CN117281764A - Fu Nuola raw injection and preparation method thereof - Google Patents

Fu Nuola raw injection and preparation method thereof Download PDF

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Publication number
CN117281764A
CN117281764A CN202210679243.7A CN202210679243A CN117281764A CN 117281764 A CN117281764 A CN 117281764A CN 202210679243 A CN202210679243 A CN 202210679243A CN 117281764 A CN117281764 A CN 117281764A
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injection
voronoi
vonolamine
nuola
sodium
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徐海
黄燚
朱朝清
张娇
林丽洋
沈利
赵栋
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Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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Sichuan Kelun Pharmaceutical Research Institute 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
    • A61K9/0012—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
    • 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
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

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Abstract

The application discloses a vonolamine hydrobromide injection and a preparation method thereof, wherein the injection comprises vonolamine hydrobromide or a crystal form thereof, an osmotic pressure regulator, a pH buffer and water, and the molar ratio of the hydrobromide to the vonolamine hydrobromide in the vonolamine hydrobromide or the crystal form thereof is 1:1. The injection of the invention adopts hydrobromic acid Fu Nuola as an active ingredient, and can obtain the voronoi injection preparation with good product quality and stability by adopting a simple preparation prescription and process, thereby meeting the clinical medication requirement.

Description

Fu Nuola raw injection and preparation method thereof
Technical Field
The invention relates to a voronoi injection and a preparation method thereof.
Background
Fu Nuola fumaric acid, also known as TAK-438, chemical name 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methanamine fumarate, which is a potassium competitive acid retarder, competitively blocks H + -K + ATPase (proton Pump) K + Binding site, inhibited K + For H + -K + Binding of atpase (proton pump) and thus inhibition of gastric acid secretion. The current marketed formulation of vonolamine fumarate is a tablet, and no other formulation has been disclosed. Because the tablet belongs to an oral preparation, the compliance of dysphagia patients, children and old people is poor when the tablet is used for medicine; and for patients with acute gastritis and gastric ulcer needing quick effect, the tablet can not meet the clinical requirement of quick effect, and has important significance for providing treatment options for more patients with medicine requirements and difficult administration of the tablet or curative effect, so that a novel fumaraca drug dosage form, such as an injection, is developed. However, the water solubility of the voronoi fumarate is poor, and it is difficult to meet the requirement of the injection on the drug solubility.
In the prior art, substituted beta-cyclodextrin is generally adopted as a solubilizer to form an inclusion compound with the voronoi fumarate, so that the stability of the preparation is improved, and the injection is prepared. However, whether the release of the fumaric acid Fu Nuola after inclusion can be completed or not can be confirmed, and whether the effective concentration can be achieved or not is not confirmed, meanwhile, beta-cyclodextrin refers to hydroxypropyl beta-cyclodextrin, the maximum dosage of the hydroxypropyl beta-cyclodextrin for intravenous injection or instillation is 0.4% recorded in an FDA inactive substance database, the dosage in the prior art exceeds the safety range in United states pharmacopoeia, and the safety is questioned; therefore, although the prior art application can solve the solubility problem under certain conditions and make the injection preparation possible, the application of the technology has safety and effectiveness problems in practical clinic.
Fumaric acid Fu Nuola is a substance which is slightly soluble in water and is prepared into injection, so that the problem of solubility exists, the problem is unavoidable, the problem of solubility is solved, the adoption of a wrapping method can solve the problem under certain conditions, but the problems of drug action and safety exist, and a reliable and effective clinical preparation is not obtained fundamentally. Therefore, there is a need to further study solid state forms of vonolamine in order to obtain new Fu Nuola salts or crystalline forms suitable for injection with further improved physicochemical properties, which are simple to prepare, easy to control, good in solubility and stability, and therapeutically effective amounts of vonolamine in order to meet more clinical demands.
Disclosure of Invention
In a first aspect, the invention provides a voronoi injection comprising voronoi hydrobromic acid or a crystal form thereof, an osmotic pressure regulator, a pH buffer and water, wherein the molar ratio of the hydrobromic acid to the voronoi hydrobromic acid in the voronoi hydrobromic acid or the crystal form thereof is 1:1.
In some embodiments of the first aspect of the invention, the osmolality adjusting agent is selected from one or more of glucose, sodium chloride, glycerol, phosphate or citrate; preferably, the osmolality adjusting agent is selected from one or more of glucose, sodium chloride or mannitol.
In some embodiments of the first aspect of the present invention, the pH buffer is selected from one or more of phosphate, acetate, citrate, borate, tartrate, boric acid buffer; preferably, the pH buffer is selected from one or more of sodium dihydrogen phosphate, sodium acetate or sodium citrate.
