CN106924179B - Liquid preparation containing Vonoprazan fumarate and preparation method thereof - Google Patents

Liquid preparation containing Vonoprazan fumarate and preparation method thereof Download PDF

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CN106924179B
CN106924179B CN201511016558.XA CN201511016558A CN106924179B CN 106924179 B CN106924179 B CN 106924179B CN 201511016558 A CN201511016558 A CN 201511016558A CN 106924179 B CN106924179 B CN 106924179B
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vonoprazan fumarate
liquid preparation
cyclodextrin
beta
acid
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CN106924179A (en
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柯潇
郑强
秦应飞
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Chengdu Kanghong Pharmaceutical Group Co ltd
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    • 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
    • A61K9/08—Solutions
    • 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
    • A61K47/16—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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

The invention discloses a liquid preparation containing vonoprazan fumarate and a preparation method thereof. The vonoprazan fumarate in the liquid preparation containing vonoprazan fumarate is high in solubility, good in stability and less in generated degradation impurities, and can be prepared into small-volume injection easily, the dosage requirement can be met by using a small volume, the use of a packaging material can be reduced, and the packaging and the transportation are facilitated.

Description

Liquid preparation containing Vonoprazan fumarate and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a liquid preparation containing vonoprazan fumarate and a preparation method thereof.
Background
The chemical name of the vonoprazan fumarate is- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine, and the molecular formula is C17H16FN3O2S.C4H4O4The structural formula is as follows:
Figure BDA0000894312700000011
vonoprazan fumarate (TAK-438) belongs to a new class of inhibitors of potassium ion (K +) competitive acid blockers (p-CAB), can stop the secretion of gastric acid in advance by inhibiting the combination of K + on H + -K + -ATP enzyme (proton pump) in the last step of gastric acid secretion of gastric parietal cells, and has strong and durable inhibition effect on gastric acid secretion.
While vonoprazan fumarate is currently marketed as a tablet, research data on vonoprazan fumarate, which is submitted by the national institute of pharmaceutical and medical devices (pMDA) in wutian, japan, show that vonoprazan fumarate is poorly soluble in acidic aqueous solutions, is easily reactive with organic acids in acids, and is also unstable in neutral or alkaline environments. Furthermore, there is a document (CN104582687A) that further discloses that when an organic acid salified with voronoi is released into a liquid, it will undergo covalent reaction with a secondary amino group in the structure of voronoi to give an adduct in the form of an analogue. CN104582687A provides a stable liquid formulation, in which the stability of the liquid formulation is improved by adding metal halide and adjusting the pH range to 3.0-5.0, but this method only obtains the maximum solubility of vonoprazan fumarate in the liquid formulation to be about 1-2 mg/ml.
Disclosure of Invention
In order to solve the technical problems of low solubility, poor stability and the like of a liquid preparation containing the vonoprazan fumarate, the invention provides the liquid preparation containing the vonoprazan fumarate, which has high solubility, good stability and simple preparation process, a preparation method thereof and the like. Wherein the liquid preparation containing the vonoprazan fumarate contains beta-cyclodextrin and derivatives thereof and amino acid.
In the liquid preparation containing vonoprazan fumarate, the molar mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 3.5: 1-0.5: 1; preferably 2:1 to 1: 1.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the vonoprazan fumarate in the liquid preparation is 0.1-120 mg/ml; preferably 1 to 100mg/ml, more preferably 10 to 20 mg/ml.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the beta-cyclodextrin and the derivative thereof in the liquid preparation is 1-400 mg/ml; preferably 20 to 200mg/ml, more preferably 40 to 100 mg/ml.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the amino acid in the liquid preparation is 1-200 mg/ml; preferably 12 to 100mg/ml, and more preferably 24 to 60 mg/ml.
In the above liquid preparation containing vonoprazan fumarate, the pH of the liquid preparation is 3.0 to 8.0, preferably 4.0 to 7.0, and more preferably 5.0 to 6.0.
