CN112569181A - Method for rapidly solubilizing epinephrine - Google Patents

Method for rapidly solubilizing epinephrine Download PDF

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CN112569181A
CN112569181A CN201910925133.2A CN201910925133A CN112569181A CN 112569181 A CN112569181 A CN 112569181A CN 201910925133 A CN201910925133 A CN 201910925133A CN 112569181 A CN112569181 A CN 112569181A
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epinephrine
solution
zinc
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zinc ions
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CN112569181B (en
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赵红卫
朱中杰
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Shanghai Advanced Research Institute of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to the technical field of pharmacy, in particular to a method for rapidly solubilizing epinephrine and an epinephrine solution prepared by the method. The invention provides an epinephrine solution comprising epinephrine, zinc ions, and water. The adrenaline solution provided by the invention can adopt normal temperature and normal pressure reaction in the preparation process, adopts a method of promoting dissolution by zinc-containing metal ions, not only improves the dissolution efficiency of adrenaline in deionized or distilled water, but also has the characteristics of economy, safety and high efficiency, and the raw materials of the solution system are easy to obtain, and the preparation process also has the advantages of simple and reasonable process, easy operation and the like.

Description

Method for rapidly solubilizing epinephrine
Technical Field
The invention relates to the technical field of pharmacy, in particular to a method for rapidly solubilizing epinephrine and an epinephrine solution prepared by the method.
Background
Adrenaline (Adrenaline/Epinephrine) is a catecholamine neurotransmitter and also an important hormone drug, plays an important role in organisms, is mainly used for treating diseases such as cardiac arrest and anaphylactic shock, is related to neurological diseases such as Parkinson and senile dementia, and is widely regarded in the fields of medicine and chemical industry. Adrenalin has very low solubility in aqueous solution, and as a therapeutic drug for neurological diseases, its solubility in water directly affects its action efficiency, and most of the compounds are hydrochloride compounds used in the treatment of diseases. The substance is easy to be oxidized and decomposed into other substances under the condition of long-term exposure to air or oxygen, so that if a stable epinephrine solution with physiological activity can be quickly obtained, important reference values can be provided for the research and development of related medicaments and medicament treatment.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a method for rapidly solubilizing epinephrine and an epinephrine solution prepared thereby, which solve the problems of the prior art.
To achieve the above and other related objects, according to one aspect of the present invention, there is provided an epinephrine solution comprising epinephrine, zinc ions, and water.
In some embodiments of the invention, the epinephrine solution is an aqueous epinephrine solution.
In some embodiments of the invention, the concentration of epinephrine in the epinephrine solution is from 1mM to 150mM, preferably from 3mM to 75 mM.
In some embodiments of the invention, the concentration of zinc ions in the epinephrine solution is between 0.5mM and 100mM, preferably between 1mM and 50 mM.
In some embodiments of the invention, the molar ratio of epinephrine to zinc ions in the epinephrine solution is 1: 0.1 to 1, preferably 1: 0.3 to 0.7.
In some embodiments of the invention, the epinephrine solution is a solution of epinephrine and zinc ions.
In some embodiments of the invention, the zinc salt is selected from the group consisting of zinc chloride, zinc sulfate, zinc nitrate, zinc acetate, zinc gluconate, and combinations of one or more thereof.
In another aspect of the present invention, there is provided a method for preparing the epinephrine solution, comprising: epinephrine is dissolved in an aqueous solution including zinc ions.
In another aspect, the present invention provides the use of an epinephrine solution as described above in the preparation of a pharmaceutical formulation comprising epinephrine.
Another aspect of the invention provides the use of zinc ions to increase the solubility of epinephrine in an aqueous solution.
Drawings
FIG. 1 is a schematic diagram showing the comparison of the concentrations of the respective solutions in example 1 of the present invention.
FIG. 2 is a schematic diagram showing calibration of ultraviolet absorption spectroscopy in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments, and other advantages and effects of the present invention will be apparent to those skilled in the art from the disclosure of the present specification.
