CN113018457B - Cyclodextrin inclusion compound and preparation method thereof - Google Patents
Cyclodextrin inclusion compound and preparation method thereof Download PDFInfo
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- CN113018457B CN113018457B CN201911356111.5A CN201911356111A CN113018457B CN 113018457 B CN113018457 B CN 113018457B CN 201911356111 A CN201911356111 A CN 201911356111A CN 113018457 B CN113018457 B CN 113018457B
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- cyclodextrin
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- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 207
- 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 title claims abstract description 148
- 150000001875 compounds Chemical class 0.000 title claims abstract description 112
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims abstract description 104
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 57
- 235000001510 limonene Nutrition 0.000 claims abstract description 52
- 229940087305 limonene Drugs 0.000 claims abstract description 52
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims abstract description 47
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims abstract description 47
- 229960005233 cineole Drugs 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 42
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 claims abstract description 36
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000001116 FEMA 4028 Substances 0.000 claims description 53
- 229960004853 betadex Drugs 0.000 claims description 53
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 52
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 50
- 238000009210 therapy by ultrasound Methods 0.000 claims description 48
- 239000007864 aqueous solution Substances 0.000 claims description 46
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 10
- 238000000527 sonication Methods 0.000 claims description 10
- 229940097362 cyclodextrins Drugs 0.000 claims description 4
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 claims description 3
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 claims description 3
- 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 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract description 5
- 239000003921 oil Substances 0.000 description 50
- 241000219927 Eucalyptus Species 0.000 description 39
- 239000003814 drug Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 10
- 229940044949 eucalyptus oil Drugs 0.000 description 9
- 239000010642 eucalyptus oil Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000005538 encapsulation Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000007957 coemulsifier Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003505 terpenes Chemical class 0.000 description 3
- 235000007586 terpenes Nutrition 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RNDWKTXORDRTGV-UHFFFAOYSA-N 2-(dimethylamino)benzaldehyde;sulfuric acid Chemical compound OS(O)(=O)=O.CN(C)C1=CC=CC=C1C=O RNDWKTXORDRTGV-UHFFFAOYSA-N 0.000 description 1
- AFQZCQOQPQIISR-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde;sulfuric acid Chemical compound OS(O)(=O)=O.CN(C)C1=CC=C(C=O)C=C1 AFQZCQOQPQIISR-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XJTKWFCOWXLOFT-UHFFFAOYSA-N acetonitrile;propan-2-ol;hydrate Chemical compound O.CC#N.CC(C)O XJTKWFCOWXLOFT-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention relates to a cyclodextrin inclusion compound and a preparation method thereof. The provided cyclodextrin inclusion compound comprises a pharmaceutical composition and cyclodextrin or a derivative thereof; the pharmaceutical composition comprises: 35-65 parts of eucalyptol, 15-50 parts of limonene and 10-30 parts of alpha-pinene. The cyclodextrin inclusion compound provided can be prepared by an ultrasonic method. The cyclodextrin inclusion compound provided by the invention has strong stability and obviously increased solubility, and can be used for preparing different dosage forms.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a cyclodextrin inclusion compound and a preparation method thereof, and specifically relates to a cyclodextrin inclusion compound containing eucalyptol, limonene and alpha-pinene and a preparation method thereof.
Background
The pharmaceutical composition containing eucalyptol, limonene and alpha-pinene is taken as a mucolytic expectorant with definite curative effect, but the pharmaceutical composition is easy to volatilize and irritant, and is easy to lose when being directly added into a preparation, so that the curative effect of the preparation can be influenced, the stability of the preparation taking the pharmaceutical composition as a raw material medicine can be influenced, and the pharmaceutical composition has certain irritation to gastrointestinal tracts after being directly taken.
Chinese patent application with application number 201910036486.7 and publication number CN109528649A discloses a self-emulsifying oral preparation of terpene pharmaceutical compositions, a preparation method and application thereof, wherein the disclosed oral preparation comprises the following components in percentage by mass (1-5): 10 and a pharmaceutical carrier; the pharmaceutical composition comprises, by total mass of the pharmaceutical composition, 40-65 wt% of eucalyptol, 25-45 wt% of limonene and 5-20 wt% of alpha-pinene; the drug carrier comprises, by weight, 10-50% of oil, 40-80% of an emulsifier and 5-30% of a co-emulsifier. By utilizing the mutual matching of the grease, the emulsifier, the co-emulsifier and the pharmaceutical composition containing the eucalyptol, the limonene and the alpha-pinene, the self-emulsifying liquid medicine of the terpene pharmaceutical composition has stable and uniform properties, the quality stability of the self-emulsifying oral preparation of the terpene pharmaceutical composition is improved, the taste of the pharmaceutical composition is covered, and the irritation of the medicine to the gastrointestinal tract is reduced. However, since self-emulsifying oral formulations need to be prepared with the aid of emulsifiers, co-emulsifiers, oils and the like, the stability of pharmaceutical compositions comprising eucalyptol, limonene and alpha-pinene may be affected over time.
