Composite preparation of P-CABs drug combined with antacid and preparation method thereof

Abstract

The invention discloses a composite preparation of a P-CABs drug and a combination of Vonoprazan fumarate and an antacid and a preparation method of the composite preparation. The formula of each unit of the preparation comprises 5-40 mg of a P-CABs drug, 400-1000 mg of sodium bicarbonate, 12 mg of a disintegrating agent and 8 mg of a lubricant. According to the compound preparation, the P-CABs medicine is combined with the antacid sodium bicarbonate, the gastric acid inhibiting effect can be rapidly, durably and mildly achieved, the disintegrating agent and the lubricating agent have the synergistic effect, the compound preparation has the advantages of being high in disintegration rate and dissolution rate when a good tabletting effect is formed, and the P-CABs medicine in the compound preparation is high in bioavailability and stability.

Description

Technical Field

[0001] The present invention relates to the field of P-CABs drugs and a preparation method thereof, and in particular to a composite preparation of a P-CABs drug combined with an antacid and a preparation method thereof. Background Art

[0002] Acid-related disorders (ARDs) are a class of gastrointestinal diseases closely related to acid attack, among which gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) are the two most common ARDs. Currently, the main drugs for treating GERD and PUD are proton pump inhibitors (PPIs). Although PPIs can irreversibly inactivate H+, K+-ATPase and thus inhibit gastric acid secretion, they have a slow onset in the body, a short duration of action, and are prone to cause nocturnal acid breakthrough (NAB) in patients due to insufficient gastric acid suppression. Moreover, PPIs are mainly metabolized by CYP2C19 in the body. The activity of this enzyme has significant genetic polymorphism in the population, which makes the acid-suppressing effect of PPIs show large inter-individual differences. At the same time, PPIs will affect the metabolism of other drugs by affecting the activity of liver CYP isoenzymes, which manifests clinically as adverse drug interactions.

[0003] Potassium-Competitive acid blockers (P-CABs) are a new type of acid-suppressing drug that can competitively and reversibly inhibit the potassium-related binding sites of H+, K+-ATPase. They have the advantages of full effect in the first dose, long-lasting acid suppression, good consistency, and low incidence of adverse reactions induced by drug interactions. Revaprazan is approved for the treatment of gastric ulcer (GU); tegoprazan is used to treat non-erosive gastroesophageal reflux disease; vonoprazan is a new type of potassium-competitive acid blocker. Because of its strong and long-lasting effect in inhibiting gastric acid, it is recommended for the treatment of gastroesophageal reflux disease, and the recommendation level is the same as that of "prazole" drugs.

[0004] P-CABs are acid-stable and are not degraded in gastric acid, so they can be administered orally without the need to prepare enteric-coated preparations. They can be used as an oral rapid-release preparation to quickly inhibit gastric acid. After taking the drug, the drug selectively accumulates in the gastric mucosa, with a concentration far higher than that in plasma (pH 7.4), and remains in a protonated form, binding to and inhibiting the proton pump. Vonoprazan is rapidly absorbed, reaching a peak blood concentration (Cmax) within 2 hours, and has a half-life (t 1 / 2) of about 7 hours, which is much longer than traditional PPIs (t 1 / 2 = 1 to 2 hours). Therefore, a full-day dose can be given at one time during clinical use.

[0005] Antacids such as sodium bicarbonate are drugs that reduce the acidity in the stomach, thereby reducing the activity of pepsin and weakening the digestive effect of gastric juice. They are weakly alkaline and can directly neutralize gastric acid after oral administration, quickly reducing or eliminating the irritation and corrosion of gastric acid on the ulcer surface. Preliminary clinical trials have shown that the composite preparation of antacids and proton pump inhibitors can quickly relieve the symptoms of stomach burning in patients with peptic ulcers, and its effect is better than the combination of the two drugs. Chinese patent CN101816641B discloses an oral rapid-release solid preparation containing omeprazole, which is a rapid-acting proton pump inhibitor composed of omeprazole, sodium bicarbonate and pharmaceutical excipients; and there are currently few studies on the preparation of P-CABs drugs combined with antacids. Therefore, it is of great research prospect to prepare a high-stability, high-bioavailability composite preparation composed of antacids and P-CABs drugs, and to promote P-CABs drugs to play "immediate effect, long-lasting acid resistance", thereby effectively improving the symptoms of patients with peptic ulcers. Summary of the invention

[0006] In view of the above problems, the object of the present invention is to provide a composite preparation of a P-CABs drug combined with an antacid and a preparation method thereof.

