Penicillin V potassium tablet and preparation method thereof

Abstract

The invention belongs to the technical field of medicine preparation processes, and provides a penicillin V potassium tablet and a preparation method thereof. The preparation method comprises the following steps: (1) putting a plain tablet of a penicillin V potassium tablet into a coating pan, preheating, spraying an enteric coating solution onto the rotating plain tablet, drying, and cooling to room temperature to obtain an enteric coated tablet; acrylic resin II and Eudragit RS100 are adopted as a coating agent of the enteric coating solution; (2) putting the enteric coated tablet into a coating pan, preheating, spraying the gastric-soluble coating liquid onto the rotating enteric coated tablet, drying, and cooling to room temperature to obtain a double-layer coated tablet; and a coating agent of the gastric-soluble coating solution adopts acrylic resin IV. The penicillin V potassium tablet prepared by the preparation method disclosed by the invention has a double-layer film coating layer and an extremely good taste masking effect, and can be slowly and stably released in intestinal tracts, and meanwhile, a coating agent adopted by the double-layer film coating layer is close to and single in component.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically, it relates to a penicillin V potassium tablet and its preparation method. Background Technology

[0002] Penicillin V potassium, a typical representative of penicillin antibiotics, is widely used in clinical practice for respiratory infections, skin and soft tissue infections, scarlet fever, and prevention of rheumatic fever recurrence due to its potent inhibitory effect on Gram-positive bacteria and some Gram-negative bacteria. It is one of the commonly used anti-infective drugs in primary healthcare and at home. Penicillin V potassium has advantages such as good oral absorption, high bioavailability, and short time to peak plasma concentration, which can greatly improve the convenience and compliance of patients, and occupies an important position in the field of anti-infective therapy.

[0003] However, penicillin V potassium tablets have some obvious side effects in clinical applications, the most obvious and common of which is the irritation of the gastrointestinal mucosa by the drug itself.

[0004] The chemical structure of penicillin V potassium contains a β-lactam ring and a potassium ion group. After oral administration, the drug component can easily come into direct contact with the gastric mucosal epithelial cells in the acidic environment of the stomach. On the one hand, this disrupts the mucus-bicarbonate barrier on the surface of the gastric mucosa, leading to damage to the mucosal epithelial cells. On the other hand, the high local concentration of potassium ions can stimulate nerve endings in the gastric wall, causing gastric smooth muscle spasms, which in turn induce symptoms such as nausea, vomiting, and upper abdominal discomfort. Simultaneously, after the drug enters the small intestine, uncontrolled rapid release can cause a sudden increase in local drug concentration in the intestine, stimulating abnormal intestinal mucosal secretion, interfering with normal intestinal peristalsis, and ultimately causing adverse reactions such as diarrhea. These side effects not only affect the patient's medication experience but, in severe cases, can lead patients to discontinue or reduce the dosage without medical advice, reducing treatment effectiveness and even increasing the risk of bacterial resistance.

[0005] In addition, penicillin V potassium itself has a distinctly bitter taste, which directly stimulates the taste buds in the mouth when taken orally. This can easily cause swallowing difficulties, oral discomfort, or even nausea, especially in children, elderly patients, and people who are sensitive to bitterness, further reducing the acceptance of the medication.

[0006] The invention patent with patent number CN2016106413098 discloses a penicillin V potassium tablet and its preparation process. It uses polyacrylic acid resin IV as a coating agent to form a thin film coating on the surface of the tablet. The penicillin V potassium tablet has the advantages of no top cracking, small tablet weight difference, and no sticking during the tableting process.

[0007] However, although the above treatment can mask the bitter taste of penicillin V potassium to some extent, the film is prone to swelling or partial dissolution in the acidic environment of the stomach, causing the drug components to be exposed prematurely. The masking effect is short-lived and cannot effectively prevent the drug from irritating the mucosa in the stomach. Summary of the Invention

[0008] In view of the above-mentioned shortcomings in the prior art, the purpose of the present invention is to provide a penicillin V potassium tablet and its preparation method. The penicillin V potassium tablet prepared by the preparation method of the present invention has a double-layer film coating layer, which has excellent taste masking effect and can achieve slow and stable release in the intestine. At the same time, the coating agent used in the double-layer film coating has similar and simple composition.

