CN113116856B - Eucalyptus and pinene enteric-coated microspheres and preparation method thereof - Google Patents
Eucalyptus and pinene enteric-coated microspheres and preparation method thereof Download PDFInfo
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- CN113116856B CN113116856B CN201911419069.7A CN201911419069A CN113116856B CN 113116856 B CN113116856 B CN 113116856B CN 201911419069 A CN201911419069 A CN 201911419069A CN 113116856 B CN113116856 B CN 113116856B
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- pinene
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- 239000004005 microsphere Substances 0.000 title claims abstract description 58
- 244000166124 Eucalyptus globulus Species 0.000 title claims abstract 4
- 238000002360 preparation method Methods 0.000 title description 22
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims abstract description 44
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000004480 active ingredient Substances 0.000 claims abstract description 32
- 229940087305 limonene Drugs 0.000 claims abstract description 22
- 235000001510 limonene Nutrition 0.000 claims abstract description 22
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960005233 cineole Drugs 0.000 claims abstract description 21
- 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 20
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims abstract description 20
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims abstract description 20
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical group [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 60
- 239000003995 emulsifying agent Substances 0.000 claims description 51
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 45
- 235000010413 sodium alginate Nutrition 0.000 claims description 44
- 239000000661 sodium alginate Substances 0.000 claims description 44
- 229940005550 sodium alginate Drugs 0.000 claims description 44
- 210000003022 colostrum Anatomy 0.000 claims description 37
- 235000021277 colostrum Nutrition 0.000 claims description 37
- 239000003921 oil Substances 0.000 claims description 35
- 239000012071 phase Substances 0.000 claims description 26
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 24
- 229920000053 polysorbate 80 Polymers 0.000 claims description 24
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 23
- 239000004359 castor oil Substances 0.000 claims description 23
- 235000019438 castor oil Nutrition 0.000 claims description 23
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 23
- -1 polyoxyethylene Polymers 0.000 claims description 22
- 239000004615 ingredient Substances 0.000 claims description 20
- 229920001661 Chitosan Polymers 0.000 claims description 17
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 14
- 239000001110 calcium chloride Substances 0.000 claims description 14
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 159000000007 calcium salts Chemical class 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 6
- 238000004132 cross linking Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 3
- 230000000536 complexating effect Effects 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 claims 2
- 229930006728 pinane Natural products 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 239000000839 emulsion Substances 0.000 description 32
- 238000005538 encapsulation Methods 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 241000219927 Eucalyptus Species 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 238000004945 emulsification Methods 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000008188 pellet Substances 0.000 description 8
- JGQMQGZHEUIYIZ-UHFFFAOYSA-L C(C)(=O)O.[Cl-].[Ca+2].[Cl-] Chemical compound C(C)(=O)O.[Cl-].[Ca+2].[Cl-] JGQMQGZHEUIYIZ-UHFFFAOYSA-L 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 238000010008 shearing Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000010642 eucalyptus oil Substances 0.000 description 5
- 229940044949 eucalyptus oil Drugs 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- DGPUYHMCOANORE-UHFFFAOYSA-L calcium;acetic acid;diacetate Chemical compound [Ca+2].CC(O)=O.CC([O-])=O.CC([O-])=O DGPUYHMCOANORE-UHFFFAOYSA-L 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 125000002006 1,8-cineol group Chemical group 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 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
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Mycology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides eucalyptus and limonene enteric-coated microspheres. The eucalyptus and pinene enteric-coated microspheres comprise: a microsphere core oil phase comprising an active ingredient comprising at least one of eucalyptol, limonene, and alpha-pinene; the microsphere skin is wrapped on the surface of the active ingredient and consists of a calcium alginate skeleton. The eucalypt-pinene enteric-coated microspheres provided by the embodiment of the invention are convenient to swallow, improve the compliance of patients, have a slow-release effect and can effectively reduce the administration times.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to eucalyptol and pinene enteric-coated microspheres and a preparation method thereof.