[0007] The technical contents of the present invention are as follows:

[0008] The present invention provides a composite preparation of a P-CABs drug combined with an antacid, wherein each unit of the preparation comprises: 5 to 40 mg of a type-one P-CABs drug, 400 to 1000 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant;

[0009] The class of P-CABs drugs include but are not limited to one of vonoprazan, repraxant, and ticloprazan;

[0010] The preparation process of the disintegrant is as follows: the polymer is treated with alkali, then added to a water-soluble mixture at a mass ratio of 1-3:4-6, and pressurized and heated for 70-90 minutes, and then dried to obtain the disintegrant;

[0011] The polymer is one of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch;

[0012] The alkali treatment is to adjust the pH of the polymer to 7-8;

[0013] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.2-0.6:6-9:1-3;

[0014] The alginic acid and the polyphenol compound in the water-soluble mixture form a hydrogen bond mixture, which reacts and compounds with the hydroxymethyl cellulose starch, thereby increasing the disintegration rate of the disintegrant and promoting the absorption of the P-CABs drug;

[0015] The heating temperature is 80-90°C and the pressure is 10-12Mpa;

[0016] The lubricant is a mixture of stearate and carboxybetaine;

[0017] The mixture is prepared by mixing stearate and carboxybetaine in a mass ratio of 2-4:1, melting the mixture at a temperature of 90-96° C., drying the mixture and then crushing the mixture;

[0018] The stearate is one of magnesium stearate, sodium stearate, potassium stearate and calcium stearate;

[0019] The stearate in the lubricant plays a role of carrier and lubrication, and the zwitterionic polycarboxy betaine has hygroscopic and absorption-promoting properties, which can make the lubricant lose viscosity under the action of gastric juice, promote the digestion and absorption of tablets, and form a stable complex system with stearate, further reducing the polarity of stearate and enhancing stability;

[0020] The fineness of the P-CABs drug passed through a 200-mesh sieve, and the fineness of the sodium bicarbonate was 150 mesh.

[0021] The present invention also provides a method for preparing a composite preparation of a P-CABs drug combined with an antacid, comprising the following steps:

[0022] Step 1: First, mix the prescribed amount of P-CABs drug, disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate evenly;

[0023] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product.

[0024] Beneficial effects: The composite preparation provided by the present invention allows the proton pump inhibitor and the antacid to be released according to the time difference of each layer, and has an excellent effect of preventing the proton pump inhibitor from being decomposed by acid even in the low pH environment of gastric juice in vivo. The composite preparation can provide a fast-acting proton pump inhibitor by increasing the dissolution rate of the proton pump inhibitor; wherein the P-CABs drug combined with the antacid can quickly, lastingly and gently inhibit gastric acid; the main raw material of the added disintegrant is a water-soluble polymer, which is subjected to alkali treatment and mixed with a water-soluble mixture for grafting to further improve its dispersibility and water solubility, and can achieve a rapid disintegration effect; wherein the lubricant contains stearate to play a lubricating and bonding role, and by mixing with a polyphenol hydroxyl substance, its water-soluble properties are improved, and the digestion and absorption utilization of the composite preparation can be increased without affecting the tableting effect; the pyridine structure of the P-CABs drug can be electrostatically bonded with the disintegrant hydrogen bond, thereby improving the absorption-promoting ability of the P-CABs drug, and thus improving the bioavailability and stability of the tablet. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below through specific implementation cases. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of protection of the present invention. After reading the present invention, various equivalent forms of modifications to the present invention by those skilled in the art are all within the scope of the claims attached to this application.

[0026] Unless otherwise specified, all raw materials and reagents of the present invention are raw materials and reagents from the conventional market.