In some embodiments of the first aspect of the invention, the Fu Nuola green injection further comprises a pH adjuster selected from one or more of hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, citrate or phosphate; preferably, the pH regulator is selected from one or two of hydrochloric acid or sodium hydroxide.
In some embodiments of the first aspect of the invention, the Fu Nuola green injection further comprises a metal complexing agent selected from one or more of DETA, citric acid, sodium citrate, tartaric acid or sodium tartrate; preferably, the metal complexing agent is selected from DETA.
In some embodiments of the first aspect of the invention, the pH of the Fu Nuola green injection is from 3.0 to 6.0, preferably from 4.0 to 5.0.
In some embodiments of the first aspect of the invention, the X-ray powder diffraction (XRPD) pattern of the Fu Nuola green crystalline form of hydrobromic acid comprises characteristic peaks at diffraction angles (2θ) at 13.8±0.2°, 15.1±0.2°, 18.3±0.2°, 19.6±0.2°, 21.9±0.2°, 25.2±0.2°, and 25.9±0.2°; preferably, characteristic peaks at diffraction angles (2θ) of 13.8±0.2°, 15.1±0.2°, 15.5±0.2°, 18.3±0.2°, 19.6±0.2°, 21.9±0.2°, 24.1±0.2° and 24.3±0.2°, 25.2±0.2°, 25.9±0.2° and 28.0±0.2° are included; preferably, the characteristic peaks at diffraction angles (2θ) of 11.4±0.2°, 13.8±0.2°, 15.1±0.2°, 15.5±0.2°, 16.5±0.2°, 18.3±0.2°, 19.6±0.2°, 20.8±0.2°, 21.1±0.2°, 21.9±0.2°, 23.0±0.2°, 24.1±0.2°, 24.3±0.2°, 25.2±0.2°, 25.9±0.2°, 26.4±0.2°, 26.8±0.2°, 27.8±0.2°, 28.0±0.2°, 29.5±0.2°, 30.4±0.2°, and 31.3±0.2° areincluded.
In some embodiments of the first aspect of the invention, the XRPD pattern of the Fu Nuola green crystalline form of hydrobromic acid comprises peaks at diffraction angles (2θ) substantially the same as shown in figure 1; preferably, the XRPD pattern of the Fu Nuola green crystalline form of hydrobromic acid is as shown in figure 1.
In some embodiments of the first aspect of the invention, the Fu Nuola green injection is a low volume injection comprising the following components in weight to volume ratios expressed in g/mL:
vonolamine hydrobromide or crystalline forms thereof: 0.1-2% by weight of Vonolamine;
sodium chloride: 0.7-0.9%;
sodium dihydrogen phosphate: 0.1-0.3%;
a proper amount of pH regulator for regulating the pH to 3.0-6.0;
the balance of water for injection.
In some embodiments of the first aspect of the invention, the Fu Nuola green injection is a high volume infusion comprising the following components in weight to volume ratios, expressed in g/mL:
vonolamine hydrobromide or crystalline forms thereof: 0.01-0.2% by weight of Vonolamine;
sodium chloride: 0.7-0.9%;
sodium dihydrogen phosphate: 0.1-0.3%;
a proper amount of pH regulator for regulating the pH to 3.0-6.0;
the balance of water for injection.
A second aspect of the present invention provides a method of preparing a voronoi injection comprising the steps of:
taking water for injection with the preparation amount of 60-80%, heating to 60-80 ℃, sequentially adding the voronoi hydrobromide or the crystal form thereof, the osmotic pressure regulator and the pH buffer, stirring until the voronoi hydrobromide or the crystal form thereof, the osmotic pressure regulator and the pH buffer are completely dissolved, then adding the pH regulator to regulate the pH to 3.0-6.0, and supplementing the water for injection to the full amount; filtering, canning and sterilizing.
In some embodiments of the second aspect of the invention, the filtration is through a 0.45 μm polypropylene filter membrane and a 0.22 μm polyether sulfone filter membrane.
In some embodiments of the second aspect of the invention, the sterilization is at a sterilization temperature of 121 ℃ for 12min.
In a third aspect, the present invention provides the use of a voronoi injection in the manufacture of a medicament for the prevention and/or treatment of erosive esophagitis, gastric ulcers, duodenal ulcers, eradication of helicobacter pylori, and related diseases caused by gastric hyperacidity.
In a fourth aspect, the present invention provides a method for preventing and/or treating erosive esophagitis, gastric ulcer, duodenal ulcer, eradication of helicobacter pylori and related diseases caused by gastric hyperacidity, comprising administering to a subject in need thereof an effective amount of the voronoi injection of the present invention.
