CN115040491A

CN115040491A - Compound preparation of potassium ion competitive acid retarder and acetylsalicylic acid and preparation method thereof

Info

Publication number: CN115040491A
Application number: CN202110257368.6A
Authority: CN
Inventors: 李函璞; 王帅; 李勇刚
Original assignee: Shanghai Tin Tsz Bio Valley Biological Engineering Co ltd
Current assignee: Shanghai Tin Tsz Bio Valley Biological Engineering Co ltd
Priority date: 2021-03-09
Filing date: 2021-03-09
Publication date: 2022-09-13

Abstract

The invention provides a potassium ion competitive acid retarder and acetylsalicylic acid compound preparation and a preparation method thereof. Specifically, the bilayer tablet includes: a first layer tablet comprising 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid as a first active ingredient and a pharmaceutically acceptable carrier; and a second ply comprising acetylsalicylic acid as a second active ingredient, and a pharmaceutically acceptable carrier. The compound preparation can control the release rate of the medicine and obviously reduce the side effect of the acetylsalicylic acid on the gastrointestinal tract.

Description

Potassium ion competitive acid retarder and acetylsalicylic acid compound preparation and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound preparation containing 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamate and acetylsalicylic acid and a preparation method thereof.

Background

The non-steroidal anti-inflammatory drug acetylsalicylic acid (aspirin) is the earliest anti-platelet aggregation drug in clinical application, and the anti-thrombus effect of the aspirin is mainly based on irreversible inhibition on platelet cyclooxygenase, so that arachidonic acid in platelets cannot be converted into prostaglandin endoperoxide, further thromboxane A2 generation of the platelets is inhibited, and finally, platelet aggregation is inhibited, so that the aim of resisting thrombus is fulfilled. Aspirin often produces the following side effects in the process of preventing and treating thrombotic diseases, such as gastrointestinal tract reactions like nausea, vomiting, epigastric discomfort or pain, and the damage of gastric and duodenal mucous membranes can be caused by long-term administration of aspirin. Research shows that the aspirin dosage or dosage forms which seem to reduce side effects such as low dosage, slow release agent and enteric coating can not really play the role of protecting the digestive tract. Over 1500 million americans take nsaids daily for the treatment of pain or inflammation. Many of these nonsteroidal anti-inflammatory drugs are associated with a high incidence of gastrointestinal complications, including gastritis, dyspepsia, gastroduodenal ulcers, perforation and bleeding.

2016.9 months, FDA approved combination of aspirin and omeprazole

The delayed-release tablet is mainly suitable for patients who need aspirin to perform secondary prevention on cardiovascular and cerebrovascular diseases and have the risk of aspirin-related gastric ulcer. After the Yoosprala enters the body, 40mg of omeprazole can be rapidly released for the first time, and then 81mg or 325mg of aspirin inner core with enteric coating is released. The rapidly released omeprazole can raise the pH value in the stomach to the gastrointestinal tract protection range (the pH value is more than or equal to 5.5), and aspirin is dissolved later, so that the occurrence risk of gastric ulcer is reduced.

However, the half-life of the prazole drugs is short, the nocturnal acid breakthrough phenomenon generally exists, and the Proton Pump Inhibitors (PPIs) are prodrugs and need to be rearranged into an active form under the action of gastric acid to irreversibly inhibit the proton pump so as to inhibit gastric acid secretion, so that the effect of the prazole PPIs is relatively slow; due to the gene diversity of the hepatic CYP2C19 metabolic system in the population, PPIs have widely varying therapeutic effects in different patients and may have drug-metabolic interactions with other drugs. Clinically, drugs with higher acid-inhibiting strength and longer acid-inhibiting duration are required.

Vonoprazan fumarate, a reversible potassium-competitive acid blocker (P-CAB) developed by Takeda, Japan, is an orally ingestible tablet. In vitro experimental research shows that the compound has 400 times of inhaul-azole inhibition capacity, can preferentially inhibit gastric acid secretion, and has the advantage of long duration. However, the compound has poor water solubility and short half-life in an animal model, T1/2 in rats (0.75mg/kg) and dogs (0.1mg/kg) after intravenous injection administration is 1.2h, and the bioavailability is 10.3 percent and 52.4 percent respectively, so that the compound is limited to play the roles of inhibiting acid and treating gastric acid related diseases.