Background
The eucalyptol, limonene and alpha-pinene medicine composition is one kind of mucolytic phlegm eliminating medicine suitable for treating respiratory diseases including acute and chronic nasosinusitis, acute and chronic bronchitis, pneumonia, etc. and has the functions of eliminating phlegm, diminishing inflammation and promoting the discharge of contrast medium. At present, the marketed preparation of the eucalyptol, limonene and alpha-pinene medicinal composition is an oral enteric soft capsule, the treatment effect of the medicine is definite, and the pungent smell of volatile oil medicaments is covered by an enteric technology. But some patients still have adverse reactions such as adverse flavor, stomach stimulation and the like after taking the medicine. The adverse reaction may be caused by the rapid release of a large amount of the drug after the enteric coating of the soft capsule is broken, which stimulates the gastrointestinal tract.
Therefore, a new enteric preparation based on eucalyptol, limonene and alpha-pinene needs to be developed, the medicine is dispersed and coated in enteric particles, and then the medicine is prepared into final preparations such as capsules or tablets according to the dosage. Each drug storage particle has an enteric effect, so that the risk of burst release of the drug in the stomach can be effectively reduced, and the irritation can be reduced.
Disclosure of Invention
The present application is based on the discovery and recognition by the inventors of the following facts and problems:
the eucalyptus limonene pinene oral enteric-coated soft capsule which is currently marketed has poor compliance for patients with dysphagia, is not suitable for children and old people to take, and the eucalyptol, limonene and alpha-pinene medicinal composition preparation which is marketed needs to be taken three times per day, and has more times of taking and easy occurrence of missing.
The present invention is directed to solving, at least in part, one of the technical problems in the related art.
The inventor utilizes the particle administration technology to develop a novel oral preparation containing eucalyptol, limonene and alpha-pinene, so that the oral preparation is convenient for swallowing and taking, the compliance of patients is improved, and meanwhile, the novel sustained-release preparation is prepared by the sustained-release technology, and the administration times are reduced.
In a first aspect of the invention, the invention provides eucalyptol and pinene enteric-coated microspheres. According to an embodiment of the present invention, the eucalyptus citrapine enteric coated microspheres include: a microsphere core oil phase comprising an active ingredient, the active ingredient comprising at least one of eucalyptol, limonene, and alpha-pinene; the microsphere skin is wrapped on the surface of the active ingredient and consists of a calcium alginate skeleton. The eucalypt-pinene enteric-coated microspheres provided by the embodiment of the invention are convenient to swallow, improve the compliance of patients, have a slow-release effect and can effectively reduce the administration times.
According to an embodiment of the present invention, the eucalyptus citrapine enteric-coated microspheres may further have at least one of the following additional technical features:
according to an embodiment of the present invention, the microsphere core oil phase further comprises an emulsifier component. Thereby improving the uniformity of the oil phase and the emulsification effect of the primary emulsion.
According to an embodiment of the invention, the emulsifier comprises at least one selected from tween 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil. The emulsifier according to embodiments of the present invention may be used as a single or a composite emulsifier.
According to an embodiment of the invention, the emulsifier consists of tween 80 and polyoxyethylene castor oil. The inventor finds that when the compound emulsifier consisting of the Tween 80 and the polyoxyethylene castor oil is adopted, the oil phase is mixed more uniformly, the colostrum emulsification effect is better, and no oil phase exists.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient is (1-4): (0.75-1.5). The inventors found that when the mass ratio of the active ingredient to the emulsifier ingredient is within the above range, the encapsulation rate of the microspheres is more than 80%.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient is (1-4): 1.25. the inventors have found that when the mass ratio of the active ingredient to the emulsifier ingredient is in the above range, the encapsulation rate of the microspheres is up to 95%, and the colostrum fluidity is good.
According to the embodiment of the invention, the mass ratio of the tween 80 to the polyoxyethylene castor oil is 1. The inventor finds that the mass ratio of the Tween 80 to the polyoxyethylene castor oil is in the range, the emulsifying effect is good, and the microsphere encapsulation rate is higher than 80%. When the mass ratio of the Tween 80 to the polyoxyethylene castor oil is 2.
According to an embodiment of the present invention, the calcium alginate backbone is formed by complex cross-linking of sodium alginate and a calcium salt.
According to an embodiment of the invention, the calcium salt comprises at least one selected from calcium chloride, calcium carbonate.