The vonolamine injection provided by the invention has the following beneficial effects:
using hydrobromic acid Fu Nuola as the active ingredient, hydrobromic acid voronoi has the following advantages: i) The crystallinity is good, the purity is high, the thermal stability is good, the process safety is high, the operation is simple, the product morphology is a bar-shaped large-grain-size crystal, the post-treatment is simple, and the crystal purity is high; 2) The solubility is good, compared with the crystal form of the fumarate in the prior art, the solubility is 5-10 times higher, and the dissolution speed is high; 3) The hygroscopicity is lower, which is beneficial to the development, storage and transportation of subsequent preparations; the preparation for the voronoi injection with good product quality and stability can be obtained by adopting a simple preparation prescription and process, and the clinical medication requirement is met.
Detailed Description
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, although other unrecited elements or method steps are not necessarily present.
The word "about" as used herein means that those of ordinary skill in the art consider within acceptable standard deviations of the values, such as + -0.05, + -0.1, + -0.2, + -0.3, + -0.5, + -1, + -2, or + -3, etc.
The term "solid form" as used herein includes all solid forms of compound I, e.g. crystalline forms.
The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, which, in contrast to amorphous solid material, results in a characteristic XRPD pattern with well-defined peaks.
The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to an experimentally observed diffraction pattern or parameter, data or value derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).
The term "2θ" as used herein refers to the peak position in degrees (°) based on the settings in the X-ray diffraction experiment, and is typically the unit of abscissa in the diffraction pattern. If the incident beam is diffracted by reflection when it makes an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle 2θ. It should be understood that reference herein to a particular 2θ value for a particular crystalline form is intended to refer to a 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein.
The term "Differential Scanning Calorimeter (DSC) profile" as used herein refers to a curve recorded by a differential scanning calorimeter.
The term "thermogravimetric analysis (TGA) profile" as used herein refers to a curve recorded by a thermogravimetric analyzer.
As used herein, the term "substantially the same" means taking into account representative peak positions and/or intensity variations. For example, for an X-ray diffraction peak, one skilled in the art will appreciate that the peak position (2θ) will show some variation, typically up to 0.1-0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. In addition, one skilled in the art will appreciate that the relative peak intensities will vary due to differences between instruments as well as the degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to those skilled in the art.
Drawings
Fig. 1 is an XRPD pattern of the Fu Nuola green crystalline form of hydrobromic acid.
Figure 2 is a DSC profile of the Fu Nuola as-crystalline form of hydrobromic acid.
Figure 3 is a TGA profile of the Fu Nuola green crystalline form of hydrobromic acid.
Figure 4 is a PLM profile (50-fold) of the Fu Nuola crude crystal form of hydrobromic acid.
Fig. 5 is a DVS profile of different salts of vonolamine.
Detailed Description
The present invention is further illustrated by the following examples, which are only for illustrating the technical scheme of the present invention and are not intended to limit the scope of the present invention, and those skilled in the art can make some insubstantial improvements and modifications, which still fall within the scope of the present invention.
Test instrument information and methods for experiments:
x-ray powder diffraction (XRPD):
using X' Pert3 Powder Diffractometer, the instrument was irradiated with a Cu target and tested using an Absolute scan at room temperature. The detection range is 3.5-40 degrees, the step length is 0.013, the residence time is 50s, and the scanning is performed for 1 time.
The Differential Scanning Calorimetry (DSC) test instrument is: TA DSC 2500;
the thermogravimetric analysis (TGA) test instrument is: METTLER tolio;
the heating rate of both DSC and TGA instruments was 10K/min.
The dynamic moisture sorption (DVS) experimental conditions were as follows:
detection was performed in DMDT mode at 25℃using DVS Intrinsic (SMS).
Nuclear magnetic NMR was measured using a Bruker NMR apparatus, model: BRUKER AVANCE III HD 400MHz; test conditions: solvent DMSO-d6, temperature 23.5 ℃.
The polarization microscope (PLM) detection instrument is: the Nikon Elipse optical microscope was used to observe the morphology of the crystals at 50 Xmagnification.
Preparation example: preparation of Fu Nuola raw crystal form of hydrobromic acid
The prepared vonolamine free base was prepared according to the method of example 5 of patent CN105524046 a, and the purity of the prepared vonolamine free base was 99.55% by HPLC, and the vonolamine free base was used in the following preparation examples.