Patent CN103951652A relates to an injection of water-soluble organic acid salt 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine pyroglutamate, the solubility of which is 1000 times higher than that of fumarate vonoprazan. The invention also discloses absorption kinetics experiments of pyroglutamate and fumarate tablets prepared into injections in rats, and acid-inhibiting secretion experiments show that the onset time of the pyroglutamate is advanced by about 30min and the time for achieving the maximum acid-inhibiting effect is advanced by about 60 min. Therefore, the pyroglutamate absorption kinetics is more advantageous and is beneficial to exerting the acid inhibition effect of free alkali.

Accordingly, there is a need in the art to provide a formulation that can control the rate of drug release and reduce the gastrointestinal side effects of acetylsalicylic acid.

Disclosure of Invention

The invention aims to provide a compound preparation which can control the release rate of a medicament and reduce the gastrointestinal side effect of acetylsalicylic acid.

In a first aspect of the present invention, there is provided a compound preparation, which is a bilayer tablet comprising:

a first layer tablet comprising 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid as a first active ingredient and a pharmaceutically acceptable carrier; and

a second ply comprising acetylsalicylic acid as a second active ingredient, and a pharmaceutically acceptable carrier.

In another preferred embodiment, in the first layer sheet, the pharmaceutically acceptable carrier is selected from the group consisting of: mannitol, microcrystalline cellulose, povidone, aerosil, or a combination thereof.

In another preferred embodiment, the first layer includes:

1-25 parts by weight of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid; preferably, 5 to 20 parts by weight, such as 10, 15 parts by weight;

15-40 parts of mannitol, preferably 20-35 parts, such as 25 and 30 parts;

30-150 parts by weight, preferably 40-80 parts by weight, such as 50, 60 parts by weight of microcrystalline cellulose;

2-15 parts of povidone, preferably 4-12 parts, such as 6, 8 or 10 parts;

0.5-5 parts by weight of aerosil, preferably 1-4 parts by weight, such as 2, 2.5 or 3 parts by weight;

2-15 parts by weight, preferably 4-12 parts by weight, such as 6, 8 or 10 parts by weight, of croscarmellose sodium; and

stearate is 0.5-5 parts by weight, preferably 1-4 parts by weight, such as 2, 2.5 or 3 parts by weight.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to mannitol in the first layer sheet is 1: 1-5, preferably 1: 1.2-4, such as 1:2 or 1: 3.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to microcrystalline cellulose in the first ply is 1: 3-20, preferably 1: 5-15, such as 1:6, 1:8, 1:10 or 1: 12.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to povidone K30 in the first ply is 1:0.5-2, preferably 1:0.8-1.5, such as 1:1, 1:1.2, 1:1.6 or 1: 1.8.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to aerosil in the first layer sheet is 1:0.05-0.5, preferably 1:0.1-0.5, such as 1:0.15, 1:0.2, 1:0.25 or 1: 0.3.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to croscarmellose sodium in the first layer tablet is 1:0.5-2, preferably 1:0.8-1.5, such as 1:1, 1:1.2, 1:1.6 or 1: 1.8.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to stearate in the first layer tablet is 1:0.05-0.5, preferably 1:0.1-0.5, such as 1:0.15, 1:0.2, 1:0.25 or 1: 0.3.

In another preferred embodiment, the first ply further comprises a stabilizer selected from the group consisting of: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid to stabilizer in the first layer sheet is 1: 0.5-3, preferably 1:1-2, such as 1: 1.5.

In another preferred embodiment, the first layer has a weight of 50-300mg, such as 100, 150, 200, 250 mg.

In another preferred embodiment, the stearate is selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, calcium stearate, or combinations thereof.

In another preferred example, the povidone is povidone K30.

In another preferred embodiment, in the second layer sheet, the pharmaceutically acceptable carrier is selected from the group consisting of: povidone, microcrystalline cellulose, modified cellulose, lactose, stearate, or combinations thereof.

In another preferred embodiment, the modified cellulose is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, croscarmellose sodium, or combinations thereof.

In another preferred example, the pharmaceutically acceptable carrier in the second ply comprises microcrystalline cellulose, lactose and stearate.

In another preferred embodiment, the modified cellulose is selected from the group consisting of: ethyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, or combinations thereof.

In another preferred embodiment, the second ply comprises:

50-500 parts by weight of acetylsalicylic acid; preferably, 100-300 parts by weight, such as 150, 200 or 250 parts by weight;

20-150 parts of microcrystalline cellulose; preferably, 30 to 100 parts by weight, such as 50, 60 or 80 parts by weight;

20-100 parts of lactose; preferably, 30 to 80 parts by weight, such as 50, 60 or 70 parts by weight;

50-500 parts of modified cellulose; preferably, 100-300 parts by weight, such as 150, 200, 250 or 300 parts by weight; and

1-20 parts of stearate; preferably 1.5 to 15 parts by weight, such as 2, 4, 8 or 10 parts by weight.