In a first aspect, the invention provides an epinephrine solution comprising epinephrine, zinc ions, and water. The solute of the solvent in the epinephrine solution may include epinephrine and zinc ions, and the solvent of the solution may include water, i.e., in the solution system, epinephrine and zinc ions are generally dispersed substances, which are generally uniformly dispersed in water as the solvent in molecular or smaller particles to form the solution system. The inventors of the present invention have unexpectedly found, through extensive studies, that a solution comprising waterZinc ions are introduced into the system, so that the solubility of epinephrine can be effectively improved, and the problem of poor solubility of epinephrine in an aqueous solution system is solved, specifically, epinephrine is quickly solubilized by adding metal zinc ions, and ZnCl is added under the concentration of 1mM2The amount of dissolved epinephrine is more than 6 times higher than that of pure water when ZnCl is used2At a concentration of 10mM, epinephrine was dissolved in an amount of more than 26 times that of pure water, thereby obtaining a high-concentration stable epinephrine solution.
In the epinephrine solution provided by the invention, the epinephrine solution is usually an epinephrine aqueous solution, namely, the solvent of the solution system is mainly water.
In the epinephrine solution provided by the invention, under the condition that zinc ions exist in the solution, the solubility of epinephrine in the epinephrine solution can be obviously improved, and the concentration of epinephrine in a solution system can be higher than that of epinephrine in a solution system taking pure water as a solvent (the solubility of epinephrine in pure water is about 0.09 mg/mL). The concentration of epinephrine in the epinephrine solution may be adjusted by one of skill in the art as desired, and in one embodiment of the present invention, the concentration of epinephrine in the epinephrine solution may be greater than or equal to 0.6mM, greater than or equal to 0.7mM, greater than or equal to 0.8mM, greater than or equal to 0.9mM, greater than or equal to 1mM, greater than or equal to 1.2mM, greater than or equal to 1.5mM, greater than or equal to 2mM, greater than or equal to 3mM, greater than or equal to 5mM, greater than or equal to 7mM, greater than or equal to 10mM, greater than or equal to 15mM, greater than or equal to 20mM, greater than or equal to 25mM, greater than or equal to 30mM, greater than or equal to 35mM, greater than or equal to 40mM, greater than or equal to 45mM, greater than or equal to 50mM, greater than or equal to 55mM, greater than or equal to 60mM, greater than or equal to 65mM, greater than or equal to 70mM, greater than or equal to 75mM, greater than or equal to 80mM, greater than or.
The solubility of adrenalin in the adrenalin solution can be effectively improved by introducing a proper amount of zinc ions into the adrenalin solution. Generally, the concentration of zinc ions in the solution system can be selected based on the desired dissolved epinephrine in the solution. The concentration of zinc ions in the epinephrine solution can be adjusted by those skilled in the art as required, and the concentration of zinc ions can be controlled, and is not usually too high, because the risk of metal poisoning may be caused by too high concentration of zinc ions, so that the concentration of zinc ions can be kept within the safe range of heavy metal ions acceptable to living organisms. In another embodiment of the present invention, the concentration of zinc ions in the epinephrine solution may be 0.5 mM-100 mM, 1 mM-50 mM, 0.5 mM-0.8 mM, 0.8 mM-1 mM, 1 mM-3 mM, 3 mM-5 mM, 5 mM-10 mM, 10 mM-15 mM, 15 mM-20 mM, 20 mM-25 mM, 25 mM-30 mM, 30 mM-35 mM, 35 mM-40 mM, 40 mM-45 mM, 45 mM-50 mM, 50 mM-60 mM, 60 mM-70 mM, 70 mM-80 mM, 80 mM-90 mM, 90 mM-100 mM.
In the epinephrine solution provided by the invention, the solubility of epinephrine has a great relationship with the concentration of zinc ions, and the solubility of epinephrine can be further improved along with the increase of the concentration of zinc ions in the solution. In an embodiment of the present invention, in the epinephrine solution, the molar ratio of epinephrine to zinc ions may be 1: 0.1-1, 1: 0.3-0.7, 1: 0.1-0.15, 1: 0.15-0.2, 1: 0.2-0.25, 1: 0.25-0.3, 1: 0.3-0.35, 1: 0.35-0.4, 1: 0.4-0.45, 1: 0.45-0.5, 1: 0.5-0.55, 1: 0.55-0.6, 1: 0.6-0.65, 1: 0.65-0.7, 1: 0.7-0.75, 1: 0.75-0.8, 1: 0.8-0.85, 1: 0.85-0.9, 1: 0.9 to 0.95, or 1: 0.95 to 1.
