CN114939176A - Preparation method of water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound - Google Patents
Preparation method of water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound Download PDFInfo
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- CN114939176A CN114939176A CN202210540115.4A CN202210540115A CN114939176A CN 114939176 A CN114939176 A CN 114939176A CN 202210540115 A CN202210540115 A CN 202210540115A CN 114939176 A CN114939176 A CN 114939176A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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Abstract
The invention discloses a preparation method of a water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound, which comprises the following steps: adding a certain amount of hydroxypropyl-beta-cyclodextrin into a reaction kettle, adding pure water into the reaction kettle, heating, stirring and dissolving to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution, weighing a certain amount of thymol, adding ethanol into the thymol, stirring and dissolving to obtain a thymol ethanol solution, and adding the thymol ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution to obtain the thymol hydroxypropyl-beta-cyclodextrin aqueous solution; and filtering the obtained thymol hydroxypropyl-beta-cyclodextrin aqueous solution, and performing centrifugal spray drying on the filtrate to obtain the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound. The thymol cyclodextrin supramolecular inclusion compound prepared by the invention has good water solubility and stable structure, does not damage the self structure and medicinal performance of thymol, and has excellent water solubility.
Description
Technical Field
The invention relates to the technical field of supramolecular inclusion, in particular to a preparation method of a water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound.
Background
Thymol is colorless crystal or colorless crystalline powder, and has odor of herba senecionis or herba Thymi vulgaris. 5-methyl-2-Isopropyl phenol (English name 5-methyl-2-Isopropyl phenol) is also called 2-Isopropyl-5-methyl phenol (2-Isopropyl-5-methyl-phenol), commonly known as thymol, thymol and thymol. Slightly soluble in water, soluble in glacial acetic acid and paraffin oil, and soluble in ethanol, chloroform, diethyl ether and olive oil. Has irritation effect on skin, eye and mucosa. Is naturally present in Thymus vulgaris of Labiatae, Thymus vulgaris, origanum vulgare Var. Variegatum, and crude fruit celery seed of Umbelliferae. It can be used for preparing perfume, medicine, indicator, etc., and is also used for treating skin mould and tinea. The molecular formula is C10H 14O. Mainly used for preparing spices, and thymol is one of 599 additives in cigarettes. Used as medicine, indicator, etc., and is also commonly used for skin mold and tinea. An indicator for measuring titanium, antimony, arsenic, nitrate, etc. As a preservative for controlling varroa mite population on honeybee hives, as a stapling and as an anesthetic added to trifluorobromoethane.
Cyclodextrins (CDs), which are second-generation supramolecular host compounds, are a class of cyclic oligosaccharides having more than 6D-glucopyranose units bonded by a-1,4, and are classified into a-CD, gamma-CD, beta-CD and the like according to the number of glucose units contained therein, wherein beta-cyclodextrin (beta-CD) has the highest yield, the lowest price and the most extensive application. The cyclodextrin compounds are characterized in that the cyclodextrin compounds have hydrophobic cavities with certain sizes, so that various types of guest molecules can be selectively included to form the supramolecular compound. Due to its unique structure, the theoretical research and practical application of cyclodextrin are rapidly developed. Has important application in the aspects of industry, agriculture, food, medicine, separation technology, environmental protection and the like.