Preparation example 1:
1.7g of Fu Nuola raw free base is weighed, added into 20mL of methanol and heated to 50 ℃ for dissolution; 714mg of 48% strength by mass aqueous hydrogen bromide solution was weighed, diluted with 20mL of methanol, and then the diluted hydrobromic acid solution was added dropwise to the free base solution at a rate of 2 mL/min. After the dripping is finished, crystallization is not carried out, and crystallization is carried out after natural cooling to room temperature. Collecting solid, washing with 20mL of methanol, drying in an oven at 40 ℃ and under vacuum degree of 0.08Mpa for 7h to obtain white solid, namely Fu Nuola raw crystal form of hydrobromic acid. The XRPD patterns of the assay are shown in fig. 1, and the DSC and TGA patterns are shown in fig. 2 and 3, respectively.
The nuclear magnetic data of the obtained solid product are as follows: 1 H NMR(400MHz,DMSO-d6)δ8.93-8.90(m,3H), 8.58(d,J＝2.07Hz,1H),7.94-7.91(m,1H),7.88(d,J＝1.76Hz,1H),7.68-7.64(m,1H), 7.58-7.52(m,1H),7.28-7.23(m,2H),7.13-7.09(m,1H),6.60(d,J＝1.66Hz,1H),4.05(s, 2H),2.56(s,3H)。
the Br content of the obtained hydrobromic acid Fu Nuola crude crystal form is 18.1% by adopting ion chromatography test; calculated according to the salt forming ratio of 1:1, the theoretical content of Br is 18.7%, so that the molar ratio of hydrobromic acid to voronoi in the obtained hydrobromic acid Fu Nuola raw crystal form is 1:1.
Preparation example 2:
weighing 34g of Fu Nuola raw free alkali, adding into 400ml of acetone, heating to 50 ℃ to dissolve, and naturally cooling to room temperature after dissolving; 14.3g of 48% strength by mass aqueous hydrogen bromide was weighed, diluted with 200mL of methanol and the diluted hydrobromic acid solution was added dropwise to the free base solution at a rate of 10 mL/min. And (3) separating out solids in the dropping process, after crystal growing for 30min after dropping, cooling to 5 ℃ at 0.5 ℃/min, continuing crystal growing for 0.5-1h, and collecting the solids. The filter cake was washed with 400ml of acetone, dried at 30℃in an oven under vacuum of 0.1MPa for 10h to give a white solid. The XRPD pattern, DSC pattern, TGA pattern, br content and the like of the product are basically consistent with those of preparation example 1, which shows that the product is a hydrobromic acid Fu Nuola raw crystal form; the PLM micrograph is shown in FIG. 4.
Preparation example 3:
30g of Fu Nuola raw free base is weighed, added into 250ml of ethyl acetate and heated to 40 ℃ for dissolution; 15.51 g% strength by mass aqueous hydrogen bromide was weighed, diluted with 15mL of methanol, and then the diluted hydrobromic acid solution was added dropwise to the free base solution at a rate of 0.5 mL/min. After the dripping is completed, crystallization is carried out, the solid is collected after the temperature is naturally reduced to room temperature, 200mL of ethyl acetate is used for washing, a 50 ℃ oven is used, the vacuum degree is 0.1Mpa, and the drying is carried out for 2 hours, thus obtaining white solid. The XRPD pattern, DSC pattern, TGA pattern, br content and the like of the sample are basically consistent with those of preparation example 1, which shows that the sample is a Fu Nuola hydrobromic acid crystal form.
Hydrobromic acid Fu Nuola in the following examples was produced as a crystalline form of hydrobromic acid Fu Nuola obtained in production example 3.
Example 1:
the prescription of Fu Nuola raw injection is as follows:
prescription of prescription Dosage of Action
Hydrobromic acid Fu Nuola (calculated as Funula Sheng, hereinafter the same applies) 1.0g Active ingredient
Sodium chloride 0.8g Osmotic pressure regulator
Sodium dihydrogen phosphate 0.1g pH buffering agent
Sodium hydroxide (1 mol/L solution) Proper amount of PH regulator
Dilute hydrochloric acid Proper amount of PH regulator
Water for injection To 100ml Solvent(s)
The preparation method of the Fu Nuola raw injection comprises the following steps:
heating 60-80% of injection water to 60-80 ℃, sequentially adding Fu Nuola raw hydrobromic acid, a osmotic pressure regulator and a pH buffer, stirring until the raw materials are completely dissolved, then adding the pH regulator to regulate the pH to 4.9, and supplementing the injection water to the full amount to obtain a liquid medicine; filtering the medicinal liquid with 0.45 μm polypropylene filter membrane and 0.22 μm polyethersulfone filter membrane, canning, and sterilizing at 121deg.C for 12min.
Stability of the voronoi injection after 30 days at 60 ℃ was examined, and the results are shown in the following table.
N.D represents undetected.
The vonolamine injection in the embodiment has no change in pH and no obvious change in impurities after being placed at 60 ℃ for 30 days, and the quality of the product after being placed is far superior to the standard requirement of medicine impurities, so that the product quality and stability are good.