The invention discloses a liquid preparation containing Vonoprazan fumarate, which is found in practical experiments, after the mass ratio of beta-cyclodextrin and derivatives thereof to amino acid is controlled, when the beta-cyclodextrin and the derivatives thereof are one or more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, methyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and 2, 6-dimethoxy-beta-cyclodextrin, the solubility of Vonoprazan can be effectively increased, and the stability of Vonoprazan can be improved, wherein one or two or even more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin can be better combined, when the sulfobutyl ether-beta-cyclodextrin is used, the effect is better. The liquid preparation containing the vonoprazan fumarate has better solubility and stability when the amino acid is one or more of arginine, lysine, histidine and aspartic acid, and has better effect when the amino acid is arginine.
The liquid preparation containing the vonoprazan fumarate can also contain a pH regulator, when the pH regulator is one or more of tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, sulfuric acid, hydrochloric acid and acetic acid, the solubility is increased and the stability is greatly improved, the effect is better for one or more of citric acid, hydrochloric acid and fumaric acid, and the effect is best for one or two of citric acid and hydrochloric acid.
In the liquid preparation containing the vonoprazan fumarate, a flavoring agent can be optionally added for improving the taste; the flavoring agent can be one or more selected from acesulfame potassium, sucralose, aspartame, stevioside, menthol, orange taste bitter masking agent, mint essence, etc.; preferably, one or both of sucralose and aspartame are used, and sucralose is more preferred.
The invention also provides a preparation method of the liquid preparation containing the vonoprazan fumarate, which comprises the following steps:
completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value with a pH regulator to obtain the compound.
The liquid preparation containing the vonoprazan fumarate can also be prepared into a freeze-dried preparation, and the invention also provides a method for preparing the liquid preparation containing the vonoprazan fumarate into a freeze-dried preparation, which comprises the following steps:
completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value by using a pH regulator; subpackaging the liquid in penicillin bottles, freeze-drying to obtain powder, and sealing for storage; or directly freeze drying the liquid, packaging in penicillin bottle, and sealing for storage.
Compared with the prior art, the liquid preparation containing the vonoprazan fumarate provided by the invention has the following advantages:
1. the liquid preparation containing the vonoprazan fumarate provided by the invention has the advantages of high solubility and good stability.
2. The liquid preparation containing the vonoprazan fumarate provided by the invention is easy to prepare into a small-volume injection, the dosage requirement can be met by using a small volume, the use of a packaging material can be reduced, and the packaging and the transportation are convenient.
3. The liquid preparation containing the vonoprazan fumarate provided by the invention can be used for injection, can be stably stored for a long time under the condition of near-neutral pH, and can obtain a satisfactory injection effect because the preparation is close to the pH value of a human body.
4. The liquid preparation containing the vonoprazan fumarate provided by the invention can be used for oral administration, has no sour and astringent taste, and can improve the compliance of patients in taking medicines.
5. The liquid preparation containing the vonoprazan fumarate provided by the invention is reasonable in formula and preparation process, low in manufacturing cost and suitable for industrial production.
Detailed Description
The following detailed description of specific embodiments of the present invention is provided to illustrate and explain the present invention and to be understood not to limit the present invention.
In the embodiment or the specific embodiment of the invention, the detection method and the evaluation indexes of the stability, the taste and the content of the liquid preparation are as follows:
1. method for detecting stability and content of medicine
The system comprises the following steps: thermofeisher ultitime 3000
A detector: ultraviolet absorption spectrophotometer
Measuring wavelength: 254nm
A chromatographic column: inertsil ODS-Sp C18, 5 μm, 4.6 mm. times.250 mm
Column temperature: constant temperature of 30 DEG C
Mobile phase A: 100% methanol
Mobile phase B: 0.01mol/L KH2pO4，pH＝2.5
Flow rate: 1.0ml/min
Wherein the gradient elution conditions are as follows:
time (min) Mobile phase A (%) Mobile phase B (%)
0 30 70
3 30 70
20 85 15
26 85 15
28 30 70
2. Taste detection and evaluation
The taste of the oral liquid preparation was evaluated by 3 subjects, and the number of no bitterness, slight bitterness, bitterness and extreme bitterness was used as evaluation indexes, and finally the maximum index number was used as the taste of the granule.