The special cage structure of the beta-cyclodextrin can enclose drug molecules to form an inclusion compound, at the moment, the drug molecules are contained in cavities of the beta-cyclodextrin molecules and have high dispersity, and meanwhile, due to the hydrophilicity of polyhydroxy outside the beta-cyclodextrin, the inclusion compound has good wettability, so that the solubilizing effect on insoluble drugs is achieved. Because beta-cyclodextrin has low solubility, modification groups are often introduced at the edge of the beta-cyclodextrin to improve the solubility of the beta-cyclodextrin, so that the application range of the beta-cyclodextrin is expanded. The introduction of the hydroxypropyl breaks the intramolecular cyclic hydrogen bond of the beta-cyclodextrin, and overcomes the main defect of poor water solubility of the beta-cyclodextrin while maintaining the cyclodextrin cavity. Is one of the most extensively studied and widely used cyclodextrin derivatives. In the fields of food and spice, the stability and long-lasting effect of the nutritional molecules can be improved, the unpleasant odor and taste of the nutritional molecules of food can be covered or corrected, and the production process and the product quality can be improved. The product has good solubility in water, and the substitution degree of 4 or above can be mixed with water at any ratio, and can also be dissolved in 50% ethanol and methanol. The cosmetic raw material is used as stabilizer, emulsifier, deodorant, etc., and can reduce irritation of organic molecules in cosmetic to skin mucosa tissue, enhance stability of effective components, and prevent volatilization and oxidation of nutritional components. It has a certain relative hygroscopicity. In the pharmaceutical industry, it is an ideal solubilizer and pharmaceutical excipient for injection because of its relatively low ratio of surface activity and hemolytic activity and no irritation to muscle. Can improve the water solubility of insoluble drugs, increase the drug stability, improve the drug bioavailability, increase the curative effect of the medicament or reduce the dosage, adjust or control the release speed of the medicament and reduce the toxic and side effects of the medicament. Can be used for oral medicine, injection, mucosa administration system (including nasal mucosa, rectum, cornea, etc.), transdermal absorption administration system, lipophilic targeting medicine carrier, and protein protective agent and stabilizer.
However, thymol has poor water solubility and has the defect of being insoluble in water. Therefore, a preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound is provided.
Disclosure of Invention
The invention aims to provide a preparation method of a soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound, aims to overcome the defect that thymol is insoluble in water, and adopts a simple, convenient and stable method to prepare a high-purity inclusion compound.
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound comprises the following steps:
s1, adding a certain amount of hydroxypropyl-beta-cyclodextrin into a reaction kettle, adding pure water into the reaction kettle, heating, stirring and dissolving to prepare a 30% hydroxypropyl-beta-cyclodextrin water solution;
s2, weighing a certain amount of thymol, adding ethanol into the thymol, and stirring to dissolve the thymol to obtain a thymol ethanol solution;
s3, adding the thymol ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution, and after the addition is finished, carrying out heat preservation and stirring at 60 ℃ for clathration for 4 hours to obtain the thymol hydroxypropyl-beta-cyclodextrin aqueous solution;
s4, filtering the obtained thymol hydroxypropyl-beta-cyclodextrin aqueous solution, and carrying out centrifugal spray drying on the filtrate to obtain the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound.
Furthermore, the mass ratio of the hydroxypropyl-beta-cyclodextrin, the pure water, the thymol and the ethanol is 9:21:1: 10.
Further, in step S1, the reaction kettle used is specifically a stainless steel reaction kettle.
Further, in step S1, the specific temperature rise temperature for raising the temperature, stirring, and dissolving is 60 ℃.
Further, in step S2, the concentration of ethanol is 95%.
Further, in step S3, the hydroxypropyl- β -cyclodextrin aqueous solution containing the thymol ethanol solution is stirred while adding the thymol ethanol solution to the hydroxypropyl- β -cyclodextrin aqueous solution.
Further, in step S3, the thymol ethanol solution is filtered to remove impurities before the thymol ethanol solution is added to the hydroxypropyl- β -cyclodextrin aqueous solution.
The preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound provided by the invention has the beneficial effects that: according to the technical scheme, hydroxypropyl-beta-cyclodextrin is used as a host molecule, thymol is used as an object molecule, ethanol and water are used as reaction solvents to perform homogeneous phase supramolecular reaction to generate a water-soluble thymol supramolecular inclusion compound, and the method is convenient to operate, safe, easy to control and easy for industrial production; the prepared thymol cyclodextrin supramolecular inclusion compound has good water solubility and stable structure, does not damage the self structure and medicinal performance of thymol, and has excellent water solubility, so that the thymol which is a medicament with poor water solubility has wider application approaches.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Examples
The preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound comprises the following steps:
s1, adding 9kg of hydroxypropyl-beta-cyclodextrin into a stainless steel reaction kettle, adding 21kg of pure water into the stainless steel reaction kettle, heating to 60 ℃, stirring and dissolving to prepare a 30% hydroxypropyl-beta-cyclodextrin water solution;
s2, weighing 1kg of thymol, adding 10kg of ethanol with the concentration of 95% into the thymol, and stirring to dissolve the thymol to obtain a thymol ethanol solution;
s3, filtering and removing impurities from the thymol ethanol solution, adding the thymol ethanol solution into hydroxypropyl-beta-cyclodextrin aqueous solution after filtering and removing impurities, continuously stirring the hydroxypropyl-beta-cyclodextrin aqueous solution containing the thymol ethanol solution in the adding process, and after adding, carrying out heat preservation and stirring at 60 ℃ for clathration for 4 hours to obtain the thymol hydroxypropyl-beta-cyclodextrin aqueous solution;
s4, filtering the obtained thymol hydroxypropyl-beta-cyclodextrin aqueous solution, and carrying out centrifugal spray drying on the filtrate to obtain the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound.
