium bismuth citrate oral solid preparation.

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