[0009] To achieve the above objectives, the solution adopted by the present invention is as follows:

[0010] A method for preparing penicillin V potassium tablets includes: (1) putting uncoated penicillin V potassium tablets into a coating pan, preheating it, spraying enteric coating solution onto the rotating uncoated tablets, drying it, and cooling it to room temperature to obtain enteric coated tablets; the coating agent of the enteric coating solution is acrylic resin II and Eudragit RS100; (2) putting the enteric coated tablets into a coating pan, preheating it, spraying enteric coating solution onto the rotating enteric coated tablets, drying it, and cooling it to room temperature to obtain double-layer coated tablets; the coating agent of the enteric coating solution is acrylic resin IV.

[0011] Further, in a preferred embodiment of the present invention, in step (1), the preparation of the enteric coating solution includes: weighing acrylic resin II and Eudragit RS100, adding them to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing through a 100-120 mesh sieve to obtain the enteric coating solution; the ratio of acrylic resin II, Eudragit RS100, first ethanol and hydroxypropyl methylcellulose is 4:2:60-64:1.

[0012] Further, in a preferred embodiment of the present invention, step (2) of preparing the gastric coating solution includes: adding polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved, then adding diethyl phthalate, titanium dioxide and polyethylene glycol while stirring, and passing the solution through a 100-120 mesh sieve to obtain the gastric coating solution; the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide and polyethylene glycol is 10:150-160:1-2:0.9-0.12:0.8-1.

[0013] Furthermore, in a preferred embodiment of the present invention, in step (1), the uncoated sheet is placed into a coating pan and preheated to 30-40°C. The settings of the coating pan are as follows: the air inlet temperature is 35-45°C, the air outlet temperature is 25-35°C, the pan rotation speed is 10-30 r / min, the compressed air pressure is 0.2-0.8 MPa, and the coating pan is started once every 1 minute to spray 0.5-0.8 parts by weight of enteric coating solution onto the rotating uncoated sheet.

[0014] Further, in a preferred embodiment of the present invention, in step (1), during the preheating stage: the air inlet temperature is set to 35-45℃ and the air outlet temperature is set to 30-35℃; during the coating stage: the air inlet temperature is set to 45-55℃ and the air outlet temperature is set to 30-40℃; during the last 10 minutes: the air inlet temperature is set to 40-50℃ and the air outlet temperature is set to 25-35℃; during the first 10 minutes of coating: the pot rotation speed is set to 10-15 r / min; during the middle section of coating: the pot rotation speed is set to 15-20 r / min; during the last 10 minutes: the pot rotation speed is set to 12-16 r / min.

[0015] Furthermore, in a preferred embodiment of the present invention, in step (1), the enteric-coated tablets are placed into a coating pan and preheated to 30-40°C. The settings of the coating pan are as follows: air inlet temperature is 40-50°C, air outlet temperature is 30-40°C, pan rotation speed is 8-18 r / min, compressed air pressure is 0.2-0.8 MPa, and the coating pan is started once every 1 minute to spray 0.3-0.6 parts by weight of the enteric coating solution onto the rotating enteric-coated tablets.

[0016] Further, in a preferred embodiment of the present invention, in step (2), the preheating stage: the air inlet temperature is set to 40-50℃ and the air outlet temperature is set to 30-40℃; the coating stage: the air inlet temperature is set to 50-60℃ and the air outlet temperature is set to 45-55℃; the last 10 minutes: the air inlet temperature is set to 50-55℃ and the air outlet temperature is set to 30-40℃; the first 10 minutes of coating: the pot rotation speed is set to 8-12 r / min; the middle section of coating: the pot rotation speed is set to 12-18 r / min; the last 10 minutes: the pot rotation speed is set to 10-15 r / min.

[0017] A penicillin V potassium tablet is prepared by the above-described preparation method.

[0018] The beneficial effects of the penicillin V potassium tablet and its preparation method provided by this invention are:

[0019] (1) The preparation method of the penicillin V potassium tablet provided by the present invention adopts a double-layer film coating design. The outer gastric coating uses acrylic resin No. IV coating agent, which can quickly dissolve and form a film in the acidic gastric juice environment, tightly wrapping the tablet core, preventing the enteric coating layer from breaking, effectively preventing the release of bitter components, and achieving an excellent taste masking effect. At the same time, diethyl phthalate is added to improve flexibility and prevent brittleness after film formation. Titanium dioxide is added to block light and prevent the active ingredients of the drug from being degraded by light. Polyethylene glycol is added to reduce the friction of the tablet on the mucosa.

