CN113101371A - Solubilization method of hydrophobic drug based on cation-pi effect - Google Patents

Solubilization method of hydrophobic drug based on cation-pi effect Download PDF

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Publication number
CN113101371A
CN113101371A CN202110370929.3A CN202110370929A CN113101371A CN 113101371 A CN113101371 A CN 113101371A CN 202110370929 A CN202110370929 A CN 202110370929A CN 113101371 A CN113101371 A CN 113101371A
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Prior art keywords
cation
hydrophobic drug
drug
solubilizing
solubility
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CN202110370929.3A
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Chinese (zh)
Inventor
方海平
张峰
王莉萍
王超群
李亚平
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Wenzhou Research Institute Of Chinese Academy Of Sciences Wenzhou Institute Of Biomaterials And Engineering
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Wenzhou Research Institute Of Chinese Academy Of Sciences Wenzhou Institute Of Biomaterials And Engineering
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Priority to CN202110370929.3A priority Critical patent/CN113101371A/en
Publication of CN113101371A publication Critical patent/CN113101371A/en
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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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Abstract

The invention provides a pharmaceutical composition, a method for solubilizing a hydrophobic drug, and the use of a cation in the preparation of a pharmaceutical composition. The pharmaceutical composition includes a hydrophobic drug and a cation. The cation forms a cation-pi interaction with the hydrophobic drug. The aim of solubilizing the medicine is achieved by utilizing the cation-pi effect formed by the metal cation and the aromatic ring in the medicine to destroy the conjugated chemical system between the aromatic rings in the medicine and the hydrophobic effect between the aromatic rings and water molecules. The solubility can be increased by 1-100 times.