Example 2:
the prescription and preparation method of Fu Nuola injection are the same as in example 1, except that the pH of the liquid medicine is adjusted to 4.0, 4.5, 5.0, 5.5, 6.0 and 6.5 respectively, and Vonolamine injection samples 1-6 are obtained respectively. Stability of the voronoi injection samples 1 to 6 after 10 days at 60℃was examined, and the results are shown in the following table.
Sample name Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6
pH 4.0 4.5 5.0 5.5 6.0 6.5
YZ2-2(％) 0.035 0.076 0.154 0.334 0.897 2.303
The YZ2-2 impurity in the Fu Nuola injection obviously increases along with the increase of the pH value, particularly the pH value is more than 6, so that the pH value of the Voronoi injection is controlled to be 3.0-6.0, preferably 4.0-5.0.
Example 3:
the preparation and preparation method of example 1 were followed to obtain a voronoi injection, except that the pH of the medicinal solution was adjusted to 4.6, and the medicinal solutions were respectively subjected to the following treatments: non-sterilized (sample 7), sterilized at 121deg.C for 12min (sample 8), sterilized at 121deg.C for 30min (sample 9), and sterilized at 124 deg.C for 12min (sample 10) to obtain Vonolamine injection samples 7-10. The properties of samples 7-10 were examined for voronoi injection, the results of which are shown in the following table.
From the experimental results, the non-sterilization and different sterilization conditions have slight differences in related substances, and the pH and osmotic pressure have no obvious differences. The longer the sterilization time, the slightly increased the related substances; the sterilization temperature has little influence on related substances, which indicates that the product is insensitive to heat and can resist high temperature. According to the sterile preparation guiding principle, under the condition of guaranteeing the quality, the sterilization condition of 121 ℃/12min is selected, so that the preparation quality and the regulation requirement can be met.
Example 4:
the prescription of Fu Nuola raw injection is as follows:
sample of Sample 11 Sample 12 Sample 13
Fu Nuola raw hydrobromic acid 1.0g 1.0g 1.0g
Sodium chloride 0.8g 0.8g 0.8g
Sodium dihydrogen phosphate 0.1g 0.2 0.3
Sodium hydroxide (1 mol/L solution) Proper amount of Proper amount of Proper amount of
Dilute hydrochloric acid Proper amount of Proper amount of Proper amount of
Water for injection To 100ml To 100ml To 100ml
Vonolamine injection was prepared in the same manner as in example 1 except that the pH of the medicinal solution was adjusted to 5.3 (samples 11 and 12) or 5.2 (sample 13) to obtain Vonolamine injection samples 11 to 13. The performance of Fu Nuola green injectants samples 11-13 was examined and the results are shown in the following table.
Sample of Sample 11 Sample 12 Sample 13
YZ2-11(％) 0.002 0.002 0.002
YZ2-2(％) 0.067 0.075 0.076
YZ2-4(％) 0.017 0.016 0.016
pH before sterilization 5.3 5.3 5.2
pH after sterilization 5.3 5.2 5.2
The dosage of the sodium dihydrogen phosphate is 0.1-0.3 percent, and the sodium dihydrogen phosphate has no obvious difference in related substances and pH values, and can meet the preparation requirements.
Example 5:
the prescription of Fu Nuola raw injection is as follows:
sample of Sample 11 Sample 14 Sample 15
Fu Nuola raw hydrobromic acid 1.0g 1.0g 1.0g
Sodium chloride 0.8g 0.8g 0.8g
Sodium dihydrogen phosphate 0.1g - -
Acetic acid sodium salt - 0.08g -
Sodium citrate - - 0.3g
Sodium hydroxide (1 mol/L solution) Proper amount of Proper amount of Proper amount of
Dilute hydrochloric acid Proper amount of Proper amount of Proper amount of
Water for injection To 100ml To 100ml To 100ml
Vonolamine injections were prepared in the same manner as in example 1 except that the pH of the drug solution was adjusted to 5.3 (sample 11) or 5.2 (samples 14 and 15) to obtain Vonolamine injection samples 11, 14 and 15. The stability of Fu Nuo Lasheng injection samples 11, 14 and 15 after 30 days of standing at 60℃was examined, and the results are shown in the following table.
Sample of Sample 11 Sample 14 Sample 15
YZ2-2(％) 0.231 0.265 0.269
YZ2-4(％) 0.015 0.015 0.015
YQ2(％) N.D 0.003 0.010
YZ1(％) N.D N.D 0.002
PH 5.3 5.2 5.2
From the results of the above table, it is clear that sodium dihydrogen phosphate, sodium acetate and sodium citrate can all act as pH buffers to stabilize pH, and have good stability under accelerated conditions.