[0020] The inner enteric coating uses a combination of acrylic resin II and Eudragit RS100 coating agents. Acrylic resin II dissolves in an environment with a pH ≥ 5.5, achieving enteric coating; Eudragit RS100, containing a low-permeability neutral polymer, controls the drug diffusion rate. The two work synergistically to achieve slow and stable release into the intestinal tract, improving patient compliance and therapeutic efficacy. Hydroxypropyl methylcellulose is also added to enhance membrane toughness and stability.

[0021] (2) In the preparation method of the penicillin V potassium tablets provided by the present invention, the coating agent for both the gastric and enteric layers is acrylic resin, and the composition of the coating agent is similar and simple.

[0022] (3) The preparation method of the penicillin V potassium tablets provided by the present invention adopts a staged temperature control and a staged change of the pot rotation speed when using enteric coating solution and gastric coating solution for coating. Combined with the coating material under the specific technical conditions of the present application, synergistic regulation is achieved, the coating efficiency is significantly improved, the production time is significantly shortened, the coating solution forms a uniform film, the taste masking effect is excellent, and the release rate in the intestinal environment is stable. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0024] The following is a detailed description of a penicillin V potassium tablet and its preparation method provided by an embodiment of the present invention.

[0025] It should be noted that in this application, the preparation of the penicillin V potassium tablets refers to the method disclosed in the invention patent "Patent No. CN2016106413098, Patent Name: A Penicillin V Potassium Tablet and Its Preparation Process", as follows:

[0026] (1) Preparation of adhesive: According to the weight ratio of povidone K30 to purified water of 11:28, add the prescribed amount of povidone K30 to purified water while stirring. After it is completely dissolved, pass it through a 120-mesh sieve.

[0027] (2) Granulation: Add potassium penicillin V to a trough mixer and mix for 2 minutes. Then add the binder and stir for 3 minutes to form a soft material that can be formed into a ball by hand and easily dispersed by light pressure. Granulate the soft material in a swing granulator equipped with a 22-mesh nylon screen to obtain wet granules.

[0028] (3) Drying: Pour the wet granules into a fluidized bed dryer for drying at a temperature of 45°C for 35 minutes. When the moisture content of the granules is controlled below 2.0%, the dry granules are obtained.

[0029] (4) Granulation: The dry granules are granulated on a granulator equipped with a 14-mesh sieve to obtain granules;

[0030] (5) Total mixing and tableting: A portion of the granules, the prescribed amount of talc powder and the prescribed amount of magnesium stearate are first put into a trough mixer for premixing for 5 minutes. Then the remaining granules are crosswise put into a two-dimensional motion mixer and mixed for 10 minutes. After passing the inspection, the tablets are directly compressed to obtain plain tablets.

[0031] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0032] Example 1

[0033] This embodiment provides a method for preparing penicillin V potassium tablets, including:

[0034] (1) Put the raw tablets into the coating pan and preheat it to 30°C. The coating pan is set with the following parameters: air inlet temperature of 35°C, air outlet temperature of 25°C, pan rotation speed of 10r / min, compressed air pressure of 0.2Mpa. Start the coating pan once every 1min and spray 0.5 parts by weight of enteric coating solution onto the rotating raw tablets. After drying, cool to room temperature to obtain enteric coated tablets.

[0035] The preparation of the enteric coating solution includes: weighing acrylic resin II and Eudragit RS100, adding them to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing through a 100-mesh sieve to obtain the enteric coating solution; the ratio of acrylic resin II, Eudragit RS100, first ethanol and hydroxypropyl methylcellulose is 4:2:60:1.

[0036] (2) Put the enteric-coated tablets into the coating pan and preheat it to 30°C. The settings of the coating pan are: air inlet temperature is 40°C, air outlet temperature is 30°C, pan rotation speed is 8r / min, compressed air pressure is 0.2MPa. Start the coating pan once every 1min and spray 0.3 parts by weight of enteric coating solution onto the rotating enteric-coated tablets. After drying, cool to room temperature to obtain double-layer coated tablets.

