CN116889577A - Musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method thereof - Google Patents
Musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method thereof Download PDFInfo
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- 241000402754 Erythranthe moschata Species 0.000 title claims abstract description 104
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 title claims abstract description 86
- 150000001875 compounds Chemical class 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001132 ultrasonic dispersion Methods 0.000 claims abstract description 14
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- 238000000034 method Methods 0.000 claims description 34
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- JHGWQSGWUPCKNT-UHFFFAOYSA-N 2-tert-butyl-4-methyl-1,3,5-trinitrobenzene Chemical compound CC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C(C(C)(C)C)=C1[N+]([O-])=O JHGWQSGWUPCKNT-UHFFFAOYSA-N 0.000 claims description 8
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- 230000008685 targeting Effects 0.000 description 3
- FACFHHMQICTXFZ-UHFFFAOYSA-N 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)ethanamine Chemical compound N1=C2C=CC=CN2C(CCN)=C1C1=CC=CC=C1 FACFHHMQICTXFZ-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 238000005411 Van der Waals force Methods 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 238000001000 micrograph Methods 0.000 description 2
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- 229940067137 musk ketone Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002464 physical blending Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous 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]
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Developmental Biology & Embryology (AREA)
- Zoology (AREA)
- Virology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of biological material preparation, and discloses a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and a preparation method thereof: (1) Adding Moschus extract into absolute ethanol, and ultrasonic dispersing to obtain solution A; (2) Adding hydroxypropyl-beta-cyclodextrin into deionized water for ultrasonic dispersion to obtain a solution B; (3) Respectively transferring a certain amount of solution A, B, slowly dripping the solution A into the solution B, clathrating at a certain temperature to obtain pure white emulsion, and marking as solution C; (4) Filtering the solution C with a filter membrane for multiple times, removing the solvent, and grinding to obtain the musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound. The obtained clathrate has high drug-loading rate and encapsulation efficiency, and the clathrate effectively improves the stability and water solubility of musk extract. Realizes the sustained release of musk extract from hydroxypropyl-beta-cyclodextrin, and achieves the effect of durable medicine action.
Description
Technical Field
The invention belongs to the field of biological material preparation, and in particular relates to a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and a preparation method thereof.
Background
Musk (moschus) is a dry secretion in mature male deer forest musk, ma She or musk capsule, has pungent taste, warm nature, returns to heart and spleen channels, has the effects of inducing resuscitation and restoring consciousness, activating blood and dredging channels, and relieving swelling and pain, and has extremely high pharmaceutical value. Along with the continuous increase of the dosage of musk and the preparation thereof, musk resources are gradually depleted, the research on musk and the preparation thereof is enhanced while artificial musk is developed and natural musk is introduced, the reasonable use of musk is promoted, and the bioavailability of musk is improved, so that the musk is an important problem to be solved at present.
The chemical composition of natural musk is very complex and can be roughly divided into macrocyclic compound musk ketone, steroid testosterone, estradiol and cholesterol, various amino acids aspartic acid and serine, inorganic salts and other components such as allantoin and protein kinase activator. The artificial musk mainly contains the substitute of musk ketone and water-soluble macromolecular components, and the pharmacological actions of the artificial musk still have some differences, so that the effectiveness and safety of the artificial musk which comprehensively replaces natural musk are yet to be further verified. At present, the Chinese patent medicine preparations such as musk heart-protecting pills, compound musk injection, musk bone-strengthening paste, musk pain-relieving liniment and the like which are developed by taking natural musk as raw materials are widely applied clinically, and the technology mainly utilizes the preparation thought of physical blending.
Zhang Siwei and the like obtain artificial musk extract by ultrasonic method, fully grind borneol and menthol, uniformly mix with polysorbate 80, add the artificial musk extract, package and sterilize after volume fixing to obtain the finished product preparation. However, the technology is difficult to achieve higher medicine availability, does not have targeting and slow-release functions, has poor solubility of active ingredients in water, namely, the amount of the medicine penetrating through the blood brain barrier is small, and is difficult to achieve effective blood concentration, so that the treatment effect is not ideal. The development of musk in the pharmaceutical field is restricted to a certain extent. Therefore, in order to endow the traditional Chinese medicine with new functions, it is necessary to explore a preparation method of a pharmaceutical formulation which improves bioavailability, enhances targeting and slow release, reduces toxic and side effects and saves traditional Chinese medicine resources.