Published in the literature of Shizhen national medicine, the research on the preparation process of the eucalyptus oil beta-cyclodextrin inclusion compound researches the preparation of the inclusion compound by mixing beta-cyclodextrin and absolute ethanol solution of eucalyptus oil (containing more than 70 percent of eucalyptol, and also containing limonene, alpha-pinene and the like). The study shows that the optimal process for inclusion is as follows: beta-cyclodextrin: eucalyptus oil 8:1, cyclodextrin: the ratio of water is 1:10, the inclusion time is 1h, and the inclusion temperature is 30 ℃. However, it is unknown how inclusion is effected by inclusion of eucalyptus oil, which contains different amounts of components. Moreover, because a large amount of beta-cyclodextrin is used during the inclusion, the eucalyptus oil component in the prepared inclusion compound is less, even the inclusion compound only contains a trace amount of the eucalyptus oil component, and the medicine components in the prepared inclusion compound can not achieve the medicine effect and can not meet the purpose of preparation.
Further improvements are therefore needed for the stability and formulation of pharmaceutical compositions comprising eucalyptol, limonene and alpha-pinene.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a cyclodextrin inclusion compound and a preparation method thereof, and particularly provides the cyclodextrin inclusion compound containing eucalyptol, limonene and alpha-pinene and the preparation method thereof.
The inClusion technique refers to a technique in which one molecule is embedded in a cavity structure of another molecule to form an inClusion Compound (inClusion Compound). The inclusion compound is formed by the addition of host mo1eCUle and guest moleCule, wherein the host moleCule has a large cavity structure enough to contain the guest molecules to form a molecular capsule. The medicine is used as guest molecule to be included, the solubility is increased, the stability is improved, the liquid medicine can be powdered, the volatilization of volatile components can be prevented, the bad smell or taste of the medicine can be covered, the medicine release rate can be adjusted, the bioavailability of the medicine can be improved, the irritation and toxic and side effects of the medicine can be reduced, and the like. The invention uses the saturated aqueous solution of cyclodextrin or cyclodextrin derivatives to perform inclusion on the pharmaceutical composition containing eucalyptol, limonene and alpha-pinene to obtain the cyclodextrin inclusion compound, which can effectively cover pungent odor, reduce drug volatilization and improve drug solubility.
Specifically, the invention provides the following technical scheme:
in a first aspect of the invention, the invention provides a cyclodextrin inclusion compound comprising: pharmaceutical compositions and cyclodextrins or derivatives thereof; the pharmaceutical composition comprises: 35-65 parts of eucalyptol, 15-50 parts of limonene and 10-30 parts of alpha-pinene. The invention uses the cyclodextrin inclusion technology and uses cyclodextrin or derivatives thereof to carry out inclusion on the pharmaceutical composition containing eucalyptol, limonene and alpha-pinene, the stability of the obtained cyclodextrin inclusion compound is obviously increased, and the solubility of the prepared inclusion compound is obviously increased. The cyclodextrin inclusion compound can be used for preparing different dosage forms, such as tablets, capsules, suspensions, ointments and other dosage forms, and has wide development prospect. In addition, the pharmaceutical composition comprising 35-65 parts by weight of eucalyptol, 15-50 parts by weight of limonene and 10-30 parts by weight of alpha-pinene is easier to be included in cyclodextrin, and the obtained cyclodextrin inclusion compound is easier to meet the requirement of medication.
According to an embodiment of the present invention, the cyclodextrin inclusion compound described above may further include the following technical features:
in some embodiments of the present invention, the mass ratio of the pharmaceutical composition to the cyclodextrin or the derivative thereof is (1-6): 1. therefore, the cyclodextrin inclusion compound with high yield can be obtained, the content of the pharmaceutical composition in the cyclodextrin inclusion compound is high, and the requirement of medicine is met.
In some embodiments of the present invention, the mass ratio of the pharmaceutical composition to the cyclodextrin or the derivative thereof is (2-5): 1. therefore, the cyclodextrin inclusion compound with high yield can be obtained, the content of the pharmaceutical composition in the cyclodextrin inclusion compound is high, and the requirement of medicine is met.
In some embodiments of the invention, the cyclodextrin comprises at least one selected from α -cyclodextrin, β -cyclodextrin, or γ -cyclodextrin; beta-cyclodextrin is preferred.
In some embodiments of the invention, the cyclodextrin derivative is selected from at least one of methyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, dihydroxypropyl- β -cyclodextrin.
In some embodiments of the invention, the pharmaceutical composition comprises: 42-55 parts of eucalyptol, 35-45 parts of limonene and 12-18 parts of alpha-pinene. For example, in some preferred embodiments, the pharmaceutical composition includes 50 parts by weight eucalyptol, 38 parts by weight limonene and 12 parts by weight alpha pinene. Under the condition, the cyclodextrin inclusion compound with high yield can be obtained.