[0027] Example 1

[0028] A compound preparation of a P-CABs drug combined with an antacid, wherein each unit of preparation comprises: 20 mg of vonoprazan, 500 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0029] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0030] Step 1: First, uniformly mix the prescribed amount of vonoprazan, a disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate;

[0031] The preparation process of the disintegrant is as follows: adjusting the pH of cross-linked carboxymethyl cellulose sodium to 7, adding the cross-linked carboxymethyl cellulose sodium to a water-soluble mixture at a mass ratio of 2:5, and heating under pressure for 80 minutes, wherein the heating temperature is 85° C. and the pressure is 11 MPa, and then drying to obtain the disintegrant;

[0032] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.4:7;

[0033] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0034] The lubricant is prepared by mixing magnesium stearate and carboxy betaine in a mass ratio of 3:1, melting the mixture at a temperature of 93° C., standing the mixture to dry, and then pulverizing the mixture.

[0035] Example 2

[0036] A compound preparation of a P-CABs drug combined with an antacid, wherein the prescription composition of each unit preparation is: 20 mg of ripraxane, 500 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0037] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0038] Step 1: First, mix the prescribed amount of Repraxane, disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate evenly;

[0039] The preparation process of the disintegrant is as follows: sodium carboxymethyl starch is adjusted to pH 7, then added to a water-soluble mixture at a mass ratio of 1:4, and pressurized and heated for 70 minutes, wherein the heating temperature is 80° C. and the pressure is 10 MPa, and then dried to obtain the disintegrant;

[0040] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.2:6;

[0041] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0042] The lubricant is prepared by mixing sodium stearate and carboxy betaine in a mass ratio of 2:1, melting the mixture at 90° C., standing the mixture to dry, and then crushing the mixture.

[0043] Example 3

[0044] A compound preparation of a P-CABs drug combined with an antacid, wherein each unit of preparation comprises: 20 mg of tigolaxan, 500 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0045] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0046] Step 1: First, evenly mix the prescribed amount of tegrassen, disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate;

[0047] The preparation process of the disintegrant is as follows: adjusting the pH of cross-linked carboxymethyl cellulose sodium to 8, adding the cross-linked carboxymethyl cellulose sodium to a water-soluble mixture at a mass ratio of 3:6, and heating under pressure for 90 minutes, wherein the heating temperature is 90° C. and the pressure is 12 MPa, and then drying to obtain the disintegrant;

[0048] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.6:9;

[0049] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0050] The lubricant is prepared by mixing potassium stearate and carboxy betaine in a mass ratio of 2-4:1, melting the mixture at a temperature of 96° C., standing the mixture to dry, and then crushing the mixture.

[0051] Example 4

[0052] A compound preparation of a P-CABs drug combined with an antacid, wherein the prescription composition of each unit preparation is: 40 mg of vonoprazan, 800 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0053] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0054] Step 1: First, uniformly mix the prescribed amount of vonoprazan, a disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate;

[0055] The preparation process of the disintegrant is as follows: adjusting the pH of cross-linked carboxymethyl cellulose sodium to 8, adding the cross-linked carboxymethyl cellulose sodium to a water-soluble mixture at a mass ratio of 3:4, heating under pressure for 75 minutes, the heating temperature is 85° C., the pressure is 12 MPa, and then drying to obtain the disintegrant;

[0056] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.4:7;

[0057] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0058] The lubricant is prepared by mixing magnesium stearate, sodium stearate, potassium stearate, calcium stearate and carboxy betaine in a mass ratio of 2:1, melting the mixture at a temperature of 96° C., standing the mixture to dry, and then pulverizing the mixture.

[0059] Example 5

[0060] A compound preparation of a P-CABs drug combined with an antacid, wherein each unit of preparation comprises: 5 mg of vonoprazan, 400 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0061] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0062] Step 1: First, uniformly mix the prescribed amount of vonoprazan, a disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate;

[0063] The preparation process of the disintegrant is as follows: sodium carboxymethyl starch is adjusted to pH 8, then added to a water-soluble mixture at a mass ratio of 3:6, and pressurized and heated for 90 minutes, wherein the heating temperature is 80° C. and the pressure is 11 MPa, and then dried to obtain the disintegrant;

[0064] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.2:9;

[0065] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0066] The lubricant is prepared by mixing magnesium stearate and carboxy betaine in a mass ratio of 3:1, melting the mixture at a temperature of 93° C., standing the mixture to dry, and then pulverizing the mixture.