According to the embodiment of the invention, the mass molar ratio of the sodium alginate to the calcium salt is (4-10) g, (0.03-0.04) mol. Further improving the probability of forming the sodium alginate spherical skeleton by complexing and crosslinking the sodium alginate and the calcium salt.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): (0.75 to 1.5): (4-10). The inventors found that when the mass ratio of the active ingredient, the emulsifier ingredient and sodium alginate is within the above range, the microspheres are spherical in appearance and have a high encapsulation efficiency.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): (0.75 to 1.5): (6-10). The inventors found that when the mass ratio of the active ingredient, the emulsifier ingredient and sodium alginate is within the above range, the microspheres have a regular white spherical appearance and a high encapsulation efficiency.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): (0.75 to 1.5): 8. the inventor finds that when the mass ratio of the active ingredient, the emulsifier ingredient and the sodium alginate is in the range, the colostrum emulsification effect is good, the appearance of the microsphere is regular white spherical, and the encapsulation rate is up to 90%.
According to the embodiment of the invention, the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): 1.25:8. the inventor finds that when the mass ratio of the active ingredient, the emulsifier ingredient and the sodium alginate is within the range, the colostrum has good emulsifying effect and good fluidity, the appearance of the microsphere is regular white spherical, and the encapsulation rate is up to 90%.
According to an embodiment of the present invention, the microsphere skin further comprises chitosan, and the chitosan is crosslinked with the sodium alginate. Further crosslinking the chitosan and the unreacted sodium alginate to block the skeleton meshes generated by the calcium alginate, so that the drug release is blocked and the slow release effect is better.
According to the embodiment of the invention, the eucalyptus and pinene enteric-coated microspheres are in a granular formulation or a suspension formulation. The eucalyptus and pinene enteric-coated microspheres are prepared into a granule or suspension dosage form, so that swallowing is facilitated, and volatilization and waste of medicines in the preparation process are reduced.
In a second aspect of the present invention, the present invention provides a method for preparing the eucalyptus pinene enteric-coated microspheres. According to an embodiment of the invention, the method comprises subjecting an aqueous phase in which a predetermined amount of sodium alginate is dissolved and an oil phase in which predetermined amounts of the active ingredient and the emulsifier ingredient are mixed to a first mixing treatment so as to obtain colostrum; and carrying out second mixing treatment on the colostrum and an acetic acid solution dissolved with a predetermined amount of calcium chloride so as to obtain the eucalyptus citrapine enteric-coated microspheres. The "predetermined amount" of the dose is as previously described. The pinene enteric-coated microspheres prepared by the method provided by the embodiment of the invention are convenient to swallow, and have high patient compliance and good sustained-release effect.
According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the first mixing process is performed at a temperature of 40 to 50 ℃ and a rotation speed of 4000 to 12000rpm for 5 to 25min. The inventor finds that the first mixing treatment is carried out under the conditions, the emulsification effect of the colostrum is good, and the encapsulation rate of the microspheres is high.
According to an embodiment of the present invention, the first mixing process is performed at 6000rpm for 15min. Further reducing the heat generation in the emulsification process, improving the stability of the colostrum, and leading the encapsulation rate of the obtained microspheres to be up to 96%.
According to an embodiment of the present invention, the acetic acid solution dissolved with calcium chloride further dissolves chitosan. Thereby improving the slow release effect of the obtained microspheres.
Detailed Description
The following describes embodiments of the present invention in detail. The following described embodiments are exemplary and are intended to be illustrative of the invention and are not to be construed as limiting the invention.
The following examples 1 to 4 screen the influence of the proportion of the active ingredient eucalyptol and limonene and alpha-pinene in the composition on the enteric microspheres.
Example 1 (Eucalyptus lemon pinene in the pharmaceutical composition is 3 g)
(1) The recipe is shown in table 1.
Table 1:
(2) Preparation method
The sodium alginate with the prescription amount is put into 300mL of distilled water and is heated in a water bath at 50 ℃ to be dissolved to be used as an aqueous phase. The formula amounts of eucalyptol, limonene, alpha-pinene and tween 80 are put into a beaker to be uniformly mixed to be used as an oil phase. Slowly dripping the oil phase into the water phase under heating in 50 deg.C water bath, and shearing at 8000rpm for 15min to obtain primary emulsion. Adding the calcium chloride with the prescription amount into a 1% acetic acid solution, and completely dissolving to obtain a calcium chloride acetic acid solution. Dripping the colostrum into calcium chloride acetic acid solution at 20 drops per minute by using an injector, and standing for 6h after dripping to obtain white pellets. The surface of the pellet is rinsed with distilled water and transferred to a vacuum drying oven for drying at 40 ℃ for 12h.