In a second aspect, the present invention provides a pharmaceutical formulation comprising a cyclodextrin inclusion complex according to any one of the embodiments of the first aspect of the present invention and a pharmaceutically acceptable excipient. The cyclodextrin inclusion compound and pharmaceutically acceptable auxiliary materials such as a lubricant, a binder, a disintegrating agent, a diluent, a sweetening agent and the like can be prepared into different dosage forms such as capsules, tablets, pills and other dosage forms to meet different requirements.
In a third aspect of the present invention, there is provided a method for preparing a cyclodextrin inclusion complex, which is the cyclodextrin inclusion complex according to any one of the embodiments of the first aspect of the present invention, comprising: preparing supersaturated aqueous solution of cyclodextrin or its derivative, filtering to obtain saturated aqueous solution of cyclodextrin or its derivative; mixing a saturated aqueous solution of the cyclodextrin or the derivative thereof with the pharmaceutical composition, and subjecting to sonication, so as to obtain the cyclodextrin inclusion compound. In the course of research, it was found that when a pharmaceutical composition as an active ingredient is included with cyclodextrin or a derivative thereof, the inclusion efficiency of cyclodextrin or a derivative thereof is affected by the difference in the preparation method. Research shows that compared with the stirring method for inclusion, the ultrasonic method can be used for effectively including the pharmaceutical composition containing the eucalyptol, the limonene and the alpha-pinene into the cyclodextrin, so that the cyclodextrin inclusion compound with high yield can be obtained.
According to an embodiment of the present invention, the above-described method for preparing a cyclodextrin inclusion compound may further include the following technical features:
in some embodiments of the present invention, the temperature of the ultrasonic treatment is 20 to 60 degrees Celsius, preferably 20 to 40 degrees Celsius, and more preferably 28 to 32 degrees Celsius. The cyclodextrin inclusion is carried out at the temperature of 20-60 ℃, so that the cyclodextrin inclusion compound with high yield can be obtained, particularly, the inclusion is carried out at the temperature of 20-40 ℃, the yield of the cyclodextrin inclusion compound is over 91 percent, the inclusion is carried out at the temperature of 30 ℃, and the yield of the cyclodextrin inclusion compound is over 94 percent.
In some embodiments of the present invention, the time of the ultrasonic treatment is 0.5 to 3 hours, preferably 1 to 1.5 hours. The cyclodextrin inclusion compound with high yield can be obtained by ultrasonic treatment for 0.5 to 3 hours, particularly ultrasonic treatment for 1 to 1.5 hours.
In some embodiments of the invention, the frequency of the sonication is between 30KHZ and 100KHZ, preferably between 40KHZ and 50 KHZ. Thus, high yields of cyclodextrin inclusion compounds can be obtained.
In some embodiments of the invention, the method comprises: providing a supersaturated aqueous solution of beta-cyclodextrin, and filtering to obtain a saturated aqueous solution of beta-cyclodextrin; mixing the saturated aqueous solution of beta-cyclodextrin with the pharmaceutical composition comprising 50 parts by weight of eucalyptol, 38 parts by weight of limonene and 12 parts by weight of alpha-pinene, and subjecting to ultrasonic treatment so as to obtain the cyclodextrin inclusion compound; the temperature of ultrasonic treatment is 30 ℃, the time of ultrasonic treatment is 1 hour, and the frequency of ultrasonic treatment is 40 KHZ. Therefore, the cyclodextrin inclusion compound with high yield and high encapsulation efficiency can be obtained.
In a fourth aspect of the present invention, there is provided a cyclodextrin inclusion compound, characterized by comprising: the pharmaceutical composition and the beta-cyclodextrin are mixed according to a mass ratio of (2-5) to 1; the pharmaceutical composition comprises: 45-55 parts of eucalyptol, 35-45 parts of limonene and 12-18 parts of alpha-pinene by weight; the cyclodextrin inclusion compound is prepared by the following method: providing a supersaturated aqueous solution of beta-cyclodextrin, and filtering to obtain a saturated aqueous solution of beta-cyclodextrin; mixing said saturated aqueous solution of β -cyclodextrin with said pharmaceutical composition, and subjecting to sonication, so as to obtain said cyclodextrin inclusion compound; the temperature of ultrasonic treatment is 28-32 ℃, the time of ultrasonic treatment is 1-1.5 hours, and the frequency of ultrasonic treatment is 40-50 KHZ. Therefore, the cyclodextrin inclusion compound with high yield and high encapsulation rate can be obtained, and the inclusion can cover the pungent odor of eucalyptol, limonene and alpha-pinene, reduce the volatilization of the medicine and improve the solubility of the medicine.
Drawings
FIG. 1 is an infrared absorption spectrum of various substances provided according to an embodiment of the present invention.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative, and is not to be construed as limiting the invention. Herein, a pharmaceutical composition consisting of eucalyptol, limonene and alpha-pinene is also referred to as eucalyptol pinene oil.