In another preferred example, the modified cellulose comprises:

20-160 parts of hydroxypropyl cellulose; preferably, 30 to 120 parts by weight, such as 50, 80 or 100 parts by weight;

20-100 parts of hydroxypropyl methyl cellulose; preferably, 30 to 80 parts by weight, such as 40, 50, 60 or 70 parts by weight; and

5-50 parts of croscarmellose sodium; preferably 8-40 parts, such as 10, 20 or 30 parts by weight.

In another preferred embodiment, the modified cellulose further comprises 10-50 parts by weight of optional ethyl cellulose; preferably 20-30 parts by weight, such as 15, 25 or 35 parts by weight.

In another preferred example, the modified cellulose comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose and croscarmellose sodium.

In another preferred example, in the modified cellulose, the weight ratio of hydroxypropyl cellulose to hydroxypropyl methyl cellulose is 1: 0.1-2, preferably 1:0.2-1, such as 1:0.25, 1:0.3 or 1: 0.5.

In another preferred embodiment, the modified cellulose has a weight ratio of hydroxypropyl cellulose to croscarmellose sodium of 1:0.1-0.5, preferably 1:0.2-0.4, such as 1:0.25 or 1: 0.3.

in another preferred embodiment, the modified cellulose has a weight ratio of hydroxypropyl cellulose to ethyl cellulose of 1:0-0.5, preferably 1:0.1-0.3, such as 1: 0.2.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to microcrystalline cellulose in the second ply is 1:0.1-1, preferably 1:0.2-0.8, such as 1:0.3 or 1: 0.5.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to lactose in the second layer tablet is 1:0.1-1, preferably 1:0.2-0.8, such as 1:0.3 or 1: 0.5.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to modified cellulose in the second ply is 1:0.5-2, preferably 1:0.8-1.5, such as 1:1 or 1: 1.2.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to hydroxypropyl cellulose in the second layer is 1:0.1-1, preferably 1:0.2-0.8, such as 1:0.3 or 1: 0.5.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to hydroxypropylmethylcellulose in the second ply is 1:0.05-0.5, preferably 1:0.1-0.4, such as 1:0.2 or 1: 0.3.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to croscarmellose sodium in the second layer sheet is 1:0.01-0.2, preferably 1:0.02-0.1, such as 1:0.05 or 1: 0.08.

In another preferred embodiment, the weight ratio of acetylsalicylic acid to stearate in the second layer is 1:0.01-0.2, preferably 1:0.02-0.1, such as 1:0.03 or 1: 0.05.

In another preferred embodiment, the weight of the second layer is 100-500mg, such as 150, 200, 250, 300, 400 mg.

In another preferred embodiment, the weight ratio of the first layer sheet to the second layer sheet is 1: 0.5-10, preferably 1: 1-5, such as 1:2, 1:3 or 1: 4.

In another preferred embodiment, 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid is present in an amount of 5mg to 20mg, such as 10, 15mg, per bilayer tablet.

In another preferred embodiment, the acetylsalicylic acid is present in an amount of 50mg to 300mg, such as 100, 150, 200, 250mg, per two-layer tablet.

In another preferred embodiment, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid and acetylsalicylic acid in each bilayer tablet is 1:1 to 30, preferably 1:5 to 25, more preferably 1:10 to 20, such as 1: 15.

In a second aspect of the present invention, there is provided a method for preparing the compound preparation according to the first aspect of the present invention, comprising the steps of:

a first layer sheet:

providing a povidone aqueous solution (such as 10-15% mass concentration):

premixing: adding 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, mannitol, microcrystalline cellulose, silica gel micropowder and croscarmellose sodium into a mixer for premixing to obtain a premixed material;

and (3) granulation: transferring the premixed material to a fluidized bed, and performing fluidized bed granulation by taking povidone aqueous solution as an adhesive;

and (3) drying: drying by a fluidized bed, and finishing drying when the moisture of the material is less than 2%; and

total mixing: transferring the dried material to a mixer, adding stearate to complete the total mixing of the first layer of material for later use;

a second ply:

premixing: adding acetylsalicylic acid, microcrystalline cellulose, lactose and modified cellulose in the second layer into a mixer for premixing;

high-shear wet granulation: after the premixing is finished, performing high-shear wet granulation by using water as a binder, and performing wet granulation;

and (3) drying: transferring the material to a fluidized bed for drying, and finishing drying when the moisture of the material is less than 3%;

transferring the dried material to a mixer, and adding stearate to complete the total mixing of the second layer; and

and adding the material obtained after the total mixing of the first layer sheets into a feeding hopper of the first layer sheets of the double-layer tablet press, adding the material obtained after the total mixing of the second layer sheets into a feeding hopper of the second layer sheets of the double-layer tablet press, and pressing the double-layer tablets to obtain the double-layer tablets.