Test examples
The water-soluble thymol hydroxypropyl- β -cyclodextrin inclusion compound obtained in the above example was added to water to measure its solubility, and the solubility of the water-soluble thymol hydroxypropyl- β -cyclodextrin inclusion compound was 10mg/ml in the case that the water temperature was 25 ℃.
In summary, the following steps: the method takes hydroxypropyl-beta-cyclodextrin as a host molecule, thymol as an object molecule and ethanol and water as reaction solvents to perform homogeneous supramolecular reaction to generate the water-soluble thymol supramolecular inclusion compound, and is convenient to operate, safe, easy to control and easy for industrial production; the prepared thymol cyclodextrin supramolecular inclusion compound has good water solubility and stable structure, does not damage the self structure and medicinal performance of thymol, and has excellent water solubility, so that the thymol which is a medicament with poor water solubility has wider application approaches.
The above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is specific and detailed, but not construed as limiting the patent of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the spirit of the invention, which falls within the scope of the invention.
Claims (7)
1. The preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound is characterized by comprising the following steps of:
s1, adding a certain amount of hydroxypropyl-beta-cyclodextrin into a reaction kettle, adding pure water into the reaction kettle, heating, stirring and dissolving to prepare a 30% hydroxypropyl-beta-cyclodextrin water solution;
s2, weighing a certain amount of thymol, adding ethanol into the thymol, and stirring for dissolving to obtain a thymol ethanol solution;
s3, adding the thymol ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution, and after the addition is finished, carrying out heat preservation and stirring at 60 ℃ for clathration for 4 hours to obtain the thymol hydroxypropyl-beta-cyclodextrin aqueous solution;
s4, filtering the obtained thymol hydroxypropyl-beta-cyclodextrin aqueous solution, and carrying out centrifugal spray drying on the filtrate to obtain the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound.
2. The preparation method of the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 1, wherein the mass ratio of hydroxypropyl-beta-cyclodextrin, pure water, thymol and ethanol is 9:21:1: 10.
3. The method for preparing the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 1, wherein in step S1, the adopted reaction kettle is specifically a stainless steel reaction kettle.
4. The method for preparing the hydroxypropyl-beta-cyclodextrin inclusion compound of water-soluble thymol according to claim 1, wherein in step S1, the specific temperature of raising the temperature and stirring for dissolution is 60 ℃.
5. The method for preparing the water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 1, wherein in step S2, the concentration of ethanol is 95%.
6. The method for producing a water-soluble thymol hydroxypropyl- β -cyclodextrin inclusion compound according to claim 1, wherein in step S3, the aqueous solution of hydroxypropyl- β -cyclodextrin containing the thymol ethanol solution is stirred while adding the thymol ethanol solution to the aqueous solution of hydroxypropyl- β -cyclodextrin.
7. The method for preparing the hydroxypropyl-beta-cyclodextrin inclusion compound of water-soluble thymol according to claim 1, wherein the ethanol solution of thymol is filtered to remove impurities before the ethanol solution of thymol is added to the aqueous solution of hydroxypropyl-beta-cyclodextrin in step S3.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210540115.4A CN114939176A (en) | 2022-05-17 | 2022-05-17 | Preparation method of water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound |
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| CN202210540115.4A CN114939176A (en) | 2022-05-17 | 2022-05-17 | Preparation method of water-soluble thymol hydroxypropyl-beta-cyclodextrin inclusion compound |
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