The invention provides a cyclodextrin inclusion compound, which comprises the following components: pharmaceutical compositions and cyclodextrins or derivatives thereof; the pharmaceutical composition comprises: 35-65 parts of eucalyptol, 15-50 parts of limonene and 10-30 parts of alpha-pinene. The provided cyclodextrin inclusion compound is verified to improve the solubility, reduce the volatilization of the medicine and cover the pungent smell of the medicine composition.
Among the useful cyclodextrins according to embodiments of the present invention are, but not limited to: α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin or the like, preferably β -cyclodextrin. Useful cyclodextrin derivatives include, but are not limited to, methyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, and the like.
According to a preferred embodiment of the invention, the pharmaceutical composition in the cyclodextrin inclusion complex comprises: 50 parts by weight of eucalyptol, 38 parts by weight of limonene and 12 parts by weight of alpha-pinene.
According to an embodiment of the present invention, the provided cyclodextrin inclusion compound may be prepared by an ultrasonic method. In at least some embodiments of the present invention, there is provided a method of preparing a cyclodextrin inclusion complex, comprising: providing a supersaturated aqueous solution of cyclodextrin or a derivative thereof, and filtering to obtain a saturated aqueous solution of cyclodextrin or a derivative thereof; mixing a saturated aqueous solution of the cyclodextrin or the derivative thereof with the pharmaceutical composition, and subjecting to sonication, so as to obtain the cyclodextrin inclusion compound. And refrigerating the product subjected to ultrasonic treatment overnight, filtering by suction filtration, and drying filter residues at the temperature of 30-50 ℃ to obtain the cyclodextrin inclusion compound.
According to the embodiment of the invention, the temperature of the ultrasonic treatment is 20-60 ℃, preferably 20-40 ℃, and more preferably 30 ℃. According to an embodiment of the present invention, the time of the ultrasonic treatment is 0.5 to 3 hours, preferably 1 to 1.5 hours. The frequency of the ultrasonic treatment can be 30KHZ to 100KHZ, and is preferably 40 KHZ.
In some preferred embodiments of the present invention, the present invention provides a cyclodextrin inclusion complex comprising a pharmaceutical composition and a β -cyclodextrin, wherein the pharmaceutical composition and the β -cyclodextrin are present in a mass ratio of 2: 1; the pharmaceutical composition comprises: 50 parts by weight of eucalyptol, 38 parts by weight of limonene and 12 parts by weight of alpha-pinene; the cyclodextrin inclusion compound is prepared by the following method: providing a supersaturated aqueous solution of beta-cyclodextrin, and filtering to obtain a saturated aqueous solution of beta-cyclodextrin; mixing said saturated aqueous solution of β -cyclodextrin with said pharmaceutical composition, and subjecting to sonication, so as to obtain said cyclodextrin inclusion compound; the temperature of ultrasonic treatment is 30 ℃, the time of ultrasonic treatment is 1 hour, and the frequency of ultrasonic treatment is 40 KHZ. Thus, the cyclodextrin inclusion compound with high yield and high encapsulation efficiency can be obtained.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
Example 1 compares the differences of cyclodextrin inclusion compounds prepared by different methods, including an ultrasonic method and a stirring method respectively, and specifically includes the following contents:
experimental group 1
Experiment group 1 cyclodextrin inclusion compound containing eucalyptus and pinene oil was prepared by ultrasonic method, and the experimental steps were as follows:
2g of beta-cyclodextrin (beta-CD) is weighed and dissolved in 100mL of purified water at the temperature of 20 ℃ to prepare supersaturated aqueous solution, and the supersaturated aqueous solution is obtained by filtration. Adding 1g of eucalyptol and pinene oil (including 0.5g of eucalyptol, 0.38g of limonene and 0.12g of alpha-pinene), performing ultrasonic treatment at 20 deg.C for 1h, refrigerating overnight, filtering, and drying the filter residue at 40 deg.C to obtain cyclodextrin clathrate containing eucalyptol and pinene oil.
Experimental group 2
Experiment group 2 a cyclodextrin inclusion compound containing eucalyptus and pinene oil was prepared by a stirring method, and the experiment steps were as follows:
2g of beta-CD is weighed and dissolved in 100mL of purified water at the temperature of 20 ℃ to prepare supersaturated aqueous solution, and the supersaturated aqueous solution is obtained by filtration. Dripping 1g of eucalyptus and limonene oil (comprising 0.5g of eucalyptol, 0.38g of limonene and 0.12g of alpha-pinene) under stirring at 20 ℃, stirring for 1h, cooling overnight, filtering by suction filtration, and drying filter residues at 40 ℃ to obtain the cyclodextrin inclusion compound containing the eucalyptus and limonene oil.