In a third aspect of the invention, there is provided the use of a combination according to the first aspect of the invention in the manufacture of a medicament for (a) inhibiting the secretion of gastric acid; and/or (b) preventing or treating a disease selected from the group consisting of: gastric Acid Related Diseases (ARDs); gastric ulcer, duodenal ulcer, reflux esophagitis, non-steroidal anti-inflammatory drug induced ARDS, gastric mucosa-associated lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura; antipyretic, analgesic, antiinflammatory, and antithrombotic effects.

In another preferred embodiment, the medicament is used for antipyretic, analgesic, anti-inflammatory, anti-thrombotic and reducing the gastrointestinal side effects of aspirin, such as gastric or duodenal ulcers and the like.

In a fourth aspect of the present invention, there is provided an antipyretic, analgesic, anti-inflammatory and/or antithrombotic method comprising the step of administering to a subject in need thereof an effective amount of a combination preparation as defined in the first aspect of the present invention, thereby antipyretic, analgesic, anti-inflammatory and/or antithrombotic.

In another preferred embodiment, the subject is a mammal, such as a human, rat, mouse, monkey.

In another preferred embodiment, the subject is a gastrointestinal sensitive subject or a subject that is not gastrointestinal tolerant to aspirin.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have made extensive and intensive studies and, as a result of extensive screening and testing, have provided a complex formulation comprising 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamate and acetylsalicylic acid, and its preparation. The invention adopts a specific preparation formula to prepare the two active ingredients into a single dosage form of a double-layer tablet, and can simultaneously control the release rates of the two active ingredients, so that the drug concentrations of the two active ingredients in intestines and stomach are always kept in a reasonable proportion in a certain time, thereby better reducing the side effect of acetylsalicylic acid. The present invention has been completed based on this finding.

Term(s)

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

As used herein, the term "room temperature" or "ambient temperature" means a temperature of 4-40 ℃, preferably, 25 ± 5 ℃.

Active ingredient

The term "first active ingredient", as used herein, refers to 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine-L-pyroglutamic acid, i.e. the salt of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine with L-pyroglutamic acid, as active ingredient.

The structure of a representative active ingredient of the present invention is shown in formula a:

in the present invention, the ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine to L-pyroglutamic acid in the active ingredient is not particularly limited, and is usually (1 ± 0.2): (1. + -. 0.2), e.g.1: 1.

The term "second active ingredient", as used herein, refers to aspirin, i.e., 2- (acetoxy) benzoic acid.

Compound preparation

The compound preparation of the invention is a double-layer tablet, which comprises:

In another preferred embodiment, in the second ply, the pharmaceutically acceptable carrier is selected from the group consisting of: povidone, microcrystalline cellulose, modified cellulose, lactose, stearate, or combinations thereof.

Typically, the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid and acetylsalicylic acid in each bilayer tablet is 1:1 to 30, preferably 1:5 to 25, more preferably 1:10 to 20, such as 1: 15.

The compound preparation of the invention can reasonably control the release of the two active ingredients. Generally, the amount of acetylsalicylic acid released in the tablet for 1 hour in water is not more than 20% of the indicated amount, and the amount released in the tablet for 4 hours is not more than 60% of the indicated amount. The 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid is eluted in water for 15min at a rate of not less than 80% and in water for 30min at a rate of not less than 90%.

Preparation method

The formulations of the present invention may be prepared by methods conventional in the art, and one typical method of preparation comprises the steps of:

a first layer sheet:

providing a povidone aqueous solution (such as 10-15% mass concentration):

pre-mixing: adding 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, mannitol, microcrystalline cellulose, silica gel micropowder and croscarmellose sodium into a mixer for premixing to obtain a premixed material;

and (3) granulation: transferring the premixed material to a fluidized bed, and performing fluidized bed granulation by using a povidone aqueous solution as an adhesive;

total mixing: transferring the dried material to a mixer, adding stearate to complete the total mixing of the first layer of materials for later use;

a second ply:

Use of

The first and second active ingredients of the present invention are known compounds, and therefore, the preparation has both activities, and can be used for treating related diseases.