Description

Solubilization method of hydrophobic drug based on cation-pi effect
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition, application of cations in preparation of the pharmaceutical composition and a solubilization method of a hydrophobic drug.
Background
More and more bioactive substances are discovered or synthesized, the obtained new chemical entities often have the problems of low biological solubility and low bioavailability, and especially, the active ingredients in natural medicines are mostly insoluble ingredients, which limits the development of the natural medicines into clinically applicable medicines to a certain extent, so how to improve the solubility of the insoluble medicines and improve the clinical curative effect of the medicines and the solubility and bioavailability of the insoluble medicines have very important effects on the clinical application of the active substances. The solubilization methods developed so far are: micelle solubilization, cosolvent or latent solvent addition, solid dispersion preparation, liposome encapsulation, cyclodextrin inclusion compound formation, salt formation and the like, the traditional method of using mixed solvent or adding surface active agents such as solubilizer, cosolvent and the like can improve the solubility of the medicine to a certain extent, but the addition of part of the surface active agents can influence the absorption and physiological activity of the preparation, and increase the irritation or toxicity of the preparation; one of the biggest problems of the solid dispersion technology is poor stability, and the prepared solid dispersion is easy to age in the storage process, so that the solubility is reduced; the liposome encapsulation can obviously improve the drug-loading rate, but the liposome is a heterogeneous system, the process is complex, and the toxicity is caused by introducing an organic solvent in the preparation process; the cyclodextrin inclusion compound is formed, although the solubility of the cyclodextrin inclusion compound is improved, the drug loading is low, the inclusion proportion is not good in reproducibility, and the solubilization effect is seriously influenced; salt formation has high requirements on the chemical structure of drug molecules, and only a few drugs can be solubilized by salt formation. Therefore, the research and development of a novel solubilization technology for improving the solubility of the drug in physiological solution and improving the bioavailability of the drug have great social significance and market value.
Disclosure of Invention
In order to overcome the technical defects of poor solubilization effect, low safety and poor stability of the drug solubilization mode in the prior art, the invention provides the application of cations in preparing hydrophobic drug solubilizers, wherein the cations are one or the combination of divalent cations and trivalent cations. The cation forms a cation-pi interaction with the hydrophobic drug. The aim of solubilizing the medicine is achieved by utilizing the cation-pi effect formed by the metal cation and the aromatic ring in the medicine to destroy the conjugated chemical system between the aromatic rings in the medicine and the hydrophobic effect between the aromatic rings and water molecules. The application overcomes the defects that in the prior art, a large amount of surfactant or organic solvent is used, toxicity exists, and the medicine is possibly separated out in the process of combining with the medicine; and the solid dispersion has the technical disadvantage of poor long-term standing stability. The solubility of the medicine containing aromatic rings in physiological solution can be effectively improved by adjusting the concentration and the type of the cation. The solubility of the hydrophobic drug is measured by ultraviolet absorption spectroscopy, and can be increased by 1-100 times.
In a second aspect of the present invention, there is provided a method for solubilizing a hydrophobic drug, comprising mixing the hydrophobic drug with a cation to form a cation-pi interaction between the cation and the hydrophobic drug, thereby increasing the solubility of the hydrophobic drug in water; the cation is one or two of divalent cation and trivalent cation.
The hydrophobic drug is selected from one or more of antineoplastic drug, antibacterial drug, antiviral drug, antipyretic analgesic and anti-inflammatory drug, blood system disease drug, urinary system disease drug, hormone and endocrine system disease drug, and immunosuppressant.
The hydrophobic drug is quercetin, artemisinin, paclitaxel, adriamycin or camptothecin.
The divalent cation is preferably a divalent metal cation, and more preferably Mg2+、Ca2+、Ba2+、Cu2+、Zn2+、Fe2+Any one or two or more of them.
The trivalent cation is preferably a trivalent metal cation, and more preferably Fe3+、Al3+、Co3+、Sc3+Any one or two or more of them.
The hydrophobic drug and the cation in the water are mixed by any one or more of shaking, vortex shaking and ultrasonic dispersion.
Further, the time for mixing the hydrophobic drug and the cation is 1-24 h.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a hydrophobic drug and a cation, wherein the cation forms a cation-pi interaction with the hydrophobic drug, and the cation is one or a combination of a divalent cation and a trivalent cation.
The concentration range of the cation is 0.1-500 mg/ml.
The concentration of the hydrophobic drug is 0.05-100 mg/ml. By controlling the concentrations of the metal cation and the drug to regulate the formation of cation-pi interactions between the aromatic ring and the cation, the solubility of different drugs at different concentrations in solutions of metal cations of appropriate concentrations can vary significantly.
After the technical scheme is adopted, compared with the prior art, the method has the following beneficial effects:
1. the invention provides a hydrophobic drug solubilization method based on cation-pi effect, which utilizes the cation-pi effect formed by metal cations and aromatic rings in the hydrophobic drug to destroy the hydrophobic effect between a conjugated chemical system between the aromatic rings in the drug and water molecules, thereby achieving the purpose of drug solubilization, effectively improving the solubility of the drug containing the aromatic rings in physiological solution, improving the solubility by 1-100 times compared with the water solubility of the drug, and having good social value and application prospect. The solubility of different drugs at different concentrations in solutions of metal cations at appropriate concentrations can vary significantly.
2. After the hydrophobic drug with proper concentration and the metal cation with proper concentration are simply mixed through one or more of shaking, vortex oscillation and ultrasonic dispersion, cation-pi interaction is formed between the metal cation and the aromatic ring. The method is simple and easy to operate, can be widely used for different types of aromatic ring drugs, does not need to add reagents such as surfactants and the like, and has good safety and high solubility.
Detailed Description
The advantages of the invention are further illustrated below with reference to specific examples. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
The experimental conditions are as follows:
normal temperature (25 deg.C) and pressure (1 standard atmospheric pressure)
The experimental method comprises the following steps:
1. preparing a known and determined concentration of quercetin ethanol solution.
2. Preparing saturated quercetin water solution with unknown concentration.
3. Reacting ZnCl2Dissolving in water to prepare ZnCl with the concentration of 0.125-2 mol/l2Aqueous solution of AlCl3Dissolving in water to prepare AlCl with the concentration of 0.3125-0.5 mol/l3An aqueous solution; the quercetin concentration is 0.1mg/ml (ethanol), and the quercetin and ZnCl are added2And AlCl3Mixing and placing in a freeze dryer, and vacuum drying ethanol to obtain mixture water solution, and detecting ultraviolet absorption spectrum of the mixture water solution with ultraviolet spectrum (U-2900, HITACHI, JAPAN). The solution A is quercetin water solution, and the solution B is Zn2++ a quercetin; the solution C is Al3++ Quercetin。
Experimental results and analysis:
the absorbance of the solution A is 0.258, and the solubility is 3 mg/ml;
the absorbance of the solution B is 0.383, and the solubility is 5 mg/ml;
the absorbance of the solution C is 0.485, and the solubility is 6.65 mg/ml;
as is clear from the above, the absorbance of the solution A was 0.258 and the solubility was 3 mg/ml. Zn2++ the absorbance of the quercetin solution was 0.383, and the solubility was 5 mg/ml. To react AlCl3After the mixed solution of the quercetin and the quercetin is kept stand for a period of time, no obvious precipitate is found through visual observation, the mixed solution is always clear and transparent, and the absorbance is 0.485, so that the solubility of the quercetin in the physiological solution of aluminum chloride is judged to be 6.65mg/ml, and Al is judged to be3+Promotes the dissolution of quercetin in physiological solution, wherein Al is3+The solubility increased by about 2.2 times. Thus, it is understood that Zn is present2+Can also play a role in solubilization to a certain extent, but Zn2+Is not as effective as Al3+Thus, Al3+The solubilization effect of (2) is the best.
It should be noted that the embodiments of the present invention have been described in terms of preferred embodiments, and not by way of limitation, and that those skilled in the art can make modifications and variations of the embodiments described above without departing from the spirit of the invention.