The cyclodextrin inclusion compounds containing eucalyptus and pinene oils prepared in experimental groups 1 and 2 were identified by first extracting the eucalyptus and pinene oils from the inclusion compounds and identifying the extracted eucalyptus and pinene oils. The method comprises the following specific steps:
extracting eucalyptus and pinene oil in the inclusion compound: 0.5g of each of the samples obtained in the experimental group 1 and the experimental group 2 was weighed, placed in a test tube, 3ml of absolute ethyl alcohol was added, sonicated in a sonicator for 30 minutes, left to stand overnight, and the supernatant was taken for the following discrimination:
(1) collecting 1 drop of supernatant, adding 1ml of chloroform for dissolving, adding 5% bromine in chloroform solution, and removing red color if the supernatant contains pharmaceutical composition (i.e. eucalyptus oil).
(2) Collecting 1 drop of supernatant, adding p-dimethylaminobenzaldehyde sulfuric acid solution, and if the supernatant contains the pharmaceutical composition, the solution should be orange yellow first and then become orange red gradually.
The results show that the phenomenon is more obvious no matter the inclusion compound prepared by the ultrasonic method in the experimental group 1 is identified by using chloroform or a dimethylaminobenzaldehyde sulfuric acid test solution compared with the inclusion compound prepared by the stirring method, so that the cyclodextrin inclusion compound containing eucalyptus and limonene oil is prepared by the ultrasonic method, the preparation yield is higher, and the method is better.
Example 2
Example 2 an ultrasonic method was used to prepare cyclodextrin inclusion compounds and study the effect of beta-cyclodextrin and eucalyptol and pinene oil on cyclodextrin inclusion compound yield under different mass ratios.
Respectively weighing 0.74g of beta-CD (beta-CD) at 20 ℃, adding purified water to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution; then, different amounts of eucalyptol and pinene oil (as shown in table 1 below, wherein eucalyptol and limonene are added in amounts of 50 wt%, 38 wt%, and 12 wt%, respectively) were added to the beta-CD: the weight ratio of eucalyptus and pinene oil is 1:1.08, 1:2, 1:5, 1:8, 1:10, 1:15(g/g, the specific weight is shown in the following table 1), ultrasonic treatment is carried out for 1h at 20 ℃, cooling is carried out overnight, suction filtration is carried out, and filter residue is dried at 40 ℃. The clathrate yield was calculated according to the following equation.
Wherein, in the formula, the actual yield is the amount of the cyclodextrin inclusion compound obtained after drying. Theoretical moles in theoretical yield refer to the moles of eucalyptus citrapine oil and the smaller moles of cyclodextrin material. The number of moles refers to the number of molecules contained in a substance having a certain mass, and the number of moles can be obtained by dividing the mass of the substance by the molecular weight. The molecular weight of the eucalyptus limonene oil is calculated by the average molecular weight of the eucalyptus limonene oil, the average molecular weight is obtained by multiplying the molecular weight of each component in the eucalyptus limonene oil by the percentage of the component, and then adding; accordingly, the moles of eucalyptus and pinene oil may be obtained by dividing the mass of the eucalyptus and pinene oil by the molecular weight of the eucalyptus and pinene oil.
TABLE 1 Cyclodextrin inclusion compounds obtained at different formulation ratios
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Beta-cyclodextrin | 0.74g | 0.74g | 0.74g | 0.74g | 0.74g | 0.74g |
| Eucalyptus and pinene oil | 0.800g | 1.486g | 3.770g | 6.021g | 7.412g | 11.119g |
| Inclusion compound | 0.642g | 0.778g | 0.772g | 0.748g | 0.725g | 0.686g |
| Yield (%) | 77.09 | 93.42 | 92.70 | 89.82 | 87.05 | 82.37 |
As can be seen from table 1, when the mass ratio of the eucalyptus limonene oil to the cyclodextrin is 2:1, the maximum yield of the prepared cyclodextrin inclusion compound is more than 93%, and when the mass ratio of the eucalyptus limonene oil to the cyclodextrin is 5:1, the yield of the prepared cyclodextrin inclusion compound is more than 92%.
Example 3
Example 3 cyclodextrin inclusion compounds were prepared by an ultrasonic method, and the effect of inclusion at different temperatures on cyclodextrin inclusion compound yield was studied.
Weighing 0.74g of beta-cyclodextrin, adding purified water to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution. Then 2 times of eucalyptus and pinene oil (the eucalyptus and pinene oil comprises 50 wt% of eucalyptol, 38 wt% of limonene and 12 wt% of alpha-pinene, the actual weight of the eucalypt and pinene oil is shown in the following table 2) is added, the cyclodextrin inclusion compound is prepared by ultrasonic at different inclusion temperatures of 20 ℃, 30 ℃, 40 ℃, 50 ℃ and 60 ℃, the ultrasonic time is 1h, the ultrasonic frequency is 40KHz, after the ultrasonic treatment, the cyclodextrin inclusion compound is cooled overnight, filtered, and the filter residue is dried at 40 ℃ to obtain the cyclodextrin inclusion compound. And the yield of the clathrate was calculated in the same manner as in example 2.