Disclosure of Invention
In order to solve the defects existing in the prior art, the invention adopts a method of adding a solubilizer into the musk extract, and forms inclusion compound by combining the solubilizer with drug molecules, thereby achieving the purposes of solubilization and slow release of the musk extract. Wherein, the solubilizer is selected as hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and the substance has a cage structure with hydrophilic outside and hydrophobic inside, and can interact with various substances through Van der Waals force, electrostatic action, non-covalent bond force such as hydrogen bond and the like. The HP-beta-CD has good solubility in water, relatively low surface activity and hemolytic activity, has no irritation to muscle, is an ideal injection solubilizer and pharmaceutical excipient, can increase the stability of the medicine, and greatly improves the utilization rate of fat-soluble medicine. The musk extract is prepared by separating, purifying and self-making musk raw materials in a laboratory.
Compared with the prior art, the invention utilizes the host-guest effect to use the hydroxypropyl-beta-cyclodextrin to carry out inclusion on the musk extract through van der Waals force, electrostatic effect, hydrogen bond and other non-covalent bond forces. The inclusion compound has raised bioavailability of musk, targeting and slow releasing functions via injection and lasting medicine effect.
In order to achieve the above purpose, the present invention provides a hydroxypropyl-beta-cyclodextrin inclusion compound, which is a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound, wherein the inclusion compound is prepared by mixing volatile oil extracted from natural/artificial musk with hydroxypropyl-beta-cyclodextrin, and the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract is 1 (0.6-2).
A method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound, the method comprising the steps of:
(1) Adding musk extract into absolute ethyl alcohol, and performing ultrasonic dispersion to obtain solution A;
(2) Adding hydroxypropyl-beta-cyclodextrin into deionized water for ultrasonic dispersion to obtain a solution B;
(3) Respectively transferring a certain amount of solution A, B, slowly dripping the solution A into the solution B, clathrating at a certain temperature to obtain pure white emulsion, and marking as solution C;
(4) Filtering the solution C with a filter membrane for multiple times, removing the solvent, and grinding to obtain the musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
In the above technical scheme, the specific step of the step (1) is to dissolve the musk extract in absolute ethyl alcohol to prepare musk extract ethanol solution with the mass concentration of 1.5-2.5%.
In the above technical scheme, further, the ultrasonic dispersion time in the step (1) is 0.5-2h.
In the above technical scheme, the specific step of the step (2) is to dissolve the hydroxypropyl-beta-cyclodextrin in deionized water to prepare an aqueous solution of the hydroxypropyl-beta-cyclodextrin with the mass concentration of 15-35%.
In the above technical scheme, further, the ultrasonic dispersion time in the step (2) is 0.5-2h.
In the above technical solution, further, the inclusion method in the step (3) is any one of a solution stirring method, an ultrasonic method and a grinding method.
In the technical scheme, further, the dropping speed in the inclusion process of the step (3) is 1-3mL/min, the inclusion temperature is 25-45 ℃, and the inclusion time is 2-4h.
In the above embodiment, further, the method for removing the solvent used in the step (4) is any one of a rotary evaporation method, a freeze drying method and a vacuum drying method.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the invention does not produce pollutants and is environment-friendly. The musk extract is included by utilizing hydroxypropyl-beta-cyclodextrin, the prepared inclusion compound has higher drug loading capacity and encapsulation rate, the aim of targeted delivery is achieved by injection to a focus part, the drug is slowly released to prolong the acting time of the drug, the bioavailability of the drug is improved, and the administration dosage is reduced on the premise of ensuring the curative effect. And improves the water-solubility and volatile property of musk.