Claims (10)

1. The use of a cation which is one or a combination of a divalent cation and a trivalent cation in the preparation of a hydrophobic drug solubilizer.
2. A method for solubilizing a hydrophobic drug, comprising mixing the hydrophobic drug with a cation so as to form a cation-pi interaction between the cation and the hydrophobic drug, thereby increasing the solubility of the hydrophobic drug in water; the cation is one or two of divalent cation and trivalent cation.
3. The method as claimed in claim 2, wherein the hydrophobic drug is selected from one or more of antineoplastic drugs, antibacterial drugs, antiviral drugs, antipyretic analgesic and anti-inflammatory drugs, blood system disease drugs, urinary system disease drugs, hormone and endocrine system disease drugs, and immunosuppressant.
4. The method for solubilizing a hydrophobic drug as claimed in claim 3, wherein said hydrophobic drug is quercetin, artemisinin, paclitaxel, doxorubicin or camptothecin.
5. The method for solubilizing a hydrophobic drug according to any of claims 2 to 4, wherein said divalent cation is selected from Mg2+、Ca2+、Ba2+、Cu2+、Zn2+、Fe2+Any one or two or more of them.
6. The method for solubilizing a hydrophobic drug according to any of claims 2 to 4, wherein said trivalent cation is selected from Fe3+、Al3+、Co3+、Sc3+Any one or two or more of them.
7. The method for solubilizing a hydrophobic drug as claimed in any one of claims 2 to 4, wherein the hydrophobic drug is mixed with the cation in water by any one or two or more of shaking, vortexing, and ultrasonic dispersion.
8. A pharmaceutical composition comprising a hydrophobic drug and a cation, wherein said cation forms a cation-pi interaction with said hydrophobic drug, and wherein said cation is one or a combination of a divalent cation and a trivalent cation.
9. The pharmaceutical composition of claim 8, wherein the cation is present at a concentration ranging from 0.1 to 500 mg/ml.
10. The pharmaceutical composition of claim 8 or 9, wherein the concentration of the hydrophobic drug is in the range of 0.05-100 mg/ml.
CN202110370929.3A 2021-04-07 2021-04-07 Solubilization method of hydrophobic drug based on cation-pi effect Pending CN113101371A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1840196A (en) * 2006-01-27 2006-10-04 无锡杰西医药科技有限公司 Dispersible preparation adaptable to indissoluble drug
CN1854120A (en) * 2004-12-06 2006-11-01 河北师范大学 Non-toxic ion liquid its production and use
CN102276633A (en) * 2011-06-23 2011-12-14 辽宁中医药大学 Quercetin-glutamic acid Cu (II) complex and preparation method and application thereof
CN102970992A (en) * 2010-05-12 2013-03-13 莱姆派克斯制药公司 Tetracycline compositions
CN106086123A (en) * 2016-06-17 2016-11-09 江苏科技大学 A kind of application ionic liquid improves the water miscible method of flavone compound
CN109847062A (en) * 2019-04-09 2019-06-07 中山大学 A kind of Quercetin metal nano drug and its preparation method and application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1854120A (en) * 2004-12-06 2006-11-01 河北师范大学 Non-toxic ion liquid its production and use
CN1840196A (en) * 2006-01-27 2006-10-04 无锡杰西医药科技有限公司 Dispersible preparation adaptable to indissoluble drug
CN102970992A (en) * 2010-05-12 2013-03-13 莱姆派克斯制药公司 Tetracycline compositions
CN102276633A (en) * 2011-06-23 2011-12-14 辽宁中医药大学 Quercetin-glutamic acid Cu (II) complex and preparation method and application thereof
CN106086123A (en) * 2016-06-17 2016-11-09 江苏科技大学 A kind of application ionic liquid improves the water miscible method of flavone compound
CN109847062A (en) * 2019-04-09 2019-06-07 中山大学 A kind of Quercetin metal nano drug and its preparation method and application

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