TABLE 2 Cyclodextrin inclusion complexes obtained by inclusion at different temperatures
| Temperature of | 20℃ | 30℃ | 40℃ | 50℃ | 60℃ |
| Beta-cyclodextrin | 0.74g | 0.74g | 0.74g | 0.74g | 0.74g |
| Eucalyptus and pinene oil | 1.482g | 1.490g | 1.474g | 1.488g | 1.480g |
| Inclusion compound | 0.766g | 0.786g | 0.762g | 0.753g | 0.728g |
| Yield (%) | 91.98 | 94.38 | 91.50 | 90.42 | 87.41 |
It can be seen from table 2 that the temperature has a slightly smaller effect on the cyclodextrin inclusion compound yield compared to the mass ratio of cyclodextrin to eucalyptol and pinene oil. The inclusion is carried out at the temperature of 20-60 ℃, the obtained cyclodextrin inclusion compound has high yield, particularly, the inclusion is carried out at the temperature of 20-40 ℃, the yield of the cyclodextrin inclusion compound is over 91 percent, the inclusion is carried out at the temperature of 30 ℃, and the yield of the cyclodextrin inclusion compound reaches over 94 percent.
Example 4
Example 4 adopts the ultrasonic method to prepare the cyclodextrin inclusion compound, and studies the influence of the ultrasonic treatment time on the cyclodextrin inclusion compound yield.
Weighing 0.74g of beta-cyclodextrin, adding purified water to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution. Then 2 times of eucalyptus and pinene oil (the eucalyptus and pinene oil comprises 50% by weight of eucalyptol, 38% by weight of limonene and 12% by weight of alpha-pinene, the actual weight of the eucalyptol and pinene oil is shown in table 3) is added, ultrasonic treatment is carried out at 30 ℃, the ultrasonic treatment time is 0.5h, 1.0h, 1.5h, 2.0h, 2.5h and 3.0h respectively, the ultrasonic frequency is 40KHz, cooling is carried out overnight after the ultrasonic treatment is finished, suction filtration is carried out, filter residues are dried at 40 ℃, and the cyclodextrin inclusion compound is obtained. And the yield of the clathrate was calculated in the same manner as in example 2.
TABLE 3 Cyclodextrin inclusion complexes obtained at different inclusion times
| Time | 0.5h | 1.0h | 1.5h | 2.0h | 2.5h | 3.0h |
| Beta-cyclodextrin | 0.74g | 0.74g | 0.74g | 0.74g | 0.74g | 0.74g |
| Eucalyptus and pinene oil | 1.492g | 1.479g | 1.480g | 1.482g | 1.488g | 1.484g |
| Inclusion compound | 0.768g | 0.789g | 0.762g | 0.758g | 0.753g | 0.75g |
| Yield (%) | 92.22 | 94.74 | 91.50 | 91.02 | 90.42 | 90.06 |
As can be readily seen from the results shown in table 3, the sonication time has a slightly less effect on the cyclodextrin inclusion complex yield compared to the mass ratio of cyclodextrin to eucalyptol and pinene oil. The cyclodextrin inclusion compound with high yield can be obtained no matter the ultrasonic treatment is carried out for 0.5 hour or 3 hours, and the yield of the obtained cyclodextrin inclusion compound is more than 90 percent. Especially, the yield of the cyclodextrin inclusion compound obtained by ultrasonic treatment for 1 hour is more than 94 percent.
Example 5
Example 5 verification of cyclodextrin inclusion complex inclusion by preparing cyclodextrin inclusion complexes and performing infrared absorption spectroscopy characterization of the prepared cyclodextrin inclusion complexes comprises the steps of:
weighing 0.74g of beta-cyclodextrin at 30 ℃, adding purified water to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution; then adding 1.486g of eucalyptol and pinene oil (comprising 42 percent by weight of eucalyptol, 43 percent by weight of limonene and 15 percent by weight of alpha-pinene) and carrying out ultrasonic treatment, wherein the ultrasonic frequency is 40KHz, the ultrasonic time is 1.0h, and the ultrasonic temperature is 30 ℃. And after the ultrasonic treatment is finished, cooling overnight, performing suction filtration, and drying filter residues at 40 ℃ to obtain the cyclodextrin inclusion compound.
The prepared cyclodextrin inclusion compound is subjected to infrared absorption spectrum characterization, and eucalyptus limonene oil, cyclodextrin blank contrast and eucalyptus limonene oil-cyclodextrin physical mixture are subjected to infrared absorption spectrum characterization, the results are shown in fig. 1 and table 4, and substances corresponding to different characteristic peak positions are shown in table 4.
TABLE 4 Eucalyptus and pinene oil characteristic peak positions
As can be seen from FIG. 1 in conjunction with Table 4, the cyclodextrin inclusion compound was observed at 2964, 1446, 1211, 984, 918, 790cm -1 The absorption of characteristic peaks at the wavelength is clearly absent, which proves that the eucalyptus limonene oil is successfully included.