According to the invention, the content ratio of raw materials is regulated, so that the encapsulation efficiency and the drug loading rate can be obviously increased, 92.60% and 15.43% can be achieved respectively, and the in-vitro release experiment shows that 90% of the drug loading rate can be released within 36 hours. The preparation method promotes reasonable use of musk, exerts medicinal value to the greatest extent, and is superior to the existing conventional preparation method.
Drawings
FIG. 1 is a scanning electron microscope image of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound, hydroxypropyl-beta-cyclodextrin and pore size distribution diagram of hydroxypropyl-beta-cyclodextrin prepared in example 1;
FIG. 2 is a thermogram of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and hydroxypropyl-beta-cyclodextrin prepared in example 1;
FIG. 3 is an in vitro release profile of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and musk extract prepared in example 1.
Detailed Description
The following examples facilitate a better understanding of the present invention, but are not intended to limit the present invention. In the following examples, materials, reagents and the like used are commercially available from biological or chemical reagent companies unless otherwise specified.
Example 1
(1) 1g of musk extract is weighed and dissolved in 50mL of absolute ethyl alcohol, and the musk extract is dispersed for 2 hours by ultrasonic waves to prepare an absolute ethyl alcohol solution of musk extract with the mass concentration of 2 percent;
(2) Weighing 15g of hydroxypropyl-beta-cyclodextrin, dissolving in 50mL of deionized water, and performing ultrasonic dispersion for 1h to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution with the mass concentration of 30%;
(3) Sequentially taking 50mL and 21.56mL of the solution according to the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract of 1:1, dropwise adding the musk extract absolute ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution at the speed of 2mL/min at the temperature of 30 ℃, and clathrating for 3h by utilizing an ultrasonic method to obtain a pure white emulsion reaction liquid;
(4) Repeatedly filtering and washing the reaction solution for 3 times, and finally, freeze-drying and grinding to obtain white powder musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
The musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound prepared in example 1 had a drug loading rate and an encapsulation efficiency of 15.43% and 92.60%.
FIG. 1 is a scanning electron microscope image of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound, hydroxypropyl-beta-cyclodextrin and pore size distribution diagram of hydroxypropyl-beta-cyclodextrin prepared in example 1, wherein (a) and (b) are apparent morphologies of hydroxypropyl-beta-cyclodextrin at different magnifications, and the apparent morphologies are spherical, have a cavity in the middle and have a relatively smooth surface; (c) The particle size distribution diagram of the spherical surface of the hydroxypropyl-beta-cyclodextrin is that the average pore size is 2.15 mu m, and the abundant pore size structure is favorable for the entry of guest molecules into the cavity. (d) And (e) and (f) are apparent morphology of the inclusion compound, and show irregular block-shaped and sheet-shaped structures, and have rough surfaces, uneven thickness and uneven size, and are obviously changed compared with pure hydroxypropyl-beta-cyclodextrin. The musk extract is embedded in the cavity structure of the hydroxypropyl-beta-cyclodextrin through intermolecular non-covalent bond to form an inclusion compound. The inclusion reaction is a dynamic process, the musk extract is compounded with the hydroxypropyl-beta-cyclodextrin continuously, and meanwhile, the musk extract is compounded continuously, so that the reaction conditions can be controlled to transfer the reaction to a direction favorable for compounding, and the inclusion compound with higher encapsulation rate and drug loading capacity is obtained. The prepared inclusion compound is dispersed in a medium to prepare injection, and the inclusion compound can be directly implanted into a diseased part through a syringe. Experiments show that the main factor influencing the release rate of musk extract is the change of the concentration of injection, and the release rate can be regulated by changing the concentration, so as to achieve the aim of slow release of the medicine.