[0037] The preparation of the gastric coating solution includes: adding polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved; then adding diethyl phthalate, titanium dioxide, and polyethylene glycol while stirring; and passing the solution through a 100-mesh sieve to obtain the gastric coating solution; the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide, and polyethylene glycol is 10:150:1:0.9:0.8.

[0038] Example 2

[0039] This embodiment provides a method for preparing penicillin V potassium tablets, including:

[0040] (1) Put the raw tablets into the coating pan and preheat it to 40°C. The coating pan is set with the following parameters: air inlet temperature of 45°C, air outlet temperature of 35°C, pan rotation speed of 20r / min, compressed air pressure of 0.8Mpa. Start the coating pan once every 1min and spray 0.8 parts by weight of enteric coating solution onto the rotating raw tablets. After drying, cool to room temperature to obtain enteric coated tablets.

[0041] The preparation of the enteric coating solution includes: weighing acrylic resin II and Eudragit RS100, adding them to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing through a 120-mesh sieve to obtain the enteric coating solution; the ratio of acrylic resin II, Eudragit RS100, first ethanol and hydroxypropyl methylcellulose is 4:2:64:1.

[0042] (2) Put the enteric-coated tablets into the coating pan and preheat it to 40°C. The settings of the coating pan are: air inlet temperature of 50°C, air outlet temperature of 40°C, pan rotation speed of 18 r / min, compressed air pressure of 0.8 MPa. Start the coating pan once every 1 min and spray 0.6 parts by weight of enteric coating solution onto the rotating enteric-coated tablets. After drying, cool to room temperature to obtain double-layer coated tablets.

[0043] The preparation of the gastric coating solution includes: adding polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved; then adding diethyl phthalate, titanium dioxide, and polyethylene glycol while stirring; and passing the solution through a 120-mesh sieve to obtain the gastric coating solution; the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide, and polyethylene glycol is 10:160:2:0.12:1.

[0044] Example 3

[0045] This embodiment provides a method for preparing penicillin V potassium tablets, including:

[0046] (1) Put the raw tablets into the coating pan and preheat it to 35°C. The coating pan is set with the following parameters: air inlet temperature of 40°C, air outlet temperature of 30°C, pan rotation speed of 15r / min, compressed air pressure of 0.5Mpa. Start the coating pan once every 1min and spray 0.6 parts by weight of enteric coating solution onto the rotating raw tablets. After drying, cool to room temperature to obtain enteric coated tablets.

[0047] The preparation of the enteric coating solution includes: weighing acrylic resin II and Eudragit RS100, adding them to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing the solution through a 110-mesh sieve to obtain the enteric coating solution; the ratio of acrylic resin II, Eudragit RS100, first ethanol and hydroxypropyl methylcellulose is 4:2:62:1.

[0048] (2) Put the enteric-coated tablets into the coating pan and preheat it to 35°C. The settings of the coating pan are: air inlet temperature is 45°C, air outlet temperature is 35°C, pan rotation speed is 12r / min, compressed air pressure is 0.6MPa. Start the coating pan once every 1min and spray 0.4 parts by weight of enteric coating solution onto the rotating enteric-coated tablets. After drying, cool to room temperature to obtain double-layer coated tablets.

[0049] The preparation of the gastric coating solution includes: adding polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved; then adding diethyl phthalate, titanium dioxide, and polyethylene glycol while stirring; and passing the solution through a 110-mesh sieve to obtain the gastric coating solution; the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide, and polyethylene glycol is 10:155:1.5:0.1:0.9.

[0050] Example 4

[0051] This embodiment provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that:

[0052] (1) Put the raw slices into the coating pan and preheat it to 35℃. During the preheating stage: the air inlet temperature is set to 35℃ and the air outlet temperature is set to 30℃. During the coating stage: the air inlet temperature is set to 45℃ and the air outlet temperature is set to 30℃. During the last 10 minutes: the air inlet temperature is set to 40℃ and the air outlet temperature is set to 25℃. During the first 10 minutes of coating: the pan rotation speed is set to 10r / min. During the middle stage of coating: the pan rotation speed is set to 15r / min. During the last 10 minutes: the pan rotation speed is set to 12r / min.