Experimental phenomena and results: the formula can prepare more uniform colostrum with slight volatile oil smell, and the white microspheres can be prepared after dripping the calcium chloride acetic acid solution, and have better shape and encapsulation rate of 80.3%.
Example 2 (high proportion of pinene in active ingredient)
(1) The prescription is shown in table 2.
Table 2:
| eucalyptol | 0.25g |
| Limonene | 0.25g |
| Alpha-pinene | 2.50g |
| Sodium alginate | 6.0g |
| Tween 80 | 0.75g |
| Calcium chloride | 3.75g |
| 1% acetic acid solution | 375mL |
(2) The preparation method is the same as example 1.
Experimental phenomena and results: the colostrum prepared by the formula is uniform and slightly smelly, and white microspheres can be prepared after calcium chloride acetic acid solution is dripped, the shape is regular, and the encapsulation rate is 78.5%.
Example 3 (active ingredient is eucalyptol only, total active ingredient 4 g)
(1) The prescription is shown in table 3.
Table 3:
(2) The preparation method is the same as example 1.
Experimental phenomena and results: the colostrum prepared by the formula has slightly oil drops on the surface and the smell of eucalyptol, and white microspheres can be prepared after the calcium chloride acetic acid solution is dripped, the shape is regular, and the encapsulation rate is 62.7%.
Example 4 (Eucalyptus amount of pinene 1 g)
(1) The prescription is shown in table 4.
Table 4:
| eucalyptus oil extract | 0.52g |
| Limonene | 0.53g |
| Alpha-pinene | 0.45g |
| Sodium alginate | 6.0g |
| Tween 80 | 0.75g |
| Calcium chloride | 3.75g |
| 1% acetic acid solution | 375mL |
(2) The preparation method is the same as example 1.
Experimental phenomena and results: the colostrum prepared by the formula is white emulsion, does not delaminate after standing, and can be prepared into white spherical microspheres after calcium chloride acetic acid solution is dripped, and the encapsulation rate is 84.8%.
Example 5 below examines the effect of different calcium salts on enteric microspheres.
Example 5 replacement of calcium chloride by calcium carbonate
(1) The prescription is shown in Table 5.
Table 5:
| eucalyptol | 1.05g |
| Limonene | 1.05g |
| Alpha-pinene | 0.9g |
| Sodium alginate | 6.0g |
| Tween 80 | 0.75g |
| Calcium carbonate | 3.38g |
| 2.1% acetic acid solution | 375mL |
(2) The preparation method comprises the following steps:
the sodium alginate in the prescription amount is put into 300mL of distilled water and heated in a water bath at 50 ℃ to be dissolved to be used as an aqueous phase. The eucalyptol, limonene, alpha-pinene and Tween 80 in the prescribed amount are put into a beaker to be uniformly mixed to be used as an oil phase. Slowly dripping the oil phase into the water phase under heating in 50 deg.C water bath, and shearing at 8000rpm for 15min to obtain primary emulsion. And adding the calcium carbonate with the prescription amount into 2.1 percent acetic acid solution, and obtaining calcium acetate-acetic acid solution after complete dissolution. Dripping the colostrum into calcium acetate-acetic acid solution at 20 drops per minute by using an injector, and standing for 6h after dripping to obtain white pellets. The surface of the pellet was rinsed with distilled water and transferred to a vacuum oven to dry at 40 ℃ for 12h.
Test phenomena and results: the process uses other soluble calcium salts as precipitating agents for the microspheres. The colostrum is white emulsion, and when calcium carbonate is added into acetic acid solution, a large amount of bubbles are generated, and when the bubbles are completely discharged, the colostrum is dripped into the calcium acetate-acetic acid solution to prepare the white microspheres. The encapsulation efficiency is similar to that of the calcium chloride acetic acid solution and is 83.1 percent.
Examples 6 to 9 below were screened for the type of emulsifier, the amount of emulsifier, and the amount of sodium alginate.
Example 6 emulsifier species screening
The formula of eucalyptus and pinene oil and sodium alginate in the formula is fixed, different emulsifiers are selected to prepare colostrum, and proper emulsifiers are screened according to the oil phase and the colostrum state.
The preliminary prescription is shown in Table 6.