In an embodiment or specific embodiment of the present invention, the drugs, reagents and instruments used are as follows:
vonoprazan fumarate (Kyoho pharmaceutical group Co., Ltd.); arginine (Tianjin Tianan pharmaceutical Co., Ltd.); sodium hydroxide (metropolis chemical reagent plant); disodium hydrogen phosphate (Jiuxiang pharmaceutical Co., Ltd., Hunan); beta-cyclodextrin (roguett); hydroxypropyl-beta-cyclodextrin (Chengmeisek science and technology, Inc.); sulfobutyl ether-beta-cyclodextrin (Zibo Qianji Biotech, Inc.); citric acid (lake nan Er kang pharmaceuticals GmbH); fumaric acid (lake nan Er kang pharmaceuticals GmbH); hydrochloric acid (Chengdu Kelong chemical reagent factory); acetic acid (Tianjin, Kemiou Chemicals, Inc.); tartaric acid (research and development center for chemical reagent engineering in Guangdong province); malic acid (Chengmeiske pharmaceutical science and technology, Inc.); lactic acid (metropolis chemical reagent plant); fumaric acid (Hunan Er kang pharmaceutical Co., Ltd.)
High performance liquid chromatography (thermolfisher ultitime 3000); an ultrasonic cleaner (Kunshan ultrasonic instruments Co., Ltd.); a freeze dryer (Beijing Bilang laboratory instruments Co., Ltd.).
3. Influence of different auxiliary material combinations on solubility and stability of Vonoprazan fumarate
The experimental research finds that the solubility of the vonoprazan fumarate in water is about 1mg/ml, in order to remarkably improve the solubility and stability of the vonoprazan fumarate in water, the applicant adopts different auxiliary materials and the vonoprazan fumarate to carry out combined research, and accidentally finds that the solubility and stability of the vonoprazan fumarate can be greatly improved after the combination of the beta-cyclodextrin and the derivatives thereof with the amino acid, and particularly, the combination of arginine, the beta-cyclodextrin and the derivatives thereof can provide a liquid preparation containing the vonoprazan fumarate with excellent stability and solubility.
The preparation method comprises the following steps: completely dissolving a prescribed amount of beta-cyclodextrin and derivatives thereof in a prescribed amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding other components into the solution B, adjusting the pH value by using a proper amount of pH regulator, taking 3ml of sample, putting the sample into a clean penicillin bottle, sealing, storing in the dark, and carrying out accelerated investigation at the temperature of 60 ℃.
TABLE 1 prescription screening of different combinations of adjuvants
Figure BDA0000894312700000061
Figure BDA0000894312700000071
The specific experimental results are shown in Table 2
Table 2 results of the study on the solubilization effect and stability of Vonoprazan fumarate by different auxiliary material combinations
Prescription Solubility in water 7-day accelerated addition of simple impurity Accelerating for 14 days to increase single impurity Appearance phenomenon
Prescription 1 4.7mg/ml 0.07％ 0.14％ Partially dissolved
Prescription 2 4.8mg/ml 0.08％ 0.13％ Partially dissolved
Prescription 3 5.1mg/ml 0.06％ 0.11％ Partially dissolved
Prescription 4 3.5mg/ml 0.09％ 0.17％ Partially dissolved
Prescription 5 6.5mg/ml 0.07％ 0.15％ Partially dissolved
Prescription 6 8.5mg/ml 0.21％ 0.34％ Partially dissolved
Prescription 7 6.9mg/ml 0.15％ 0.26％ Partially dissolved
Prescription 8 20mg/ml 0.05％ 0.10％ Completely dissolve
Prescription 9 20mg/ml 0.02％ 0.05％ Completely dissolve
Prescription 10 20mg/ml 0.04％ 0.09％ Completely dissolve
Prescription 11 20mg/ml 0.07％ 0.12％ Completely dissolve
Prescription 12 20mg/ml 0.03％ 0.07％ Completely dissolve
Prescription 13 20mg/ml 0.06％ 0.11％ Completely dissolve
Accelerated tests were performed at 60 ℃.