Example 6
Example 6 the effect of the temperature and time of sonication and the mass ratio of cyclodextrin to pharmaceutical composition on the yield of cyclodextrin inclusion compound and the encapsulation efficiency when the inclusion was performed by sonication was investigated by orthogonal experiments. The method comprises the following steps: the set values for the various factors of the orthogonal experiment are shown in table 5, and the different protocols designed according to the different factor levels, as well as the yields of the clathrates obtained and the encapsulation yields are given in table 6. Wherein the used pharmaceutical composition comprises 50 percent by weight of eucalyptol, 38 percent by weight of limonene and 12 percent by weight of alpha-pinene. Specific inclusion procedure referring to experimental group 1 of example 1 above, cyclodextrin inclusion compound containing eucalyptus and pinene oil was prepared by an ultrasonic method.
TABLE 5 factor level table
TABLE 6 orthogonal experimental design sheet
The encapsulation efficiency of the cyclodextrin inclusion compound is detected by a high performance liquid chromatography method, and the specific detection conditions are as follows:
weighing appropriate amount of cyclodextrin clathrate, adding anhydrous ethanol, performing ultrasonic treatment, standing overnight, collecting supernatant to obtain extractive solution, and detecting with high performance liquid chromatography. The chromatographic conditions are as follows: a chromatographic column: agilent C184.6 × 250mm, 5 μm; mobile phase: acetonitrile-water-isopropanol (volume ratio 65:32: 3); flow rate: 1 ml/min; detection wavelength: 205 nm; column temperature: 35 ℃; sample introduction amount: 20 μ L. Detecting the content of the three substances in the extracting solution, and calculating the encapsulation efficiency.
The content detected in the formula is the amount of eucalyptol, limonene and alpha-pinene detected by a high-phase liquid chromatography method, and the theoretical mole number refers to the mole number of substances with smaller mole number in eucalyptol and cyclodextrin. Wherein the mol number of the eucalyptus limonene oil is the same as the mol number of the eucalyptus limonene oil in the formula 1.
The results are shown in Table 6. According to the results of orthogonal experiments, the clathrate compound can be successfully prepared by different proportions and different processes, but the optimal preparation conditions are as follows: the mass ratio of the beta-cyclodextrin to the eucalyptus citrapini oil is 1:2, the preparation temperature is 30 ℃, and the preparation time is 1.0 hour.
Comparative example 1
Cyclodextrin inclusion compounds were prepared according to the raw material ratios in table 7: weighing 1.85g of beta-cyclodextrin, adding water at 25 ℃ to prepare supersaturated aqueous solution, filtering to obtain saturated aqueous solution, adding mixed eucalyptus and pinene oil (mixed according to the components in Table 7), placing in an ultrasonic cleaner for ultrasonic treatment at 30 ℃, ultrasonic frequency of 40KHz and ultrasonic time of 1.0h, refrigerating overnight, filtering, and drying filter residue at 40 ℃ to obtain the clathrate.
TABLE 7 raw material proportions
| Eucalyptol | 0.15g |
| Limonene | 0.09g |
| Alpha-pinene | 0.03g |
| Beta-cyclodextrin | 1.85g |
| Purified water | 100g(ml) |
| Total up to | 102.12g |
The calculated yield of the cyclodextrin inclusion compound reaches 73.5 percent, but the identification reaction does not appear in the process of extracting eucalyptus limonene oil and identifying, which indicates that eucalyptus limonene oil cannot be extracted from the inclusion compound prepared by the formula, and proves that the inclusion compound does not wrap medicines or the medicine content is extremely low, the prepared inclusion compound possibly cannot meet the requirement of the medicine effect, so the formula is not used for carrying out experiments.
Comparative example 2
Preparing cyclodextrin inclusion compound according to the raw material ratio in table 8: weighing 4.00g of beta-cyclodextrin, adding water at 25 ℃ to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution. Adding eucalyptol, ultrasonic cleaning at 30 deg.C and 40KHz for 1.0 hr in an ultrasonic cleaner, refrigerating overnight, filtering, and drying the residue at 40 deg.C to obtain clathrate.
TABLE 8 raw material proportions
| Eucalyptus oil extract | 1.0811g(1ml) |
| Beta-cyclodextrin | 4.0035g |
| Purified water | 212g(ml) |
| Total up to | 217.0846g |
The calculated inclusion compound yield is only 77%, which shows that the beta-cyclodextrin is utilized to carry out inclusion on a single medicine component, and the cyclodextrin inclusion compound yield is not high. Whereby the pungent odor of the drug cannot be effectively masked by inclusion.
Comparative example 3
Cyclodextrin inclusion compounds were prepared according to the raw material ratios in table 9: weighing 5.00g of beta-cyclodextrin, adding water at 25 ℃ to prepare supersaturated aqueous solution, and filtering to obtain saturated aqueous solution. Adding the mixed eucalyptus and pinene oil (mixed according to the components in Table 9), placing in an ultrasonic cleaner for ultrasonic treatment at 30 deg.C and 40KHz for 1.5h, refrigerating overnight, filtering, and drying the filter residue at 40 deg.C to obtain the clathrate.
