CN114762687A - Premix of potassium ion competitive acid retarder and preparation thereof - Google Patents

Premix of potassium ion competitive acid retarder and preparation thereof Download PDF

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Publication number
CN114762687A
CN114762687A CN202110031884.7A CN202110031884A CN114762687A CN 114762687 A CN114762687 A CN 114762687A CN 202110031884 A CN202110031884 A CN 202110031884A CN 114762687 A CN114762687 A CN 114762687A
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premix
acid
group
stabilizer
combinations
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李函璞
李勇刚
王帅
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Shanghai Tin Tsz Bio Valley Biological Engineering Co ltd
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Shanghai Tin Tsz Bio Valley Biological Engineering Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

The invention relates to a premix of a potassium ion competitive acid retarder and preparation thereof, and particularly provides a premix which comprises 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid serving as an active ingredient, a stabilizer and an optional pharmaceutically acceptable excipient. Wherein the stabilizer is selected from the following group: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof. The premix significantly reduces the maximum increase of single impurities and total impurities, improves the stability of the active ingredients of the invention, has good powder properties, and can be directly subjected to tablet compression or capsule filling.

Description

Premix of potassium ion competitive acid retarder and preparation thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a premix of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid and a preparation method thereof.
Background
5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid is a novel potassium ion competitive acid retarder and has strong and lasting effect of inhibiting gastric acid secretion.
It was developed with the aim of inhibiting K in the last step of gastric acid secretion in parietal cells+Binding of H-K-ATPase (proton pump) prematurely stops gastric acid secretion. Compared with the traditional proton pump inhibitor lansoprazole, the compound can rapidly relieve digestive tract symptoms, enzyme activity is recovered after dissociation, adverse reactions are few, and the compound has obvious treatment effects on erosive esophagitis, duodenal ulcer, gastric ulcer, reflux esophagitis, non-steroidal anti-inflammatory drug induced ARD, gastric mucosa-related lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura and the like.
The chemical property of the 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid is unstable, the activity is greatly degraded along with the prolonging of the standing time, and certain hidden danger is brought to the administration of patients.
Therefore, it is highly desirable to develop a stable premix of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine-L-pyroglutamic acid.
Disclosure of Invention
It is an object of the present invention to provide a chemically stable premix of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine-L-pyroglutamic acid.
It is another object of the present invention to provide a process for the preparation of the premixes of the invention.
In a first aspect of the invention, there is provided a premix of a potassium-ion competitive acid blocker comprising:
(A) 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid as an active ingredient in the present invention;
(B) a stabilizer; and
(C) optionally a pharmaceutically acceptable excipient;
wherein the stabilizer is selected from the following group: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof;
(A) the weight ratio of (A) to (B) is 5:1-0.5: 1.
In another preferred embodiment, the contents of components (A), (B) and (C) in the premix are each independently from 5 to 20% by weight, from 3 to 20% by weight and from 40 to 90% by weight, based on the total mass of the premix.
In another preferred embodiment, the weight ratio of components (A) and (B) is from 4:1 to 1:1, more preferably from 3:1 to 1: 1.
In another preferred embodiment, the stabilizer of the premix is selected from the group consisting of: fumaric acid, citric acid, tartaric acid, or combinations thereof.
In another preferred embodiment, the excipients in the premix comprise: a filler, glidant, disintegrant, binder, lubricant, or combination thereof;
in another preferred embodiment, the filler is selected from the group consisting of: microcrystalline cellulose, mannitol, sorbitol, trehalose, betacyclodextrin, dibasic calcium phosphate, starch, pregelatinized starch, or a combination thereof;
the glidant is selected from the group consisting of: talc powder, aerosil, or a combination thereof;
the disintegrant is selected from the group consisting of: dry starch, sodium carboxymethyl starch, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, or combinations thereof;
the binder is selected from the group consisting of: starch slurry, cellulose derivatives, povidone, gelatin, polyethylene glycol, or combinations thereof;
the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol, or combinations thereof.
In another preferred embodiment, the filler is present in the excipient in an amount of 40-90 wt%, preferably 45-85 wt%, more preferably 50-80 wt%; the content of the glidant is 0.5-3 wt%; the content of the disintegrant is 2-6 wt%; the content of the adhesive is 3-10 wt%; the lubricant is present in an amount of 0.5 to 3 wt.%, based on the total weight of the premix.