Table 6:
| eucalyptus oil extract | 1.50g |
| Limonene | 1.05g |
| Alpha-pinene | 0.45g |
| Sodium alginate | 6.0g |
| Emulsifier | 1.0g |
| Calcium chloride | 3.75g |
| Chitosan | 0.8g |
| 1% acetic acid solution | 375mL |
The types and amounts of emulsifiers were selected as shown in Table 7.
Table 7:
| test number | Emulsifier | Amount of the composition |
| 1 | Tween 80 | 1g |
| 2 | Polyoxyethylene Castor oil | 1g |
| 3 | Polyoxyethylene hydrogenated castor oil | 1g |
| 4 | Tween 80+ polyoxyethylene castor oil | 0.5g+0.5g |
| 5 | Tween 80+ polyoxyethylene hydrogenated castor oil | 0.5g+0.5g |
The preparation method comprises the following steps: the sodium alginate in the prescription amount is put into 300mL of distilled water and heated in a water bath at 50 ℃ to be dissolved to be used as an aqueous phase. The formula amount of eucalyptol, limonene, alpha-pinene and emulsifier are put into a beaker to be uniformly mixed to be used as an oil phase. Slowly dripping the oil phase into the water phase under heating in 50 deg.C water bath, and shearing at 8000rpm for 15min to obtain primary emulsion. And adding the prescription amount of calcium chloride into the 1% acetic acid solution, and adding the prescription amount of chitosan after completely dissolving to obtain a calcium chloride-chitosan acetic acid solution. Dripping the colostrum into calcium chloride-chitosan acetic acid solution at the speed of 20 drops per minute by using an injector, and standing for 6 hours after dripping to obtain white pellets. The surface of the pellet was rinsed with distilled water and transferred to a vacuum oven to dry at 40 ℃ for 12h.
The test phenomena and results are shown in Table 8.
Table 8:
| test number | Oil phase phenomenon | Colostrum phenomenon |
| 1 | Can be mixed uniformly | White emulsion with oil droplets |
| 2 | After being stirred, the components are mixed evenly | White emulsion without oil drop |
| 3 | Separate layers and cannot mix uniformly | White emulsion without oil drop |
| 4 | Can be mixed uniformly | White emulsion without oil drop |
| 5 | Cannot be mixed | White emulsion without oil drop |
According to the oil phase and the colostrum phenomenon, the screened No. 4 emulsifier is better, is easy to mix and has good emulsification effect. Therefore, the compound emulsifier Tween 80+ polyoxyethylene castor oil is selected as a subsequent emulsifier.
Example 7 Complex emulsifier ratio
The prescription of eucalyptus, pinine oil and sodium alginate in the prescription is fixed and the proportion of the compound emulsifier Tween 80-polyoxyethylene castor oil is screened, and the proper emulsifier is screened according to the oil phase, the colostrum state and the encapsulation rate.
The preliminary prescription is shown in Table 9:
table 9:
| eucalyptus oil extract | 1.50g |
| Limonene | 1.05g |
| Alpha-pinene | 0.45g |
| Sodium alginate | 6.0g |
| Compound emulsifier | 1.0g |
| Calcium chloride | 3.75g |
| Chitosan | 0.8g |
| 1% acetic acid solution | 375mL |
The types and amounts of the selected emulsifiers are shown in Table 10.
Table 10:
the preparation method is the same as example 5.
The test phenomena and results are shown in Table 11.
Table 11:
| test number | Oil phase phenomenon | Colostrum phenomenon | Encapsulation efficiency |
| 1 | Slightly heated and mixed | Translucent white emulsion, no oil drop | 87.3％ |
| 2 | Mixing uniformly | White emulsion without oil drop | 90.0％ |
| 3 | Mixing uniformly | White emulsion without oil drop | 88.7％ |
| 4 | Mixing uniformly | White emulsion without oil drop | 81.9％ |
| 5 | Mixing uniformly | White emulsion, slightly oil-dripping | 72.4％ |
According to the test result, the screened No. 2 has better proportion, good emulsification effect and higher encapsulation. Thus the complex emulsifier tween 80 was selected: the ratio of the polyoxyethylene castor oil is 2.
Example 8 sodium alginate dosage Screen
The formula of eucalyptus and lemon pinene oil and the compound emulsifier in the formula are fixed, the sodium alginate dosage is screened, and the sodium alginate dosage is screened according to the colostrum state and the encapsulation rate.