Example 6:
the prescription of Fu Nuola raw injection is as follows:
the preparation method of the Fu Nuola raw injection comprises the following steps:
taking water for injection with the preparation amount of 60-80%, heating to 60-80 ℃, sequentially adding Fu Nuola raw hydrobromic acid and a osmotic pressure regulator, stirring until the water is completely dissolved, then adding a pH regulator to regulate the pH to 4.0-5.0, and supplementing the water for injection to the full amount to obtain a liquid medicine, namely 16-20 of the Vonolamine injection sample. The properties of the Voronoi injection samples 16-20 were examined and the results are shown in the following table.
The dosage of sodium chloride is 0.63-0.99% and related substances are not different, and the osmotic pressure requirement is met.
Example 7:
the prescription of Fu Nuola raw injection is as follows:
sample of Sample 21 Sample 22
Fu Nuola raw hydrobromic acid 1.0g 1.0g
Sodium chloride 0.9g -
Glucose - 5g
Sodium hydroxide (1 mol/L solution) Proper amount of Proper amount of
Dilute hydrochloric acid Proper amount of Proper amount of
Water for injection To 100ml To 100ml
Samples 21-22 were prepared according to the same preparation method as in example 1. The properties of Fu Nuola green injectants samples 21 and 22 were examined after 10 days at 60℃and the results are shown in the following table.
From the above results, it is clear that sodium chloride and glucose can meet the osmotic pressure requirement of the preparation, and therefore, sodium chloride and glucose can be used as osmotic pressure regulator.
Example 8:
the prescription of Fu Nuola raw injection is as follows:
sample of Sample 23 Sample 24
Fu Nuola raw hydrobromic acid 1.0g 1.0g
Sodium chloride 0.8g 0.8g
Sodium dihydrogen phosphate 0.1g 0.1g
Edetic acid disodium salt - 0.02g
Sodium hydroxide (1 mol/L solution) Proper amount of Proper amount of
Dilute hydrochloric acid Proper amount of Proper amount of
Water for injection To 100ml To 100ml
The preparation method of example 1 was followed to prepare a voronoi injection, except that the pH of the liquid medicine was adjusted to 5.3, and a stainless steel block was added to the liquid medicine to soak for 24 hours, to obtain voronoi injection samples 23 to 24. The properties of samples 23-24 of the Vonolamine injection were examined and the results are shown in the following table.
Sample of Sample 23 Sample 24
YZ2-2(％) 0.087 0.073
YZ2-4(％) 0.016 0.015
PH 5.3 5.3
After EDTA-NA and stainless steel blocks are added into the liquid medicine for soaking, the related substances of the liquid medicine and the pH value have no obvious difference, which proves that the injection has no compatibility problem with metal ions.
Test example 1: solubility investigation
Sample to be measured:
fu Nuola raw fumaric acid: prepared according to the method of patent CN200680040789.7, and has a purity of 99.9%.
Hydrobromic acid Fu Nuola: the purity of the preparation obtained in preparation example 2 is 99.99%.
Vonolamine fumarate and hydrobromic acid Fu Nuola are added to water for injection at 70deg.C in amounts of 10mg/mL and 20mg/mL concentrations, respectively. It was observed that both 10mg/mL and 20mg/mL concentrations of voronoi hydrobromide were completely soluble, indicating that Fu Nuola hydrobromide had a solubility in water of greater than 20mg/mL at 70 ℃; vonopraz fumarate is not completely soluble and has a solubility of less than 5mg/mL.
The fumaric acid Fu Nuola with the concentration of 10mg/mL can be completely dissolved after the pH is regulated to be more than or equal to 6.5. The stability change conditions of the unsterilized, sterilized (sterilized at 121 ℃ for 12 min) and accelerated at 60 ℃ for 10 days were measured by taking 10mg/mL of a voronoi hydrobromide aqueous solution and 10mg/mL of a voronoi fumarate aqueous solution (pH. Gtoreq.6.5), respectively, and the results are shown in the following table.
"/" indicates undetected.
Compared with the solubility of the voronoi fumarate, the solubility of the voronoi hydrobromide is greatly improved, and the dissolution rate of the voronoi hydrobromide is observed to be very high in the test process. The solubility of the fumarase is very poor, the solubility of the fumarase needs to be slightly increased under the condition of about alkaline pH, the impurity YZ2-2 is influenced by the pH, the more alkaline the pH is, the more obvious the increase is, and the problem of quality stability exists if the solubility of the fumarase is met, so that the fumarase is unfavorable for the development of liquid preparations.