[0053] (2) Put the enteric-coated tablets into the coating pan and preheat it to 35°C. During the preheating stage: the air inlet temperature is set to 40°C and the air outlet temperature is set to 30°C. During the coating stage: the air inlet temperature is set to 50°C and the air outlet temperature is set to 45°C. During the last 10 minutes: the air inlet temperature is set to 50°C and the air outlet temperature is set to 30°C. During the first 10 minutes of coating: the pan rotation speed is set to 8 r / min. During the middle stage of coating: the pan rotation speed is set to 12 r / min. During the last 10 minutes: the pan rotation speed is set to 10 r / min.

[0054] Example 5

[0055] This embodiment provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that:

[0056] (1) Put the raw slices into the coating pan and preheat it to 35℃. During the preheating stage: the air inlet temperature is set to 45℃ and the air outlet temperature is set to 35℃. During the coating stage: the air inlet temperature is set to 55℃ and the air outlet temperature is set to 40℃. During the last 10 minutes: the air inlet temperature is set to 50℃ and the air outlet temperature is set to 35℃. During the first 10 minutes of coating: the pan rotation speed is set to 15r / min. During the middle stage of coating: the pan rotation speed is set to 20r / min. During the last 10 minutes: the pan rotation speed is set to 16r / min.

[0057] (2) Put the enteric-coated tablets into the coating pan and preheat it to 35°C. During the preheating stage: the air inlet temperature is set to 50°C and the air outlet temperature is set to 40°C. During the coating stage: the air inlet temperature is set to 60°C and the air outlet temperature is set to 55°C. During the last 10 minutes: the air inlet temperature is set to 55°C and the air outlet temperature is set to 40°C. During the first 10 minutes of coating: the pan rotation speed is set to 12 r / min. During the middle stage of coating: the pan rotation speed is set to 18 r / min. During the last 10 minutes: the pan rotation speed is set to 15 r / min.

[0058] Example 6

[0059] This embodiment provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that:

[0060] (1) Put the raw slices into the coating pan and preheat it to 35℃. During the preheating stage: the air inlet temperature is set to 40℃ and the air outlet temperature is set to 32℃. During the coating stage: the air inlet temperature is set to 50℃ and the air outlet temperature is set to 35℃. During the last 10 minutes: the air inlet temperature is set to 45℃ and the air outlet temperature is set to 30℃. During the first 10 minutes of coating: the pan rotation speed is set to 12r / min. During the middle stage of coating: the pan rotation speed is set to 18r / min. During the last 10 minutes: the pan rotation speed is set to 14r / min.

[0061] (2) Put the enteric-coated tablets into the coating pan and preheat it to 35°C. During the preheating stage: the air inlet temperature is set to 45°C and the air outlet temperature is set to 35°C. During the coating stage: the air inlet temperature is set to 55°C and the air outlet temperature is set to 50°C. During the last 10 minutes: the air inlet temperature is set to 52°C and the air outlet temperature is set to 35°C. During the first 10 minutes of coating: the pan rotation speed is set to 10 r / min. During the middle stage of coating: the pan rotation speed is set to 15 r / min. During the last 10 minutes: the pan rotation speed is set to 12 r / min.

[0062] Comparative Example 1

[0063] This comparative example provides a method for preparing penicillin V potassium tablets, including: first, putting the obtained raw tablets into a coating pan, preheating to 35°C, adjusting the compressed air pressure to 0.4 MPa, the inlet temperature to 85°C, the outlet temperature to 65°C, the pan rotation speed to 4 r / min, adjusting the spray gun angle and height so that the coating solution can be evenly sprayed onto the rotating raw tablets, and packaging to obtain penicillin V potassium tablets; preparation of the coating solution: adding polyacrylic acid resin IV to 95% ethanol while stirring, letting it stand for 12 hours, and after dissolving, adding magnesium stearate according to the prescription amount while stirring evenly, and passing it through a 120-mesh sieve for later use.