TABLE 9 raw material proportions
| Eucalyptus oil extract | 0.75g |
| Limonene | 1.38g |
| Alpha-pinene | 0.35g |
| Beta-cyclodextrin | 5.00g |
| Purified water | 270g(ml) |
| Total up to | 277.48g |
The calculated result shows that the yield of the inclusion compound is 44%, and the result shows that when the amount of the eucalyptus citrapine oil is less than that of the beta-cyclodextrin, the yield of the prepared cyclodextrin is extremely low.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (11)
1. A cyclodextrin inclusion complex, comprising: pharmaceutical compositions and cyclodextrins or derivatives thereof;
the pharmaceutical composition comprises:
35 to 65 parts by weight of eucalyptol,
15 to 50 parts by weight of limonene and
10 to 30 parts by weight of alpha-pinene,
wherein the mass ratio of the pharmaceutical composition to the cyclodextrin or the derivative thereof is (2-5): 1,
the cyclodextrin is beta-cyclodextrin,
the preparation method of the cyclodextrin inclusion compound comprises the following steps:
providing a supersaturated aqueous solution of cyclodextrin or a derivative thereof, and filtering to obtain a saturated aqueous solution of cyclodextrin or a derivative thereof;
mixing a saturated aqueous solution of said cyclodextrin or derivative thereof with said pharmaceutical composition, sonicating to obtain said cyclodextrin inclusion compound,
wherein the temperature of the ultrasonic treatment is 20-60 ℃,
the ultrasonic treatment time is 0.5-3 hours,
the ultrasonic treatment frequency is 30 KHZ-100 KHZ.
2. The cyclodextrin inclusion complex of claim 1, wherein the cyclodextrin derivative comprises at least one selected from the group consisting of methyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, dihydroxypropyl- β -cyclodextrin.
3. The cyclodextrin inclusion complex of claim 1, wherein said pharmaceutical composition comprises: 42-55 parts of eucalyptol, 35-45 parts of limonene and 12-18 parts of alpha-pinene.
4. A pharmaceutical preparation, comprising the cyclodextrin inclusion compound of any one of claims 1 to 3, and a pharmaceutically acceptable excipient.
5. A method for preparing the cyclodextrin inclusion compound of any one of claims 1 to 3, comprising:
providing a supersaturated aqueous solution of cyclodextrin or a derivative thereof, and filtering to obtain a saturated aqueous solution of cyclodextrin or a derivative thereof;
mixing a saturated aqueous solution of said cyclodextrin or derivative thereof with said pharmaceutical composition, sonicating to obtain said cyclodextrin inclusion compound,
wherein the temperature of the ultrasonic treatment is 20-60 ℃,
the ultrasonic treatment time is 0.5-3 hours,
the ultrasonic treatment frequency is 30 KHZ-100 KHZ.
6. The method according to claim 5, wherein the temperature of the ultrasonic treatment is 20 to 40 degrees Celsius.
7. The method according to claim 5, wherein the temperature of the ultrasonic treatment is 28 to 32 degrees Celsius.
8. The method according to claim 5, wherein the time of the ultrasonic treatment is 1 to 1.5 hours.
9. The method of claim 5, wherein the sonication has a frequency of 40-50 KHz.
10. The method of claim 5, comprising:
providing a supersaturated aqueous solution of beta-cyclodextrin, and filtering to obtain a saturated aqueous solution of beta-cyclodextrin;
mixing the saturated aqueous solution of beta-cyclodextrin with the pharmaceutical composition comprising 50 parts by weight of eucalyptol, 38 parts by weight of limonene and 12 parts by weight of alpha-pinene, and subjecting to ultrasonic treatment so as to obtain the cyclodextrin inclusion compound;
the temperature of ultrasonic treatment is 30 ℃, the time of ultrasonic treatment is 1 hour, and the frequency of ultrasonic treatment is 40 KHZ.
11. A cyclodextrin inclusion complex, comprising: the pharmaceutical composition and the beta-cyclodextrin are mixed according to a mass ratio of (2-5) to 1;
the pharmaceutical composition comprises: 42-55 parts of eucalyptol, 35-45 parts of limonene and 12-18 parts of alpha-pinene by weight;
the cyclodextrin inclusion compound is prepared by the following method:
providing supersaturated aqueous solution of beta-cyclodextrin, and filtering to obtain saturated aqueous solution of beta-cyclodextrin;
mixing said saturated aqueous solution of β -cyclodextrin with said pharmaceutical composition, and subjecting to sonication, so as to obtain said cyclodextrin inclusion compound;
the temperature of ultrasonic treatment is 28-32 ℃, the time of ultrasonic treatment is 1-1.5 hours, and the frequency of ultrasonic treatment is 40-50 KHZ.
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