The prescription is shown in table 12.
Table 12:
| eucalyptus oil extract | 1.50g |
| Limonene | 1.05g |
| Alpha-pinene | 0.45g |
| Sodium alginate | Proper amount of |
| Tween 80 | 0.4g |
| Polyoxyethylene Castor oil | 0.6g |
| Calcium chloride | 3.75g |
| Chitosan | 0.8g |
| 1% acetic acid solution | 375mL |
The amount of sodium alginate used was selected as shown in Table 13.
Table 13:
| test number | 1 | 2 | 3 | 4 | 5 |
| Sodium alginate (g) | 2 | 4 | 6 | 8 | 10 |
The preparation method is the same as example 5.
The test phenomena and results are shown in Table 14.
Table 14:
| test number | Colostrum phenomenon | Appearance of microspheres | Encapsulation efficiency |
| 1 | White emulsion | Is difficult to form | 82.6％ |
| 2 | White emulsion | Irregular spherical shape | 87.1％ |
| 3 | White emulsion, yellowish | White ball | 89.3％ |
| 4 | Light yellow emulsion | White ball | 92.5％ |
| 5 | Relatively viscous and light yellow emulsion | White ball | 91.8％ |
According to the test result, the screened No. 4 has better proportion, good emulsification effect and higher encapsulation. A prescription amount of 8g of sodium alginate was therefore chosen.
EXAMPLE 9 emulsifier dosage screening
Other amounts in the fixed formula and tween 80: the proportion of the polyoxyethylene castor oil is unchanged, and the dosage of the composite emulsifier is screened according to the colostrum state and the encapsulation rate.
Table 15:
| test number | Tween 80 (g) | Polyoxyethylene Castor oil (g) | Total amount of emulsifier (g) |
| 1 | 0.2 | 0.3 | 0.5 |
| 2 | 0.3 | 0.45 | 0.75 |
| 3 | 0.4 | 0.6 | 1.0 |
| 4 | 0.5 | 0.75 | 1.25 |
| 5 | 0.6 | 0.9 | 1.5 |
The preparation method is the same as example 5.
Test phenomena and results.
Table 16:
| test number | Appearance of colostrum | Encapsulation efficiency |
| 1 | White emulsion, yellowish | 78.9％ |
| 2 | White emulsion, yellowish | 86.4％ |
| 3 | White emulsion, yellowish | 91.3％ |
| 4 | White emulsion | 95.7％ |
| 5 | White emulsion | 96.0％ |
According to test results, the screened No. 4 has the advantages of good proportion, good emulsification effect, high encapsulation and good colostrum fluidity. Therefore, the dosage of the emulsifier is 80.5g of Tween and 0.75g of polyoxyethylene castor oil.
Examples 10-11 below colostrum shear rate and time were screened
EXAMPLE 10 colostrum shear rate screening
The dosage of each material in the fixed prescription is unchanged, the shear rotation speed of the colostrum in the preparation method is screened by taking the encapsulation rate as an index, and the screening scheme is shown in the table 17.
Table 17:
the test results are shown in Table 18.
Table 18:
| test number | Appearance of colostrum | Encapsulation efficiency |
| 1 | White emulsion | 94.4％ |
| 2 | White emulsion | 96.3％ |
| 3 | White emulsion | 95.8％ |
| 4 | White emulsion | 92.4％ |
| 5 | White emulsion | 90.1％ |
According to the test result, the No. 2 screened shear rotation speed is better, so that the shear rotation speed is determined to be 6000rpm.
EXAMPLE 11 colostrum shear time screening
The amount of each material in the prescription was fixed and the shear time of colostrum in the preparation method was screened using the encapsulation efficiency as an index, the screening protocol is as follows in table 19.
Table 19:
the test results are shown in Table 20.
Table 20:
according to the test result, the shearing time of No. 3 is better, so that the shearing time is determined to be 15min.
The optimal eucalyptol pinene sodium alginate microsphere formula obtained by screening in the embodiments 6 to 11 is shown in table 21.