[0064] Comparative Example 2

[0065] This comparative example provides a method for preparing penicillin V potassium tablets, including: placing uncoated tablets into a coating pan, preheating it to 35°C, and setting the parameters of the coating pan as follows: inlet temperature 45°C, outlet temperature 35°C, pan rotation speed 12 r / min, compressed air pressure 0.6 MPa, starting the coating pan once every 1 min, spraying 0.4 parts by weight of gastric coating solution onto the rotating uncoated tablets, drying, and cooling to room temperature to obtain coated tablets; the preparation of the gastric coating solution includes: adding polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved, then adding diethyl phthalate, titanium dioxide, and polyethylene glycol while stirring, and passing the solution through a 110-mesh sieve to obtain the gastric coating solution; the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide, and polyethylene glycol is 10:155:1.5:0.1:0.9.

[0066] Comparative Example 3

[0067] This comparative example provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that: the preparation of the enteric coating solution includes: weighing acrylic resin II, adding it to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing it through a 110-mesh sieve to obtain the enteric coating solution; the ratio of acrylic resin II, first ethanol and hydroxypropyl methylcellulose is 6:62:1.

[0068] Comparative Example 4

[0069] This comparative example provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that the ratio of acrylic resin II, Eudragit RS100, first ethanol and hydroxypropyl methylcellulose in the enteric coating solution is 5:1:65:1.

[0070] Comparative Example 5

[0071] This comparative example provides a method for preparing penicillin V potassium tablets, which differs from Example 3 in that the ratio of polyacrylic acid resin IV, second ethanol, diethyl phthalate, titanium dioxide and polyethylene glycol in the gastric coating solution is 10:165:0.5:0.15:1.2.

[0072] Experiment Example 1: Electronic Tongue Bitterness Detection Test

[0073] Bitterness evaluation: Using an electronic tongue sensor to simulate the human taste system, the signal intensity of bitter substances released by the penicillin V potassium tablets provided in Examples 1-6 and Comparative Examples 1-5 in artificial saliva was detected.

[0074] The results of the electronic tongue sensor were analyzed using principal component analysis. The distance between the penicillin V potassium tablets and penicillin V potassium tablets provided in Examples 1-6 and Comparative Examples 1-5 was calculated. The closer the distance, the closer the taste of the two tablets. The farther the distance, the better the taste-masking effect of the variety.

[0075] It uses the SA402B electronic tongue (INSENT, Japan).

[0076] Electronic tongue detection method:

[0077] 1) Solution preparation: Standard solution (30mM potassium chloride + 0.3mM tartaric acid); Negative (cathode) solution: 500mL water + 300mL ethanol + 8.3mL hydrogen chloride, bring to a final volume of 1000mL; Positive (anode) solution: 7.46g potassium chloride + 500mL water + 300mL ethanol + 0.56g potassium hydroxide, bring to a final volume of 1000mL; Internal solution: 3.33M potassium chloride + saturated silver chloride solution; Reference electrode immersion solution (3.33M potassium chloride solution);

[0078] Blank solution: Dissolve 1.49g of potassium chloride in 2L of purified water to form a blank solution;

[0079] Reference solution: Take 65.7 mg of penicillin V potassium tablets (provided in Example 1), add 100 g of blank solution to dissolve and form a reference solution;

[0080] Test solution: Take 1 tablet of test sample, add 150g of blank solution, disintegrate and filter to obtain the test solution.

[0081] 2) Detection method: Transfer the test solution to the graduation mark on the test cup, select the AN0 sensor, and activate the sensor and reference electrode for 24 hours. Run the equipment for detection. After each test, clean with negative and positive solutions respectively.

[0082] The test results are shown in Table 1.

[0083] Table 1

[0084] Group number Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Bitterness value × 100% 4.22％ 4.04％ 3.88％ 1.86％ 1.48％ 1.22％ Group number Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Plain slices Bitterness value × 100% 28.64％ 18.44％ 1.66％ 5.22％ 25.42％ 100％

[0085] Table 1 shows that, with the bitterness value of the active pharmaceutical ingredient defined as 100%, the bitterness values ​​of the penicillin V potassium tablets provided in Examples 1-6 of this application are all significantly reduced, and the bitterness is also significantly reduced compared to Comparative Example 1. This indicates that the penicillin V potassium tablets of this application have an excellent masking effect on the bitterness of the raw tablets.