The solubility of the Vonoprazan cannot be obviously improved by singly using the beta cyclodextrin or the derivative or the amino acid thereof, and the pH value is adjusted by adding acid and alkali on the basis of adding the cyclodextrin, so that the solubility is not obviously improved, and the stability is poor; if arginine is added on the basis of adding cyclodextrin, the solubility can be obviously improved, and the stability of the medicament is also obviously improved.
4. Influence of the amount of auxiliary materials
The preparation method comprises the following steps: completely dissolving the hydroxypropyl-beta-cyclodextrin with the prescription amount in 1ml of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding arginine into the solution B, adjusting the pH value to 3 by using a proper amount of hydrochloric acid, placing a sample with the maximum solubility of the Vonoprazan under each formula into a clean penicillin bottle, sealing, storing in a dark place, and performing accelerated investigation at the temperature of 60 ℃. The specific prescription and the test results are shown in Table 3.
Table 3 comparison of the amounts of cyclodextrin and amino acid used to determine the solubility of voronozan fumarate and its stability
Figure BDA0000894312700000081
Figure BDA0000894312700000091
5. Influence of different amino acids on stability and solubility of vonoprazan fumarate-containing liquid preparations table 4 influence of different amino acids on stability and solubility of vonoprazan fumarate-containing liquid preparations
Figure BDA0000894312700000092
The preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding amino acid in the formula amount into the solution B, adding a proper amount of citric acid or hydrochloric acid to adjust the pH value, taking 3ml of sample, putting the sample into a clean penicillin bottle, sealing, storing in the dark, and carrying out accelerated investigation at the temperature of 60 ℃. The specific test results are shown in Table 5.
TABLE 5 influence of different amino acids on solubility of Vonoprazan fumarate and its stability results
Prescription 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Prescription 26 0.05％ 0.09％ 10mg/ml
Prescription 27 0.08％ 0.18％ 10mg/ml
Prescription 28 0.07％ 0.10％ 10mg/ml
Prescription 29 0.05％ 0.12％ 10mg/ml
Prescription 30 0.09％ 0.21％ 10mg/ml
Prescription 31 0.04％ 0.07％ 10mg/ml
Prescription 32 0.07％ 0.14％ 10mg/ml
Prescription 33 0.05％ 0.10％ 10mg/ml
Prescription 34 0.04％ 0.07％ 10mg/ml
Prescription 35 0.08％ 0.17％ 10mg/ml
6. Effect of different pH conditions on stability
The prescription composition is as follows:
Figure BDA0000894312700000101
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation, wherein the detection results are shown in Table 6.
TABLE 6 Effect on sample stability at different pH values
Prescription pH value 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Prescription 36 2 0.09％ 0.21％ 10mg/ml
Prescription 37 3 0.03％ 0.15％ 10mg/ml
Prescription 38 4 0.02％ 0.09％ 10mg/ml
Prescription 39 5 0.02％ 0.04％ 10mg/ml
Prescription 40 6 0.01％ 0.07％ 10mg/ml
Prescription 41 7 0.06％ 0.12％ 10mg/ml
Prescription 42 8 0.06％ 0.18％ 10mg/ml
Prescription 43 9 0.21％ 0.34％ 10mg/ml
As can be seen from the results of the measurements in Table 6, the formulations of the present invention all have satisfactory solubility and good stability at a pH of 3-8.
7. Comparative examples
Comparative example 1
The prescription composition is as follows:
Figure BDA0000894312700000111
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of hydrochloric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 2
The prescription composition is as follows:
Figure BDA0000894312700000121
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of glucuronic acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 3
The prescription composition is as follows:
Figure BDA0000894312700000131
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of hydrochloric acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 4
The prescription composition is as follows:
Figure BDA0000894312700000132
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine in a prescription amount into the solution B, adding a proper amount of citric acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample in a clean penicillin bottle to obtain powder, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 5
The prescription composition is as follows:
Figure BDA0000894312700000141
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of phosphoric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation.