In another preferred embodiment, the water content in the premix is from 0.5 to 5 wt%, preferably from 0.8 to 3 wt%; more preferably from 1.5 to 2.5 wt%, based on the total weight of the premix.
In another preferred embodiment, the premix is prepared by the method of the second aspect of the present invention.
In a second aspect of the present invention, there is provided a method for preparing the premix, comprising the steps of:
(1) pretreating raw materials and auxiliary materials: sieving 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid through a 40 mesh sieve;
(2) preparing an adhesive: preparing an adhesive aqueous solution;
(3) premixing: adding solid active ingredients, a stabilizer, a filler and a disintegrating agent into a mixer, and premixing;
(4) fluidized bed granulation: adding the premixed materials into a fluidized bed, and adding an adhesive aqueous solution for fluidized bed granulation;
(5) and (3) drying: drying by a fluidized bed, and finishing drying when the moisture of the material is less than 2%;
(6) total mixing: transferring the dried material to a mixer, adding a lubricant, and completing the total mixing to obtain the premix of the first aspect of the invention;
in another preferred embodiment, the stabilizer is selected from the group consisting of: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising or consisting of a premix according to the invention.
In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral formulation.
In another preferred embodiment, the oral preparation comprises tablets and capsules.
In another preferred embodiment, the composition is prepared by direct compression or capsule filling of the premix.
In a fourth aspect of the invention, there is provided a use of the premix of the invention for the preparation of a medicament for:
(a) inhibiting 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, and idiopathic thrombocytopenic purpura.
In another preferred embodiment, the gastric acid related disease comprises erosive esophagitis.
In another preferred embodiment, the medicament is for inhibiting helicobacter pylori.
In a fifth aspect of the invention, there is provided a method of treatment comprising the steps of: administering a pre-mix according to the first aspect of the invention or a pharmaceutical composition according to the third aspect of the invention to a patient in need of treatment.
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 have unexpectedly found that a premix comprising 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid and an acid stabilizer which provides an acidic environment, and a pharmaceutically acceptable excipient solves the problem of degradation of the active ingredient of the present invention, and significantly improves the storage stability of the active ingredient. Experiments show that the maximum increase in monohybrid and total hybrid of the premix according to the invention is significantly reduced compared to a premix without added stabilizer. In addition, the premix has good powder properties, can be directly compressed into tablets or directly filled into capsules, and is used for pharmaceutical compositions of related diseases. Based on the above findings, the inventors have completed the present invention.
Active ingredient
The term "active ingredient of the present invention", 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:
Figure BDA0002892698650000041
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), i.e. 1.2: 0.8-0.8: 1.2.
stabilizer
As used herein, the stabilizer that provides the acidic environment of the premix is selected from the group consisting of: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof. Preferably fumaric acid, citric acid, tartaric acid, or a combination thereof.
The weight ratio of the active ingredient to the stabilizer is 5:1-0.5: 1.
In another preferred embodiment, the weight ratio of components (A) and (B) is from 4:1 to 1:1, more preferably from 3:1 to 1: 1.
In another preferred embodiment, the stabilizer is present in the premix in an amount of 3 to 20 wt% based on the total mass of the premix.
Pharmaceutically acceptable excipients
As used herein, the term "pharmaceutically acceptable excipient" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of blending with and between the premixes of the invention without significantly reducing the efficacy of the premix.
Excipients for a pre-mix for tableting or capsule filling generally include (but are not limited to): a filler, glidant, disintegrant, binder, lubricant, or combination thereof;
wherein the filler is selected from the group consisting of: microcrystalline cellulose, mannitol, sorbitol, trehalose, betacyclodextrin, dibasic calcium phosphate, starch, pregelatinized starch, or a combination thereof;
the glidant is selected from the group consisting of: talc powder, aerosil, or a combination thereof;
the disintegrant is selected from the group consisting of: dry starch, sodium carboxymethyl starch, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, or combinations thereof;
the binder is selected from the group consisting of: starch slurry, cellulose derivatives, povidone, gelatin, polyethylene glycol, or combinations thereof;
the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol, or combinations thereof.