[0067] Example 6

[0068] A compound preparation of a P-CABs drug combined with an antacid, wherein each unit of preparation comprises: 30 mg of vonoprazan, 600 mg of sodium bicarbonate, 12 mg of a disintegrant, and 8 mg of a lubricant.

[0069] A method for preparing a composite preparation of P-CABs drugs combined with antacids

[0070] Step 1: First, uniformly mix the prescribed amount of vonoprazan, a disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate;

[0071] The preparation process of the disintegrant is as follows: sodium carboxymethyl starch is adjusted to pH 8, then added to a water-soluble mixture at a mass ratio of 1:5, and pressurized and heated for 80 minutes, wherein the heating temperature is 85° C. and the pressure is 11 MPa, and then dried to obtain the disintegrant;

[0072] The water-soluble mixture is a mixture of alginic acid and anthocyanin in a mass ratio of 0.6:6;

[0073] Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product;

[0074] The lubricant is prepared by mixing calcium stearate and carboxy betaine in a mass ratio of 3:1, melting the mixture at a temperature of 93° C., standing the mixture to dry, and then crushing the mixture.

[0075] The contents of the ingredients of the compound preparations of Comparative Examples 1-3 are shown in Table 1, wherein the preparation methods of the ingredients are the same as that of Example 1.

[0076] Table 1 Prescription of each unit of compound preparation

[0077]

[0078] Comparative Example 4

[0079] The difference between Comparative Example 4 and Example 1 is that the disintegrant in Comparative Example 4 is cross-linked sodium hydroxymethyl cellulose, and the other contents remain unchanged.

[0080] Comparative Example 5

[0081] The difference between Comparative Example 5 and Example 1 is that, during the preparation process of the disintegrant in Comparative Example 5, the polymer is not subjected to alkali treatment, and the other conditions remain unchanged.

[0082] Comparative Example 6

[0083] The difference between Comparative Example 6 and Example 1 is that no water-soluble mixture is added during the preparation of the disintegrant in Comparative Example 6, and the other conditions remain unchanged.

[0084] Comparative Example 7

[0085] The difference between Comparative Example 7 and Example 1 is that the lubricant in Comparative Example 7 is magnesium stearate, and the other ingredients remain unchanged.

[0086] 1. Dissolution Determination of Compound Preparations

[0087] Effect of compound preparation on pH value of gastric juice in mice

[0088] After the proton pump inhibitor compound preparation was administered to Balb / c mice, the gastric pH value was measured. Six-week-old female Balb / c mice, 18 g ± 2 g, a total of 20 mice. They were fed routinely after purchase and randomly divided into groups, 10 mice / cage.

[0089] The rearing conditions are as follows: rearing in an ordinary environment, with a temperature of 22±4℃, a humidity of 55±10%, changing the bedding once a week, a daily light intensity of 12 hours of day and night, 24-hour ventilation, regular disinfection of the environment every week, regular feed, water prepared by a pure water instrument and sterilized by high pressure, and free access to food and water.

[0090] After 7 days of transitional feeding, the gastric pH value of mice was tested. The gastric pH value test scheme of mice was as follows: aspirate solution A with a sterile syringe and inject 250uL of solution A into each mouse by intraperitoneal injection; the composition of solution A was 0.1mg preparation / mouse, and the solvent was sterile saline. The test was performed at 30min, 45min, 60min, 75min, 90min, 105min, 120min, 135min, 150min, and 165min after intraperitoneal injection of solution A; the gastric pH value of 2 mice was tested at each time point, and the average value of all time points of mice in the group is shown in the table.

[0091] Before slaughtering the mice, they were deprived of food and water for 24 hours. Without violating animal ethics, the mice were killed by cervical dislocation. The abdomen of the mice was wiped and disinfected with 75% alcohol cotton balls, and the abdominal cavity of the mice was cut open with surgical scissors to take out the stomach.

[0092] The whole stomach of the mouse was cut open along the greater curvature of the stomach, and an appropriate amount of gastric fluid was taken with a pipette and dropped onto the pH test paper. The pH test paper was from Hangzhou Shisan Technology Co., Ltd. For details on the use of the pH test paper, please refer to the pH test paper manual. The test results are shown in Table 2.