TABLE 7 test results of comparative examples 1 to 5
Figure BDA0000894312700000142
Accelerated tests were performed at 60 ℃.
Example 1
The prescription composition is as follows:
Figure BDA0000894312700000151
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, uniformly mixing, taking a sample of 3ml in a clean penicillin bottle, sealing and keeping in the dark at 60 ℃ for accelerated investigation. The results are shown in Table 8.
Table 8 test results of the liquid formulation in example 1
Examples pH value 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Example 1 7 0.08％ 0.15％ 120mg/ml
Example 2
The prescription composition is as follows:
Figure BDA0000894312700000152
Figure BDA0000894312700000161
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding lysine in a prescribed amount into the solution B, adding an appropriate amount of citric acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing, keeping in the dark and storing at 60 ℃ for accelerated investigation. The results are shown in Table 9.
Table 9 test results of the liquid formulation in example 2
Examples pH value 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Example 2 7 0.01％ 0.04％ 1mg/ml
Example 3
The prescription composition is as follows:
Figure BDA0000894312700000162
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine in the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample in a washed penicillin bottle, sealing and storing in a dark place at 60 ℃ for accelerated investigation. The results are shown in Table 10.
Table 10 test results of the liquid formulation in example 3
Examples pH value 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Example 3 7 0.02％ 0.06％ 0.1mg/ml
Example 4
The prescription composition is as follows:
Figure BDA0000894312700000171
the preparation method comprises the following steps:
completely dissolving the beta-cyclodextrin in the prescription amount into the water in the prescription amount to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of malic acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing and storing in a dark place at 60 ℃ for accelerated investigation. The results are shown in Table 11.
Table 11 test results of the liquid formulation in example 4
Examples pH value 7 days of acceleration of newly added single impurity Accelerating the growth of new single impurity for 14 days Content (wt.)
Example 4 7 0.05％ 0.14％ 20mg/ml
Example 5
The prescription composition is as follows:
Figure BDA0000894312700000181
the preparation method comprises the following steps:
completely dissolving the beta-cyclodextrin in the prescription amount into the water in the prescription amount to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and the sucralose into the solution B according to the prescription amount, uniformly mixing, adding a proper amount of malic acid to adjust the pH value, taking 3ml of sample, placing the sample in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation. The results are shown in Table 12.
Table 12 test results of the liquid formulation in example 5
Figure BDA0000894312700000182
Example 6
The prescription composition is as follows:
Figure BDA0000894312700000183
Figure BDA0000894312700000191
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and the aspartame into the solution B according to the prescription amount, uniformly mixing, adding a proper amount of tartaric acid to adjust the pH value, taking 3ml of sample, placing the sample into a clean penicillin bottle, sealing and keeping away from light, and performing accelerated investigation at the temperature of 60 ℃. The results are shown in Table 13.
Table 13 test results of the liquid formulation in example 6
Figure BDA0000894312700000192
Example 7
The prescription composition is as follows:
Figure BDA0000894312700000193
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 14.
Table 14 test results of the liquid formulation in example 7
Figure BDA0000894312700000201
Example 8
The prescription composition is as follows:
Figure BDA0000894312700000202
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 15.
TABLE 15 test results of the liquid formulation in example 8
Figure BDA0000894312700000211
Example 9
The prescription composition is as follows:
Figure BDA0000894312700000212
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and stevioside into the solution B according to the prescription amount, mixing uniformly, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample into a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation. The results are shown in Table 16.
Table 16 test results of the liquid formulation in example 9
Figure BDA0000894312700000213
Example 10
The prescription composition is as follows:
Figure BDA0000894312700000221
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample, freeze-drying the sample in a clean penicillin bottle to obtain powder, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 17.
TABLE 17 test results of the liquid formulation in example 10
Figure BDA0000894312700000222
Example 11
The prescription composition is as follows:
Figure BDA0000894312700000223
Figure BDA0000894312700000231
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 18.