[0086] Experimental Example 2: In vitro simulated digestive tract pH gradient release test

[0087] (1) Simulated gastric juice: Artificial simulated gastric juice was prepared according to the appendix of Part II of the 2005 edition of the Chinese Pharmacopoeia. The specific preparation method is as follows: 9 mL of concentrated hydrochloric acid was added to about 800 mL of pure water and stirred evenly to obtain artificial simulated gastric juice with a pH value of 1.2.

[0088] (2) Simulated intestinal fluid: Artificial simulated intestinal fluid was prepared according to the appendix of Part II of the 2005 edition of the Chinese Pharmacopoeia. The specific preparation method is as follows: Dissolve 6.8g of potassium dihydrogen phosphate in 500mL of pure water, then adjust the pH value to 6.8 with a sodium hydroxide aqueous solution with a concentration of 0.4mol / L, and then add pure water to make up to 1000mL to obtain artificial simulated intestinal fluid.

[0089] (3) The penicillin V potassium tablets provided in Examples 1-6 and Comparative Examples 1-5 were placed in simulated gastric fluid (0-4h) and simulated intestinal fluid (4-12h) to test the cumulative release of penicillin V potassium:

[0090] According to the method for determination of dissolution and release (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II), the above-mentioned artificial simulated gastric fluid was used as the dissolution medium, the temperature was 37±0.5℃, the rotation speed was 150 rpm, and a settling basket was added. After 1 h, 2 h, and 4 h, 5 mL of the dissolution solution was collected, filtered, and the filtrate was used as the test solution. At 1 h and 2 h, the same volume of dissolution medium at the same temperature was added simultaneously.

[0091] After 4 hours, discard the medium in each dissolution vessel. Then, add artificial simulated intestinal fluid preheated to 37±0.5℃ to each dissolution vessel. Keep the rotation speed constant and continue the operation according to the procedure. Take 5 mL of the dissolution solution at 2 hours, 4 hours, 6 hours and 8 hours respectively, filter it, and take the filtrate as the test solution. At the same time, add the same volume of dissolution medium at the same temperature. Determine the cumulative dissolution amount (%) by high performance liquid chromatography.

[0092] Table 2 shows the cumulative dissolution (%) of penicillin V potassium tablets provided in Examples 1-6 and Comparative Examples 1-5 at different time periods and in different dissolution media:

[0093] Table 2

[0094] Group number 1h 2h 4h 6h 8h 10h 12h Example 1 0.0％ 0.0％ 0.0％ 23.47％ 60.12％ 82.04％ 98.42％ Example 2 0.0％ 0.0％ 0.0％ 22.88％ 62.14％ 83.05％ 98.14％ Example 3 0.0％ 0.0％ 0.0％ 23.61％ 63.04％ 85.12％ 98.04％ Example 4 0.0％ 0.0％ 0.0％ 25.23％ 50.11％ 76.14％ 98.51％ Example 5 0.0％ 0.0％ 0.0％ 24.66％ 49.08％ 74.38％ 98.12％ Example 6 0.0％ 0.0％ 0.0％ 24.41％ 49.12％ 73.24％ 98.33％ Comparative Example 1 84.42％ 100％ / / / / / Comparative Example 2 72.13％ 100％ / / / / / Comparative Example 3 0.0％ 0.0％ 0.0％ 100％ / / / Comparative Example 4 0.0％ 0.0％ 0.0％ 44.23％ 72.64％ 88.23％ 100％ Comparative Example 5 0.0％ 0.0％ 0.0％ 25.66％ 50.08％ 75.38％ 98.32％

[0095] As shown in the table, the penicillin V potassium tablets provided in Examples 1-6 of this application did not dissolve in simulated gastric fluid, but were released in simulated intestinal fluid. This indicates that the penicillin V potassium tablets prepared using the method of this application are almost not released in the stomach, but only begin to be released in the intestinal environment, and have sustained-release characteristics with a stable release rate.

[0096] In summary, the penicillin V potassium tablets and their preparation method provided by this invention, and the penicillin V potassium tablets prepared by the preparation method of this invention, have a double-layer film coating layer, which has an excellent taste masking effect and can achieve slow and stable release in the intestine. At the same time, the coating agents used in the double-layer film coating have similar and simple components.