[0093] Table 2 pH value of mouse gastric juice

[0094]

[0095] 10 g of the compound preparation prepared in the examples and comparative examples was placed in artificial gastric juice (purchased from Maiji Biotechnology), stirred in a stirring device at a speed of 60 r / min, and the solution was extracted every 10 minutes to detect the release amount of the P-CABs drug. The test results are shown in Table 3.

[0096] Table 3 Drug release of P-CABs

[0097]

[0098]

[0099] It can be seen from Table 2 and Table 3 that the compound preparation prepared by the present invention has good solubility, can be released quickly, and can adjust the pH of gastric juice; it can be seen from Comparative Examples 4-7 that the compound preparation of the present invention is compounded by adding a homemade disintegrant, a lubricant and sodium bicarbonate, and the preparation disintegrates quickly and has high bioavailability.

[0100] 2. Stability determination of compound preparations

[0101] The composite preparations prepared in Example 1 and the comparative example were placed in an environment under light and room temperature conditions for 0 h, 25 days, and 50 days, and the vonoprazan content of the composite preparations was detected. The test results are shown in Table 4.

[0102] Table 4 Compliance rate of vonoprazan labeled content

[0103]

[0104] As shown in Table 4, the compound preparation of the present invention has high stability and can be stored for a long time under light and non-refrigerated conditions.

[0105] In summary, in the compound preparation of the P-CABs drug combined with an antacid of the present invention, the disintegrant prepared by the traditional alkali-treated sodium hydroxymethylcellulose with a disintegrating effect and a water-soluble mixture has a high disintegration rate and promotes the absorption and utilization of the P-CABs drug; the lubricant has high stability and bioavailability by increasing the polarity of the stearate.

Claims

1. A composite preparation of a P-CABs drug combined with an antacid, characterized in that: The prescription composition of each unit preparation is: 5-40 mg of Class I P-CABs drug, 400-1000 mg of sodium bicarbonate, 12 mg of disintegrant, and 8 mg of lubricant.

2. A composite preparation of a P-CABs drug combined with an antacid according to claim 1, characterized in that: The preparation process of the disintegrant is as follows: the polymer is treated with alkali, then added into a water-soluble mixture at a mass ratio of 1-3:4-6, and the mixture is pressurized and heated for 70-90 minutes, and then dried.

3. A composite preparation of a P-CABs drug combined with an antacid according to claim 2, characterized in that: The polymer is one of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

4. A composite preparation of a P-CABs drug combined with an antacid according to claim 2, characterized in that: The alkali treatment is to adjust the pH of the polymer to 7-8.

5. A composite preparation of a P-CABs drug combined with an antacid according to claim 2, characterized in that: The water-soluble mixture is a mixture of alginate and anthocyanin in a mass ratio of 0.2-0.6:6-9.

6. A composite preparation of a P-CABs drug combined with an antacid according to claim 2, characterized in that: The heating temperature is 80-90°C and the pressure is 10-12Mpa.

7. A composite preparation of a P-CABs drug combined with an antacid according to claim 1, characterized in that: The lubricant is a mixture of stearate and carboxybetaine.

8. A composite preparation of a P-CABs drug combined with an antacid according to claim 7, characterized in that: The mixture is prepared by mixing stearate and carboxybetaine in a mass ratio of 2-4:1, melting the mixture at a temperature of 90-96° C., standing the mixture to dry, and then crushing the mixture.

9. A composite preparation of a P-CABs drug combined with an antacid according to claim 1, characterized in that: The stearate is one of magnesium stearate, sodium stearate, potassium stearate and calcium stearate.

10. A method for preparing a composite preparation of a P-CABs drug combined with an antacid according to any one of claims 1 to 9, characterized in that: The following steps are involved: Step 1: First, mix the prescribed amount of P-CABs drug, disintegrant and 1 / 2 of the prescribed amount of sodium bicarbonate evenly; Step 2: Add 1 / 4 of the prescribed amount of sodium bicarbonate and mix well; finally, add the remaining amount of sodium bicarbonate and lubricant and mix well to obtain the product.

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