Table 21:
| eucalyptus oil extract | 1.6g |
| Limonene | 1.05g |
| Alpha-pinene | 0.35g |
| Sodium alginate | 8.0g |
| Tween 80 | 0.5g |
| Polyoxyethylene Castor oil | 0.75g |
| Calcium chloride | 3.75g |
| Chitosan | 0.8g |
| 1% acetic acid solution | 375mL |
The optimal preparation method is as follows:
the sodium alginate with the prescription amount is put into 300mL of distilled water and is heated in a water bath at 50 ℃ to be dissolved to be used as an aqueous phase. The eucalyptol, the limonene, the alpha-pinene, the tween 80 and the polyoxyethylene castor oil in the prescription amount are put into a beaker to be uniformly mixed to be used as an oil phase. Slowly dripping the oil phase into the water phase under heating in 50 deg.C water bath, and shearing at 6000rpm for 15min to obtain primary emulsion. And adding the prescription amount of calcium chloride into the 1% acetic acid solution, and adding the prescription amount of chitosan after completely dissolving to obtain a calcium chloride-chitosan acetic acid solution. Dripping the colostrum into calcium chloride-chitosan acetic acid solution at the speed of 20 drops per minute by using an injector, and standing for 6 hours after dripping to obtain white pellets. The surface of the pellet was rinsed with distilled water and transferred to a vacuum oven to dry at 40 ℃ for 12h.
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 will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, 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 (14)
1. A eucalyptus and pinene enteric-coated microsphere is characterized by comprising:
a microsphere core oil phase comprising an active ingredient, the active ingredient comprising at least one of eucalyptol, limonene, and alpha-pinene;
the microsphere skin is wrapped on the surface of the active ingredient and consists of a calcium alginate skeleton;
the microsphere core oil phase further comprises an emulsifier component;
the emulsifier comprises Tween 80 and polyoxyethylene castor oil, wherein the mass ratio of the Tween 80 to the polyoxyethylene castor oil is 1;
the calcium alginate skeleton is formed by complexing and crosslinking sodium alginate and calcium salt, and the mass molar ratio of the sodium alginate to the calcium salt is (4-10) g, (0.03-0.04) mol;
the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): (0.75 to 1.5): (4-10).
2. The eucalypt-pinene enteric microsphere according to claim 1, wherein the mass ratio of the active ingredient to the emulsifier ingredient is (1-4): (0.75-1.5).
3. The eucalypt-pinene enteric-coated microspheres according to claim 1, wherein the mass ratio of the active ingredient to the emulsifier ingredient is (1-4): 1.25.
4. the eucalypt-pinene soluble microsphere according to claim 1, wherein the mass ratio of the tween 80 to the polyoxyethylene castor oil is 2.
5. The eucalypt-pinene enteric microsphere according to claim 1, wherein the calcium salt comprises at least one selected from calcium chloride and calcium carbonate.
6. The eucalypt-pinene enteric-coated microspheres according to any one of claims 2 to 5, wherein the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): (0.75 to 1.5): (6-10).
7. The eucalypt pinene enteric microsphere according to claim 6, wherein the mass ratio of the active ingredient, the emulsifier ingredient and the sodium alginate is (1-4): (0.75 to 1.5): 8.
8. the eucalypt-pinene enteric-coated microsphere according to claim 7, wherein the mass ratio of the active ingredient to the emulsifier ingredient to the sodium alginate is (1-4): 1.25:8.
9. the eucalypt-pinene enteric microsphere according to claim 1, wherein the microsphere skin further comprises chitosan, and the chitosan is cross-linked with the sodium alginate.
10. The eucalypt and pinene enteric-coated microspheres according to claim 1, wherein the eucalypt and pinene enteric-coated microspheres are in the form of granules or suspensions.
11. A method for preparing eucalypt and pinene enteric microspheres according to any one of claims 1 to 10, characterized in that the aqueous phase in which sodium alginate is dissolved and the oil phase in which the active ingredient and the emulsifier ingredient are mixed are subjected to a first mixing treatment so as to obtain colostrum;
and carrying out second mixing treatment on the colostrum and an acetic acid solution dissolved with calcium salt so as to obtain the eucalyptol and pinane enteric-coated microspheres.
12. The method according to claim 11, wherein the first mixing treatment is performed at a temperature of 40 to 50 ℃ and a rotation speed of 4000 to 12000rpm for 5 to 25 minutes.
13. The method according to claim 12, wherein the first mixing treatment is carried out at 6000rpm for 15min.
14. The method of claim 11, wherein the acetic acid solution with the calcium salt dissolved therein further dissolves chitosan.
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