In the epinephrine solution provided by the present invention, the zinc ions may be provided by a zinc-containing compound that can provide zinc ions when dissolved in water, i.e., the zinc-containing compound is generally water-soluble, and may be provided by dissolving the zinc-containing compound in a solvent. The zinc-containing compound can be organic zinc, inorganic zinc and the like, or can be zinc salt and the like, and the zinc salt generally refers to a compound formed by metal ion zinc and acid radical ion. The zinc-containing compound generally has some solubility in water by itself so that a suitable concentration as described above can be provided in the epinephrine solution. For example, the zinc-containing compound can be selected from a combination of one or more of zinc chloride, zinc sulfate, zinc nitrate, zinc acetate, zinc gluconate, and the like.
In a second aspect, the present invention provides a method for preparing an epinephrine solution provided in the first aspect, including: epinephrine is dissolved in an aqueous solution including zinc ions. Specifically, epinephrine may be added to an aqueous solution including zinc ions to form a homogeneous solution during the preparation process, or epinephrine may be first mixed with water to form a mixture with zinc ions (e.g., zinc salt or a solution of zinc salt) to form a homogeneous solution.
In the preparation method provided by the invention, the preparation process can be usually carried out at room temperature, and specifically can be carried out at 10-30 ℃, 10-15 ℃, 15-20 ℃, 20-25 ℃, 25-30 ℃ or lower or higher temperature, so that other auxiliary conditions such as heating, ultrasound and the like can be avoided, a uniform solution system can be formed, and the chemical structure of epinephrine can be prevented from being damaged in the preparation process of the solution. During the preparation process, epinephrine may generally be added in increments (e.g., in portions) to ensure that epinephrine is dissolved in the solution in a timely manner to avoid oxidative decomposition of epinephrine into other substances. In the preparation process, when the concentration of adrenaline in the solution is low, the color of the solution is pink initially, and gradually deepens to brown yellow along with the increase of time and the dissolution amount of adrenaline. The prepared solution is usually suitable for being protected from light and refrigerated storage because epinephrine can be decomposed under the conditions of illumination and high temperature.
In a third aspect, the invention provides the use of an epinephrine solution provided in the first aspect of the invention in the preparation of a pharmaceutical formulation comprising epinephrine. As described above, in the epinephrine solution provided by the application, the solubility of epinephrine is greatly improved compared with that of a common aqueous solution, and the concentration of epinephrine is relatively adjustable compared with that of zinc ions, so that the application of epinephrine-related pharmaceutical preparations is effectively expanded.
In a fourth aspect the invention provides the use of zinc ions to increase the solubility of epinephrine in an aqueous solution. As mentioned above, when zinc ions are present in the solution system including water, the solubility of epinephrine in the solution can be significantly improved, and the solubility of epinephrine is greatly related to the concentration of zinc ions, and the solubility of epinephrine can be further improved as the concentration of zinc ions in the solution increases.
The adrenaline solution provided by the invention can adopt normal temperature and normal pressure reaction in the preparation process, adopts a method of promoting dissolution by zinc-containing metal ions, not only improves the dissolution efficiency of adrenaline in deionized or distilled water, but also has the characteristics of economy, safety and high efficiency, and the raw materials of the solution system are easy to obtain, and the preparation process also has the advantages of simple and reasonable process, easy operation and the like. Compared with the traditional preparation of hydrochloride medicaments, the method has obvious high efficiency and economic benefit and good industrialization prospect.
The invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.
Example 1
1. Preparing a dissolving solution: 136.29mg of ZnCl are weighed out2Dissolving the solid powder in 10mL deionized or distilled water, and stirring and mixing uniformly to completely dissolve the solid powder to obtain 100mM ZnCl210mL of the solution. 100mM of ZnCl2Diluting according to a certain proportion to obtain 1mM, 10mM, 20mM, 30mM, 40mM and 50mM ZnCl respectively2Standing the solution for later use.
2. Epinephrine dissolved in 1mM ZnCl2Solution: 0.55mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was used in a concentration of 1mM2Placing 1mL of the solution in a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ at room temperature, uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of adrenaline of 3 mM.
3. Epinephrine dissolved in 10mM ZnCl2Solution: 2.38mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was used in a concentration of 10mM2Placing 1mL of the solution into a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ at room temperature, uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of adrenaline of 13 mM.