FIG. 2 is a thermal analysis of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and hydroxypropyl-beta-cyclodextrin prepared in example 1, showing that hydroxypropyl-beta-cyclodextrin loses weight by about 10% at a first stage of 20-100℃, and is mainly affected by moisture in hydroxypropyl-beta-cyclodextrin. The heat stability is better at 100-300 ℃, and no obvious weightlessness is caused. Thereafter, the weight loss was about 90% in the second stage at 300-600 ℃ with an initial decomposition temperature of 305 ℃ and a maximum decomposition rate reached at 360 ℃ and 60% weight loss. When the temperature is above 395 ℃, the cyclodextrin is substantially completely decomposed. The clathrate compound is roughly divided into three sections of weightlessness, wherein the part of the first stage at 20-100 ℃ is that water in the clathrate compound volatilizes, and the weightlessness is 5%. The second stage 120-240 ℃ is probably due to the decomposition of part of the small molecular drugs in the musk extract and the volatile oil with low boiling point volatilizing weight loss, and the weight loss rate reaches the maximum at 200 ℃ and the weight loss is 25%. The third stage weight loss temperature is 300-600 ℃, and likewise, the decomposition rate reaches the maximum at 360 ℃, mainly due to the fracture degradation weight loss of the inclusion compound main chain. From this, it was found that the thermal stability of the inclusion compound after drug loading was substantially consistent with that of cyclodextrin at a high temperature of 300 ℃.
FIG. 3 is a simulated in vitro release profile of musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound and musk extract prepared in example 1, as shown by the drug release profile of the inclusion compound prepared in pure drug and ultrasound method. As can be seen from the figure, the musk extract alone released more than 50% of the drug in 3 hours, and released up to 92% of the drug in substantially all of 6 hours. The inclusion compound had a very fast drug release rate in the first 6 hours, and exhibited abrupt release. This is probably because the interaction force between the drug molecule and the hydroxypropyl-beta-cyclodextrin is weak, resulting in weak binding. The release rate was then slow and reached 61% within 6 hours, respectively, which was doubled slower than the pure drug. 90% of the drug loading was cumulatively released over 36 hours.
Example 2
(1) 1g of musk extract is weighed and dissolved in 50mL of absolute ethyl alcohol, and the musk extract is dispersed for 2 hours by ultrasonic waves to prepare an absolute ethyl alcohol solution of musk extract with the mass concentration of 2 percent;
(2) Weighing 15g of hydroxypropyl-beta-cyclodextrin, dissolving in 50mL of deionized water, and performing ultrasonic dispersion for 1h to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution with the mass concentration of 30%;
(3) Sequentially taking 50mL and 12.94mL of the solution according to the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract of 1:0.6, dropwise adding the musk extract absolute ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution at the speed of 2mL/min at the temperature of 30 ℃, and clathrating for 3h by utilizing an ultrasonic method to obtain a pure white emulsion reaction liquid;
(4) Repeatedly filtering and washing the reaction solution for 3 times, and finally, freeze-drying and grinding to obtain white powder musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
The musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound prepared in example 2 had drug loading rate and encapsulation efficiency of 7.31% and 41.76%.
Example 3
(1) 1g of musk extract is weighed and dissolved in 50mL of absolute ethyl alcohol, and the musk extract is dispersed for 2 hours by ultrasonic waves to prepare an absolute ethyl alcohol solution of musk extract with the mass concentration of 2 percent;
(2) Weighing 15g of hydroxypropyl-beta-cyclodextrin, dissolving in 50mL of deionized water, and performing ultrasonic dispersion for 1h to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution with the mass concentration of 30%;
(3) Sequentially taking 50mL and 17.24mL of the solution according to the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract of 1:0.8, dropwise adding the musk extract absolute ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution at the speed of 2mL/min at the temperature of 30 ℃, and clathrating for 3h by utilizing an ultrasonic method to obtain a pure white emulsion reaction liquid;
(4) Repeatedly filtering and washing the reaction solution for 3 times, and finally, freeze-drying and grinding to obtain white powder musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
The musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound prepared in example 3 had drug loading rate and encapsulation efficiency of 8.76% and 52.50%.