Premix
As used herein, the term "Premix (Premix)" refers to a mixture formed by mixing an active ingredient with one or more accessory ingredients. Generally, the active and adjunct ingredients are highly mixed in the premix and thus can be used to improve certain properties of the active ingredient, such as solubility, stability, and the like. Typically, the premix is a granular or powdered mixture.
As used herein, the term "premix of the present invention" refers to a premix containing the active ingredients of the present invention and a specific stabilizer.
Typically, the premixes of the invention comprise:
(A) 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid as an active ingredient in the present invention;
(B) a stabilizer; and
(C) optionally a pharmaceutically acceptable excipient;
wherein the stabilizer is selected from the following group: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof;
(A) and (B) in a weight ratio of 5:1 to 0.5: 1.
Preferably, in the premix, the contents of components (A), (B) and (C) are each independently from 1 to 20 wt.%, from 3 to 20 wt.% and from 50 to 90 wt.%, based on the total mass of the premix.
Preferably, the weight ratio of components (A) and (B) is from 4:1 to 1:1, more preferably from 3:1 to 1: 1.
Pharmaceutical composition
Since 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid has a strong and lasting effect of inhibiting gastric acid secretion, the pharmaceutical composition containing the premix of the present invention has a significant therapeutic effect on erosive esophagitis, gastric ulcer, duodenal ulcer, reflux esophagitis, non-steroidal anti-inflammatory drug-induced ARDS, gastric mucosa-associated lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura, etc.
The pharmaceutical composition of the present invention contains the premix of the present invention in a safe and effective amount range, comprising the active ingredient of the present invention and an acid stabilizer that provides an acidic environment, and pharmaceutically acceptable excipients. Wherein "safe and effective amount" means: the amount of premix is sufficient to significantly improve the condition without causing serious side effects. Typically, the dosage of the pharmaceutical composition is 50-300mg per dose, more preferably, 100-200mg of the premix/dose of the invention. Preferably, said "dose" is a capsule or tablet.
The mode of administration of the pharmaceutical composition of the present invention is mainly by oral administration.
Solid dosage forms for oral administration include capsules and tablets. The premix can be directly compressed into tablet, or filled into capsule to make into capsule. Capsules can be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the premix in such capsules may be released in a delayed manner in a certain part of the alimentary tract. Examples of embedding components which can be used are polymeric substances and wax-like substances.
The pharmaceutical compositions of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the premix of the present invention is administered to a mammal (e.g., human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically considered effective dose, and for a human having a body weight of 60kg, the daily dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Preparation method
The premix of the present invention can be prepared by the following method, however, the conditions of the method, such as excipients, amounts of the respective ingredients, preparation temperature, time required for preparation, and the like, are not limited to the following explanation. The premixes of the invention may also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, such combinations being readily performed by those skilled in the art to which the invention pertains.
Specifically, the method comprises the steps of:
pretreating raw materials and auxiliary materials: sieving 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid through a 40 mesh sieve;
preparing an adhesive: preparing an adhesive aqueous solution with a certain mass concentration;
premixing: adding the active ingredients, the excipient and the stabilizer in the prescription amount into a mixer for premixing;
fluidized bed granulation: adding the premixed materials into a fluidized bed, and then adding an adhesive to carry out fluidized bed granulation;
and (3) drying: drying by a fluidized bed, and finishing drying when the moisture of the material is less than 2%;
total mixing: transferring the dried material to a mixer, adding a lubricant according to the prescription amount, and finishing the total mixing to obtain a 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid premix;
tableting and/or capsule filling: the premix may be directly tabletted or capsule filled.
Detection method
According to the high performance liquid chromatography (Chinese pharmacopoeia 2015 edition four parts general rules 0512) test, octadecylsilane chemically bonded silica is used as a filler (Waters Symmetry C18 column, 250 x 4.6mm, 5 μm or chromatographic column with equivalent efficiency); 0.02mol/L dipotassium hydrogen phosphate solution (pH is adjusted to 2.5 by phosphoric acid) is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is carried out according to the following table, the flow rate is 1.0ml per minute, the column temperature is 30 ℃, and the detection wavelength is 210 nm. Precisely measuring 10 μ l of each of the detection solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
If an impurity peak exists in the chromatogram of the detection solution, the content of the impurity is calculated according to a main component self-comparison method multiplied by a correction factor, the peak area of a single impurity is not more than the main peak area (0.20%) of the comparison solution, and the sum of the peak areas of the impurities is not more than 5 times (1.0%) of the main peak area of the comparison solution.