[0097] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing penicillin V potassium tablets, characterized in that: include: (1) Put the uncoated tablets of penicillin V potassium tablets into a coating pan, preheat it, spray the enteric coating solution onto the rotating uncoated tablets, dry it and cool it to room temperature to obtain enteric coated tablets; the coating agent of the enteric coating solution is acrylic resin II and Eudragit RS100. (2) The enteric-coated tablets are placed into a coating pan, preheated, and then the gastric coating solution is sprayed onto the rotating enteric-coated tablets. After drying, the tablets are cooled to room temperature to obtain double-layer coated tablets. The coating agent of the gastric coating solution is acrylic resin No. IV.

2. The method for preparing penicillin V potassium tablets according to claim 1, characterized in that: In step (1), the preparation of the enteric coating solution includes: weighing the acrylic resin II and the Eudragit RS 100, adding them to 95% first ethanol, stirring until completely dissolved, adding hydroxypropyl methylcellulose, stirring to disperse, and passing through a 100-120 mesh sieve to obtain the enteric coating solution; The ratio of acrylic resin II, Eudragit RS100, the first ethanol, and the hydroxypropyl methylcellulose is 4:2:60-64:

1.

3. The method for preparing penicillin V potassium tablets according to claim 1, characterized in that: In step (2), the preparation of the gastric coating solution includes: adding the polyacrylic acid resin IV to 95% second ethanol while stirring until completely dissolved, then adding diethyl phthalate, titanium dioxide and polyethylene glycol while stirring, and passing the solution through a 100-120 mesh sieve to obtain the gastric coating solution. The ratio of the polyacrylic acid resin IV, the second ethanol, the diethyl phthalate, the titanium dioxide, and the polyethylene glycol is 10:150-160:1-2:0.9-0.12:0.8-1.

4. The method for preparing penicillin V potassium tablets according to claim 1, characterized in that: In step (1), the raw sheet is placed into the coating pan and preheated to 30-40°C. The coating pan is set with the following parameters: air inlet temperature of 35-45°C, air outlet temperature of 25-35°C, pan rotation speed of 10-30 r / min, compressed air pressure of 0.2-0.8 MPa, and the coating pan is started once every 1 minute to spray 0.5-0.8 parts by weight of the enteric coating solution onto the rotating raw sheet.

5. The method for preparing penicillin V potassium tablets according to claim 4, characterized in that: In step (1), during the preheating stage, the air inlet temperature is set to 35-45℃ and the air outlet temperature is set to 30-35℃; during the coating stage, the air inlet temperature is set to 45-55℃ and the air outlet temperature is set to 30-40℃; and during the last 10 minutes, the air inlet temperature is set to 40-50℃ and the air outlet temperature is set to 25-35℃. For the first 10 minutes of coating: set the pot rotation speed to 10-15 r / min; for the middle stage of coating: set the pot rotation speed to 15-20 r / min; for the last 10 minutes: set the pot rotation speed to 12-16 r / min.

6. The method for preparing penicillin V potassium tablets according to claim 1, characterized in that: In step (1), the enteric-coated tablets are placed into the coating pan and preheated to 30-40°C. The coating pan is set with the following parameters: air inlet temperature of 40-50°C, air outlet temperature of 30-40°C, pan rotation speed of 8-18 r / min, and compressed air pressure of 0.2-0.8 MPa. The coating pan is started once every 1 minute, and 0.3-0.6 parts by weight of the enteric coating solution is sprayed onto the rotating enteric-coated tablets.

7. The method for preparing penicillin V potassium tablets according to claim 1, characterized in that: In step (2), during the preheating stage, the air inlet temperature is set to 40-50℃ and the air outlet temperature is set to 30-40℃; during the coating stage, the air inlet temperature is set to 50-60℃ and the air outlet temperature is set to 45-55℃; and during the last 10 minutes, the air inlet temperature is set to 50-55℃ and the air outlet temperature is set to 30-40℃. For the first 10 minutes of coating: set the pot rotation speed to 8-12 r / min; for the middle stage of coating: set the pot rotation speed to 12-18 r / min; for the last 10 minutes: set the pot rotation speed to 10-15 r / min.

8. A penicillin V potassium tablet, characterized in that: It is prepared by the preparation method according to any one of claims 1-7.