Test example 2: DVS hygroscopicity investigation
Sample to be measured:
fu Nuola p-toluenesulfonate salt form a: 0.17g Fu Nuola g (free base form) was weighed, 2mL of isopropanol was added, and the solution was magnetically stirred at 40℃to give a clear solution of voronoi free base. Weighing 10.31mg of p-toluenesulfonic acid solid, adding 1mL of purified water for dissolution, slowly dropwise adding the solution into the vonolamine free alkali clear solution, magnetically stirring for reaction for 2h, circularly heating and cooling at 5-40 ℃ for 20h, centrifugally collecting the solid, and drying in a vacuum oven at 25 ℃ for 24h to obtain a white solid which is p-toluenesulfonate crystal form A.
Fu Nuola L-malate salt form A: weigh 0.17g Fu Nuola g (free base form), add 2ml 1, 4-dioxane, magnetically stir the solution to give vonolamine free base clear solution. 80.45mg of L-malate is weighed and added into Fu Nuola raw free alkali clear solution, the mixture is magnetically stirred and reacted for 10 hours to obtain white solid, the solid is centrifugally collected and dried in a vacuum oven at 25 ℃ for 24 hours to obtain solid which is L-malate crystal form A.
Fu Nuola maleate salt form a: 1.7g of Fu Nuola g (free base form) was weighed into 20mL of acetonitrile and the solution was stirred to give a clear solution of vonolamine free base. 70.50mg of maleic acid was weighed, 20mL of acetonitrile was added, and 2mL of purified water was dissolved to obtain a maleic acid solution. Slowly dripping maleic acid solution into Fu Nuola raw free alkali clear solution at 60 ℃ and the speed of 0.5mL/min, stirring for 2h, the stirring speed is 250r/min, performing thermal filtration by using a filter membrane with the speed of 0.25 mu m to obtain clear solution, still clarifying at room temperature, starting cooling, performing thermal filtration at the cooling speed of 0.5, cooling to 3, collecting solid, and drying in a 25-set vacuum oven for 24h to obtain solid which is maleate crystal form A.
Crystalline form a of vonolatrexed diacid salt: 0.17g Fu Nuola g (free base form) was weighed, 2mL of methanol was added, and the solution was magnetically stirred to give a clear solution of voronoi free base. 72.0 mg of succinic acid solid is weighed, 1mL of methanol is used for dissolution, then the solution is slowly dripped into Fu Nuola raw free alkali clear solution at 60 ℃, magnetic stirring reaction is carried out for 2h, the temperature is circularly increased and decreased for 10h at 5-40 ℃ to obtain white solid, the solid is centrifugally collected, and the solid is dried in a vacuum oven at 25 ℃ for 24h to obtain the solid which is succinate crystal form A.
Fu Nuola the hydrobromide crystalline form: prepared in preparation example 2.
And (3) drying the sample to be tested in a vacuum oven at 25 ℃ for 48 hours, and testing the hygroscopicity of the sample to be tested at 25 ℃ by using a DVS dynamic moisture adsorption instrument (DVS Intrinsic), wherein the humidity step length of RH% is 10%, the humidity interval RH is 0-90%, and the dm/dt mode is balanced.
As shown in fig. 5, the DVS hygroscopicity test data shows that the Fu Nuola hydrobromide crystal form has the lowest hygroscopicity, which is beneficial to the storage and transportation of the raw material API and the operation of the preparation process.
Test example 3: stability investigation
The Fu Nuola raw crystal forms of hydrobromic acid prepared in preparation example 2 are respectively placed under three conditions of high temperature 60 ℃, high humidity 40 ℃/RH=92.5% and acceleration 40 ℃/RH=75%, and the chemical stability and the crystal form stability change conditions are respectively examined in 11 days and 32 days. The change in the crystal form was measured by XRPD and DSC, and the change in the chemical stability was measured by HPLC, and the results are shown in the following table.
The stability investigation result shows that the chemical purity value and the crystal form of the hydrobromic acid Fu Nuola raw crystal form are not obviously changed under the conditions of high temperature, high humidity and acceleration, and the chemical stability and the crystal form stability are good.
While the methods and products of this application have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications can be applied to the methods and products described herein without departing from the spirit and scope of this application. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the application.

Claims (10)

1. The vonolamine hydrobromide injection is characterized by comprising vonolamine hydrobromide or a crystal form thereof, an osmotic pressure regulator, a pH buffer and water, wherein the mole ratio of the hydrobromide to the vonolamine in the vonolamine hydrobromide or the crystal form thereof is 1:1.
2. The vonolamine injection according to claim 1 wherein the osmolality adjusting agent is selected from one or more of glucose, sodium chloride, mannitol, glycerol, phosphate or citrate; preferably, the osmolality adjusting agent is selected from one or more of glucose, sodium chloride or mannitol.