For example, the first active ingredient is a potassium competitive acid blocker, useful for the prevention and/or treatment of a disease selected from the group consisting of (but not limited to): gastric Acid Related Diseases (ARDs); gastric ulcer, duodenal ulcer, reflux esophagitis, non-steroidal anti-inflammatory drug induced ARDS, gastric mucosa-associated lymphoid tissue lymphoma, and idiopathic thrombocytopenic purpura.

In particular, the compound preparation of the invention is more suitable for diseases which can be treated by aspirin, including but not limited to, antipyretic, analgesic, anti-inflammatory, antithrombotic and the like.

More particularly, two active ingredients of the compound preparation of the invention can play a synergistic role. The aspirin-like therapeutic effect is exerted, and meanwhile, the gastrointestinal side effects (such as gastric ulcer or duodenal ulcer and the like) of the aspirin are reduced. Is especially suitable for gastrointestinal tract sensitive subjects or subjects intolerant to aspirin gastrointestinal tract.

The precise amount of the compound that provides a therapeutically effective amount to an individual will depend on the mode of administration, the type and severity of the disease and/or condition, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to drugs. One of ordinary skill in the art will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, the "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable dosages for approved therapeutics are known and can be adjusted by one of ordinary skill in the art depending on the individual condition, the type of disorder being treated, and the amount of the compound of the invention to be used, for example, dosages reported in the literature and recommended in the physicians' Desk Reference (57 th edition, 2003). Preferably, the aspirin is administered in an amount to achieve the standard amount. More preferably, the release rate of the bilayer tablet according to the present invention may be administered at a frequency of 1-4 times a day, such as 1, 2, 3 or 4 times a day.

The main advantages of the invention include:

1. the 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid/acetylsalicylic acid compound preparation is a novel potassium ion competitive acid retarder (P-CAB)/acetylsalicylic acid compound preparation, and can improve the defects of low bioavailability, slow effect, poor patient compliance and the like of the conventional proton pump inhibitor (aspirin/omeprazole) due to dosage forms, solubility and the like.

2. Because the acetylsalicylic acid can be used as a non-steroidal anti-inflammatory drug mainly used for treating pain and resisting platelet aggregation, the acetylsalicylic acid can be used for resisting platelet aggregation by being taken for a long time, and simultaneously reducing/treating the side effect of acetylsalicylic acid gastric ulcer or duodenal ulcer.

The double-layer tablet of the invention can release the medicine in a reasonable time, thereby better playing the treatment effect and reducing the side effect.

3. The compound preparation of the invention can reasonably control the release of two active ingredients and protect gastrointestinal tracts, thereby having better drug absorption and drug effect, playing a role in cooperative treatment, and having good stability, low cost and convenient use.

The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Examples 1 to 6

The preparation method comprises the following steps:

and sieving and weighing the raw and auxiliary materials of the first layer slice.

The adjuvant povidone K30 of the first layer tablet was formulated into a 10% (mass concentration) aqueous solution.

Adding 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, mannitol, microcrystalline cellulose, silica gel micropowder and croscarmellose sodium into a mixer for premixing;

the premixed material was transferred to a fluidized bed and fluidized bed granulation was carried out with a 10% (mass concentration) aqueous solution of povidone K30 as a binder.

A drying procedure: and (5) drying by a fluidized bed, and finishing the drying when the moisture of the material is less than 2%.

A total mixing procedure: and transferring the dried materials to a mixer, and adding sodium stearyl fumarate with the amount of the prescription to complete the total mixing of the first layer of materials for later use.

And sieving the raw and auxiliary materials of the second layer slice and weighing.

The second layer tablet of acetylsalicylic acid, microcrystalline cellulose, lactose, ethyl cellulose, hydroxypropyl methylcellulose, and croscarmellose sodium were added to a mixer and premixed.

High-shear wet granulation: after the premixing, high-shear wet granulation was performed using water as a binder, and wet granulation was performed with 18 mesh.

And (3) drying: and transferring the material to a fluidized bed for drying, and finishing the drying when the moisture of the material is less than 3%.

The dried material was transferred to a blender and the prescribed amount of sodium stearyl fumarate was added to complete the second ply total blend.