Example 4
(1) 1g of musk extract is weighed and dissolved in 50mL of absolute ethyl alcohol, and the musk extract is dispersed for 2 hours by ultrasonic waves to prepare an absolute ethyl alcohol solution of musk extract with the mass concentration of 2 percent;
(2) Weighing 15g of hydroxypropyl-beta-cyclodextrin, dissolving in 50mL of deionized water, and performing ultrasonic dispersion for 1h to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution with the mass concentration of 30%;
(3) Sequentially transferring 50mL and 25.86mL of the solution according to the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract of 1:1.2, dropwise adding the musk extract absolute ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution at the speed of 2mL/min at the temperature of 30 ℃, and clathrating for 3h by utilizing an ultrasonic method to obtain a pure white emulsion reaction liquid;
(4) Repeatedly filtering and washing the reaction solution for 3 times, and finally, freeze-drying and grinding to obtain white powder musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
The musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound prepared in example 4 had drug loading rate and encapsulation efficiency of 13.72% and 80.78%.
Example 5
(1) 1g of musk extract is weighed and dissolved in 50mL of absolute ethyl alcohol, and the musk extract is dispersed for 2 hours by ultrasonic waves to prepare an absolute ethyl alcohol solution of musk extract with the mass concentration of 2 percent;
(2) Weighing 15g of hydroxypropyl-beta-cyclodextrin, dissolving in 50mL of deionized water, and performing ultrasonic dispersion for 1h to prepare a hydroxypropyl-beta-cyclodextrin aqueous solution with the mass concentration of 30%;
(3) Sequentially taking 50mL and 30.17mL of the solution according to the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract of 1:1.4, dropwise adding the musk extract absolute ethanol solution into the hydroxypropyl-beta-cyclodextrin aqueous solution at the speed of 2mL/min at the temperature of 30 ℃, and clathrating for 3h by utilizing an ultrasonic method to obtain a pure white emulsion reaction liquid;
(4) Repeatedly filtering and washing the reaction solution for 3 times, and finally, freeze-drying and grinding to obtain white powder musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
The musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound prepared in example 5 had drug loading rate and encapsulation efficiency of 10.29% and 62.66%.
The above-described embodiments are only preferred embodiments of the invention, and not all embodiments of the invention are possible. Any obvious modifications thereof, which would be apparent to those skilled in the art without departing from the principles and spirit of the present invention, should be considered to be included within the scope of the appended claims.
Claims (9)
1. A musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound is characterized in that volatile oil extracted from natural/artificial musk and hydroxypropyl-beta-cyclodextrin are prepared into the inclusion compound, and the molar ratio of the hydroxypropyl-beta-cyclodextrin to the musk extract is 1 (0.6-2).
2. A method for preparing musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound, which is characterized by comprising the following steps:
(1) Adding musk extract into absolute ethyl alcohol, and performing ultrasonic dispersion to obtain solution A;
(2) Adding hydroxypropyl-beta-cyclodextrin into deionized water for ultrasonic dispersion to obtain a solution B;
(3) Respectively transferring a certain amount of solution A, B, slowly dripping the solution A into the solution B, clathrating at a certain temperature to obtain pure white emulsion, and marking as solution C;
(4) Filtering the solution C with a filter membrane for multiple times, removing the solvent, and grinding to obtain the musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound.
3. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the specific step (1) is to dissolve musk extract in absolute ethyl alcohol to prepare an ethanol solution of musk extract with a mass concentration of 1.5-2.5%.
4. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the ultrasonic dispersion time in the step (1) is 0.5 to 2 hours.
5. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the specific step of the step (2) is to dissolve the hydroxypropyl-beta-cyclodextrin in deionized water to prepare an aqueous solution of the hydroxypropyl-beta-cyclodextrin with a mass concentration of 15-35%.
6. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the ultrasonic dispersion time in the step (2) is 0.5 to 2 hours.
7. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the inclusion method in the step (3) is any one of a solution stirring method, an ultrasonic method and a grinding method.
8. The method for preparing musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the dropping speed in the inclusion process in the step (3) is 1-3mL/min, the inclusion temperature is 25-45 ℃, and the inclusion time is 2-4h.
9. The method for preparing a musk extract/hydroxypropyl-beta-cyclodextrin inclusion compound according to claim 2, wherein the method for removing the solvent used in the step (4) is any one of rotary evaporation, freeze-drying and vacuum-drying.
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