Figure BDA0002892698650000071
Figure BDA0002892698650000081
The main advantages of the present invention include:
1. the invention provides a premix of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, which successfully solves the degradation problem and remarkably improves the storage stability after a stabilizer is added. In addition, the premix has good powder properties, can be directly compressed into tablets or directly filled into capsules to obtain the pharmaceutical composition, and is suitable for commercial production.
2. The invention provides a preparation method of the premix.
The invention is further described 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. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
EXAMPLE 1 preparation of premix No.1
Premix No.1 was prepared according to formulation 1:
Figure BDA0002892698650000082
Figure BDA0002892698650000091
the preparation method comprises the following steps:
the prescribed amount of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, microcrystalline cellulose, mannitol, aerosil, croscarmellose sodium and tartaric acid, which were initially sieved (40 mesh sieve), were weighed and premixed in a mixer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material was then granulated with 6% povidone K30 aqueous solution in the fluid bed and dried until the moisture content of the material was less than 2%. And then transferring to a mixer, and adding the magnesium stearate with the prescribed amount for total mixing to obtain the premix.
EXAMPLE 2 preparation of premix No.2
Premix No.2 was prepared according to formulation 2:
Figure BDA0002892698650000092
the preparation method comprises the following steps:
the prescribed amount of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, microcrystalline cellulose, mannitol, aerosil, croscarmellose sodium and fumaric acid, which were initially sieved (40 mesh sieve), were weighed out and premixed in a mixer as a stabilizer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material was then granulated with 6% povidone K30 aqueous solution in the fluid bed and dried until the moisture content of the material was less than 2%. And then transferring the mixture to a mixer, and adding the magnesium stearate with the prescribed amount to the mixer for total mixing to obtain the premix.
Example 3 preparation of premix No.3
Premix No.3 was prepared according to formulation 3:
Figure BDA0002892698650000101
the preparation method comprises the following steps:
the prescribed amount of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid which is primarily sieved (40 mesh sieve), microcrystalline cellulose, mannitol, aerosil, croscarmellose sodium and citric acid are weighed as stabilizers and premixed in a mixer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material was then granulated with 6% povidone K30 aqueous solution in the fluid bed and dried until the moisture content of the material was less than 2%. And then transferring to a mixer, and adding the magnesium stearate with the prescribed amount for total mixing to obtain the premix.
Example 4 preparation of premix No.4
Premix No.4 was prepared according to formulation 4:
Figure BDA0002892698650000102
Figure BDA0002892698650000111
the preparation method comprises the following steps:
weighing 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, microcrystalline cellulose, mannitol, superfine silica gel powder and croscarmellose sodium which are screened primarily (40-mesh screen) according to the prescription amount, adding three stabilizing agents such as tartaric acid, fumaric acid and citric acid, and premixing in a mixer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material and 6% povidone K30 aqueous solution were then added together to the fluid bed for granulation and drying until the moisture of the material was less than 2%. And then transferring the mixture to a mixer, and adding the magnesium stearate with the prescribed amount for total mixing to obtain the premix.
Comparative example 1 preparation of premix No.5
Premix No.5 was prepared according to formulation 5:
Figure BDA0002892698650000112
Figure BDA0002892698650000121
the preparation method comprises the following steps:
weighing 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid which is preliminarily screened (40-mesh screen) according to the prescription amount, microcrystalline cellulose, mannitol, aerosil and croscarmellose sodium, and premixing in a mixer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material was then granulated with 6% povidone K30 aqueous solution in the fluid bed and dried until the moisture content of the material was less than 2%. And then transferring to a mixer, and adding the magnesium stearate with the prescribed amount for total mixing to obtain the premix.
Comparative example 2 preparation of premix No.6
Premix No.6 was prepared according to formulation 6:
Figure BDA0002892698650000122
the preparation method comprises the following steps:
weighing 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid which is preliminarily screened (40-mesh screen) according to the prescription amount, microcrystalline cellulose, mannitol, aerosil and croscarmellose sodium, and premixing in a mixer. Weighing 6mg of povidone K30, and adding water to prepare povidone K30 water solution with the mass concentration of 6%. The pre-blended material was then granulated with 6% povidone K30 aqueous solution in the fluid bed and dried until the moisture content of the material was less than 2%. And then transferring to a mixer, and adding the magnesium stearate with the prescribed amount to the mixer for total mixing to obtain the premix.