Table 18 test results of the liquid formulation in example 11
Figure BDA0000894312700000232

Claims (19)

1. The liquid preparation containing vonoprazan fumarate is characterized by containing beta-cyclodextrin and derivatives thereof and amino acid, wherein the amino acid is selected from arginine, the mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 3.5-0.5: 1, the pH value of the liquid preparation is 3.0-8.0, and the beta-cyclodextrin and the derivatives thereof are selected from one or more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin.
2. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 2: 1-1: 1.
3. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the concentration of vonoprazan fumarate in the liquid preparation is 0.1-120 mg/ml.
4. The liquid preparation containing vonoprazan fumarate according to claim 3, wherein the concentration of vonoprazan fumarate in the liquid preparation is 1-100 mg/ml.
5. The liquid preparation containing vonoprazan fumarate according to claim 4, wherein the concentration of the vonoprazan fumarate in the liquid preparation is 10-20 mg/ml.
6. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 1-400 mg/ml.
7. The liquid preparation containing vonoprazan fumarate according to claim 6, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 20-200 mg/ml.
8. The liquid preparation containing vonoprazan fumarate according to claim 7, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 40-100 mg/ml.
9. The liquid voronoazan fumarate-containing formulation according to claim 8, wherein the β -cyclodextrin and its derivatives are selected from sulfobutyl ether- β -cyclodextrin.
10. The liquid formulation of vonoprazan fumarate-containing according to claim 1, wherein a pH adjusting agent is contained in the liquid formulation.
11. The liquid preparation containing vonoprazan fumarate according to claim 10, wherein the pH adjusting agent is one or more selected from tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, sulfuric acid, hydrochloric acid, and acetic acid.
12. The liquid preparation containing vonoprazan fumarate according to claim 11, wherein the pH adjusting agent is one or more selected from citric acid, hydrochloric acid and fumaric acid.
13. The liquid preparation containing vonoprazan fumarate according to claim 12, wherein the pH adjusting agent is one or two selected from citric acid and hydrochloric acid.
14. The vonoprazan fumarate-containing liquid formulation according to claim 1, wherein a flavoring agent is contained in the vonoprazan fumarate-containing liquid formulation.
15. The liquid preparation containing vonoprazan fumarate according to claim 14, wherein the flavoring agent is selected from one or more of acesulfame potassium, sucralose, aspartame, stevioside, menthol, orange taste bitter masking agent, and peppermint essence.
16. The liquid preparation containing vonoprazan fumarate according to claim 15, wherein the flavoring agent is one or both of sucralose and aspartame.
17. The liquid formulation of vonoprazan fumarate-containing according to claim 16, wherein the flavoring agent is sucralose.
18. A production method for producing the liquid preparation containing vonoprazan fumarate according to any one of claims 1 to 13, comprising the steps of: completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value with a pH regulator to obtain the compound.
19. The liquid preparation containing vonoprazan fumarate according to any one of claims 1-17, wherein the liquid preparation is prepared as a lyophilized preparation.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1250372A (en) * 1997-03-13 2000-04-12 赫克萨尔股份公司 Stabilization of acid sensitive benzimidazoles with amino acid/cyclodextrin combinations
CN101020059A (en) * 2006-02-15 2007-08-22 中国科学院上海药物研究所 Medicine composition containing docetaxel matter and its prepn process
CN102145001A (en) * 2011-01-24 2011-08-10 山东鲁抗立科药物化学有限公司 Stable aztreonam composition and preparation method thereof
CN102892310A (en) * 2010-03-13 2013-01-23 伊斯顿庞德实验室有限公司 Fat-binding compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1250372A (en) * 1997-03-13 2000-04-12 赫克萨尔股份公司 Stabilization of acid sensitive benzimidazoles with amino acid/cyclodextrin combinations
CN101020059A (en) * 2006-02-15 2007-08-22 中国科学院上海药物研究所 Medicine composition containing docetaxel matter and its prepn process
CN102892310A (en) * 2010-03-13 2013-01-23 伊斯顿庞德实验室有限公司 Fat-binding compositions
CN102145001A (en) * 2011-01-24 2011-08-10 山东鲁抗立科药物化学有限公司 Stable aztreonam composition and preparation method thereof

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