3. The voronoi injection according to claim 1 or 2, wherein said pH buffer is selected from one or more of phosphate, acetate, citrate, borate, tartrate, boric acid buffer; preferably, the pH buffer is selected from one or more of sodium dihydrogen phosphate, sodium acetate or sodium citrate.
4. The voronoi injection according to any of claims 1-3, wherein the voronoi injection further comprises a pH adjustor selected from one or more of hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, citrate, or phosphate; preferably, the pH regulator is selected from one or two of hydrochloric acid or sodium hydroxide.
5. The voronoi injection according to any of claims 1-4, wherein said voronoi injection further comprises a metal complexing agent selected from one or more of DETA, citric acid, sodium citrate, tartaric acid, or sodium tartrate; preferably, the metal complexing agent is selected from DETA.
6. The voronoi injection as claimed in any of claims 1 to 5, wherein the pH of the voronoi injection is 3.0-6.0, preferably 4.0-5.0.
7. The voronoi injection according to any of claims 1-6, wherein the X-ray powder diffraction pattern of the Fu Nuola green crystalline form of hydrobromic acid comprises characteristic peaks at diffraction angles (2Θ) at 13.8±0.2°, 15.1±0.2°, 18.3±0.2°, 19.6±0.2°, 21.9±0.2°, 25.2±0.2° and 25.9±0.2°; preferably, characteristic peaks at diffraction angles (2θ) of 13.8±0.2°, 15.1±0.2°, 15.5±0.2°, 18.3±0.2°, 19.6±0.2°, 21.9±0.2°, 24.1±0.2° and 24.3±0.2°, 25.2±0.2°, 25.9±0.2° and 28.0±0.2° are included; preferably, the diffraction angle (2θ) of the diffraction pattern is selected from the group consisting of characteristic peaks at 11.4±0.2°, 13.8±0.2°, 15.1±0.2°, 15.5±0.2°, 16.5±0.2°, 18.3±0.2°, 19.6±0.2°, 20.8±0.2°, 21.1±0.2°, 21.9±0.2°, 23.0±0.2°, 24.1±0.2°, 24.3±0.2°, 25.2±0.2°, 25.9±0.2°, 26.4±0.2°, 26.8±0.2°, 27.8±0.2°, 28.0±0.2°, 29.5±0.2°, 30.4±0.2°, and 31.3±0.2°;
preferably, the XRPD pattern of the Fu Nuola green crystalline form of hydrobromic acid comprises peaks at substantially the same diffraction angles as shown in figure 1; preferably, the XRPD pattern of the Fu Nuola green crystalline form of hydrobromic acid is as shown in figure 1.
8. The voronoi injection as claimed in any one of claims 1 to 7, wherein the voronoi injection is a low volume injection comprising the following components in weight to volume ratio in g/mL:
vonolamine hydrobromide or crystalline forms thereof: 0.1-2% by weight of Vonolamine;
sodium chloride: 0.7-0.9%;
sodium dihydrogen phosphate: 0.1-0.3%;
a proper amount of pH regulator for regulating the pH to 3.0-6.0;
the balance of water for injection;
or, the voronoi injection is a high-capacity infusion and comprises the following components in weight-volume ratio, wherein the unit of the weight-volume ratio is g/mL:
vonolamine hydrobromide or crystalline forms thereof: 0.01-0.2% by weight of Vonolamine;
sodium chloride: 0.7-0.9%;
sodium dihydrogen phosphate: 0.1-0.3%;
a proper amount of pH regulator for regulating the pH to 3.0-6.0;
the balance of water for injection.
9. A process for the preparation of a voronoi injection as claimed in any one of claims 1 to 8, comprising the steps of:
taking water for injection with the preparation amount of 60-80%, heating to 60-80 ℃, sequentially adding the voronoi hydrobromide or the crystal form thereof, the osmotic pressure regulator and the pH buffer, stirring until the voronoi hydrobromide or the crystal form thereof, the osmotic pressure regulator and the pH buffer are completely dissolved, then adding the pH regulator to regulate the pH to 3.0-6.0, and supplementing the water for injection to the full amount; filtering, canning and sterilizing;
preferably, the filtration is through a 0.45 μm polypropylene filter membrane and a 0.22 μm polyethersulfone filter membrane.
Preferably, the sterilization is performed at a sterilization temperature of 121 ℃ for 12min.
10. Use of the voronoi injection according to any one of claims 1 to 8, in the manufacture of a medicament for the prevention and/or treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, eradication of helicobacter pylori and related diseases caused by gastric hyperacidity.
CN202210679243.7A 2022-06-16 2022-06-16 Fu Nuola raw injection and preparation method thereof Pending CN117281764A (en)

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