And adding the material after the first layer slice total mixing into a feeding hopper of a first layer slice of a double-layer tablet press, adding the material after the second layer slice total mixing into a feeding hopper of a second layer slice of the double-layer tablet press, and pressing the double-layer tablet.

The formulations of examples 1-6 are shown in table 1 below:

TABLE 1

As described above, the tablet of the present invention is useful as a combination drug of a potassium ion competitive acid blocker and acetylsalicylic acid.

Example 7 dissolution Curve measurements of test samples

Dissolution conditions: measuring by high performance liquid chromatography (0512 in the fourth division of the pharmacopoeia 2015 edition) by the second method, taking 900ml of aqueous solution as a dissolution medium, degassing the dissolution medium at 37 +/-0.5 ℃ and 75 revolutions per minute, taking a proper amount of solution, filtering, injecting into a liquid chromatograph, and recording a chromatogram.

Table 2 example 3 sample dissolution profile determination

Table 3 example 3 sample dissolution profile determination

As can be seen from tables 2 and 3, in the bilayer tablet of the present invention, the sustained release layer and the immediate release layer are separated from each other and the compatibility of the drugs is not interfered with each other, and based on this, the first layer tablet can rapidly release 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid within 45min after administration, while the second layer tablet can continuously release acetylsalicylic acid within 12H, and the number of administration of the drug can be reduced as compared with the conventional acetylsalicylic acid tablet, and those skilled in the art understand that acetylsalicylic acid has irritation to the gastrointestinal tract, and the risk of gastrointestinal ulcer is greatly increased when a large amount of the tablet is taken for a long time (for example, for rheumatism and inhibition of platelet aggregation), and the 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) of the present invention ) the-1H-pyrrole-3-methylamine-L-pyroglutamic acid can inhibit gastric acid secretion, and can obviously reduce side effects such as intestinal complications and the like, thereby improving the compliance of patients.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound preparation is characterized in that the compound preparation is a double-layer tablet, and the double-layer tablet comprises:

2. The combination of claim 1, wherein the pharmaceutically acceptable carrier in the first layer is selected from the group consisting of: mannitol, microcrystalline cellulose, povidone, aerosil, or a combination thereof.

3. The combination of claim 2, wherein the first layer comprises:

15-40 parts of mannitol, preferably 20-35 parts, such as 25 and 30 parts;

2-15 parts of povidone, preferably 4-12 parts, such as 6, 8 or 10 parts;

2-15 parts by weight of croscarmellose sodium, preferably 4-12 parts by weight, such as 6, 8 or 10 parts by weight; and

4. The combination formulation of claim 1, wherein the pharmaceutically acceptable carrier in the second layer is selected from the group consisting of: povidone, microcrystalline cellulose, modified cellulose, lactose, stearate, or combinations thereof.

5. The combination formulation of claim 4, wherein the modified cellulose is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, croscarmellose sodium, or combinations thereof.

6. The combination of claim 5, wherein the second layer comprises:

50-500 parts of acetylsalicylic acid; preferably, 100-300 parts by weight, such as 150, 200 or 250 parts by weight;

1-20 parts by weight of stearate; preferably 1.5 to 15 parts by weight, such as 2, 4, 8 or 10 parts by weight.

7. The combination formulation of claim 1, wherein the weight ratio of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine-L-pyroglutamic acid and acetylsalicylic acid in each bilayer tablet is 1:1 to 30, preferably 1:5 to 25, more preferably 1:10 to 20, such as 1: 15.

8. A method of preparing a compound formulation as claimed in claim 1, comprising the steps of:

a first layer sheet:

providing a povidone aqueous solution (such as 10-15% mass concentration):

a second ply:

premixing: adding the acetylsalicylic acid, the microcrystalline cellulose, the lactose and the modified cellulose of the second layer sheet into a mixer for premixing;

9. The use of a combination according to claim 1 for the preparation of a medicament for (a) inhibiting gastric acid secretion; and/or (b) preventing or treating a disease selected from the group consisting of: gastric Acid Related Diseases (ARDs); gastric ulcer, duodenal ulcer, reflux esophagitis, non-steroidal anti-inflammatory drug induced ARDS, gastric mucosa-associated lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura; antipyretic, analgesic, antiinflammatory, and antithrombotic effects.

10. The use according to claim 9, wherein the medicament is for antipyretic, analgesic, anti-inflammatory, anti-thrombotic and reducing the gastrointestinal side effects of aspirin, such as gastric or duodenal ulcers.