4. Adrenal glandPlain dissolved in 20mM ZnCl2Solution: 5.46mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was used in a concentration of 10mM2Placing 1mL of the solution into a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ at room temperature, uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of adrenaline of 29.8 mM.
5. Epinephrine dissolved in 30mM ZnCl2Solution: 6.9mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was used in a concentration of 30mM2Placing 1mL of the solution into a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ and uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of the adrenaline of 37.66 mM.
6. Epinephrine dissolved in 40mM ZnCl2Solution: 11.07mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was used in a concentration of 40mM2Placing 1mL of the solution into a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ and uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of the adrenaline of 60.42 mM.
7. Epinephrine dissolved in 50mM ZnCl2Solution: 13.69mg (purity 99.99%) of epinephrine solid powder was weighed, and ZnCl prepared in 1 above was taken at a concentration of 50mM2Placing 1mL of the solution into a centrifuge tube, gradually adding the adrenaline solid powder into the centrifuge tube in batches, carrying out experiment operation at about 20 ℃ and uniformly shaking, and observing that the solid matter is completely dissolved to be transparent after a few minutes to obtain the concentration of the adrenaline of 74.73 mM.
8. Control experiment: weighing 0.1mg of epinephrine powder, dissolving in 1mL of water, oscillating for 10min, obtaining suspension without complete dissolution, centrifuging, taking supernatant, diluting by 10 times, and calibrating by ultraviolet absorption spectroscopy, wherein the solubility of epinephrine in pure water is about 0.09mg/mL, and the concentration is about 0.49 mM.
The concentration of adrenaline in the solution configured in the above embodiment approaches the maximum solubility, which is intended to illustrate that the solution can greatly promote the dissolution of adrenaline after adding metal zinc ions, and the specific concentration diagram of each solution is shown in table 1.
Example 2
The calibration by ultraviolet absorption spectrometry was carried out by adding excess epinephrine to pure water and a solution containing metal zinc ions (aqueous solution containing 1mM zinc chloride), respectively, and taking a small amount of supernatant to dilute by the same factor at 8000 rpm centrifugation for 20min, 40min, and 60min, respectively, and the detailed results are shown in FIG. 2.
As can be seen from fig. 2, the ultraviolet absorption spectra of the solutions were substantially the same and the data were stable in the three concentration calibrations of 20min, 40min and 60min for both the normal aqueous solution and the aqueous solution containing 1mM zinc chloride, and therefore, it is considered that the solutions formed in both cases were stable aqueous solutions containing epinephrine as a whole. In addition, as the absorption peak of the aqueous solution containing 1mM zinc chloride in the map is obviously enhanced relative to the absorption peak of the common aqueous solution, the solubility of epinephrine can be greatly improved in an epinephrine solution system when zinc ions exist.
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (10)

1. An epinephrine solution comprising epinephrine, zinc ions, and water.
2. The epinephrine solution of claim 1, wherein the epinephrine solution is an aqueous epinephrine solution.
3. The epinephrine solution of claim 1, wherein the concentration of epinephrine is from 1mM to 150mM, preferably from 3mM to 75 mM.
4. The epinephrine solution of claim 1, wherein the concentration of zinc ions in the epinephrine solution is between 0.5mM and 100mM, and between 1mM and 50 mM.
5. The epinephrine solution of claim 1, wherein the epinephrine solution has a molar ratio of epinephrine to zinc ions of 1: 0.1 to 1, preferably 1: 0.3 to 0.7.
6. The epinephrine solution of claim 1, wherein the zinc ions are provided by a zinc-containing compound selected from organic zinc and/or inorganic zinc.
7. The epinephrine solution of claim 6, wherein the zinc-containing compound is selected from the group consisting of zinc chloride, zinc sulfate, zinc nitrate, zinc acetate, and zinc gluconate, in combination with one or more of the foregoing.
8. A process for the preparation of an epinephrine solution according to any of claims 1 to 7, comprising: epinephrine is dissolved in an aqueous solution including zinc ions.
9. Use of an epinephrine solution according to any one of claims 1 to 7 for the preparation of a pharmaceutical formulation comprising epinephrine.
10. Use of zinc ions to increase the solubility of epinephrine in an aqueous solution.
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