Example 5
Stability test
The premixes prepared in examples 1 to 4 and comparative examples 1 to 2 were each prepared as an aqueous solution (5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid aqueous solution having a final concentration of 1 mg/ml), left at 60 ℃ for 10 days to accelerate degradation, and the substances involved were measured, and the amount of the increase in impurities was used as a quality evaluation of the product.
Figure BDA0002892698650000131
And (4) conclusion:
1. the stabilizer-added premixes prepared according to the invention are very stable.
2. Compared with the premix without the added stabilizer, the premix provided by the invention has the advantages that the maximum single impurity and total impurity increment is greatly reduced, the impurity generation is reduced, and the medicine safety is improved.
All documents mentioned in this application are incorporated by reference in 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 (10)

1. A premix of a potassium competitive acid retarder comprising:
(A) 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid as an active ingredient in the present invention;
(B) a stabilizer; and
(C) optionally a pharmaceutically acceptable excipient;
wherein the stabilizer is selected from the group consisting of: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof;
(A) and (B) in a weight ratio of 5:1 to 0.5: 1.
2. The premix according to claim 1, wherein the stabilizer of the premix is selected from the group consisting of: fumaric acid, citric acid, tartaric acid, or combinations thereof.
3. The premix of claim 1, wherein the excipients in the premix comprise: a filler, glidant, disintegrant, binder, lubricant, or combination thereof;
wherein the filler is selected from the group consisting of: microcrystalline cellulose, mannitol, sorbitol, trehalose, betacyclodextrin, dibasic calcium phosphate, starch, pregelatinized starch, or a combination thereof;
the glidant is selected from the group consisting of: talc powder, aerosil, or a combination thereof;
the disintegrant is selected from the group consisting of: dry starch, sodium carboxymethyl starch, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, or combinations thereof;
the binder is selected from the group consisting of: starch slurry, cellulose derivatives, povidone, gelatin, polyethylene glycol, or combinations thereof;
the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol, or combinations thereof.
4. The premix according to claim 3, wherein the filler content in the excipient is 40 to 90 wt%; the content of the flow aid is 0.5-3 wt%; the content of the disintegrant is 2-6 wt%; the content of the adhesive is 3-10 wt%; the lubricant is present in an amount of 0.5 to 3 wt.%, based on the total weight of the premix.
5. The premix of claim 1, wherein the water content of the premix is from 0.5 to 5 wt%, based on the total weight of the premix.
6. The premix of claim 1, wherein the premix is prepared by a process comprising the steps of:
(1) pretreating raw materials and auxiliary materials: sieving 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid through a 40 mesh sieve;
(2) preparing an adhesive: preparing an adhesive aqueous solution;
(3) premixing: adding 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine-L-pyroglutamic acid, a stabilizer, a filler and a disintegrating agent into a mixer, and premixing;
(4) fluidized bed granulation: adding the premixed materials into a fluidized bed, and then adding an adhesive aqueous solution for fluidized bed granulation;
(5) and (3) drying: drying by a fluidized bed, and finishing drying when the moisture of the material is less than 2%;
(6) total mixing: transferring the dried materials into a mixer, adding a lubricant, and completing total mixing to obtain the premix of claim 1;
the stabilizer is selected from the group consisting of: fumaric acid, pyroglutamic acid, citric acid, tartaric acid, succinic acid, malic acid, or combinations thereof.
7. A pharmaceutical composition comprising or consisting of the premix of claim 1.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is prepared by direct compression or capsule filling of the premix of claim 1.
9. Use of a premix according to claim 1 for the preparation of a medicament for (a) inhibiting 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, and idiopathic thrombocytopenic purpura.
10. A method of treatment, comprising the steps of: administering the premix of claim 1 or the pharmaceutical composition of claim 7 to a patient in need of treatment.
CN202110031884.7A 2021-01-11 2021-01-11 Premix of potassium ion competitive acid retarder and preparation thereof Pending CN114762687A (en)

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